15th international thyroid congress program and

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Luca Persani. Yun-Bo Shi ... Pregnancy. Alex S. Stagnaro-Green ...... Tatiana L. Fonseca ...... Philadelphia, PA; 2Department of Medicine, Mercy Catholic Medi-.
THYROID Volume 25, Supplement 1, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/thy.2015.29004.abstracts

15th International Thyroid Congress Scientific Program – Sunday, October 18 6:30 AM – 8:30 PM

15th ITC Registration Open

Convention Foyer 1/2 Lobby/Third Level

6:30 AM – 6:30 PM

Speaker Ready Room Open (open to meeting faculty only)

Australia 2 Room Lobby/Third Level

7:00 AM – 5:15 PM

Endocrine Neck Advanced Ultrasound Course with Practicum (Satellite Program, separate registration required)

Asia 4 Room Lobby/Third Level

8:00 AM – 4:00 PM

E. Chester Ridgway (Ridgway) Clinical Trainee Conference (Pre-registration required for Sunday’s pre-conference programming; full agenda available in trainees section of program book)

Southern Hemisphere IV-V Fifth Level

The Ridgway Trainee Conference is named to memorialize Dr. E. Chester ‘‘Chip’’ Ridgway, for his large contributions to the field of thyroidology, his great devotion to education of fellows over many years, and especially to honor his creation and establishment of a full day seminar led by thyroid experts teaching the full breadth of thyroidrelated endocrine subjects. The ATA Annual Meeting trainee track has been combined with the Endocrine Fellows Conference to serve clinical, basic, surgical and pediatric endocrine fellows and trainees. The Ridgway legacy fund, supported by colleagues, fellows and friends of Dr. E. Chester Ridgway is to be of continuing support to the Ridgway Trainee Conference. 8:00 AM – 6:00 PM

15th ITC Exhibit and Poster Hall Open (Open for exhibitor-setup only)

Atlantic Hall Ground/First Level

8:50 AM – 2:15 PM

Iodine Global Network Satellite Program (Satellite Program, separate registration required)

Asia 3 Room Lobby/Third Level

11:30 AM – 3:00 PM

E. Chester Ridgway (Ridgway) Basic Trainee Conference: Genomic Regulation of Gene Expression (Open to all interested ITC meeting attendees; lunch reserved for trainees only; full agenda available in trainees section of program book)

Americas Seminar Room Fifth Level

P-2

MEETING PROGRAM

1:00 PM – 3:00 PM

P-3

Asia 1 Room Lobby/Third Level

ATA Alliance for Patient Education Public Forum (Open to the general public and all meeting attendees) Sponsored by the ATA Alliance members: American Thyroid Association, Bite Me Cancer, Graves’ Disease and Thyroid Foundation, Light of Life Foundation, Thyca: Thyroid Cancer Survivors’ Association, Thyroid Cancer Alliance, Thyroid Cancer Canada and Thyroid Federation International

5:15 PM – 5:45 PM

Northern Hemisphere BCD Fifth Level

15th ITC Welcome Ceremony Introduction by ATA leadership, acknowledgement to all thyroid sister societies, acknowledgement to the Program Organizing Committee Welcome remarks by Robert C. Smallridge, President, ATA John C. Morris, III Secretary/COO, ATA John Armstrong, Surgeon General and Secretary, Florida Department of Health

5:45 PM – 7:30 PM

Autoimmunity Thyroid Cancer Thyroid Hormone Action Clinical Thyroidology 7:30 PM – 9:00 PM

Northern Hemisphere BCD Fifth Level

15th ITC Opening Session – Progress in Thyroid Research: Highlights from the Last Decade Chair: Rebecca S. Bahn

15th ITC Welcome Reception (Meeting registration/badge required for entry)

Sandra M. McLachlan Martin Schlumberger Douglas Forrest David S. Cooper Swan and Dolphin Pool and Beach Area (Outside)

15th International Thyroid Congress Scientific Program – Monday, October 19 6:30 AM – 5:30 PM

15th ITC Registration Open

Convention Foyer 1/2 Lobby/Third Level

6:30 AM – 5:30 PM

Speaker Ready Room Open (open to meeting faculty only)

Australia 2 Room Lobby/Third Level

6:30 AM – 8:00 AM

Early Riser Symposium Continental Breakfast

Pacific Hall Ground/First Level

7:00 AM – 8:20 AM

Early Riser Symposium: New Modalities in the Treatment of Medullary Thyroid Cancer (MTC) Co–Chairs: Ana O. Hoff and Laura Fugazzola

Pacific Hall Ground/First Level

P-4

MEETING PROGRAM

Molecular Mechanisms of MTC Targeted Therapeutic Agents for MTC Management of Side Effects of Long– Term Tyrosine Kinase Inhibitor Treatment Update on MTC Guidelines

Rui M. B. Maciel Rossella Elisei

8:35 AM – 9:20 AM

Opening Plenary Session: Advancing Individualized Medicine with Public–Private Partnerships Introduction by Robert C. Smallridge

William W. Chin

9:00 AM – 4:30 PM

15th ITC Exhibit and Poster Hall Open (Open at 8:00 AM for poster presenters only)

Atlantic Hall Ground/First Level

9:20 AM – 9:45 AM

Poster Review Session and Break in the Exhibit Hall

Atlantic Hall Ground/First Level

9:30 AM – 11:00 AM

Ridgway Trainee Conference Clinical Track: Case Discussions – Thyroid Function

9:45 AM – 11:00 AM

Symposium: Nontraditional TSHR Signaling Co–Chairs: Basil Rapoport and Syed Morshed Selective TSHR Signaling by TSHR Antibodies TSHR–Arrestin–1 Mediated Pathways TSHR–IGF–1 Interactions

9:45 AM – 11:00 AM

Gisah Carvalho Stephanie L. Lee Peter A. Singer

Symposium: Thyroid Cancer – Translating Basic Science Discoveries to the Clinic Co-Chairs: Edna T. Kimura and Ileana Gabriela de Rubio

Northern Hemisphere BCD Fifth Level

Southern Hemisphere IV-V Fifth Level Southern Hemisphere I Fifth Level

Terry F. Davies Susanne E. Neumann Terry J. Smith Southern Hemisphere II Fifth Level

Sheue-yann Cheng J.H. Duncan Bassett Carla Moran Robin P. Peeters Southern Hemisphere III Fifth Level

Symposium: New Concepts in the Management of Thyroid Nodules Co-Chairs: Stephanie A. Fish and Finn Bennedbaek Epidemiology of Benign Thyroid Nodules Who Should Be Screened for Thyroid Nodules? Follow–Up of Benign Nodules?

9:45 AM – 11:00 AM

Samuel A. Wells, Jr.

Symposium: TR Alpha Mutations – Bench to Bedside Co–Chairs: V Krishna Chatterjee and Marcel Meima Animal Models Treatment of Animal Models Human Mutations Treatment of Patients

9:45 AM – 11:00 AM

Barbara Jarzab

Shuhang Xu Arthur B. Schneider Susan J. Mandel Northern Hemisphere BCD Fifth Level

MEETING PROGRAM

P-5

Redifferentiation of RAI–Refractory Thyroid Cancer Somatic Mutations Analysis for Molecular Diagnosis Targeted Therapy

James A. Fagin

11:00 AM – 11:50 AM

DD1 – Discussion/Debates Clinical: A Case-Based Discussion of International Hypothyroidism Guidelines

Jacqueline Jonklaas Gla´ucia Mazeto Salman Razvi

Southern Hemisphere I Fifth Level

11:00 AM – 11:50 AM

DD2 – Discussion/Debates Clinical: Targeted Therapy for Thyroid Cancer: When and What?

Steven I. Sherman Johannes W.A. Smit

Northern Hemisphere BCD Fifth Level

11:00 AM – 11:50 AM

DD3 – Discussion/Debates Clinical: Unusual Thyroid Function Tests Moderator: Mark P. Vanderpump

Inge Bu¨low Pedersen Brian W. Kim Shu Wang Helton Estrela Ramos

Northern Hemisphere E3-E4, Fifth Level

11:00 AM – 11:50 AM

DD4 – Discussions/Debates Clinical: Management of Thyroid Storm

Henry B. Burch Tetsurou Satoh

Northern Hemisphere E1-E2, Fifth Level

11:00 AM – 11:50 AM

DD5 – Discussion/Debates Clinical: Is There a Role for Long-Term Anti-Thyroid Drug Therapy?

Stig Andersen Douglas S. Ross

Southern Hemisphere III Fifth Level

11:00 AM – 11:50 AM

DD6 – Discussion/Debates Basic/ Translational: TSHR Activation and Its Impact on Body Composition and Graves’ Orbitopathy

Marian Ludgate Lei Zhang

Americas Seminar Room Fifth Level

11:00 AM – 11:50 AM

DD7 – Discussion/Debates Basic/ Translational: Oxidative Stress on Thyrocytes

Denise Pires De Carvalho Xavier De Deken

Asia 1 Room Lobby/Third Level

11:00 AM – 11:50 AM

DD8 – Discussion/Debates Basic/ Translational: Immunity and Thyroid Cancer: Prospects for Immune Therapy

Lisa Zhang Mabel M. Ryder

Northern Hemisphere A1-A2, Fifth Level

11:00 AM – 11:50 AM

DD9 – Discussion/Debates Basic/ Translational: Interactions Between Hypothalamic Pituitary Thyroid Axis and Other Pituitary Dysfunction

Ulla Feldt–Rasmussen Salvatore Benvenga

Northern Hemisphere A3-A4, Fifth Level

11:00 AM – 11:50 AM

DD10 – Discussion/Debates Basic/ Translational: Vertebrate Models for Study of TH Action

Luca Persani Yun-Bo Shi

Asia 2 Room Lobby/Third Level

12:00 PM – 1:00 PM

Poster Review Session and Lunch in the Exhibit Hall

12:00 PM – 1:00 PM

Ridgway Trainee Conference Clinical and Basic Lunch Session: How to Get your Work Published (Open to all trainees; lunch ticket required for meal)

Yuri Nikiforov Sophie Leboulleux

Atlantic Hall Ground/First Level Peter A. Kopp

Southern Hemisphere IV-V Fifth Level

P-6

MEETING PROGRAM

12:00 PM – 1:00 PM

15th ITC Expo Theater Presented by Eisai, Inc. (Only U.S. health care professionals are permitted to attend this program; space limited – first come, first served; lunch included)

Atlantic Hall Ground/First Level

1:05 PM – 1:45 PM

American Thyroid Association (ATA) Van Meter Prize Lecture (Awardee Announced Onsite at Time of Lecture)

Northern Hemisphere BCD Fifth Level

Established in 1930, the ATA Van Meter Award Lecture recognizes outstanding contributions to research on the thyroid gland or related subjects. The award is given each year to an investigator who is not older than the age of 45 in the year of the award. The Van Meter award winner is kept secret until the time of the award lecture during the meeting. Funded by support from Mary Ann Liebert, Inc., Publishers; and a Van Meter endowment in memory of Jacob (Jack) Robbins created by Jean Robbins in 2014. Presentation of ATA Distinguished Service Award to 2015 awardee Peter A. Kopp In recognition and honor of an ATA member who has made important and continuing contributions to the Association. John B. Stanbury Thyroid Pathophysiology Medal Presented to 2015 awardee Sheue-yann Cheng In recognition of outstanding research contributions, either conceptual or technical, to the understanding of thyroid physiology or the pathophysiology of thyroid disease, as evidenced by having a major impact on research or clinical practice related to thyroid diseases. 1:50 PM – 3:05 PM

Pregnancy Hashimoto’s Thyroiditis Graves’ Disease 1:50 PM – 3:05 PM

Southern Hemisphere I Fifth Level

Symposium: Clinical Utility of Anti–Thyroid Antibody Measurements Co-Chairs: Patricia de Fatima dos Santos Teixeira and Yuji Hiromatsu

Symposium: TH Transport Co-Chairs: Ulrich Schweizer and Grant W. Anderson

Alex S. Stagnaro-Green Mario Rotondi Eijun Nishihara Southern Hemisphere II Fifth Level

MEETING PROGRAM

1:50 PM – 3:05 PM

P-7

Animal Models of TH Transporter Disease Therapeutic Studies Using Animal Models

Heike Heuer

Human TH Transporter Mutations Clinical Trials in Allan Herndon Dudley Syndrome

Theo J. Visser W. Edward Visser Southern Hemisphere III Fifth Level

Symposium: T4/T3 Combination Therapy for Hypothyroidism Co-Chairs: Elizabeth A. McAninch and Birte Nygaard Do Patients Prefer T4/T3 Therapy, and Why? What is the Mechanism for Enhanced Weight Loss with T3? Risks/Safety of Combination Therapy

1:50 PM – 3:05 PM

Alexandra M. Dumitrescu

Colin M. Dayan Francesco S. Celi Anne R. Cappola Northern Hemisphere BCD Fifth Level

Symposium: Prognostic Assessment of Thyroid Cancer Co-Chairs: Mario Vaisman and Duncan Topliss Functional Imaging Clinical Risk Stratification Real Time Prognostication

Byeong-Cheol Ahn Furio Pacini R. Michael Tuttle

2:00 PM – 5:30 PM

Ridgway Trainee Conference Clinical Track: Thyroid Ultrasound Course (Open to clinical travel grant trainees only)

Asia 4 Room Lobby/Third Level

3:05 PM – 4:00 PM

Poster Review Session and Break in the Exhibit Hall

Atlantic Hall Ground/First Level

3:05 PM – 4:00 PM

15th ITC Expo Theater Presented by Hoverstate (Limited seating; first-come, first served)

Atlantic Hall Ground/First Level

4:00 PM – 4:30 PM

Monday Short Oral Communications 1 Co-Chairs: J. Paul Banga and Susanne Neumann

Southern Hemisphere I Fifth Level

ABSTRACT # 17 - ORBITAL FIBROBLAST HYPOXIC RESPONSE IMPACTS TISSUE REMODELING IN GRAVES’ ORBITOPATHY

Gina–Eva Go¨rtz

ABSTRACT # 18 - REPLICATION OF GRAVES’ ORBITOPATHY MOUSE MODEL IN TWO CENTRES REVEALS A LONG TERM T CELL RESPONSE TO TSH-RECEPTOR ANTIGEN

Utta Berchner-Pfannschmidt

ABSTRACT # 19 - ORBITAL FIBROBLASTS FROM GRAVES’ ORBITOPATHY PATIENTS MEET ALL CRITERIA THAT DEFINE MESENCHYMAL STEM CELLS

Utta Berchner-Pfannschmidt

P-8

4:00 PM – 4:30 PM

4:00 PM – 4:30 PM

MEETING PROGRAM

ABSTRACT # 20 - FAILURE OF G PROTEIN ACTIVATION BY TSH RECEPTOR ANTIBODIES DICTATES THYROCYTE DEATH – IMPLICATIONS FOR AUTOIMMUNITY

Syed Morshed

ABSTRACT # 21 - INCREASED LEVELS BUT IMPAIRED FUNCTION OF REGULATORY B CELLS (BREG) IN HASHIMOTO’S THYROIDITIS AND ASSOCIATED AUTOIMMUNE DISORDERS

Marco Centanni

Southern Hemisphere II Fifth Level

Monday Short Oral Communications 2 Co-Chairs: Marius Stan and Salvatore Benvenga ABSTRACT # 22 - DIPLOPIA, SEVERITY SCORE, AND SMOKING IMPACT QUALITY OF LIFE IN THYROID-ASSOCIATED ORBITOPATHY – A PROSPECTIVE STUDY

Elena Kampmann

ABSTRACT # 23 - THYROID AUTOIMMUNITY AS A BIOMARKER OF OUTCOME IN WOMEN WITH BREAST CANCER – LARGE SCALE STUDY USING DATA FROM THE TAXOTERE AS ADJUVANT CHEMOTHERAPY (TACT) TRIAL (CRUK01/001)

Ilaria Muller

ABSTRACT # 24 - USEFULNESS OF THYROID STIMULATING ANTIBODY AT THE TIME OF ANTITHYROID DRUG WITHDRAWAL IN PREDICTING RELAPSE OF GRAVES’ HYPERTHYROIDISM

Hyemi Kwon

ABSTRACT # 25 - GWAS OF GRAVES’ ORBITOPATHY PATIENTS HIGHLIGHTS THE PRIMACY OF HLA IN AUTOIMMUNE THYROID DISEASE

Terry F. Davies

ABSTRACT # 26 - TRIPLE THERAPY (GLUCOCORTICOID + CICLOSPORIN + ORBITAL IRRADIATION) FOR DIPLOPIA (DIP) OF MODERATE–TO– SEVERE GRAVES’ ORBITOPATHY (MSGO). A PROSPECTIVE FOLLOW–UP STUDY

Peter Laurberg

Monday Short Oral Communications 3 Co-Chairs: Virginia Sarapura and W. Edward Visser

Southern Hemisphere III Fifth Level

MEETING PROGRAM

4:00 PM – 4:30 PM

P-9

ABSTRACT # 27 - DOT1L, THE H3K79 METHLTRANSFERASE, ACTS AS A NOVEL THYROID HORMONE RECEPTOR CO– ACTIVATOR

Luan Wen

ABSTRACT # 28 - IODINE EXCESS EXPOSURE DURING PREGNANCY/LACTATION IMPAIRS THYROID HORMONES PRODUCTION, METABOLISM AND TRANSPLACENTAL TRANSFER IN RAT DAMS

Caroline Serrano Do Nascimento

ABSTRACT # 29 - A FULL– LENGTH MODEL OF THE THYROTROPIN RECEPTOR SUPPORTED BY EXPERIMENTAL DATA FROM MASS SPECTROMETRY AND TARGETED RECEPTOR MUTATION

Joerg Schaarschmidt

ABSTRACT # 30 HYPERTHYROID BUT NOT HYPOTHYROID PATIENTS ARE AT HIGHER RISK OF REHOSPITALISATION AND INCREASED CARDIOVASCULAR MORBIDITY–A MATCHED CASE– CONTROL STUDY

Barbara Torlinska

ABSTRACT # 31 - DETECTION OF NOVEL GENE VARIATIONS IN CONGENITAL HYPOTHYROIDISM WITH TARGETED NEXT–GENERATION SEQUENCING

Jukka Kero

Northern Hemisphere A1-A2, Fifth Level

Monday Short Oral Communications 4 Co-Chairs: Elizabeth McAninch and Joao Romaldini ABSTRACT # 32 - RESISTANCE TO THYROID HORMONE (RTH) WITHOUT MUTATIONS IN THE THYROID HORMONE RECEPTOR BETA (THRB) GENE (NONTR– RTH): THE CHICAGO EXPERIENCE

Theodora Pappa

ABSTRACT # 33 - COAGULATION AND FIBRINOLYSIS IN PATIENTS WITH RESISTANCE TO THYROID HORMONE DUE TO A THYROID HORMONE RECEPTOR ß–GENE MUTATION

Laura Elbers

ABSTRACT # 34 - DECIPHERING THE POTENTIAL OF 3– IODOTHYROMINE (T1AM) IN REGULATING LIPID METABOLISM

Fariba Assadi–Porter

P-10

4:00 PM – 4:30 PM

4:00 PM – 4:30 PM

MEETING PROGRAM

ABSTRACT # 35 - BISPHENOL–A IN RATS PRESENTS DIFFERENT THYROID HORMONE DISRUPTING PROFILES DEPENDING ON THE WINDOW OF EXPOSURE

Maria Izabel Chiamolera

ABSTRACT # 36 - MICE WITH GENE INACTIVATION OF a2C– ADRENOCEPTOR ARE RESISTANT TO HYPERTHYROIDISM–INDUCED BONE LOSS

Marilia Grecco Teixeira

Northern Hemisphere A3-A4, Fifth Level

Monday Short Oral Communications 5 Co-Chairs: John Al Copland and Markus Eszlinger ABSTRACT # 37 IDENTIFICATION OF KIAA1217– RET AS A NOVEL FUSION GENE IN PAPILLARY THYROID CANCER

Endong Chen

ABSTRACT # 38 - P21– ACTIVATED KINASE 4 REGULATES PAPILLARY THYROID CANCER CELL PROLIFERATION, MIGRATION AND INVASION

Xiaochen Xie

ABSTRACT # 39 - METFORMIN INHIBITS THE PROLIFERATION OF THYROID CANCER STEM CELLS BY UP–REGULATING TUMOR SUPPRESSOR MIRNAS

Guofang Chen

ABSTRACT # 40 - LOSS OF XB130 CAUSES DYSHORMONOGENESIS ASSOCIATED WITH IODIDE ORGANIFICATION DEFECT AND THE DEVELOPMENT OF MULTINODULAR GOITER

Hae-Ra Cho

ABSTRACT # 41 - ETV5, AN ETS FAMILY TRANSCRIPTION FACTOR, IS A MARKER FOR RAS–DEPENDENT THYROID CANCER PROGRESSION

Oorvashi Roy Puli

Northern Hemisphere E1-E2, Fifth Level

Monday Short Oral Communications 6 Co-Chairs: Stefan Grebe and Tania Pilli ABSTRACT # 42 - INHIBITION OF MITOCHONDRIAL COMPLEX 4 INCREASES GLUCOSE CONSUMPTION IN THYROID CANCER CELLS

Kirk E. Jensen

MEETING PROGRAM

4:00 PM – 4:30 PM

P-11

ABSTRACT # 43 - HIGHLY EXPRESSED PROTEIN FAM83F INCREASES RESISTANCE TO DOXORUBICIN IN PAPILLARY THYROID CANCER

Cesar S. Fuziwara

ABSTRACT # 44 - UMORIGENIC ROLE OF MICRORNA MIR-17-92 CLUSTER VIA DEREGULATION OF TGFb SIGNALING PATHWAY IN THYROID FOLLICULAR CELLS

Cesar S. Fuziwara

ABSTRACT # 45 - THE INVITRO EFFECTS OF METFORMIN ON THYROID CANCER CELL LINES

Safar Kheder

ABSTRACT # 46 - INDUCTION OF THE ONCOTIC DEATH PATHWAY IN THYROID CANCER CELLS

Athanasios Bikas

Northern Hemisphere E3-E4, Fifth Level

Monday Short Oral Communications 7 Co-Chairs: Paolo Vitti and Ramona Dadu ABSTRACT # 47 - THE STRATIFICATION OF PATIENT’S RISK DEPENDING ON THE SIZE AND RATIO OF METASTATIC LYMPH NODES IN PAPILLARY THYROID CARCINOMA

Ja Sung Bae

ABSTRACT # 48 - SHEAR–WAVE ELASTOGRAPHY VS FINE– NEEDLE ASPIRATION BIOPSY FOR PREDICTING CANCER IN THYROID NODULES: NO CORRELATION IN PROSPECTIVE STUDY OF 5000 CONSECUTIVE PATIENTS

Ilya Sleptsov

ABSTRACT # 49 - BETHESDA CATEGORIZATION OF THYROID NODULE CYTOLOGY & PREDICTION OF THYROID CANCER TYPE AND PROGNOSIS

Xiaoyun Liu

ABSTRACT # 50 - THE FREQUENCY OF HIGH RISK CHARACTERISTICS REQUIRING TOTAL THYROIDECTOMY FOR 1–4 CM WELL DIFFERENTIATED THYROID CANCER

Wouter Pieter Kluijfhout

ABSTRACT # 51 - THE IMPACT OF RET AND RAS MUTATION STATUS ON OVERALL SURVIVAL IN THE EXAM TRIAL, A PHASE 3 STUDY OF CABOZANTINIB (CABO) IN PATIENTS (PTS) WITH PROGRESSIVE, METASTATIC MEDULLARY THYROID CANCER (MTC)

Steven I. Sherman

P-12

4:00 PM – 4:30 PM

4:30 PM – 5:30 PM

MEETING PROGRAM

Americas Seminar Room Fifth Level

Monday Short Oral Communications 8 Co-Chairs: Iwao Sugitani and Jennifer Sipos ABSTRACT # 52 - COMPARISON OF EMPIRIC FIXED DOSING WITH A WHOLE BODY/BLOOD CLEARANCE DOSIMETRY BASED MANAGEMENT APPROACH TO RADIOACTIVE IODINE TREATMENT IN PATIENTS WITH RAI AVID DISTANT METASTASES FROM DIFFERENTIATED THYROID CANCER

R. Michael Tuttle

ABSTRACT # 53 - SECOND PRIMARY MALIGNANCIES IN BELARUS, PATIENTS WITH POST–CHERNOBYL PAPILLARY THYROID CARCINOMA

Michael Fridman

ABSTRACT # 54 - SUB– CLASSIFICATION OF INDETERMINATE CATEGORIES OF THYROID CYTOPATHOLOGY IMPROVES RISK STRATIFICATION AND COULD BE USED TO SELECT AND INTERPRET THE RESULTS OF MOLECULAR MARKER TESTS

Pablo Valderrabano

ABSTRACT # 55 - OUTCOMES BY SITE OF METASTASIS FOR PATIENTS WITH RADIOIODINE– REFRACTORY DIFFERENTIATED THYROID CANCER TREATED WITH LENVATINIB VERSUS PLACEBO: RESULTS FROM A PHASE 3, RANDOMIZED TRIAL

Mouhammed Habra

ABSTRACT # 56 - AMPK OVERACTIVATION IN BCPAP TUMOR CELLS INDUCES CELL DEATH THROUGH INCREASED REACTIVE OXYGEN SPECIES (ROS)

Denise Pires De Carvalho

Southern Hemisphere I Fifth Level

Highlighted Oral Abstracts 1 Co-Chairs: Yaron Tomer and Tanja Diana ABSTRACT # 1 -STRUCTURE AND ACTIVATION OF THE TRANSMEMBRANE DOMAIN OF THE TSH RECEPTOR

Ricardo Nunez Miguel

ABSTRACT # 2 -A UNIQUE HLADR POCKET PREDISPOSES TO BOTH AUTOIMMUNE THYROIDITIS AND DIABETES BY PRESENTING THYROID AND ISLET PEPTIDES

Cheuk Wun Li

MEETING PROGRAM

4:30 PM – 5:30 PM

4:30 PM – 5:30 PM

P-13

ABSTRACT # 3 - CHEMICAL CHAPERONES RESCUE THE PATHOGENIC ?PHE501 MUTATION IN MONOCARBOXYLATE TRANSPORTER 8

Doreen Braun

ABSTRACT # 4 - TRANSCRIPTION FACTOR PAIRED–BOX 8 REGULATES NA + /I-SYMPORTER GENE EXPRESSION IN SMALLINTESTINE ABSORPTIVE ENTEROCYTES

Juan Nicola

Southern Hemisphere II Fifth Level

Highlighted Oral Abstracts 2 Co-Chairs: Marco Centanni and Rosalind Brown ABSTRACT # 5 - THYROID FUNCTION AND THE RISK OF DEMENTIA: THE ROTTERDAM STUDY

Layal Chaker

ABSTRACT # 6 - BMP AND FGF SIGNALING ARE REQUIRED FOR DIRECTED DIFFERENTIATION OF PLURIPOTENT STEM CELLS INTO FUNCTIONAL THYROID FOLLICLES

Maria Serra

ABSTRACT # 7 - TREATMENT OF HYPOTHYROIDISM WITH LEVOTHYROXINE PLUS TRIIODOTHYRONINE: A RANDOMIZED, DOUBLE–BLIND CROSSOVER STUDY

Gilberto Paz–Filho

ABSTRACT # 8 - ATYPICAL HIPPOCAMPAL FUNCTIONING DURING VERBAL MEMORY RECALL IN YOUTH WITH CONGENITAL HYPOTHYROIDISM

Joanne Rovet

Northern Hemisphere BCD Fifth Level

Highlighted Oral Abstracts 3 Co-Chairs: Gerard Doherty and Haixia Guan ABSTRACT # 9 CHARACTERIZATION OF THE CANCER GENOME OF ADVANCED THYROID TUMORS IDENTIFIES DISTINCT MOLECULAR HALLMARKS OF POORLY DIFFERENTIATED AND ANAPLASTIC THYROID CANCERS

In˜igo Landa

ABSTRACT # 10 - A 2015 SURVEY OF ENDOCRINOLOGISTS ON THE MANAGEMENT OF THYROID NODULES

Nicole Odette Vietor

P-14

4:30 PM – 5:30 PM

MEETING PROGRAM

ABSTRACT # 11 - TSH OVERCOMES BRAFV600E– INDUCED SENESCENCE TO PROMOTE TUMOR PROGRESSION VIA DOWN– REGULATION OF P53 EXPRESSION IN PAPILLARY THYROID CANCER

Yufei Shi

ABSTRACT # 12 SUBCATEGORIZATION OF ATYPIA OF UNDETERMINED SIGNIFICANCE/FOLLICULAR LESION OF UNDETERMINED SIGNIFICANCE (AUS/FLUS): A STUDY APPLYING THYROID IMAGING REPORTING AND DATA SYSTEM (TIRADS)

Jung Hyun Yoon

Southern Hemisphere III Fifth Level

Highlighted Oral Abstracts 4 Co-Chairs: Ana Maria Masini-Repiso and Joseph Koehrle ABSTRACT # 13 - ALTERNATIVE SPLICING OF TRA IS ESSENTIAL TO ORCHESTRATE NORMAL SKELETAL DEVELOPMENT AND ADULT BONE MAINTENANCE

J.H. Duncan Bassett

ABSTRACT # 14 - TRAGS AND TRßGS KNOCK–IN MICE DEMONSTRATE PHYSIOLOGICAL RELEVANCE OF NON–CLASSICAL THYROID HORMONE ACTION

Sebastian Ho¨nes

ABSTRACT # 15 - D2KO ZEBRAFISH AS A NON– MAMMALIAN MODEL TO STUDY THE ROLE OF LOCAL THYROID HORMONE ACTIVATION

Veerle M. Darras

ABSTRACT # 16 - THYROID HORMONE ANALOG THERAPY IN PATIENTS WITH THE ALLAN–HERNDON–DUDLEY SYNDROME (AHDS): THE TRIAC TRIAL

Stefan Groeneweg

5:30 PM – 7:00 PM

American Thyroid Association (ATA) Annual Business Meeting (for ATA members only)

Northern Hemisphere E3-E4, Fifth Level

5:30 PM – 7:00 PM

Asia and Oceania Thyroid Association (AOTA) Annual Business Meeting (for AOTA members only)

Northern Hemisphere E1-E2, Fifth Level

5:30 PM – 7:00 PM

European Thyroid Association (ETA) Annual Business Meeting (for ETA members only)

Northern Hemisphere A1-A2, Fifth Level

MEETING PROGRAM

5:30 PM – 7:00 PM

P-15

Northern Hemisphere A3-A4, Fifth Level

Latin American Thyroid Society (LATS) Annual Business Meeting (for LATS members only)

15th International Thyroid Congress Scientific Program – Tuesday, October 20 6:30 AM – 4:30 PM

15th ITC Registration Open

Convention Foyer 1/2 Lobby/Third Level

6:30 AM – 4:30 PM

Speaker Ready Room Open (open to meeting faculty only)

Australia 2 Room Lobby/Third Level

6:30 AM – 8:00 AM

Early Riser Symposium Continental Breakfast

Pacific Hall Ground/First Level

7:00 AM – 8:20 AM

Early Riser Symposium: Differences Between Pediatric and Adult Differentiated Thyroid Cancer Chair: Rossana Corbo

Pacific Hall Ground/First Level

Thyroid Cancer Phenotypes Approach to Radioiodine Treatment Thyroid Cancer Outcome Thyroid Cancer Guidelines

Sylvia L. Asa Christoph Reiners Fernanda Vaisman Steven G. Waguespack

8:35 AM – 9:20 AM

Plenary Lecture: Choice of Therapy for Graves’ Hyperthyroidism Introduction by Furio Pacini

Luigi Bartalena

9:00 AM – 4:00 PM

15th ITC Exhibit and Poster Hall Open (Open at 8:00 AM for poster presenters only)

Atlantic Hall Ground/First Level

9:20 AM – 9:45 AM

Poster Review Session and Break in the Exhibit Hall

Atlantic Hall Ground/First Level

9:30 AM – 11:00 AM

Ridgway Trainee Conference Clinical Track: Case Discussions – Thyroid Nodule (Open to all trainees)

9:45 AM – 11:00 AM

Tuesday Basic Oral Abstracts 1: Thyroid Cancer Genetics/Genomics Co-Chairs: Rafaelle Ciampi and Rebecca Schweppe

Susan J. Mandel Laszlo Hegedus Hans Graf

Northern Hemisphere BCD Fifth Level

Southern Hemisphere IV-V Fifth Level

Southern Hemisphere I Fifth Level

ABSTRACT # 57 - ASSOCIATION BETWEEN TERT PROMOTER AND NRAS MUTATIONS AND THEIR COOPERATIVE UP– REGULATION OF TERT EXPRESSION

Rengyun Liu

ABSTRACT # 58 - A NOVEL MECHANISM INVOLVING WIPF1 OVEREXPRESSION VIA PROMOTER HYPOMETHYLATION BY BRAF V600E IN THYROID TUMORIGENESIS

Tao Zhang

P-16

9:45 AM – 11:00 AM

MEETING PROGRAM

ABSTRACT # 59 - NEXT GENERATION SEQUENCING MUTATION PROFILING REVEALS NOVEL PUTATIVE TUMOR CANDIDATES IN ANAPLASTIC THYROID CARCINOMA

So¨ren Latteyer

ABSTRACT # 60 - HABP2 IS A NOVEL TUMOR SUPPRESSOR GENE THAT CAUSES FAMILIAL NONMEDULLARY THYROID CANCER

Sudheer Kumar Gara

ABSTRACT # 61 - A CHEMICAL PROTEOMICS APPROACH TO IDENTIFY MECHANISMS OF RESISTANCE TO THE SRC INHIBITOR, DASATINIB

Katie Marie Mishall

Southern Hemisphere II Fifth Level

Tuesday Basic Oral Abstracts 2: Thyroid Signaling Metabolism and Action Co-Chairs: Sheue-yann Cheng and Juan Nicola ABSTRACT # 62 MESENCHYMAL STEM CELL– MEDIATED SODIUM IODIDE SYMPORTER (NIS) GENE DELIVERY IN A MOUSE MODEL OF PANCREATIC DUCTAL ADENOCARCINOMA USING NIS AS REPORTER GENE

Christina Schug

ABSTRACT # 63 - USING THE HYPOXIA RESPONSE NETWORK FOR TUMOUR-TARGETED 131I THERAPY OF ORTHOTOPIC HEPATOCELLULAR CARCINOMA (HCC) XENOGRAFTS AFTER MESENCHYMAL STEM CELL (MSC)-MEDIATED SODIUM IODIDE SYMPORTER (NIS) GENE DELIVERY

Andrea Mueller

ABSTRACT # 64 - ROLE AND MECHANISM OF TYPE 2 IODOTHYRONINE DEIODINASE UBIQUITINATION OF PITUITARY IN IODINE INDUCED TSH ELEVATION

Xiaowen Zhang

ABSTRACT # 65 - THYROID HORMONE SIGNALING REGULATES ENDOGENOUS HYDROGEN SULFIDE PRODUCTION

Hyo–jeong Kim

ABSTRACT # 66 - MEMBRANETRAVERSING MECHANISM FOR THYROID HORMONE TRANSPORT AT MCT8

Gerd Krause

MEETING PROGRAM

9:45 AM – 11:00 AM

9:45 AM – 11:00 AM

P-17

Northern Hemisphere BCD Fifth Level

Tuesday Clinical Oral Abstracts 1: Autoimmunity and Pregnancy Co-Chairs: Yasumasa Iwasaki and Maria Cabanillas ABSTRACT # 67 - MATERNAL THYROID FUNCTION DURING EARLY PREGNANCY IS ASSOCIATED WITH TOTAL CEREBRAL GRAY MATTER AND CORTEX VOLUME IN SCHOOLAGE CHILDREN

Tim Korevaar

ABSTRACT # 68 - CLINICAL RELEVANCE OF THYROID STIMULATING ANTIBODIES IN HASHIMOTO’S THYROIDITIS AND ASSOCIATED ORBITOPATHY

George J. Kahaly

ABSTRACT # 69 - THE NATURAL HISTORY OF SUBCLINICAL HYPERTHYROIDISM DUE TO GRAVES’ DISEASE – THE RULE OF THIRDS

Salman Razvi

ABSTRACT # 70 - EFFECTS OF LEVOTHYROXINE THERAPY ON PREGNANCY OUTCOMES IN WOMEN WITH SUBCLINICAL HYPOTHYROIDISM

Spyridoula Maraka

ABSTRACT # 71 - THYROID HORMONE LEVELS IN NORMAL PREGNANT WOMEN: THE INFLUENCE OF BODY MASS INDEX

Lorena Mosso

Southern Hemisphere III Fifth Level

Tuesday Clinical Oral Abstracts 2: Thyroid Cancer Therapy Co-Chairs: Duncan Topliss and Sara Ahmadi ABSTRACT # 72 - OUTCOMES IN RESPONSE TO AGGRESSIVE MULTIMODAL THERAPY IN ANAPLASTIC THYROID CANCER: THE MAYO CLINIC EXPERIENCE

Aditi Kumar

ABSTRACT # 73 CABOZANTINIB IN PATIENTS WITH RADIOIODINEREFRACTORY DIFFERENTIATED THYROID CANCER WHO PROGRESSED ON PRIOR VEGFRTARGETED THERAPY: RESULTS OF NCI- AND ITOG-SPONSORED MULTICENTER PHASE II CLINICAL TRIAL

Manisha H. Shah

P-18

MEETING PROGRAM

ABSTRACT # 74 - RECENT CHANGES IN THE CLINICAL OUTCOME OF PAPILLARY THYROID CARCINOMA WITH CERVICAL LYMPH NODE METASTASIS

Min Ji Jeon

ABSTRACT # 75 -LONG–TERM OUTCOME OF LOCALIZED THYROID MUCOSAASSOCIATED LYMPHOID TISSUE LYMPHOMA: RETROSPECTIVE ANALYSIS OF 106 CONSECUTIVE CASES

Natsuko Watanabe

ABSTRACT # 76 - TREATMENT OF CHILDHOOD AND ADOLESCENT THYROID CANCER IN FUKUSHIMA AFTER FUKUSHIMA DAIICHI NUCLEAR POWER PLANT ACCIDENT ON MARCH 11, 2011

Shinichi Suzuki

11:00 AM – 11:50 AM

DD11 – Discussion/Debates Clinical: How Reliable are Free Thyroid Hormone Assays?

Stefan Karl Guenther Grebe Steven Soldin

Southern Hemisphere III Fifth Level

11:00 AM – 11:50 AM

DD12 – Discussion/Debates Clinical: Rituximab Therapy for Graves’ Orbitopathy

Mario G. Salvi Marius N. Stan

Northern Hemisphere A1-A2, Fifth Level

11:00 AM – 11:50 AM

DD13 – Discussion/Debates Clinical: Maternal Isolated Hypothyroxinemia: What Do We Know and What Do We Not Know?

Marco Medici Chrysoula Dosiou

Southern Hemisphere I Fifth Level

11:00 AM – 11:50 AM

DD14 – Discussion/Debates Clinical: Is it Possible to Improve Outcomes in Congenital Hypothyroidism?

Stephen H. LaFranchi Toni Torresani

Asia 2 Room Lobby/Third Level

11:00 AM – 11:50 AM

DD15 – Discussion/Debates Clinical: Emerging Concepts In The Management of Recurrent Thyroid Cancer

Kenneth D. Burman Enrico Papini

Northern Hemisphere BCD Fifth Level

11:00 AM – 11:50 AM

DD16 – Discussion/Debates Basic/ Translational: Clinical and Basic Aspects of Bone Turnover by Thyroid Hormone

John G. Logan Bente Langdahl

Northern Hemisphere E1-E2, Fifth Level

11:00 AM – 11:50 AM

DD17 – Discussion/Debates Basic/ Translational: Roles of TSH from Pars Tuberalis and Pars Distalis

Takashi Yoshimura

Northern Hemisphere A3-A4, Fifth Level

11:00 AM – 11:50 AM

DD18 – Discussion/Debates Basic/ Translational: Thyroid Function and Metabolic Syndrome

Gabriela Brenta Jiajun Zhao

Americas Seminar Room Fifth Level

11:00 AM – 11:50 AM

DD19 – Discussion/Debates Basic/ Translational: Deiodinases and Cancer

Stephen A. Huang Domenico Salvatore

Northern Hemisphere E3-E4, Fifth Level

MEETING PROGRAM

P-19

11:00 AM – 11:50 AM

DD20 – Discussion/Debates Basic/ Translational: TSHR Structure

Jane Sanders Ricardo Nunez Miguel

Asia 1 Room Fifth Level

12:00 PM – 1:00 PM

Poster Review Session and Lunch in the Exhibit Hall

12:00 PM – 1:30 PM

Ridgway Trainee Conference Clinical Track Lunch Session: Setting Up a Thyroid Practice (Open to all trainees; lunch ticket required for meal)

Brittany Bohinc Henderson Mark A. Lupo

Southern Hemisphere IV-V Fifth Level

12:00 PM – 1:00 PM

Ridgway Trainee Conference Basic Track Lunch Session: Genome Editing with CRISPR/Cas9 and TALEN Nucleases (Open to all trainees; lunch ticket required for meal)

Daniel Buchholz

Asia 3 Room Lobby/Third Level

12:00 PM – 1:00 PM

15th ITC Expo Theater Presented by Veracyte, Inc. (Limited seating; first-come, firstserved; lunch included)

Atlantic Hall Ground/First Level

1:00 PM – 1:30 PM

Tuesday Short Oral Communications 1 Co-Chairs: Anja Eckstein and Ulla Feldt-Rasmussen

Southern Hemisphere I Fifth Level

Atlantic Hall Ground/First Level

ABSTRACT # 77 - ASSOCIATIONS OF POLYMORPHISMS IN GENE ENCODING PRI-MIR-125A AND THE MATURE MIR-125A EXPRESSION WITH THE PROGNOSIS OF AUTOIMMUNE THYROID DISEASES

Mikio Watanabe

ABSTRACT # 78 - CXCL10, CXCL9, AND CXCL11 aCHEMOKINES CIRCULATING LEVELS ARE INCREASED IN GRAVES’ OPHTHALMOPATHY PATIENTS, AND REDUCED BY CORTICOSTEROIDS TREATMENT

Alessandro Antonelli

ABSTRACT # 79 GLUCOCORTICOID RECEPTOR, NF-KB, AND AP-1 EXPRESSION IN ORBITAL FAT AND EXTRAOCULAR MUSCLE IN PATIENTS WITH GRAVES’ ORBITOPATHY

Adriano Cury

ABSTRACT # 80 - VITAMIN-D SUPPLEMENTATION REDUCES THYROID PEROXIDASE ANTIBODY LEVELS IN PATIENTS WITH AUTOIMMUNE THYROID DISEASE: AN OPEN LABELED RANDOMIZED CONTROLLED TRIAL

Sandeep Chaudhary

P-20

MEETING PROGRAM

ABSTRACT # 81 - SYSTEMATIC ASSESSMENT OF NONENDOCRINE AUTOIMMUNE DISORDERS IN A LARGE COHORT OF CONSECUTIVE PATIENTS WITH AUTOIMMUNE THYROIDITIS 1:00 PM – 1:30 PM

1:00 PM – 1:30 PM

Camilla Virili

Southern Hemisphere II Fifth Level

Tuesday Short Oral Communications 2 Co-Chairs: Anthony Hollenberg and Risheng Ma ABSTRACT # 82 - MULTIPLE TRANSDUCTION PATHWAYS MEDIATE TSH RECEPTOR SIGNALING IN BONE

Alisa Boutin

ABSTRACT # 83 - THE THR92ALA SUBSTITUTION IN COMBINATION WITH LOWNORMAL THYROID FUNCTION IS ASSOCIATED WITH INCREASED ODDS OF A SUBOPTIMAL IQ SCORE IN CHILDREN

Peter N. Taylor

ABSTRACT # 84 - BIRTH DEFECTS, AGRANULOCYTOSIS AND LIVER FAILURE ASSOCIATED WITH THE USE OF ANTITHYROID DRUGS IN THE POPULATION IN GENERAL AND IN PREGNANCY: A DANISH NATIONWIDE STUDY

Stine Linding Andersen

ABSTRACT # 85 - MUTATIONS IN THE ANTI-APOPTOTIC FACTOR BCL2L12 IN PATIENTS WITH THYROID AGENESIS

Marina Malta Letro Kizys

ABSTRACT # 86 - WHOLE EXOME SEQUENCING ANALYSIS OF PATIENTS WITH CONGENITAL HYPOTHYROIDISM DUE TO HYPOPLASIA REVEALS MUTATIONS ON HOXA2 GENE

Marina Malta Letro Kizys

Southern Hemisphere III Fifth Level

Tuesday Short Oral Communications 3 Co-Chairs: Nancy Carrasco and Mario Salvi ABSTRACT # 87 - PARADOXICAL D1 ALONG WITH BRAINPROTECTIVE D2 EFFECTS OF THYROTOXIC T4 CONCENTRATIONS ON HUMAN THYROID HORMONE REGULATION DYNAMICS

Joseph J. DiStefano, III

MEETING PROGRAM

1:00 PM – 1:30 PM

P-21

ABSTRACT # 88 - IMMUNE THERAPIES TARGETING THE THYROID: NEW INSIGHTS FROM A COMPREHENSIVE REVIEW OF PEMBROLIZUMAB-INDUCED THYROIDITIS CASES AT MAYO CLINIC

Danae Anastasia Delivanis

ABSTRACT # 89 - AUTOIMMUNE THYROID DISEASES AND THYROID DYSFUNCTION IN HIROSHIMA AND NAGASAKI ATOMIC-BOMB SURVIVORS EXPOSED IN CHILDHOOD

Misa Imaizumi

ABSTRACT # 90 - NF-jB P65 SNITROSYLATION INHIBITS TSHINDUCED NA + /I- SYMPORTER EXPRESSION

Juan Nicola

ABSTRACT # 91 - THE EFFECT OF IODINE STATUS ON PAPILLARY THYROID CARCINOMA – A META-ANALYSIS

Joon–hyop Lee

Northern Hemisphere A1-A2, Fifth Level

Tuesday Short Oral Communications 4 Co-Chairs: Frances Carr and Joao Werneck De Castro ABSTRACT # 92 - 3IODOTHYRONAMINE EFFECT ON LONG-TERM POTENTIATION: RESCUING b-AMYLOIDINDUCED NEURONAL DYSFUNCTION

Alice Accorroni

ABSTRACT # 93 - TR SUMOYLATION INFLUENCES PREADIPOCYTE PROLIFERATION VIA G1 PHASE CELL CYCLE REGULATORS

Yan-Yun Liu

ABSTRACT # 94 - ABSENCE OF UCP3 BLUNTS THE STIMULATORY EFFECT OF TRIIODOTHYRONINE ON ENERGY EXPENDITURE IN HYPOTHYROID MICE

Assunta Lombardi

ABSTRACT # 95 - 3,5-DIIODO-LTHYRONINE (T2) AND NOT 3,5,3’TRIIODO-L-THYRONINE (T3) REDUCES LIPOGENIC SIGNALING PATHWAYS IN RATS RECEIVING A HIGH-FAT DIET

Pieter De Lange

ABSTRACT # 96 - PUTATIVE ROLE OF HEPATOCYTE NUCLEAR FACTOR-4ALPHA (HNF4ALPHA) IN THE 3,5-DIIODOTHYRONINEDRIVEN CHOLESTEROL REDUCTION IN LDL RECEPTOR KNOCK-OUT MICE (LDLR-/- )

Maria Moreno

P-22

1:00 PM – 1:30 PM

1:00 PM – 1:30 PM

MEETING PROGRAM

Northern Hemisphere A3-A4, Fifth Level

Tuesday Short Oral Communications 5 Co-Chairs: Christine Spitzweg and Hiroki Shimura ABSTRACT # 97 - MICRORNA– 146B MEDIATES PTEN SILENCING PROMOTING PI3K/AKT PATHWAY HYPERACTIVATION LEADING TO THYROID CANCER PROGRESSION

Leon Wert-Lamas

ABSTRACT # 98 - AUTOPHAGY INHIBITION SENSITIZES BRAFMUTANT THYROID CANCER TO VEMURAFENIB

Weibin Wang

ABSTRACT # 99 - A SPONTANEOUS KRAS(G12D) MUTATION FOLLOWING LONGTERM VEMURAFENIB TREATMENT DRIVES ACQUIRED BRAF INHIBITOR (BRAFI) RESISTANCE IN A BRAF(V600E) PTC CELL LINE

Brian P. Danysh

ABSTRACT # 100 - PAPILLARY THYROID CANCER-DRIVING ONCOGENE BRAFV600E INDUCES TOLL-LIKE RECEPTOR 4 OVEREXPRESSION

Victoria Peyret

ABSTRACT # 101 - A NOVEL MODULATOR OF CELLULAR INVASION AND METASTASIS IN THYROID CANCER

Waraporn Imruetaicharoenchoke

Northern Hemisphere E1-E2, Fifth Level

Tuesday Short Oral Communications 6 Co-Chairs: Richard Kloos and Brittany Bohinc Henderson ABSTRACT # 102 - PROMISING ROLE OF CIRCULATING MICRORNAS IN THE DIFFERENTIAL DIAGNOSIS OF THYROID NODULES PARTICULARLY WITH INDETERMINATE CYTOLOGY

Tania Pilli

ABSTRACT # 103 - PAZOPANIB IN PATIENTS WITH PROGRESSIVE, RADIOACTIVE IODINE– REFRACTORY, METASTATIC DIFFERENTIATED THYROID CANCER LACKING THYROGLOBULIN ANTIBODIES: MAYO PHASE 2 CONSORTIUM STUDY RESULTS

Keith C. Bible

ABSTRACT # 104 - A 6 BP IN FRAME GERMLINE DELETION IN EXON 7 OF THE RET GENE LEADS TO INCREASED RET PHOSPHORYLATION, MAPK/ERK AND PI3K ACTIVATION AND MEN2A

So¨ren Latteyer

MEETING PROGRAM

1:00 PM – 1:30 PM

1:00 PM – 1:30 PM

P-23

ABSTRACT # 105 - C–MET– MEDIATED REACTIVATION OF PI3K/AKT SIGNALING CONTRIBUTES TO DRUG INSENSITIVITY AND EPITHELIAL–MESENCHYMAL TRANSITION OF BRAF(V600E) MUTANT THYROID CANCER TO BRAF INHIBITION

Yoon Woo Koh

ABSTRACT # 106 COMBINATORIAL TARGETING WITH ANTI–BRAFV600E AND ANTI–ANGIOGENESIS THERAPY ENHANCES CELL DEATH AND SUPPRESSES CELL MIGRATION IN METASTATIC PAPILLARY THYROID CARCINOMA

Carmelo Nucera

Northern Hemisphere E3-E4, Fifth Level

Tuesday Short Oral Communications 7 Co-Chairs: Won Bae Kim and M. Regina Castro ABSTRACT # 107 - EXAMINING THE ROLE OF PREOPERATIVE POSITRON EMISSION TOMOGRAPHY (PET)/ COMPUTERIZED TOMOGRAPHY (CT) IN DISCRIMINATING BENIGN FROM MALIGNANT THYROID NODULES DEFINED CYTOLOGICALLY AS INDETERMINATE

Michele Marie Merten

ABSTRACT # 108 - TREATMENT OF BENIGN CYSTIC THYROID NODULES BY ETHANOL ABLATION: COMPARISON OF ETHANOL RETENTION AND ASPIRATION

Hye Sun Park

ABSTRACT # 109 - PROGNOSTIC VALUES IN MEDULLARY THYROID CARCINOMA: CLINICAL UTILITY OF 18F-FDG PET/CT

Ji Hoon Yang

ABSTRACT # 111 - THERMAL ABLATION THERAPY FOR PMTC WITH CAREFUL OBSERVATION COULD BE THE ALTERNATIVE TO THYROID SURGERY?

Toru Nishikawa

Americas Seminar Room Fifth Level

Tuesday Short Oral Communications 8 Co-Chairs: Yan-Song Lin and Erik Alexander ABSTRACT # 112 INVESTIGATING THE ROLE OF POLYMORPHISM RS2910164 IN MIR146A IN CANCER PREDISPOSITION

Terri Mcveigh

P-24

MEETING PROGRAM

ABSTRACT # 113 - ANALYSIS OF 40696 FNAB OF THYROID NODULES PERFORMED IN ONE CENTER

Viktor Makarin

ABSTRACT # 114 - AUTOIMMUNE THYROIDITIS AND DIFFERENTIATED THYROID CARCINOMA DO NOT AFFECT SERUM CT LEVELS IN PATIENTS WITH NODULAR DISAESE

Maria Castagna

ABSTRACT # 115 THYROIDECTOMY DURING PREGNANCY: AN ANALYSIS OF THE AMERICAN COLLEGE OF SURGEONS NATIONAL SURGICAL QUALITY IMPROVEMENT PROGRAM (ACS NSQIP) DATASET

Douglas Hirth

ABSTRACT # 116 INTRATHYROIDAL ECTOPIC THYMIC TISSUE MIMICKING THYROID CANCER IN CHILDREN

Hyun Suk Cho

1:30 PM – 2:15 PM

Asia and Oceania Thyroid Association (AOTA) Prize Lecture: Toward Best Management of Thyroid Cancer Introduction by Takashi Akamizu

Akira Miyauchi

2:20 PM – 3:35 PM

Symposium: Clark T. Sawin Historical Vignettes Moderator: Leonard Wartofsky History of the ITC History of AOTA LATS and Regional Thyroid Highlights Thoughts about the History of the ETA

2:20 PM – 3:35 PM

2:20 PM – 3:35 PM

Southern Hemisphere I Fifth Level

Lewis E. Braverman Shigenobu Nagataki Eduardo A. Pretell Wilmar M. Wiersinga

Southern Hemisphere II Fifth Level

Symposium: TH Metabolism – Translational Physiology Co-Chairs: Anne Van Der Spek and Salvatore Benvenga Genetic and Functional Variation in Type 2 Deiodinase

Elizabeth A. McAninch

Animal Models of Non-Thyroidal Illness

Emmely Marije De Vries

Metabolism in Human NTI

Greet Van Den Berghe Southern Hemisphere III Fifth Level

Symposium: Fetal Programming in Maternal Thyroid Disease Co-Chairs: Daniel Glinoer and Joanne Rovet Thyroid Hormone and Brain Development Brain Morphological Changes in Children Born to Mothers with Hypothyroidism

Northern Hemisphere BCD Fifth Level

Juan Bernal Georg Brabant

MEETING PROGRAM

P-25

Neurodevelopmental Disorders in Children Born to Mothers with Thyroid Dysfunction 2:20 PM – 3:35 PM

Stine Linding Andersen

Northern Hemisphere BCD Fifth Level

Symposium: Emerging Genes and Pathways in Thyroid Cancer Co-Chairs: Sissy M. Jhiang and Keith Bible Molecular Genetics of Thyroid Tumor Progression

Paula Soares

Genetics of Radiation-Associated Thyroid Cancer

Horst Zitzelsberger

Molecular Determinants of Signaling and Differentiation in Thyroid Cancer

Pilar Santisteban

3:40 PM – 4:30 PM

Women in Thyroidology Networking Meeting: The Mentor Within (Pre-registration required, admission with ticket only)

Ofelia A. Olivero

4:00 PM – 10:00 PM

15th ITC Disney Afternoon and Evening at EPCOT (open to all meeting attendees; advance ticket purchase required) Join your friends and colleagues for an evening of networking and fun. Tickets are available at registration for 4:00 PM or 8:30 PM access to EPCOT.* *Afternoon at EPCOT ticket includes: 4 PM EPCOT park admission ticket, access to Epcot International Food & Wine Festival Presented by Chase and ITC reception with IllumiNations firework display in private ITC viewing area. Private transportation not provided for event. Please plan to walk or take complimentary water taxis or hotel shuttles to EPCOT. ITC Reception guests should enter through the International Gateway Entrance at EPCOT. EPCOT Guides will meet and direct guests to the ITC private reception area.

Americas Seminar Room Fifth Level

Walt Disney World EPCOT

P-26

8:30 PM – 10:00 PM

MEETING PROGRAM

Walt Disney World EPCOT

15th ITC Networking Evening at EPCOT Reception Only (open to all meeting attendees; additional fee required) Join your friends and colleagues for an evening of networking and fun. Tickets are available at registration for 4:00 PM or 8:30 PM access to EPCOT.** **Evening at EPCOT ticket includes: evening 15th ITC reception with IllumiNations firework display in private ITC viewing area only. Access to EPCOT begins at 8:00PM only (full park admission ticket not included). Private transportation not provided for event. Please plan to walk or take complimentary water taxis or hotel shuttles to EPCOT. ITC Reception guests should enter through the International Gateway Entrance at EPCOT. EPCOT Guides will meet and direct guests to the ITC private reception area.

15th International Thyroid Congress Scientific Program – Wednesday, October 21 6:30 AM – 5:30 PM

15th ITC Registration Open

Convention Foyer 1/2 Lobby/Third Level

6:30 AM – 5:30 PM

Speaker Ready Room Open (open to meeting faculty only)

Australia 2 Room Lobby/Third Level

6:30 AM – 8:00 AM

Early Riser Symposium Continental Breakfast

Pacific Hall Ground/First Level

7:00 AM – 8:20 AM

Early Riser Symposium: New Developments in Thyroid Surgery Co-Chairs: Ling Zhang and Claudio Cernea

Pacific Hall Ground/First Level

Nerve Monitoring Remote Access Thyroid Surgery Prevention and Treatment of PostSurgical Hypoparathyroidism

Kerstin Lorenz Woong Youn Chung Saba Balasubramanian

8:35 AM – 9:20 AM

Plenary Lecture: Radiation and the Thyroid: from Hiroshima/ Nagasaki, Chernobyl to Fukushima Introduction by Yoshiharu Murata

Shigenobu Nagataki

9:00 AM – 4:30 PM

15th ITC Exhibit and Poster Hall Open (Open at 8:00 AM for poster presenters only)

Atlantic Hall Ground/First Level

9:20 AM – 9:45 AM

Poster Review Session and Break in the Exhibit Hall

Atlantic Hall Ground/First Level

Northern Hemisphere BCD Fifth Level

MEETING PROGRAM

P-27

9:30 AM – 11:00 AM

Ridgway Trainee Conference Clinical Track: Case Discussions – Thyroid Cancer (Open to all trainees) Moderator: R. Michael Tuttle

9:45 AM – 11:00 AM

Symposium: Lessons from Animal Models of Thyroid Autoimmunity Co-Chairs: Sun Wook Kim and Marian Ludgate Graves’ Orbitopathy Graves’ Disease Hashimoto’s Thyroiditis

9:45 AM – 11:00 AM

9:45 AM – 11:00 AM

J. Paul Banga Yuji Nagayama Basil Rapoport Southern Hemisphere II Fifth Level

Jens Mittag Paul M. Yen Tatiana L. Fonseca

Southern Hemisphere III Fifth Level

Symposium: Emerging Strategies in Pregnancy Screening for Thyroid Dysfunction Co-Chairs: Marcos Abalovich and Peter Laurberg NIH Pregnancy Study Chinese Screening Study (SHEP) Similarities/Differences in International Recommendations

Southern Hemisphere IV-V Fifth Level

Southern Hemisphere I Fifth Level

Symposium: Novel Actions of Thyroid Hormone on Metabolism Co-Chairs: Peter A. Kopp and Anja Van Gucht TH Action in Control of Cardiovascular Function TH Action Control of Hepatic Cholesterol and Lipid Metabolism Deiodinase Mediated TH Action in the Liver

9:45 AM – 11:00 AM

Rossella Elisei Ana O. Hoff Paolo Miccoli Martin Schlumberger

Brian M. Casey Weiping Teng John H. Lazarus

Northern Hemisphere BCD Fifth Level

Symposium: Genetics and Biomarkers of Thyroid Cancer Co-Chairs: Pilar Santisteban and Tesuo Kondo Is TSH a Risk Factor for Thyroid Cancer? Molecular Profiling of Thyroid Neoplasms Genetic Models of Thyroid Cancer

Gisah A. Carvalho

11:00 AM – 11:50 AM

DD21 – Discussion/Debates Clinical: Core and Fine Needle Biopsy: Pros and Cons

Jung Hwan Baek Teresa Cristina Santos Cavalcanti

Northern Hemisphere A1-A2, Fifth Level

11:00 AM – 11:50 AM

DD22 – Discussion/Debates Clinical: Technical and Clinical Pitfalls in Thyroglobulin Assays

Carole A. Spencer Cosimo Durante

Southern Hemisphere III Fifth Level

11:00 AM – 11:50 AM

DD23 – Discussion/Debates Clinical: Drug-Induced Thyroid Dysfunction

Leonidas Duntas Sahzene Yavuz

Americas Seminar Room Fifth Level

Carine Maenhaut Antonio Di Cristofano

P-28

MEETING PROGRAM

11:00 AM – 11:50 AM

DD24 – Discussion/Debates Clinical: Remnant Ablation in Thyroid Cancer: Selective vs. Routine

Sebastiano Filetti Bryan McIver

Northern Hemisphere BCD Fifth Level

11:00 AM – 11:50 AM

DD25 – Discussion/Debates Clinical: Long-Term Consequences of Subclinical Hyperthyroidism

Christian Selmer Bernadette Biondi

Southern Hemisphere I Fifth Level

11:00 AM – 11:50 AM

DD26 – Discussion/Debates Basic/ Translational: Thyroid Function and Cognition Across the Life Span

Fabio Monzani Jacoba J. Bongers-Schokking

Asia 1 Room Lobby/Third Level

11:00 AM – 11:50 AM

DD27 – Discussion/Debates Basic/ Translational: Central Control of TH Availability

Bala´zs Gereben

Asia 2 Room Lobby/Third Level

11:00 AM – 11:50 AM

DD28 – Discussion/Debates Basic/ Translational: Thyronamines and Other TH Metabolites

Carolin S. Ho¨fig Pieter De Lange

Northern Hemisphere E3-E4, Fifth Level

11:00 AM – 11:50 AM

DD29 – Discussion/Debates Basic/ Translational: Central and Peripheral Control of Energy Expenditure by TH

Eric Fliers

Northern Hemisphere A3-A4, Fifth Level

11:00 AM – 11:50 AM

DD30 – Discussion/Debates Basic/ Translational: Molecular Testing in Thyroid Nodules

Ralf Paschke Janete Maria Cerutti

Southern Hemisphere II Fifth Level

12:00 PM – 1:00 PM

Poster Review Session and Lunch in the Exhibit Hall

12:00 PM – 1:00 PM

Ridgway Trainee Conference Clinical Track Lunch Session: Clinical Career Tracks (Open to all trainees; lunch ticket required for meal)

Susan A. Sherman Elizabeth N. Pearce James A. Magner

Southern Hemisphere IV-V Fifth Level

12:00 PM – 1:00 PM

Ridgway Trainee Conference Basic Track Lunch Session: Career Tracks Discussion (Open to all trainees; lunch ticket required for meal)

Natasha Mott Richard T. Kloos Daniel Buchholz Barbara Demeneix

Asia 3 Room Lobby/Third Level

12:00 PM – 1:00 PM

15th ITC Expo Theater Presented by Bayer Healthcare (Limited seating; first come, first served; lunch included)

1:00 PM – 1:45 PM

Plenary Lecture: Congenital Thyroid Disorders Introduction by Roy E. Weiss

1:50 PM – 3:05 PM

Symposium: Advances in the Treatment of Graves’ Orbitopathy Co-Chairs: Yushu Li and Wilmar M. Wiersinga Selenium in Mild Graves’ Orbitopathy: What’s New? Optimal Use of Intravenous Steroids Orbital Surgery

Atlantic Hall Ground/First Level

Atlantic Hall Ground/First Level

Samuel Refetoff

Northern Hemisphere BCD Fifth Level Southern Hemisphere I Fifth Level

Claudio Marcocci George J. Kahaly Peter Dolman

MEETING PROGRAM

1:50 PM – 3:05 PM

P-29

Intestinal Epithelium Neural Stem Cell Fate Muscle Satellite Cells Pre-Adipocytes 1:50 PM – 3:05 PM

Michelina Plateroti Sylvie Remaud Monica Dentice Gregory A. Brent Southern Hemisphere III Fifth Level

Symposium: Iodine Deficiency Throughout Life Co-Chairs: Sun Y. Lee and Elizabeth N. Pearce Pregnancy Childhood Adults

1:50 PM – 3:05 PM

Southern Hemisphere II Fifth Level

Symposium: The Role of TH in Stem Cell Renewal Co-Chairs: Arturo Hernandez and Heike Biebermann

Zhongyan Shan Maria Andersson Eduardo A. Pretell Northern Hemisphere BCD Fifth Level

Symposium: Controversies in Thyroid Surgery Co-Chairs: Quan–Yang Duh and Amy Y. Chen Routine or Selective Central Neck Dissection for Low–Risk PTC? Routine or Selective Central Neck Dissection for Low–Risk PTC? Advantages and Disadvantages of Minimally Invasive Thyroidectomy Advantages and Disadvantages of Minimally Invasive Thyroidectomy

Hang–Seok Chang

1:50 PM – 3:05 PM

Ridgway Trainee Conference Clinical Track: How to Communicate About the Thyroid (Open to all trainees)

Gerard M. Doherty Sylvia L. Asa Andrew G. Gianoukakis

3:05 PM – 4:00 PM

Poster Review Session and Break in the Exhibit Hall

Atlantic Hall Ground/First Level

3:15 PM – 4:30 PM

Ethical Issues in the World of Thyroidology Moderator: Valeria C. Guimaraes

Northern Hemisphere BCD Fifth Level

Experience from Oregon and The Netherlands in Assisted Suicide in Anaplastic Thyroid Cancer Thyroid Cancer Previvors: A New Global Patient Population Global Health Disparities in Thyroidology: A Distributive Justice Problem 4:00 PM – 4:30 PM

Wednesday Short Oral Communications 1 Co-Chairs: Yugi Nagayama

Lisa A. Orloff Paolo Miccoli Henning Dralle

Southern Hemisphere IV-V Fifth Level

Johannes W.A. Smit

Peter Angelos M. Sara Rosenthal

Southern Hemisphere I Fifth Level

P-30

4:00 PM – 4:30 PM

MEETING PROGRAM

ABSTRACT # 465 - POSSIBLE ROLE FOR THYROTROPIN RECEPTOR VARIANT (TSHRV) AS A BINDING PROTEIN FOR TSHR LIGANDS IN GRAVES’ ORBITOPATHY (GO)?

Lei Zhang

ABSTRACT # 466 - BETA1/2– ADRENERGIC AND M2R MUSCARINIC AUTOANTIBODIES AND THYROID HORMONE FACILITATE INDUCTION OF ATRIAL TACHYARRHYTHMIAS IN THE RABBIT

Taylor Murphy

ABSTRACT # 467 - THE STUDY OF THE CHANGES AND MECHANISMS OF MICRORNA326 IN IODINE-INDUCED AUTOIMMUNE THYRODITIS MODEL OF NODCH-2H4 MICE

Li Yu–Shu

ABSTRACT # 468 - THE EXPRESSION OF FCcRIIB ON B CELLS IN PATIENTS WITH HASHIMOTO’S THYROIDITIS

Yalei Liu

ABSTRACT # 469 - SPHK1/S1P/ S1PR1 AXIS MAY ACT AS NOVEL THERAPEUTIC TARGET FOR AUTOIMMUNE THYROIDITIS

Cheng Han

Southern Hemisphere II Fifth Level

Wednesday Short Oral Communications 2 Co-Chairs: Susana Ebner and Ove Torring ABSTRACT # 470 - DO THE RECENT AMERICAN THYROID ASSOCIATION GUIDELINES ACCURATELY GUIDE THE BIOPSY ACCORDING TO THE NODULE SIZE? A RETROSPECTIVE REVIEW

Muhammad Ahmed Farooq Anwar

ABSTRACT #471 EFFECTIVENESS OF LEVOTHYROXINE THERAPY TARGETING A THYROTROPIN LEVEL LOWER THAN 2.5 MU/L DURING THE FIRST TRIMESTER IN PREVENTING MISCARRIAGE: A PROSPECTIVE STUDY AT A SINGLE INSTITUTION

Sakiko Kobayashi

ABSTRACT # 472 LONGITUDINAL EVALUATION OF A GERIATRIC POPULATION – RELATIONSHIP BETWEEN DEPRESSIVE SYMPTOMS AND SUBCLINICAL HYPOTHYROIDISM DEFINED BY AGE–ADJUSTED CRITERIA FOR SERUM TSH

Patricia Teixeira

MEETING PROGRAM

4:00 PM – 4:30 PM

4:00 PM – 4:30 PM

P-31

ABSTRACT # 473 - BIOCHEMICAL PARAMETERS IN A SUBGROUP REQUIRING T4 PLUS T3 REPLACEMENT TO REVERSE SYMPTOMS OF HYPOTHYROIDISM

Gary M. Pepper

ABSTRACT # 474 - QUICK VISION IMPROVEMENT OF SEVERE GRAVES’ OPHTHALMOPATHY WITH A PARENTERAL PPAR– GAMMA ANTAGONIST AND COX-2 INHIBITOR – SODIUM DICLOFENAC

Walter Bloise

Southern Hemisphere III Fifth Level

Wednesday Short Oral Communications 3 Co-Chairs: Peter Arvan and Robin Peeters ABSTRACT # 475 - NEW INSIGHTS INTO THYROID HORMONE (TH) MECHANISM OF ACTION IN DENDRITIC CELLS (DCS): CHARACTERIZATION OF TH TRANSPORT AND METABOLISM

Nicola´s Gigena

ABSTRACT # 476 - EFFECT OF NACETYLCYSTEINE ON SERUM T3 LEVELS AND HEART FUNCTION IN A RAT MODEL OF LOW T3 SYNDROME

Simone Wajner

ABSTRACT # 477 - THE ROLES OF AMDHD1 GENE, A DIRECT TARGET GENE OF THYROID HORMONE, DURING ADULT INTESTINAL STEM CELL DEVELOPMENT

Morihiro Okada

ABSTRACT # 478 - EXPORT OF IODOTYROSINES BY HUMAN MCT8 AND MCT10

Elaine Cristina Lima De Souza

ABSTRACT # 479 - DIFFERENT EFFECTS OF PTU AND MMI ON THYROID-SPECIFIC GENE EXPRESSION

Aya Yoshihara

Northern Hemisphere A1-A2, Fifth Level

Wednesday Short Oral Communications 4 Co-Chairs: Thomas Scanlan and Pieter De Lange ABSTRACT # 480 - MULTI-OMICS CHARACTERIZATION OF A HUMAN THYROTOXICOSIS MODEL

Maik Pietzner

ABSTRACT # 481 THYROTROPIN-RELEASING HORMONE (TRH) REGULATES COLD-INDUCED ADAPTIVE THERMOGENESIS IN BROWN ADIPOSE TISSUE

Atsushi Ozawa

P-32

4:00 PM – 4:30 PM

4:00 PM – 4:30 PM

MEETING PROGRAM

ABSTRACT # 482 - THYROID HORMONE UPTAKE AND EFFLUX PROFILES DIFFER AT THE L-TYPE AMINO ACID TRANSPORTER 2

Katrin Manuela Hinz

ABSTRACT # 483 TRIIODOTHYRONINE (T3) MAY PREVENT FASTING-INDUCED SKELETAL MUSCLE ATROPHY IN VITRO AND IN VIVO

Cecilia Verga Falzacappa

ABSTRACT # 484 - FURTHER INSIGHTS INTO THYROID HORMONE (TH) ACTION AT THE INITIATION OF ADAPTIVE IMMUNITY: TRIIODOTHYRONINE (T3) TILTS THE BALANCE TOWARDS A PRO-INFLAMMATORY PROFILE

Vanina Alamino

Northern Hemisphere A3-A4, Fifth Level

Wednesday Short Oral Communications 5 Co-Chairs: Keith Bible and Aime Franco ABSTRACT # 485 - SIMILARITY OF GENE EXPRESSION PROFILES BETWEEN THYROID STEM CELLS AND ANAPLASTIC THYROID CARCINOMA

Manabu Iwadate

ABSTRACT # 486 - INHIBITION OF SRC SIGNALING PROMOTES AN INCREASED RELIANCE ON THE MITOGEN ACTIVATED PROTEIN KINASE PATHWAY IN PAPILLARY AND ANAPLASTIC THYROID CANCER

Thomas Clinton Beadnell, Jr.

ABSTRACT # 487 - NOVEL THERAPIES IDENTIFIED IN PATIENT DERIVED THYROID CANCER XENOGRAFTS

John A. Copland, III

ABSTRACT # 488 DEVELOPMENT OF AN ORAL SMALL MOLECULE TSH RECEPTOR AGONIST FOR DIAGNOSIS OF RESIDUAL/ RECURRENT THYROID CANCER

Robert Place

ABSTRACT # 489 - GENISTEIN-A POTENTIAL THERAPEUTIC FACTOR FOR HIGH RISK PAPILLARY THYROID CARCINOMA WITH BRAFV600E MUTATION

Zhiyan Liu

Wednesday Short Oral Communications 6 Co-Chairs: Tsuneo Imai and Jennifer Morrison

Northern Hemisphere E1-E2, Fifth Level

MEETING PROGRAM

4:00 PM – 4:30 PM

P-33

ABSTRACT # 490 - GENETIC BACKGROUND AND PROTEIN PROFILING RELATED TO TELOMERASE ACTIVATION IN MEDULLARY THYROID CARCINOMA

Na Wang

ABSTRACT # 491 - IMMUNE MARKERS IN MEDULLARY THYROID CANCER (MTC) AND THEIR CLINICAL SIGNIFICANCE

Ramona Dadu

ABSTRACT # 492 - PROGNOSTIC MARKERS AND RESPONSE TO VANDETANIB THERAPY IN SPORADIC MEDULLARY THYROID CANCER PATIENTS

Vera Tiedje

ABSTRACT # 493 THYROIDPRINT: A NEW AND SIMPLE GENETIC CLASSIFIER THAT ACCURATELY RULES-OUT MALIGNANCY IN INDETERMINATE THYROID NODULES

Hernan E. Gonzalez

ABSTRACT # 494 - ETV6-NTRK3 FUSION ONCOGENE WAS IDENTIFIED IN SPORADIC ADULT PAPILLARY THYROID CARCINOMA

Andre´ Bastos

Northern Hemisphere E3-E4, Fifth Level

Wednesday Short Oral Communications 7 Co-Chairs: Fabian Pitoia and Chris Umbricht ABSTRACT # 495 - PRESENTING FEATURES OF THYROID LYMPHOMA: THE MAYO CLINIC EXPERIENCE

Anu Sharma

ABSTRACT # 496 - CORE NEEDLE BIOPSY AS A FIRST-LINE BIOPSY METHOD FOR INITIALLY DETECTED THYROID NODULE: A COMPARATIVE STUDY USING PROPENSITY SCORE MATCHING

Hyun Kyung Lim

ABSTRACT # 497 - THE ROLE OF CORE NEEDLE BIOPSY AS FIRSTLINE IN DIAGNOSIS OF THYROID NODULES IN LARGE POPULATION

Dong Gyu Na

ABSTRACT # 498 - REMOTE ACCESS ROBOTIC FACELIFT THYROIDECTOMY: A MULTIINSTITUTIONAL EXPERIENCE

William Sterling Duke

ABSTRACT # 499 - ONCOGENIC MUTATIONS IN THYROID CARCINOMA AND THEIR POWER TO DETECT MALIGNANCY IN DIVERSE THYROID NEOPLASMS

Richard T. Kloos

P-34

4:00 PM – 4:30 PM

4:30 PM – 5:30 PM

MEETING PROGRAM

Americas Seminar Room Fifth Level

Wednesday Short Oral Communications 8 Co-Chairs: John Morris and Dora Aranda ABSTRACT # 500 - DUAL INHIBITION OF HDAC AND PI3K– AKT PATHWAYS HAS POTENT ANTI-CANCER ACTIVITY IN THYROID CANCER CELLS

Shweta Kotian

ABSTRACT # 501- KNOWLEDGE OF PATHOLOGICALLY VS. CLINICALLY NEGATIVE LYMPH NODES IS ASSOCIATED WITH REDUCED USE OF RADIOACTIVE IODINE POST-THYROIDECTOMY FOR LOW RISK PAPILLARY THYROID CANCER

Ewa Ruel

ABSTRACT # 502 - SHALL WE TEMPORARILY HOLD ANTIPLATELET AND ANTICOAGULANT AGENTS BEFORE PATIENTS UNDERGO FNA OF THYROID NODULES?

Esha Sharma

ABSTRACT # 503 - THE INTERNATIONAL ANAPLASTIC THYROID CANCER TISSUE BANK AND DATABASE PROJECT (INATT)

Laura Moss

ABSTRACT # 504 - INCIDENCE OF NON THYROIDAL PRIMARY MALIGNANCY (NTPM) AND THE ASSOCIATION WITH I-131 TREATMENT IN PATIENTS WITH DIFFERENTIATED THYROID CANCER (DTC)

Dania Hirsch

Southern Hemisphere I Fifth Level

Wednesday Basic Oral Abstracts 1: TSH Receptor Autoimmunity Co-Chairs: George Kahaly and Marian Ludgate ABSTRACT # 449 - DISCOVERING NOVEL SMALL MOLECULES WHICH ABROGATE TSH RECEPTOR SIGNALING

Rauf Latif

ABSTRACT # 450 CONTRASTING DISEASE SPECTRUM IN PRECLINICAL MODELS OF GRAVES’ ORBITOPATHY IN BALB/C AND C57BL/6 MICE

Sajad Moshkelgosha

ABSTRACT # 451 - TSH RECEPTOR ANTIBODIES TO THE CLEAVAGE REGION (C-TSHRABS) INDUCE ENDOPLASMIC RETICULUM STRESS MEDIATED BY REACTIVE OXYGEN SPECIES (ROS)

Syed Morshed

MEETING PROGRAM

P-35

ABSTRACT # 452 - COOPERATIVE INHIBITION OF ORBITAL FIBROBLAST ACTIVATION BY SIMULTANEOUS TREATMENT WITH TSH RECEPTOR AND IGF1 RECEPTOR SMALL MOLECULE ANTAGONISTS 4:30 PM – 5:30 PM

4:30 PM – 5:30 PM

Christine Krieger

Southern Hemisphere II Fifth Level

Wednesday Basic Oral Abstracts 2: Thyroid Cancer Signaling Pathways and Targets Co-Chairs: Rui M.B. Maciel and Denise Pires De Carvalho ABSTRACT # 453 - Simultaneous Suppression of BRAFV600E and Histone Deacetylase Synergistically Restores Robust Thyroid Gene Expression and Radioiodine Uptake in Thyroid Cancer Cells

Weiwei Cheng

ABSTRACT # 454 - Follicular Thyroid Cancer and uncoupling of mTOR – AMPK pathways

Suresh Chandra Kari

ABSTRACT # 455 - IL–12 Immunotherapy of BrafV600E– induced Papillary Thyroid Cancer in a Mouse Model

Yufei Shi

ABSTRACT # 456 - Murine Follicular Thyroid Tumors Recruit a Tumor Microenvironment Enriched with Myeloid and Lymphoid Derived Immune Cells

Aime T. Franco

Southern Hemisphere III Fifth Level

Wednesday Clinical Oral Abstracts 1: Advances in Clinical Thyroidology Co-Chairs: Natsuko Watanabe and Angela Leung ABSTRACT # 457 - THYROID FUNCTION AND SUDDEN CARDIAC DEATH: A POPULATION-BASED COHORT STUDY

Layal Chaker

ABSTRACT # 458 - SYSTEMIC NON-VIRAL CMET/HGFRTARGETED GENE DELIVERY USING THE THERANOSTIC FUNCTION OF THE SODIUM IODIDE SYMPORTER (NIS)

Sarah Hacker

ABSTRACT # 459 - DIVERSE GENOTYPES AND PHENOTYPES OF T3 RECEPTOR TRA MUTATIONS

Anja Van Gucht

ABSTRACT # 460 RADIOFREQUENCY VERSUS ETHANOL ABLATION FOR TREATING PREDOMINANTLY CYSTIC THYROID NODULES: A RANDOMIZED CLINICAL TRIAL

Hye Sun Park

P-36

4:30 PM – 5:30 PM

7:30 PM – 11:00 PM

MEETING PROGRAM

Northern Hemisphere BCD Fifth Level

Wednesday Clinical Oral Abstracts 2: Thyroid Cancer Clinical Biomarkers Co-Chairs: Alfredo Pontecorvi and Jeffrey Knauf ABSTRACT # 461 - MULTI–GENE NEXT GENERATION SEQUENCING (THYROSEQ) ASSAY ON LOCALLY INVASIVE T4 WELL DIFFERENTIATED THYROID CANCER

Umamaheswar Duvvuri

ABSTRACT # 462 - DISCOVERY STAGE OF GENOME WIDE ASSOCIATION STUDY FOR PAPILLARY THYROID CANCER IN KOREA

Yul Hwangbo

ABSTRACT # 463 PROGRAMMED DEATH LIGAND 1 EXPRESSION CORRELATES WITH AGGRESSIVE METASTATIC PAPILLARY THYROID CARCINOMA

Paul G. Walfish

ABSTRACT # 464 - TERT PROMOTER MUTATIONS CAN BENEFIT HIGH-RISK PATIENTS OF DIFFERENTIATED THYROID CANCER IN THE PREDICTION OF MORTALITY AND RECURRENCE

Young Shin Song

15th ITC Banquet and Gala: Show Us Your Character! (Pre-registration required, admission with ticket only)

Pacific Hall Ground/First Level

Who is your favorite literary, comic book, movie character? "Show us your Character" at this fun filled event featuring laugh shots, dancing with thyroid experts and dining with friends and colleagues all rolled into one evening of fun!

15th International Thyroid Congress Scientific Program – Thursday, October 22 6:30 AM – 5:30 PM

15th ITC Registration Open

Convention Foyer 1/2 Lobby/Third Level

6:30 AM – 5:30 PM

Speaker Ready Room Open (open to meeting faculty only)

Australia 2 Room Lobby/Third Level

6:30 AM – 8:00 AM

Early Riser Symposium Continental Breakfast

Southern Hemisphere IV-V Fifth Level

7:00 AM – 8:20 AM

Early Riser Symposium: Update on Differentiated Thyroid Cancer – Molecular Mechanisms and Treatment Co-Chairs: Josef Koehrle and Manisha H. Shah

Northern Hemisphere BCD Fifth Level

MEETING PROGRAM

P-37

Altered Cell Metabolism in Thyroid Cancer Targeting the Thyroid Cancer Microenvironment Single or Combination Targeted Therapy? Comparison of Latest Guidelines on Differentiated Thyroid Cancer

Haixia Guan

8:35 AM – 9:20 AM

Latin American Thyroid Society Prize Lecture: Pediatric and Adult Thyroid Carcinoma: Far Beyond Biomarkers Discovery Introduction by Rui M.B. Maciel

Janete Maria Cerutti

9:00 AM – 1:30 PM

15th ITC Exhibit and Poster Hall Open (Open at 8:00 AM for poster presenters only)

Atlantic Hall Ground/First Level

9:20 AM – 10:20 AM

Poster Review Session and Break in the Exhibit Hall

Atlantic Hall Ground/First Level

10:20 AM – 11:35 AM

Case-Based Symposium: International Perspectives on Treatment of Graves’ Disease Moderator: David S. Cooper

Southern Hemisphere I Fifth Level

Asia and Oceania Thyroid Association Latin American Thyroid Association European Thyroid Association American Thyroid Association 10:20 AM – 11:35 AM

10:20 AM – 11:35 AM

Marcia S. Brose Matthew D. Ringel

Ana Luiza S. Maia Helena Filipsson Nystro¨m M. Regina Castro Southern Hemisphere II Fifth Level

Tania M. Ortiga Anthony N. Hollenberg Cecilia H.A. Gouveia Southern Hemisphere III Fifth Level

Symposium: Thyroid Hormone Axis – A Target for Endocrine Disrupting Compounds (EDC) Gregory A. Brent and Noriyuki Koibuchi Novel Non-Radioactive Screening Assays for Testing EDC Action Thyroid Disrupting Effects of Chemicals Found in Human Amniotic Fluid

Josef Koehrle

Perchlorate and the Thyroid Axis in Human Pregnancy and Lactation

Angela M. Leung

Symposium: Emerging Approaches to Papillary Microcarcinoma Management Co-Chairs: Leonidas Duntas and Akira Miyauchi

Northern Hemisphere BCD Fifth Level

Won Bae Kim

Symposium: Target Tissue Responses to Thyroid Hormone Co-Chairs: Carmen Pazos De Moura and Donald L. St. Germain Hypothalamic Pituitary Thyroid Axis Role of Co-Factors in TR and TissueSelective Thyroid Hormone Action Skeleton

10:20 AM – 11:35 AM

Laura S. Ward

Barbara Anne Demeneix

Northern Hemisphere BCD Fifth Level

P-38

MEETING PROGRAM

Epidemiology Active Surveillance Risk Factors for Persistent and Recurrent Disease

Anna M. Sawka Yasuhiro Ito Fabian Pitoia

11:40 AM – 12:30 PM

DD31 – Discussion/Debates Clinical: Pharmacologic and Destructive Therapies for Benign Nodules

Laszlo Hegedus Jeong Hyun Lee

Northern Hemisphere BCD Fifth Level

11:40 AM – 12:30 PM

DD32 – Discussion/Debates Clinical: Controversies in the Treatment of Graves’ Disease in Children

Scott A. Rivkees Juliane Leger

Northern Hemisphere E3-E4, Fifth Level

11:40 AM – 12:30 PM

DD33 – Discussion/Debates Clinical: Optimal Ultrasound and Scintigraphy for Thyroid Cancer

Jin Young Kwak Markus Luster

Southern Hemisphere II Fifth Level

11:40 AM – 12:30 PM

DD34 – Discussion/Debates Clinical: Minimizing Birth Defects after Use of Anti-Thyroid Drugs in Pregnancy

Jorge H. Mestman Bijay Vaidya

Americas Seminar Room Fifth Level

11:40 AM – 12:30 PM

DD35 – Discussion/Debates Clinical: Technique and Extent of Lymph Node Dissection for Thyroid Cancer

Zvonimir Luka Milas Ashok R. Shaha

Northern Hemisphere A1-A2, Fifth Level

11:40 AM – 12:30 PM

DD36 – Discussion/Debates Basic/ Translational: New Molecular Drivers In Thyroid Cancer

Mingzhao Xing Minho Shong

Southern Hemisphere III Fifth Level

11:40 AM – 12:30 PM

DD37 – Discussion/Debates Basic/ Translational: Negative Regulation of Target Genes by TH

Fredric E. Wondisford

Asia 1 Room Lobby/Third Level

11:40 AM – 12:30 PM

DD38 – Discussion/Debates Basic/ Translational: Genetics of Thyroid Development

Roberto Di Lauro

Northern Hemisphere E1-E2, Fifth Level

11:40 AM – 12:30 PM

DD39 – Discussion/Debates Basic/ Translational: Selenium and the Thyroid: International Studies and Experiences

Bingyin Shi Kristian Winther

Northern Hemisphere A3-A4, Fifth Level

11:40 AM – 12:30 PM

DD40 – Discussion/Debates Basic/ Translational: Key Steps in Thyroglobulin Iodination and Thyroid Hormonogenesis

Juan Nicola Peter Arvan

Asia 2 Room Lobby/Third Level

12:30 PM – 1:30 PM

Poster Review Session and Lunch in the Exhibit Hall

Atlantic Hall Ground/First Level

12:30 PM – 1:30 PM

15th ITC Expo Theater Presented by CBLPath (Limited seating; first come, first served; lunch included)

Atlantic Hall Ground/First Level

1:30 PM

15th ITC Exhibit Hall Closes

Atlantic Hall Ground/First Level

MEETING PROGRAM

P-39

1:30 PM – 2:15 PM

European Thyroid Association Prize Lecture: Disorders of Thyroid Hormone Action: Insights from Human Genetics Introduction by Furio Pacini

2:20 PM – 3:35 PM

Symposium: IgG4–Related Sclerosing Disease and the Thyroid Co-Chairs: Marius N. Stan and Mitsuyasu Itoh Clinical Overview of IgG4–Related Sclerosing Disease IgG4 in Thyroiditis in Hashimoto’s and Reidel’s Graves’ Orbitopathy and IgG4 Ocular Disease

2:20 PM – 3:35 PM

2:20 PM – 3:35 PM

Kennichi Kakudo James A. Garrity Southern Hemisphere II Fifth Level

Karine Gauthier Lars C. Moeller Maria Tereza Nunes Southern Hemisphere III Fifth Level

Denise Zwanziger ˚ svold Bjørn Olav A Laura Boucai Northern Hemisphere BCD Fifth Level

Symposium: Novel Therapies for Thyroid Autoimmune Diseases Co-Chairs: Takashi Akamizu and Terry F. Davies Small Molecule TSHR Antagonists Blocking Antigen Presentation Future Therapeutic Targets in Graves’ Orbitopathy

3:40 PM – 5:10 PM

Arezou Khosroshahi

Symposium: Longevity in Thyroid Status Co-Chairs: Patricia de Fatima dos Santos Teixeira and Anne R. Cappola Animal Studies on Thyroid and Aging Survival Data from Epidemiologic Studies TSH Thresholds for Therapy

Northern Hemisphere BCD Fifth Level

Southern Hemisphere I Fifth Level

Symposium: Non-Genomic Actions of TH Co-Chairs: Riccardo Zucchi and Claudia Pellizas Overview Nuclear Receptor Mediated Non-Genomic Actions Membrane Reception Mediated Non-Genomic Actions

2:20 PM – 3:35 PM

V Krishna K. Chatterjee

Marvin C. Gershengorn Yaron Tomer Wilmar M. Wiersinga Northern Hemisphere BCD Fifth Level

Short Call Oral Abstract Session Co-Chairs: Peter Arvan and Stephanie A. Fish SHORT CALL ABSTRACT # 1 BRANCHING MORPHOGENESIS INVOLVING A SOX9-FGF10 PATHWAY REGULATES THYROID DEVELOPMENTAL GROWTH

Mikael Nilsson

SHORT CALL ABSTRACT # 2 THYROID CONVERSION OF MOUSE ESC-DERIVED ANTERIOR FOREGUT THROUGH TRANSIENT OVEREXPRESSION OF NKX2-1

Keri Dame

P-40

5:15 PM – 6:00 PM

MEETING PROGRAM

SHORT CALL ABSTRACT # 3 COEXISTING BRAF V600E AND TERT PROMOTER MUTATIONS DEFINE ROBUSTLY THE HIGHEST MORTALITY IN PAPILLARY THYROID CANCER—AN EXTENDED STUDY

Mingzhao Xing

SHORT CALL ABSTRACT # 4 MOLECULAR TUMORIGENESIS OF PAPILLARY THYROID MICROCARCINOMA

Nikoletta Sidiropoulos

SHORT CALL ABSTRACT # 5 CONTROLLED ANTENATAL THYROID SCREENING STUDY: OBSTETRIC OUTCOMES

Peter N. Taylor

SHORT CALLABSTRACT # 6 RECURRENT EZH1 MUTATIONS IN AUTONOMOUS THYROID ADENOMAS

Ralf Paschke

Northern Hemisphere BCD Fifth Level

Short Call Short Oral Communications Co-Chairs: Victor J. Bernet and Antonio C. Bianco SHORT CALL ABSTRACT # 7 DISSECTING CONGENITAL HYPOTHYROIDISM MECHANISMS USING PLURIPOTENT STEM CELLS AND TARGETED GENOME EDITING

Sabine Costagliola

SHORT CALL ABSTRACT # 8 DISRUPTION OF THE TYPE-2 DEIODINASE IN ASTROCYTES RESULTS IN ANXIETYDEPRESSIVE-LIKE BEHAVIOR

Barbara Bocco

SHORT CALL ABSTRACT # 9 SIMPLIFIED INDUCTION OF THYROID-SPECIFIC GENE EXPRESSION IN HUMAN EMBRYONIC STEM CELLS USING TAZ ACTIVATION

Risheng Ma

SHORT CALL ABSTRACT # 10 COMBINING BRAF INHIBITOR AND ANTI PD-L1 ANTIBODY DRAMATICALLY IMPROVES TUMOR REGRESSION AND ANTI TUMOR IMMUNITY IN AN IMMUNOCOMPETENT MURINE MODEL OF ANAPLASTIC THYROID CANCERS

Eran Brauner

MEETING PROGRAM

P-41

SHORT CALL ABSTRACT # 11 WEEKLY PACLITAXEL ADMINISTRATION IN PATIENTS WITH ANAPLASTIC THYROID CARCINOMA. A NATIONWIDE PROSPECTIVE CLINICAL STUDY

Naoyoshi Onoda

SHORT CALL ABSTRACT # 12 IDENTIFICATION OF DIFFERENTIALLY EXPRESSED LNCRNA WITH BIOLOGIC FUNCTION IN THYROID CANCER

Myriem Boufraqech

SHORT CALL ABSTRACT # 13 THE IN VITRO ANTIADIPOGENIC EFFECTS OF BIMATOPROST IN THYROID ASSOCIATED ORBITOPATHY

Lisa Chen

15th International Thyroid Congress Scientific Program – Friday, October 23 7:30 AM – 11:30 AM

15th ITC Registration Open

Northern Hemisphere BCD Foyer, Lobby/ Third Level

7:30 AM – 11:30 AM

Speaker Ready Room Open (open to meeting faculty only)

Australia 2 Room Lobby/Third Level

7:30 AM – 9:00 AM

15th ITC Continental Breakfast

Northern Hemisphere BCD Fifth Level

8:15 AM – 8:30 AM

Presentation of 16th ITC Site Selection in 2020 by the Asia and Oceania Thyroid Association (AOTA)

Northern Hemisphere BCD Fifth Level

8:30 AM – 9:15 AM

Plenary Lecture: Progress in the Surgical Management of Neoplasia and Hyperthyroidism Introduction by Electron Kebebew

9:15 AM – 11:00 AM

Thyroid Cancer Tumor Board Moderator: Bryan R. Haugen

Endocrinology Medical Oncology Molecular Biology Nuclear Medicine Pathology Radiation Oncology Surgery 11:00 AM

15th ITC Adjourns

Sally E. Carty

Northern Hemisphere BCD Fifth Level

Northern Hemisphere BCD Fifth Level Jen–Der Lin Kate Newbold Thomas J. Giordano Douglas Van Nostrand Virginia A. LiVolsi Robert Amdur Celso Frigugliettii

DOI: 10.1089/thy.2015.29004.abstracts

Monday, October 19, 2015 Oral 1 Autoimmunity Monday Oral Basic 4:30 PM STRUCTURE AND ACTIVATION OF THE TRANSMEMBRANE DOMAIN OF THE TSH RECEPTOR R. Nu´n˜ez Miguel, J. Sanders, J. Furmaniak, B. Rees Smith FIRS Laboratories, RSR Ltd, Cardiff, United Kingdom To date the structures of at least 25 GPCRs have been solved and are useful templates for comparative modelling of the TSH receptor (TSHR) transmembrane domain (TMD). A comparative model of the structure of the TMD of the TSHR in its inactive conformation was built based on the crystal structures of 16 GPCRs in their inactive conformations. In addition, models of the TSHR TMD in the inactive and active conformations were generated using crystal structures from 3 GPCRs for which structures of fully active and inactive conformations are available (b2-adrenergic receptor, rhodopsin and the M2 muscarinic acetylcholine receptor). The models of the TSHR TMD in the active and inactive conformations show the typical core of 7 membrane spanning helices (TM) and helix 8 parallel to the membrane. The highly variable extracellular loop 2 acquired a structure similar to that of rhodopsin. A GPCR conserved a-bulge is observed in the structure of TM2 but not in TM5. A proline distortion, characteristic of GPCRs, is observed in TM4 and proline kinks are observed in the structures of TM6 and TM7. The TSHR TMD shows the GPCR conserved motif sequence ERW in TM3 and Asp619 in TM6 consistent with forming an ionic lock. During activation, TM2 and TM4 of the TSHR TMD do not make appreciable movements. TM3 and TM6 displace towards the extracellular space. TM7 displaces inwards (towards the core of the helix bundle). The extracellular end of TM1 displaces inwards and its cytoplasmic end outwards (away from the core of the helix bundle). The extracellular end of TM5 does not move, but its cytoplasmic end displaces inwards. The cytoplasmic end of TM6 displaces outwards and rotates approximately 600. Our models suggest that these conformational changes and modifications of important interactions within the TMD during activation lead to opening of the G-protein binding site at the cytoplasmic end of the TMD structure. The models of the TSHR TMD and proposed activation process have been validated in a study of constitutive activating and silencing mutations. Also, it is likely that similar movements occur in the FSHR and LHR TMDs during activation.

Oral 2 Autoimmunity Monday Oral Basic 4:45 PM A UNIQUE HLA-DR POCKET PREDISPOSES TO BOTH AUTOIMMUNE THYROIDITIS AND DIABETES BY PRESENTING THYROID AND ISLET PEPTIDES C. Li1, F. Menconi1, R. Osman1, E. Concepcion1, C. David2, Y. Tomer1,3 1 Icahn School of Medicine at Mount Sinai, New York, NY; 2 Immunology, Mayo Clinic, Rochester, MN; 3James J. Peters VA Medical Center, Bronx, NY There is strong genetic association between autoimmune thyroiditis (AITD) and Type 1 diabetes (T1D), and the co-occurrence of both AITD + T1D in the same individual is referred to as Autoimmune polyglandular syndrome type 3 variant (APS3v). HLA-DR3 is the major allele associated with APS3v. Recently, we identified 5 amino acids within the DR3 peptide binding pocket as key to the association

with APS3v. However, it is not known whether the DR pocket created by these 5 a.a.’s can bind and present to T-cells both thyroid and islet derived peptides or whether DR3 binds mostly thyroid peptides while DQ2 (in strong LD with DR3) binds islet peptides. Our aim was to analyze thyroid and islet peptides’ binding to the APS3v-DR pocket, and their presentation to T-cells. We tested binding of a panel of peptides derived from the key thyroid and islet proteins in AITD and T1D-Tg, TSHR, TPO, insulin, and GAD65, for binding to the APS3v HLA-DR. We used a novel in vitro assay we developed utilizing Baculovirus-generated recombinant APS3v-DR. We then tested these peptides for their ability to stimulate T-cell responses in a ‘‘humanized’’ mouse model, NODDR3 that express HLA-DR3, with the 5 key APS3v-specific DR pocket a.a.’s. We immunized NOD-DR3 mice with the thyroidal/islet peptides and assessed T-cell proliferative and cytokine responses. We identified 11 peptides that bound to the APS3v-specific DR in vitro: 2 derived from Tg, 6 from TPO, one from insulin, 2 from GAD65. So far, only 4 peptides induced T-cell responses in NODDR3 mice-2 Tg peptides, Tg.1571, Tg.1951, one GAD65 peptide, GAD.492, and one TPO peptide, TPO.758 (testing of TPO peptides is still ongoing). Our results suggested that the APS3v-specific HLADR pocket variant we identified can bind both thyroidal and islet peptides and present them to stimulate T-cell responses. Our data support the hypothesis that the APS3v-specific HLA-DR pocket variant predisposes to both AITD + T1D by presenting both thyroid- and islet-derived peptides by itself, and not through linkage disequilibrium with HLA-DQ2. Our findings set the stage for new therapeutic strategies by blocking this pocket.

Oral 3 Iodine Uptake & Metabolism Monday Oral Basic 5:00 PM CHEMICAL CHAPERONES RESCUE THE PATHOGENIC 6PHE501 MUTATION IN MONOCARBOXYLATE TRANSPORTER 8 D. Braun, U. Schweizer Institut fu¨r Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms Universita¨t Bonn, Bonn, Germany Mutations in the highly specific thyroid hormone transporter MCT8 (monocarboxylate transporter) lead to the Allan-Herndon-Dudley syndrome (AHDS), a severe mental retardation disease caused by a disturbed thyroid hormone uptake into different cells (e.g. brain) during critical stages of embryonic development. Symptoms of AHDS include neurological deficits, muscle weakness, absent of speech and inability to walk. Most MCT8 mutations lead to complete loss of transporter function. Some AHDS patients are not as severely affected as others. Fibroblasts from these patients show residual thyroid hormone uptake activity. One of these mutations is a deletion of phenylalanine 501. Patients with MCT86Phe501 are able to walk with some help and articulate words. Mutation of 6Phe501 was introduced into human MCT8 by site directed mutagenesis and stably transfected into MDCK1 (MadinDarby canine kidney) cells. The cells were treated with increasing concentrations of chaperones for two days. Western blotting and radioactive thyroid hormone-uptake experiments were performed to analyze chaperone effects. Deletion of phenylalanine 501 destabilizes protein structure and induces rapid degradation of the MCT86Phe501 protein in stably transfected MDCK1 cells. Interestingly, we could rescue expression and transport activity of MCT86Phe501-MDCK1 cells by applying the chemical chaperone 4-phenylbutyrate (4-PB) or the soy

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MONDAY, OCTOBER 19, 2015 isoflavone genistein. 4-PB is a common drug used for the treatment of urea cycle defects and cystic fibrosis. Thus, MCT8 mutations did not only affect the transport activity of the protein but also its stability and localization at the cell surface. We did not find a complete loss of the unstable MCT86Phe501 protein, which might explain the residual activity and the milder phenotype of the patients. Whether other MCT8 mutations of AHDS patients with milder phenotypes (e.g. L434W, L492P, L568P, R445C) also respond to chaperone treatment needs to be investigated. However, the administration of chemical chaperones, which are safe for humans, could be a new tool for the therapy of MCT8 deficiency to improve the patient’s quality of life.

Oral 4 Iodine Uptake & Metabolism Monday Oral Basic 5:15 PM TRANSCRIPTION FACTOR PAIRED-BOX 8 REGULATES NA + /I - SYMPORTER GENE EXPRESSION IN SMALLINTESTINE ABSORPTIVE ENTEROCYTES J.P. Nicola, A.M. Masini-Repiso Departamento de Bioquı´mica Clı´nica, Facultad de Ciencias Quı´micas, Universidad Nacional de Co´rdoba, Co´rdoba, Argentina Iodine is an essential constituent of the thyroid hormones, the only iodine-containing molecules in vertebrates. Dietary iodide (I - ) absorption in the gastrointestinal tract constitutes the first step in I metabolism, as the diet is the unique source of I- for land-dwelling vertebrates. The Na + /I - symporter (NIS), an integral plasma membrane glycoprotein located in the brush border of enterocytes, i.e. the finger-like projections that protrude from the apical membrane of absorptive enterocytes into the intestinal lumen, constitutes a central component of the I - absorption system in the small intestine. Here, we investigated the mechanisms controlling NIS gene expression in small-intestine absorptive enterocytes. Experiments were performed in male Wistar rats and the rat small intestine-derived IEC-6 cell line. Pax8 expression was evaluated by RT-PCR, western blot and immunofluorescence. Analysis of NIS gene regulatory sequence and Pax8 transcriptional activity were evaluated using gene reporter assays. Considering the key role of Pax8 controlling NIS gene expression in thyroid cells, we evaluated Pax8 expression in small-intestine absorptive enterocytes. Consistently with NIS being expressed exclusively on the brush border, we detected Pax8 expression in isolated villus-tip enterocytes. In agreement, we evidenced Pax8 expression in the nucleus of IEC-6 cells. Moreover, we observed a significant induction of the Pax8 reporter vector in IEC-6 cells, thus revealing Pax8 transcriptional activity. We further evaluated the role of Pax8 modulating the activity of NIS gene regulatory sequence. Deletion analysis of the NIS promoter revealed the requirement of the NIS upstream enhancer, i.e. NIS promoter region containing Pax8 binding sites, for NIS expression in enterocytes. Interestingly, the activity of the NIS promoter mutant missing Pax8-binding sites was significantly impaired. Consistently with the role of Pax8 controlling NIS expression in enterocytes, ChIP analysis revealed Pax8 binding to the NIS upstream enhancer. We report the first evidence supporting the role of the transcription factor Pax8 controlling NIS gene expression in small-intestine absorptive enterocytes.

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Thyroid Center, Erasmus Medical Center, Rotterdam, Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands; 3Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands; 4Department of Radiology, Erasmus Medical Center, Rotterdam, Netherlands

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A link between thyroid dysfunction and dementia has been suggested, but not investigated across the range of thyroid function. Therefore we aimed to assess the association of thyroid function with dementia risk and MRI related brain structures. Participants ‡ 45 years from the Rotterdam Study with thyroid function measurements and dementia assessment were included in the study. We evaluated the association of thyroid function, defined by thyroid-stimulating hormone (TSH) and free thyroxine (FT4), and dementia through cox-proportional hazards regressions. Multivariable models adjusted for age, sex, multiple cardiovascular risk factors and highest attained education. The association of thyroid function with MRI related brain structures, including hippocampal and total parenchymal volumes, were assessed with linear regression. Additional analyses included 1) stratification and interaction by age and sex 2) restricting to subjects with TSH and FT4 within the normal range. We included 9495 participants (mean age 64.9 years.) with mean follow-up of 7.8 years (Interquartile range 5.4–10.7). Of these participants, 603 developed dementia. Higher TSH levels were associated with lower dementia risk in the full and normal range of thyroid function (Hazard Ratio [HR] 0.90 (95% Confidence Interval [CI], 0.83–0.98 and HR 0.76, 95% CI 0.64–0.91 respectively). The risk of dementia was significantly higher with higher levels of FT4 (HR 1.04, 95% CI, 1.01–1.07). There was a differential risk by sex in the TSH analyses. In women, the absolute 10-year risk of dementia decreased with higher TSH levels from 6% to almost 3%, but not in men. In older participants, higher FT4 levels were associated with smaller parenchymal volumes ( - 2.1 ml per 1pmol/L increase of FT4), but not hippocampal volumes. High thyroid function, even in the normal range, is associated with an increased relative and absolute risk of dementia in women, but not

Oral 5 Disorders of Thyroid Function Monday Oral Clinical 4:30 PM THYROID FUNCTION AND THE RISK OF DEMENTIA: THE ROTTERDAM STUDY L. Chaker1,2, F. Wolters2,3, D. Bos2,4, A. Dehghan2, T.I. Korevaar1,2, A. Hofman2, O. Franco2, M. Vernooij4,2, M. Ikram3,2, R. Peeters1

Absolute 10 year risk of dementia, taking the competing risk of death into account, plotted against thyroid-stimuatling hormone (TSH) in the normal range for those younger and older than 65 years of age and seperately for men and women.

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in men. In elderly, high thyroid function is associated with smaller parenchymal volumes. These data suggest a role of thyroid function in pathways leading to dementia.

Oral 6 Thyroid & Development Monday Oral Basic 4:45 PM BMP AND FGF SIGNALING ARE REQUIRED FOR DIRECTED DIFFERENTIATION OF PLURIPOTENT STEM CELLS INTO FUNCTIONAL THYROID FOLLICLES A.A. Kurmann1,2, M. Serra2,3, F. Hawkins2,3, S. Rankin4, M. Mori2,3, I. Astapova1, S. Ullas5, S. LIn9, M. Bilodeau6, J. Rossant6,7, J.C. Jean2,3, L. Ikonomou2,3, R. Deterding8, J. Shannon9, A. Zorn4, D.N. Kotton2,3, A. Hollenberg1 1 Divison of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA; 2Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA; 3The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA; 4Division of Developmental Biology, Perinatal Institute, Cincinnati Children’s Hospital, Cincinnati, OH; 5Longwood Small Animal Imaging Facility, Beth Israel Deaconess Medical Center, Boston, MA; 6Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; 7Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; 8Breathing Institute at the Children’s Hospital Colorado and Section of Pediatric Pulmonary Medicine, University of Colorado, Aurora, CO; 9Division of Pulmonary Biology, Cincinnati Children’s Hospital, Cincinnati, OH The signals regulating early thyroid development are incompletely known, precluding prior attempts to generate functional thyroid epithelia from pluripotent stem cells (PSCs) via directed differentiation. To accomplish this we employed mouse embryonic stem cells and targeted the Nkx2-1 allele with a fluorophore to allow us to sort Nkx21 + cells destined to become thyroid follicular cells. The mouse PSC in vitro model system along with Xenopus and mouse in vivo models were utilized to identify key conserved signaling pathways regulating thyroid lineage specification from foregut endoderm in vivo. We find BMP and FGF signaling pathways are necessary and sufficient to specify Nkx2-1 + thyroid progenitors from endodermal precursors in Xenopus developing embryos and mouse foregut explants. Moreover, by stimulating these pathways we derive human thyroid progenitors from normal and disease-specific induced pluripotent stem cells generated from patients with hypothyroidism due to NKX2-1 haploinsufficiency. Thyroid progenitors derived from mouse PSCs can be matured in 3D culture conditions into thyroid follicular organoids that exhibit functional capacity to produce T4 in vitro and to secrete thyroid hormones in vivo and rescue hypothyroid mouse after transplantation. Thus we have identified the mechanisms of early thyroid organogenesis, and developed a cell-based model to study the effects of NKX2-1 haploinsufficiency, thyroid hormone, metabolites, and drugs on thyroid development. We demonstrate the potential feasibility of cell-based regenerative therapy for hypothyroidism.

Oral 7 Disorders of Thyroid Function Monday Oral Clinical 5:00 PM TREATMENT OF HYPOTHYROIDISM WITH LEVOTHYROXINE PLUS TRIIODOTHYRONINE: A RANDOMIZED, DOUBLE-BLIND CROSSOVER STUDY G.J. Paz-Filho1, J. Kaminski2, F.Y. Miasaki2, G.A. de Carvalho2 1 John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia; 2Endocrine Division (SEMPR), Department of Internal Medicine, Clinical Hospital of the Federal University of Parana, Curitiba, Brazil

T3, fT4 and TSH mean levels while on LT4 or LT4 + T3 therapy. Treatment of hypothyroidism with the combination therapy levothyroxine/liothyronine (LT4/LT3) is controversial. LT4 alone may not lead to euthyroidism in some tissues, and the combination therapy may benefit select patients. This is a randomized, double-blind, crossover study. Adults with primary hypothyroidism (n = 32, age 42.6 – 13.3, 30 females) on stable doses of LT4 for ‡ 6 months (125 or 150 lg/day) were randomized to continue LT4 treatment (G1, n = 17), or to start LT4 + LT3 therapy (75 lg + 15 lg/day; G2, n = 15). After 8 weeks, participants switched treatment for 8 more weeks. Thyroid function, lipid profile, plasma glucose, body weight, electrocardiogram (ECG), vital signs and quality of life were evaluated at baseline, and at the end of weeks 8 and 16. Baseline characteristics were similar between groups. Significant changes over the study were observed only for mean free T4 (fT4; P < .001 in both groups), and mean TSH levels (only in G1; P < .05). In both groups, mean fT4 levels were significantly lower when patients were on LT4/LT3, when compared to while on LT4 treatment (in G1, 1.07 – 0.29 at week 16 vs. 1.65 – 0.46 ng/dl at week 8; in G2, 0.97 – 0.26 at week 8 vs. 1.63 – 0.43 ng/dl at week 16). Overall, neither median TSH nor T3 levels were affected by type of therapy, in both groups. However, more patients had T3 levels above the upper limit after being on LT4/ LT3 (15% vs. 3%). Moreover, the combination therapy led to an increase in heart rate, with no significant changes in ECG and arterial blood pressure. Other parameters of lipid profile, body weight and quality of life (evaluating physical, energy/well-being, and mood/emotions complaints) remained unchanged between the treatment groups. The combination therapy LT4/LT3 in patients with hypothyroidism led to significantly lower levels of mean fT4. Neither intranor inter-group differences in T3 levels were observed throughout the study. Despite the fact more patients on LT4/T3 had elevated T3 levels, this did not lead to significant alterations in lipid profile, arterial blood pressure, cardiac rhythm, body weight and quality of life. No clear clinical benefit of the studied formulation LT4/LT3 could be observed in patients treated for 8 weeks. Future trials need to evaluate different formulations, and the impact of the combined therapy in select populations with deiodinase polymorphisms.

Oral 8 Thyroid & Development Monday Oral Translational 5:15 PM ATYPICAL HIPPOCAMPAL FUNCTIONING DURING VERBAL MEMORY RECALL IN YOUTH WITH CONGENITAL HYPOTHYROIDISM J.F. Rovet1,2, V. McLelland4, S. Wheeler2, M. McAndrews3,2 1 Psychology, The Hospital for Sick Children, Toronto, ON, Canada; 2 Psychology, University of Toronto, Toronto, ON, Canada; 3 Neuropsychology, Toronto Western Hospital, Toronto, ON, Canada; 4Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, ON, Canada The hippocampus is critical for learning and recalling verbal information. Studies on rodents show structural and functional integrity of the hippocampus critically depends on an adequate early supply of thyroid hormone (TH). In humans, congenital hypothyroidism (CH) contributes to an early brief period of TH insufficiency. Affected

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Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY; 2Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; 3Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; 4Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY; 5Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY; 6Pathology, Memorial Sloan Kettering Cancer Center, New York, NY

Hippocampal regions showing differential activation for processing of word pairs versus single words (left) and percent signal change difference results for corresponding regions (right). Typically developing controls show significantly more activation in left middle hippocampus ( - 32 - 24 - 16; upper) and right anterior hippocampus (36 16 - 20; lower) when recognizing word pairs over single words, whereas CH showed no significant hippocampal effects (and so not shown). Percent signal-change analyses found that whereas controls (dark grey) demonstrated strong activation for pairs and deactivation for items, these effects were very diminished in CH (light grey). children show memory weaknesses, particularly for new word associations and reduced size of left hippocampus, which is critical for verbal processing. Using a visuospatial task, we previously reported they showed atypical hippocampal functioning but their hippocampal functioning on verbal memory tasks was not studied. Participants were 14 CH and 14 typically developing control (TDC) adolescents. All underwent functional magnetic resonance imaging (fMRI) with a verbal paired-associates paradigm, which in adults identified the specific hippocampal regions that were differentially activated for word pairs and deactivated for single words. Participants first learned a series of novel word pairs by silently forming sentences and later in scanner judged if pairs or individual words were seen before. Contrasts used to analyze the fMRI data compared specific hippocampal regions that were more engaged for all pairs versus all items or for old pairs versus old items. Groups did not differ in overall accuracy. Two hippocampal regions that were differentially activated when recognizing pairs versus items were the left middle hippocampus (LMH) and right anterior hippocampus (RAH). This effect was only significant for TDC and substantially reduced in CH (see Figure). Compared with TDC, CH showed a significantly smaller distinction between pair and item trials in RAH. These findings were not associated with TH levels at time of diagnosis. Our finding that youth with CH show reduced LMH and RAH response to paired versus single verbal stimuli than TDC signifies reduced hippocampal integrity for verbal memory processing in CH. Lack of correlation in CH between activation patterns and TH levels at neonatal diagnosis suggests time of need for TH in the hippocampus may extend beyond the newborn period.

Oral 9 Thyroid Cancer Monday Oral Translational 4:30 PM CHARACTERIZATION OF THE CANCER GENOME OF ADVANCED THYROID TUMORS IDENTIFIES DISTINCT MOLECULAR HALLMARKS OF POORLY DIFFERENTIATED AND ANAPLASTIC THYROID CANCERS I. Landa1, T. Ibrahimpasic2, L. Boucai3, R. Sinha4,5, J.A. Knauf1, R.H. Shah1, S. Dogan6, J.C. Ricarte-Filho1, N. Schultz1, M. Berger1,6, C. Sander4, R.A. Ghossein6, B.S. Taylor1,4, I. Ganly2, J.A. Fagin1,3

The Cancer Genome Atlas (TCGA) recently completed a comprehensive genomic landscape study of papillary thyroid carcinomas (PTC). Poorly differentiated (PDTC) and anaplastic (ATC) cancers, which account for 5–10% of thyroid tumors but one third of deaths, were not investigated. Here we report a comprehensive cancer genome assessment of 117 PDTCs and ATCs, which were subjected to MSK-IMPACT targeted sequencing of 341 cancer genes, from which we evaluated somatic mutations, fusions and copy number alterations, as well as mRNA expression analysis of a representative subset. We found remarkable differences between the two entities, with ATCs harboring more frequent alterations than PDTCs in TERT promoter (73% vs. 40%), TP53 (73% vs. 8%), PIK3CA (18% vs. 2%), PTEN (15% vs. 4%) and NF1 (9% vs. 0%). PDTCs were enriched for RET, PAX8-PPARG and ALK rearrangements (0% in ATCs vs. 13%, combined). In addition, EIF1AX mutations were more prevalent in PDTC + ATCs (10% vs. 1% in PTC), had a striking pattern of co-occurrence with RAS mutations (14/15, p < 0.0001) and were associated with worse survival in PDTC (p = 0.048). We also found mutations in genes not previously reported in thyroid cancer, mostly affecting PI3K/AKT/mTOR pathway, the SWI/SNF chromatin remodeling complex, histone

FIGURE 1. Landscape of the cancer genome alterations in 84 poorly-differentiated (PDTC) and 33 anaplastic thyroid cancers (ATC). A. Mutation density across the PDTC and ATC cohorts, expressed as number of genetic alterations found in 341 genes present in MSKIMPACT; B. Sample type, patient’s age and gender, tumor metastasis site, sample preservation, normal tissue availability, estimated tumor purity, histological phenotype, growth pattern and PDTC definition. Color key is shown in the right-most panel; C-G. Oncoprints showing the molecular hallmarks of PDTCs (left) and ATCs (right). Middle panel shows percentages of tumors altered for each event; red asterisks denote significant Fisher’s exact test p-values in frequencies when comparing PDTCs vs. ATCs. Color key for genetic alteration types is shown in the bottom-most panel.

A-6 methyltransferases and mismatch repair proteins, particularly for ATCs. We identified recurrent chromosomal losses of 1p, 8p, 13q, 15q, 17p and 22q, and gains in 1q and 20q, which occurred in a tumor type and genetic context-specific fashion. We also found distinct global, M2 macrophage and thyroid differentiation (TDS) transcriptomic signatures between PDTCs and ATCs. Interestingly, the application of the TCGA-derived BRAF-RAS expression score (BRS) to advanced tumors proved a preserved dependence on their driver alteration (BRAF/RAS mutations), with the exception of RAS-mutant ATCs that were more BRAF-like. Our study also emphasizes the importance and efficacy of ultradeep sequencing for these heavily infiltrated tumors, which pose a challenge for characterization by conventional Sanger or NGS approaches with lighter sequence coverage.

Oral 10 Thyroid Nodules & Goiter Monday Oral Clinical 4:45 PM A 2015 SURVEY OF ENDOCRINOLOGISTS ON THE MANAGEMENT OF THYROID NODULES N.O. Vietor1, K. Burman2, D. Cooper3, J. Hennessey4, H. Burch1 1 Endocrinology, Walter Reed National Military Medical Center, Bethesda, MD; 2Medstar Washington Hospital Center, Washington DC, DC; 3Johns Hopkins Medical Center, Baltimore, MD; 4Beth Israel Deaconess Med Center, Boston, MA To assess practice trends in the management of thyroid nodules, members of the American Thyroid Association (ATA), the Endocrine Society (TES), and the American Association of Clinical Endocrinologists (AACE) were asked to take a web-based survey consisting of 36 questions regarding diagnosis and management of thyroid nodules. There were 897 respondents (661 TES, 464 AACE, 365 ATA) with 63.0% from North America (NA), 12.2% Europe (E), 10.8% Latin America (LA), 6.5% Asia (A), 5.6% Middle East/Africa (ME), 1.9% Oceania (O). Initial evaluation included TSH (99.4%), thyroid ultrasound (US) (52.1% in clinic, 57.2% in radiology), and serum calcitonin (8.4%). 68.5% would assess cervical lymph nodes on initial US. Only 4.5% would obtain radio-scintigram. Fine needle aspiration (FNA) was performed by an endocrinologist (56.6%), radiologist (31.9%), or pathologist (6.3%). 83.3% of respondents use US to guide FNA and 56.6% use some form of analgesia. Overall, 58.5% of participants use molecular analysis. Participants were presented with 6 nodule cases; 5 low-risk, 1 high-risk. 93.8% would recommend FNA of the high-risk nodule and 40.5% the low-risk nodules. The majority of respondents (64.2%) would be less likely to recommend FNA in an elderly patient and 34.1% would postpone FNA until after pregnancy. Benign FNA results would be followed by at least one repeat US (65.6%). Patients with atypia of unknown significance /follicular lesion of undetermined significance (AUS/FLUS) would be sent for molecular analysis (38.8%), repeat FNA (31.5%), or surgery (24.4%). Patients with follicular neoplasm would be sent for molecular analysis (29.0%) or lobectomy (46.6%). Patients with a suspicious FNA would be referred for lobectomy (43.0%) or total thyroidectomy (43.1%) with only 9.5% sending molecular analysis. Regional diversity was apparent in the evaluation of thyroid nodules. For example, molecular analysis is routinely used by participants from NA (73.9%), E (43.1%), A (41.4%), O (41.2%), LA (40.2%), ME (34.0%). In summary, management of a thyroid nodule is highly variable and differs from societal guidelines in multiple areas. Regional differences exist with regard to FNA, particularly the use of molecular analysis.

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Oral 11 Thyroid Cancer Monday Oral Basic 5:00 PM TSH OVERCOMES BRAFV600E-INDUCED SENESCENCE TO PROMOTE TUMOR PROGRESSION VIA DOWNREGULATION OF P53 EXPRESSION IN PAPILLARY THYROID CANCER Y. Shi1, M. Zou1, E. Baitei1, R. Al-Rijjala1, R. Parhar6, F. Al-Mohanna6, S. Kimura3, C. Pritchard2, H. BinEssa1, A. Alzahrani4, A. Assiri5, B. Meyer1 1 Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 2Biochemistry, University of Leicester, Leicester, United Kingdom; 3Laboratory of Metabolism, National Cancer Institute, Bethesda, MD; 4Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 5Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 6Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia The BRAFV600E mutation is found in approximately 40% of papillary thyroid cancers (PTC).In humans, serum thyroid stimulating hormone (TSH) increases with age and mean TSH is significantly higher in thyroid cancer patients. Even serum TSH is within normal range from 0.4 to 4.0 (mIU/L) in most PTC patients, the frequency of malignancy increases when TSH is greater than 0.9 mU/L. Mice with thyroid-specific expression of BrafV600E (TPO-BrafV600E) develop PTC rapidly with high levels of serum TSH. It is unclear to what extent the elevated TSH contributes to tumor progression. To investigate the progression of BrafV600E-induced PTC (BVEPTC) under normal TSH, we used TPO-BrafV600E transgenic mice where BrafV600E is exclusively expressed in thyroid follicular cells and PTC develops as early as 6 weeks of age. BVE-PTC tumors were transplanted subcutaneously into nude and TPO-BrafWT mice. Regression of the transplanted tumors was observed in both nude and TPO-BrafWT mice. They were surrounded by heavy lymphocyte infiltration and oncogene-induced senescence (OIS) was demonstrated by strong b-gal staining and absence of Ki-67 expression. In contrast, BVE-PTC transplants continued to grow when transplanted into TPO-BrafV600E mice. The expression of Trp53 was increased in tumor transplants undergoing OIS. Trp53 inactivation reversed OIS and enabled tumor transplants to grow in nude mice with characteristic cell morphology of anaplastic thyroid cancer (ATC). PTC-toATC transformation was also observed in primary BVE-PTC tumors. One allelic inactivation of Trp53 is sufficient for ATC transformation and TSH-independent tumor growth. ATC cells derived from Trp53 knockout tumors had increased PI3K/AKT signaling and became resistant to BrafV600E inhibitor PLX4720, which could be overcome by combined treatment of PI3K inhibitor LY294002 and PLX4720. BVE-PTC progression could be contained via p53-dependent OIS and TSH is a major disruptor of this balance. Simultaneous targeting of both MAPK and PI3K/AKT pathways offer a better therapeutic outcome against ATC. The current study reinforces the importance of rigorous control of serum TSH in PTC patients.

Oral 12 Thyroid Imaging Monday Oral Clinical 5:15 PM SUBCATEGORIZATION OF ATYPIA OF UNDETERMINED SIGNIFICANCE/FOLLICULAR LESION OF UNDETERMINED SIGNIFICANCE (AUS/FLUS): A STUDY APPLYING THYROID IMAGING REPORTING AND DATA SYSTEM (TIRADS) J. Yoon1, H. Kwon2, E. Kim1, H. Moon1, J. Kwak1 1 Department of Radiology, Severance Hospital, Yonsei University, College of Medicine, Seoul, Korea (the Republic of); 2Department of

MONDAY, OCTOBER 19, 2015 Pathology, Yonsei University, Wonju College of Medicine, Wonju, Korea (the Republic of) To evaluate the clinical significance and compare the imaging features according to the Thyroid Image Reporting and Data System (TIRADS) between atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) subcategories. A total of 192 thyroid nodules in 188 patients (mean age: 50.2 – 11.8 years) that had been initially diagnosed as AUS/FLUS on US-guided fine needle aspiration (US-FNA) has been included. One cytopathologist retrospectively reviewed the cytology slides, subcategorizing cytology results into AUS and FLUS. A TIRADS category was assigned to each thyroid nodule according to the number of suspicious US features. Clinical, US features, and malignancy rates were compared between the two subcategories. Of the 192 AUS/FLUS lesions, 149 (77.6%) were subcategorized as AUS, and 43 (22.4%) as FLUS. Of the 192 AUS/FLUS nodules, 82 (42.7%) were malignant. Malignancy rate between AUS and FLUS subcategories did not show significant differences, 45.6% to 32.6%, respectively (P = 0.127). When applying TIRADS, significant differences were seen in TIRADS category between benign and malignant nodules of AUS subcategory (P < 0.001), but not in the FLUS subcategory (P = 0.414). Malignancy rate of TIRADS category 3, 4a, 4b, 4c, and 5 was 15.4%, 22.2%, 33.3%, 57.1%, and 80.0% (P < 0.001) in AUS nodules and 40.0%, 50.0%, 23.5%, 22.2%, and 0.0% (P = 0.414) in FLUS nodules, respectively. Suspicious US features are useful in predicting malignancy among AUS subcategory but has limitations in FLUS subcategory. Subcategorization of AUS/FLUS may provide additional clinical information that can be useful in deciding upon treatment or management of thyroid nodules.

Oral 13 Thyroid Hormone Action Monday Oral Translational 4:30 PM ALTERNATIVE SPLICING OF TRa IS ESSENTIAL TO ORCHESTRATE NORMAL SKELETAL DEVELOPMENT AND ADULT BONE MAINTENANCE J.H. Bassett1, K. Nordstrom3, N.C. Butterfield1, A. Boyde2, B. Vennstrom3, G.R. Williams1 1 Imperial College London, London, United Kingdom; 2Queen Mary University of London, London, United Kingdom; 3Karolinska Institute, Stockholm, Sweden Hypothyroidism delays skeletal development and impairs bone turnover whereas thyrotoxicosis accelerates growth and causes osteoporosis in adults. Thus, T3 is essential for bone development and maintenance. TRa is the predominant T3 receptor isoform in bone, and its a1 and a2 splice variants have a unique pattern of expression during post-natal growth. We hypothesized that regulated alternative splicing of TRa1 and a2 coordinates skeletal development and bone mineralization. To address this hypothesis we compared a series of TRa-mutant mice: (i) TRa0/0 (deletion of TRa1 and a2), (ii) TRa1 - / - (deletion of TRa1, normal TRa2 expression), (iii) TRa2 - / - (6-fold increased TRa1 expression, deletion of TRa2) and (iv) TRa1GFP/GFP (2-fold increased TRa1 expression, deletion of TRa2). Mice that lack TRa1 (TRa0/0, TRa1 - / - ) had normal prenatal skeletal development, whereas mice overexpressing TRa1 (TRa2 - / - , TRa1GFP/GFP) exhibited developmental delay. Thus, during the prenatal period when T3 availability is limiting, skeletal development is exquisitely sensitive to the level of TRa1 but does not require expression of TRa2. By contrast, mice lacking TRa1 (TRa0/0, TRa1 - / - ) or markedly overexpressing TRa1 (TRa2 - / - ) had delayed postnatal growth, whilst mice with only a small increase in TRa1 (TRa1GFP/GFP)

A-7 were normal. Thus, during rapid postnatal growth when T3 concentrations are increasing, skeletal maturation requires TRa1 and the level of its expression is critical. In adults, bone mass and strength were increased in mice lacking TRa1 (TRa0/0), decreased in mice with marked overexpression of TRa1 (TRa2 - / - ), but normal in mice with only a small increase in TRa1 (TRa1GFP/GFP). Thus, in adults when T3 availability is not limiting, the rate of bone turnover is determined by the concentration of TRa1 but is independent of TRa2. Together, these data indicate the level of TRa1 is critical for skeletal development and bone maintenance but that TRa2 is dispensable. These findings suggest a mechanism whereby regulated alternative splicing of TRa1 and TRa2 matches availability of TRa1 to the supply of T3 in order to orchestrate intrauterine growth, the postnatal growth spurt and maintenance of adult bone mass and strength.

Oral 14 Thyroid Hormone Action Monday Oral Basic 4:45 PM TRaGS AND TRbGS KNOCK-IN MICE DEMONSTRATE PHYSIOLOGICAL RELEVANCE OF NON-CLASSICAL THYROID HORMONE ACTION S. Ho¨nes1, S. Latteyer1, E. Werbenko3, X. Liao2, K. Engels1, H. Rakov1, K. Strucksberg1, D. Zwanziger1, S. Refetoff2, J.H. Bassett3, G.R. Williams3, D. Fu¨hrer1, L.C. Moeller1 1 Endocrinology & Metabolism, University of Duisburg-Essen, Essen, Germany; 2Department of Medicine, The University of Chicago, Chicago, IL; 3Molecular Endocrinology Laboratory, Imperial College, London, United Kingdom Thyroid hormone (TH) and TH receptors (TRs) can act either classically via binding to TH response elements (TREs) on promoters of target genes or non-classically via activating the phosphatidylinositol 3-kinase (PI3K) signaling pathway. In order to determine which of these two mechanisms is used to mediate the various TH effects, we generated knock-in mice with a mutation in the DNA-binding domain of the TRs that abrogates binding to TREs (TRaGS and TRbGS mice). Consequently, classical action of the TRs on TREs is lost, preserving only the non-classical PI3K activation. TRaGS and TRbGS mice were generated using zinc finger nucleases. Despite complete loss of the classical TR action and similar TH concentrations, the phenotype of TRaGS and TRbGS mice is not the same as that of mice with global inactivation of TRa or TRb by gene knock-out (KO). Rather, the phenotype of TR GS mice resembles that of TR wild type (WT) mice. This indicates that the remaining non-classical TH/TR action mediates several TH effects: Heart rate in TRaGS mice was not altered compared to TRaWT mice (749 and 740/min, respectively, n.s.) although reduced in TRaKO mice (694/min, P < 0.001). Similarly, cardiac expression of adrenergic receptor beta 1 was not altered in TRaGS mice, but reduced in TRaKO mice, which may contribute to normal heart rate in TRaGS mice. Rapid T3 mediated reduction in blood glucose was observed in TRbWT and TRbGS mice but not in TRbKO mice (Fig. 1), indicating again a non-classical effect of T3. Furthermore, body temperature was about 1 C higher in TRbGS mice than in TRbKO mice (37.7 C vs. 36.6 C). Triglycerides (TG) were the same in TRbWT and TRbGS mice (152 and 123 mg/dl, n.s.), but elevated in TRbKO mice (300 mg/dl, P < 0.002). In accordance with TG levels, expression of a key enzyme in TG synthesis, stearoyl-CoA desaturase 1, was elevated in TRbKO mice but not in TRbGS mice, indicating a negative regulation through non-classical TH/TRb action.

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MONDAY, OCTOBER 19, 2015 (dpf). Larval swim bladder inflation is substantially delayed or even completely absent, in the latter case resulting in death around 8-9 dpf. Larval growth is reduced but D2KO fish ultimately reach normal adult body size. Homozygous mutants are fertile but spawning frequency, egg number per batch as well as percentage of fertilized eggs are reduced, suggesting that both female and male reproduction may be affected. These D2KO zebrafish lines represent a valuable tool to study the effect of permanent D2 deficiency in vertebrates at early stages as well as during adult life. A detailed comparison with the D2KO mouse phenotype will contribute to our understanding of the role of local thyroid hormone activation in different tissues. Moreover, external development makes zebrafish an excellent model to study early embryonic development.

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FIGURE 1. Rapid decrease in glucose is a non-classical TRb effect. Injection of T3 led to a reduction of blood glucose within 60 minutes in TRbWT mice, but not in TRbKO mice. This effect of T3 was completely preserved in TRbGS mice despite loss of classical TH/TRb action (mean – SEM; one-way ANOVA, post-hoc Dunnett’s test; *P < 0.05; n = 4). These data demonstrate that non-classical TR signaling is relevant in vivo, challenging the current paradigm that the main TH effects are mediated through the regulation of gene transcription at the nuclear level.

Oral 15 Thyroid Hormone Metabolism & Regulation Monday Oral Basic 5:00 PM D2KO ZEBRAFISH AS A NON-MAMMALIAN MODEL TO STUDY THE ROLE OF LOCAL THYROID HORMONE ACTIVATION A.M. Houbrechts, J. Delarue, V. Darras Laboratory of Comparative Endocrinology, Biology Department, KU Leuven, Leuven, Belgium Iodothyronine deiodinase (D) enzymes are important to control local thyroid hormone activation and inactivation and hence 3,5,3’triiodothyronine (T3) action in tissues throughout the body. Different D-deficient models have been used to study their functions, but so far mice were the only available model with permanent D knockout (KO). We recently generated the first alternative KO model in zebrafish by targeting the dio2 gene, coding for the major thyroid hormone activating enzyme D2. KO was accomplished using the zinc finger nuclease technology and homozygous mutant lines were checked for the absence of offtarget mutations. The phenotype of homozygous D2KO zebrafish was compared to wild type in relation to early development, growth and adult fertility. We obtained two different homozygous D2KO zebrafish lines. One has a 9 base pair deletion resulting in the elimination of 3 conserved amino acids while the other one has a 4 base pair insertion inducing a frame shift and premature stop codon. Both mutations lead to a permanent abolishment of D2 activity and substantially reduce T3 content as tested in liver, eye, brain and muscle of adult fish. Early development of D2KO fish is clearly disturbed. Body length, absolute and relative eye and ear size are reduced as measured in embryos at 29 hours and larvae at 4 and 7 days post fertilization

Thyroid Hormone Metabolism & Regulation Monday Oral Clinical 5:15 PM THYROID HORMONE ANALOG THERAPY IN PATIENTS WITH THE ALLAN-HERNDON-DUDLEY SYNDROME (AHDS): THE TRIAC TRIAL S. Groeneweg1, I. de Coo2, I. van Beynum3, F. Aarsen4, Y. de Rijke1, R. Peeters1, T. Visser1, E. Visser1 1 Internal Medicine, Erasmus MC, Rotterdam, Netherlands; 2Pediatric Neurology, Erasmus MC, Rotterdam, Netherlands; 3Pediatric Cardiology, Erasmus MC, Rotterdam, Netherlands; 4Pediatric Neuropsychology, Erasmus MC, Rotterdam, Netherlands Mutations in the thyroid hormone transporter MCT8 result in AHDS, characterized by severe psychomotor retardation and abnormal serum thyroid function tests (TFTs) (low-normal T4, high T3, high-normal TSH). High T3 levels cause symptoms of peripheral thyrotoxicosis. At present, no effective treatment is available. Recent findings suggest that the T3 analog Triac is a promising candidate to 1) normalize serum T3 levels and hence alleviate the thyrotoxicosis and 2) provide adequate thyromimetic effects in the brain. We conduct a world-wide prospective interventional trial in which 30-40 AHDS patients receive Triac for 1 year. The primary end-point is the reduction of serum T3 levels, and secondary endpoints are reduction of heart rate (HR), improvement of body weight (BW) and serum parameters that reflect thyroid hormone action in peripheral tissues. In addition, the neuropsychological phenotype and motor function are assessed before and after 1 year of Triac treatment. Currently, 13 patients have been enrolled (age: 1–66 yr). All patients show a severely disturbed neuropsychological development, primitive reflexes, elevated tendon reflexes, dystonia and central hypotonia. Triac treatment (average duration: 6 months) effectively suppressed serum TSH levels (median [IQR]: 3.1 [1.6 - 5.1] to 0.9 [0.5 - 1.5] mU/L; p = 0.003), resulting in a strong reduction of T3 levels (4.4 [3.5 - 5.1] to 2.0 [1.6 - 2.7] nmol/L; p = 0.003). In addition, peripheral markers are slightly improving. Alkaline phosphatase (145 [113 - 188] to 207 [114 - 232] U/l; p = 0.028), sex hormone binding globulin (179 [86 - 244] to 151 [86–195] nmol/L; p = 0.062) and creatinine (37 [30 - 50] to 43 [37–62] lmol/L; p = 0.005) serum levels show (near-)significant responses to Triac treatment; whereas HR, BW and serum cholesterol levels show non-significant changes. Triac treatment effectively results in normalization of serum T3 levels. This interim analysis suggests that Triac treatment may have a beneficial effect on the peripheral phenotype of AHDS. A longer follow-up period and inclusion of more patients will further substantiate these findings. This abstract is submitted on behalf of the Triac Trial research group.

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Short Oral Communication 17

We recently described a new model of experimental Graves’ orbitopathy (GO), induced by close field genetic immunisation of hTSHR A-subunit plasmid by muscle electroporation in female BALB/c mice. The induced antibodies to TSHR lead to onset of either hyperor hypothyroidism, with the orbital pathology developing over few months post-immunisation, characterised by muscle inflammation, adipogenesis and fibrosis. In this follow up study we investigated the reproducibility of the model and T cell responses to the TSH receptor. Given the complexity of the immunisation procedure and long time frame for disease development, we have examined the role of environment by studying reproducibility of the model, run in parallel in two different centres using essentially identical strains of BALB/c mice maintained in conventional clean rooms. Moreover, the role of antigen specific T cells to TSHR antigen was examined using multidye proliferation assays and whether this correlates with signs of disease by orbital pathology. Independent histopathological evaluation showed concordant orbital tissue damage in mice undergoing GO in the two centres, manifest by perifascicular atrophy of orbital muscles and/or onset of adipogenesis and fibrosis. Quantification of the respective changes showed variable degrees in individual mice just like observed in GO patients. A total disease score was set up for evaluation of the mouse model and revealed statistically significant disease onset. Furthermore, high T cell responses in vitro to TSHR antigen in both the centres provide evidence on the critical role of cell mediated immunity to orbital pathology. Although no inflammatory infiltrate was apparent in the orbital tissue in either of the centres, the appearances are consistent with a dysimmune myopathy by ‘hit and run’ immunemediated inflammatory event that results in orbital tissue damage. Our results show that the new model is robust, which reproducibly resamples the clinical features of GO patients allowing mechanistic studies into disease pathogenesis and evaluation of novel therapeutic approaches.

Autoimmunity Monday Short Oral Communication Basic 4:00 PM ORBITAL FIBROBLAST HYPOXIC RESPONSE IMPACTS TISSUE REMODELING IN GRAVES’ ORBITOPATHY G. Go¨rtz1, M. Horstmann1, B. Delos Reyes2, J. Fandrey2, A. Eckstein1, U. Berchner-Pfannschmidt1 1 Molecular Ophthalmology, University Duisburg-Essen, Essen, Germany; 2Institute of Physiology, University Duisburg-Essen, Essen, Germany Purpose: The complex pathophysiology of Graves’ orbitopathy (GO) includes orbital inflammation, adipogenesis and fibrosis mediated by orbital fibroblasts (OF). However, inflammation and tissue expansion are well known to cause tissue hypoxia and consequently induce hypoxia-dependent signaling in cells. In this study we investigated the hypoxic response in OF and its impact on tissue remodeling in GO. Methods: Orbital fibroblasts were derived from orbital fat biopsies of GO patients and control healthy persons undergoing plastic surgery (Ctrl). To investigate the general hypoxic response in OF we analyzed HIF-1 (Hypoxia-inducible factor-1) dependent gene expression by Western-blot, immunofluorescence, RTPCR and ELISA. Involvement of oxygen label HIF-1a or HIF-2a subunits was proved using siRNA approach. The vascularization of the orbital tissue was quantified with CD31-immunostained sections. The impact of hypoxic conditions on adipogenic differentiation was analyzed with Oil Red O staining. Results: In response to hypoxia the oxygen label HIF-1a was more pronounced stabilized in GO-OF than in Ctrl-OF and correlated with clinical activity score of GO patients while HIF-2a was not expressed. These findings strongly suggest that hypoxic HIF-1a signaling is involved in pathogenesis of GO. Consequently, HIF-1a dependent gene expression of vascular endothelial growth factor (VEGF), glucose transporter 1 and adiponectin was strongly induced in GO-derived OF. Furthermore, VEGF secretion of GO-OF was enhanced which can stimulate angiogenesis. In agreement with this, we found vessel density increased in GO fat tissue by quantification of CD31 histology. Moreover, hypoxia just like TSHR stimulation strongly stimulated adipogenesis of GO-derived OF. Conclusions: Our results indicate that hypoxia impacts tissue remodeling and fat expansion in GO by stimulating angiogenesis and adipogenesis. GO-derived OF which show a stronger hypoxic response than Ctrl-OF, contribute with increasing VEGF secretion and adipogenic differentiation.

Short Oral Communication 18 Autoimmunity Monday Short Oral Communication Basic 4:06 PM REPLICATION OF GRAVES’ ORBITOPATHY MOUSE MODEL IN TWO CENTRES REVEALS A LONG TERM T CELL RESPONSE TO TSH-RECEPTOR ANTIGEN U. Berchner-Pfannschmidt1, S. Moshkelgosha1, B. Edelmann2, S. Diaz-Cano3, G. Go¨rtz1, M. Horstmann1, A. Noble4, W. Hansen5, A. Eckstein1, J. Banga6,1 1 Molecular Ophthalmology, University Duisburg-Essen, Essen, Germany; 2Institute of Molecular Biology, University DuisburgEssen, Essen, Germany; 3Department of Pathology, King’s College Hospital NHS Trust, London, United Kingdom; 4Faculty of Life Sciences & Medicine, King’s College London, London, United Kingdom; 5Instiute of Medical Microbiology, University DuisburgEssen, Essen, Germany; 6Division of Diabetes and Nutritional Sciences, King’s College London School of Medicine, London, United Kingdom

Short Oral Communication 19 Autoimmunity Monday Short Oral Communication Basic 4:12 PM ORBITAL FIBROBLASTS FROM GRAVES’ ORBITOPATHY PATIENTS MEET ALL CRITERIA THAT DEFINE MESENCHYMAL STEM CELLS S. Brandau2, G. Go¨rtz1, S. Mattheis2, S. Lang2, A. Eckstein1, U. Berchner-Pfannschmidt1 1 Molecular Ophthalmology, University Duisburg-Essen, Essen, Germany; 2Department of Otorhinolaryngology, University Duisburg-Essen, Essen, Germany In Graves’ orbitopathy (GO) inflammation, adipogenesis and fibrosis of the orbital tissue is the result of activation and differentiation of orbital fibroblasts (OF). In a previous study we observed OF expressed some of the consensus surface marker described for mesenchymal stem cells (MSC). To further elucidate the MSC characteristics of OF we compared them with orbital MSC. We simultaneously obtained OF and MSC with different isolation methods from the same retrooular fat biopsies of GO patients. The biological characteristics of these cell lines were compared along criteria that define MSC suggested by the International Society for Cellular Therapy: 1. Plastic adherence and fibroblastic-like growth, 2. MSC surface marker profile, 3. Multi-lineage differentiation potential. Furthermore we compared the immunomodulatory function of orbital MSC and OF. To this purpose suppression of T cell proliferation and cytokine production was measured. We obtained the following biological characteristics of the cell lines: 1. Orbital MSC were plastic adherent fibroblast-like cells that proliferate and produce hyaluronan similar to OF. 2. Both, the MSC

A-10 and the OF expressed a MSC surface marker profile: they were positive for CD29, CD73, CD90, CD105 and negative for CD31, CD34, CD45 and CD71. 3. Orbital MSC as well as OF displayed adipogenic, osteogenic, chondrogenic, myogenic and neuronal differentiation potential in response to specific differentiation media, although OF with a lower capacity. In addition, when compared to MSC, the OF showed less suppressive effect on T cell proliferation and secreted less amounts IL-6 suggesting a lower immunosuppressive potential. Herein we report on the isolation and characterization of orbital fat-derived MSC from GO patients. Comparative analysis of orbital MSC with OF revealed strong similarities: both meet all criteria that define mesenchymal stem cells.

Short Oral Communication 20 Autoimmunity Monday Short Oral Communication Basic 4:18 PM FAILURE OF G PROTEIN ACTIVATION BY TSH RECEPTOR ANTIBODIES DICTATES THYROCYTE DEATH - IMPLICATIONS FOR AUTOIMMUNITY S.A. Morshed1,2, R. Ma1,2, R. Latif1,2, T. Davies1,2 1 Endocrinology, Icahn School of Medicine at Mount Sinai, Bronx, NY; 2Thyroid Research Unit, James J Peters VA Medical Center, Bronx, NY Antibodies to the TSHR (TSHR-Abs) may activate TSHR signaling or inhibit TSH action. However, the consequences of TSHR signaling may differ. In particular, there is a marked contrast between stimulating TSHR-Abs which recognize conformational epitopes and can induce thyroid hormone synthesis and secretion compared to TSHR-Abs to linear epitopes in the ‘‘cleavage’’ region (C-TSHRAb, sometimes called neutral antibodies) of the ectodomain which may induce thyroid cell apoptosis if unopposed. By using luciferase reporter assays for Gas, Gaq, Gbg and Ga12, examining live cell imaging, immunostaining and immunoblot analyses. We demonstrated that stimulating TSHR-Abs (S-TSHR-Ab) produced activation of Gas and to a lesser extent Gaq but C-TSHR-Abs were unable to activate G proteins and failed to induce endosomal vesicular trafficking leaving the antibodies trapped inside the cytoplasm. While S-TSHR-Ab- and TSH-receptor complexes undergo normal vesicular trafficking ( > 90% over 3 days)) the C-TSHR-Abreceptor complexes failed to do so ( < 5% over 3 days). Consequently, as an alternative signaling response, those cells with trapped C-TSHRAbs induced robust ROS accumulation in different organelles including the ER, endosomal vesicles and mitochondria leading to apoptotic cell death. These data show that while S-TSHR-Abs may contribute to thyrocyte function via activation of major G proteins with their downstream signaling cascades, the C-TSHR-Abs fail to achieve the same signaling effects resulting in cellular stress and apoptosis. This scenario of antibody-induced cellular injury implicates the innate immune response leading to loss of self-tolerance and may aggravate the local inflammatory infiltrate within the thyroid or in the retro-orbit.

Short Oral Communication 21 Autoimmunity Monday Short Oral Communication Translational 4:24 PM INCREASED LEVELS BUT IMPAIRED FUNCTION OF REGULATORY B CELLS (BREG) IN HASHIMOTO’S THYROIDITIS AND ASSOCIATED AUTOIMMUNE DISORDERS I. Gatto1, G. Mangino1, M. Santaguida1, C. Virili1, P. Fallahi3, A. Antonelli3, S. Del Duca1, G. Romeo1, M. Centanni1,2

MONDAY, OCTOBER 19, 2015 1

Medico-surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; 2Endocrine Unit, AUSL Latina, Latina, Italy; 3Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

Hashimoto’s thyroiditis (HT) is characterized by a prevalent CD4 + Th1 and Th17 polarization. Recently, the role of T and B regulatory cells (Treg and Breg) gained attention. Indeed, Breg may contribute to the pathogenesis of autoimmune disorders by IL-10 production or by direct interaction with CD4 + T cells. Little is known about the behaviour of these Breg cells in Hashimoto’s thyroiditis isolated or associated with other non endocrine autoimmune disorders (NEAD) and this represented the aim of our study. Breg subsets were analyzed in 69 subjects (62 women, 7 men, mean age: 45 – 13 years) enrolled following tight inclusion criteria. Twenty patients had isolated HT, 8 had HT + atrophic gastritis (AG), 6 HT + celiac disease (CD), 11 HT + vitiligo (V), and 6 HT + systemic sclerosis (SSc). Eighteen healthy donors (HD) were the internal control. Freshly PBMCs were assessed by FACS to characterize Breg lymphocytes specific phenotype. The mean percentage of unstimulated Breg lymphocytes in HD and in isolated HT were similar (2.4 – 0.9% vs 2.0 – 0.7%;p = ns). However, after CpG oligonucleotide stimulation, while the percentage of total IL-10 + B cells remained similar, we found significantly increased levels of IL-10-producing Breg cells in patients with isolated HT as compared with HD (5.5 – 4.3% vs 2.4 – 1.2%;p = 0.0482). In patients with HT + NEAD, the percentage of unstimulated Breg was increased when compared to both HD and patients with isolated HT (4.1 – 1.8%; p = 0.0003 and p < 0.0001). This difference was significant even when the results were analyzed in each HT-associated disorder. Surprisingly enough, both IL-10 + B cells (3.1 – 2.4% vs 1.4 – 1.2%; p = 0.0152) and IL-10 + Breg (5.5 – 4.3% vs 2.1 – 2.0%; p = 0.0075) were significantly higher in HT than in HT + NEAD patients. Noticeably, however, this last finding may be due to a very low IL-10 production from both B and Breg subsets (0.3% – 0.3 and 0.4% – 0.4 respectively; p < 0.05) in HT + SSc patients. In conclusion, patients with isolated HT showed a similar percentage of both total IL-10 + B and -Breg cells, which were, however, higher than in healthy donors upon stimulation. In patients with HT + NEAD, increased levels but impaired function of regulatory B cells has been observed.

Short Oral Communication 22 Autoimmunity Monday Short Oral Communication Clinical 4:00 PM DIPLOPIA, SEVERITY SCORE, AND SMOKING IMPACT QUALITY OF LIFE IN THYROID-ASSOCIATED ORBITOPATHY - A PROSPECTIVE STUDY E. Kampmann1, D. Hoppe2, S. Pitz1, T. Diana1, G.J. Kahaly1 1 Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany; 2Dept. of Psychology, Technical University, Darmstadt, Germany Thyroid dysfunction impacts the course of thyroid-associated orbitopathy (TAO). We aimed to look for further variables contributing to poor quality of life (QoL), clinical severity and activity of TAO. At an academic orbital center with a joint thyroid-eye clinic, complete ophthalmic, serological, and endocrine investigations as well as assessment of disease-specific QoL (EUGOGO questionnaire) were performed in patients with TAO. A total of 100 consecutively followed-up euthyroid patients with moderate-to-severe and active TAO (median age 51 years, range 23– 75 years, 72 female, 57 smokers, median duration of TAO 9.5 months, 1–225 months) were enrolled. Diplopia was present in 68

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patients with 16 having constant double vision. Chemosis, corneal lesions and asymmetric TAO were present in 29, 25 and 22 patients, respectively. Median clinical activity (CAS) and severity (CSS) scores were 4 (3–7) and 6.25 (1–11), respectively. Median palpebral aperture and proptosis were 11 mm (5–17) and 21.4 mm (12–30), respectively. All patients were TSH-receptor blocking antibody negative while 91 were TSH-R stimulating antibody positive (chimeric TSH-R cell-based bioassay). The mean QoL scores were 66.1 – 23 for the subscale visual functioning (VF) and 66.1 – 21 for the subscale appearance. Using stepwise linear regression, the diplopia score, the CSS and age, best predicted the VF score (P < 0.01, adjusted R-square = 0.24), whereas CAS, proptosis and chemosis were excluded in the statistical process. Current smoking and sex (both P < 0.01) predicted the appearance score. Appearance was also associated with younger age (P = 0.02). Both QoL scales positively correlated with clinical severity of TAO (VF, P = 0.001; appearance, P = 0.05). The homogenously moderate-to-severe clinical TAO phenotype might explain missing significant correlations between CSS, CAS and the demographic parameters age, sex and smoking history. Subsequent to elimination of dysthyroidism, these novel data in a large collective of TAO patients imply further non-ophthalmic negative impact factors for impaired QoL.

95% CI: 0.78–1.19; p = 0.75) and/or thyroid function [unadjusted HR (hypothyroid v normal) = 1.15 95% CI: 0.79–1.68; p = 0.46, HR (hyperthyroid v normal) = 1.14 95% CI: 0.82–1.61; p = 0.44]. Similar results were obtained for OS and TTR. Sensitivity analyses in a 123 pts subgroup with serum collected before BC adjuvant therapy also showed no evidence of TPOAb prognostic ability. In the largest retrospective study to date investigating prognostic role of TA in BC there was no evidence that TPOAb and thyroid function are prognostic markers for BC recurrence. Confounding due to BC adjuvant treatment is unlikely to significantly alter results.

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Relapse of hyperthyroidism in Graves’ disease (GD) after antithyroid drug (ATD) withdrawal is common. The Role of thyrotropin receptor antibody (TRAb) measurement at ATD withdrawal in outcome prediction is controversial. This study was to compare thyroidstimulatory antibody (TSAb) and thyrotropin-binding inhibitory immunoglobulin (TBII) at ATD withdrawal in predicting relapse. This study enrolled patients with GD who were treated by ATDs and whose serum TSH levels were normal after low-dose ATDs. ATD therapy was stopped irrespective of TRAb positivity after additional 6 months of low-dose ATD therapy. Patients were followed by thyroid function tests and TSAb (TSAb group, n = 35) or TBII (TBII group, n = 39) every 3–6 months for 2 years after ATD withdrawal. Twenty-eight patients (38%) relapsed during median 22 months of follow-up, and there were no differences in baseline clinical characteristics between TSAb and TBII groups. In the TSAb group, relapse was more common in TSAb-positive patients (67%) at ATD withdrawal than in TSAb-negative patients (17%, p = 0.007). Relapse-free survival was shorter in TSAb-positive patients. In the TBII group, there were no differences in relapse rate and relapse-free survivals according to TBII positivity. For predicting relapse of GD, the sensitivity and specificity of TSAb were 63% and 83%, respectively, whereas those of TBII were 28% and 65%, respectively. TSAb at ATD withdrawal could predict relapse of Graves’ hyperthyroidism, but TBII could not. Measurement of TSAb at ATD withdrawal could be helpful for clinical decision-making in patients with GD.

Autoimmunity Monday Short Oral Communication Clinical 4:06 PM THYROID AUTOIMMUNITY AS A BIOMARKER OF OUTCOME IN WOMEN WITH BREAST CANCER LARGE SCALE STUDY USING DATA FROM THE TAXOTERE AS ADJUVANT CHEMOTHERAPY (TACT) TRIAL (CRUK01/001) I. Muller1, L.S. Kilburn2, M.E. Ludgate1, P.N. Taylor1, P. Barrett-Lee3, J.M. Bliss2, C.M. Dayan1 1 School of Medicine, Institute of Molecular & Experimental Medicine, Cardiff University, Cardiff, United Kingdom; 2Clinical Trials & Statistics Unit (ICR-CTSU), The Institute of Cancer Research, London, Surrey, United Kingdom; 3Breast Cancer Centre, Velindre NHS Trust, Cardiff, United Kingdom An association between breast cancer (BC) and thyroid autoimmunity (TA) has been frequently observed and several small-scale studies correlated the presence of thyroid peroxidase (TPO) autoantibodies (TPOAb) with an improved BC outcome. We hypothesized the presence of an immune response to shared thyroid/breast antigens and we recently reported that TPO is expressed in BC tissue (Muller et al. IJC 2014). We aimed to clarify in a large cohort of patients (pts) whether circulating TPOAb are prognostic for BC recurrence. Available serum samples for pts with node + ve or high risk nodeve early BC previously enrolled in TACT trial (Ellis et al. Lancet 2009, Bliss et al. Cancer Res Suppl. 2012) were measured (standard assays) for TPOAb (dichotomized; + ve ‡ 6kU/L), free-thyroxine and thyroid stimulating hormone (combined; normal, hypothyroid, hyperthyroid). Prognostic significance of these markers was assessed for disease free survival (DFS), overall survival (OS) and time to recurrence (TTR) using Cox regression models stratified by chemotherapy regimen and ER status. Univariate and multivariable analysis were performed, considering other known prognostic factors for BC (nodal status, HER2 status, age, tumour grade, tumour size) and type of surgery. The median follow-up was 97.5 months. 1974 (47.4%) pts had serum available, taken £ 2yr after BC surgery with majority taken during/after adjuvant treatment for BC. Baseline characteristics of this subset were similar to the whole TACT population. 406 (20.6%) pts were TPOAb + ve. There was no evidence of difference in DFS by TPOAb status (unadjusted HR = 0.97,

Short Oral Communication 24 Autoimmunity Monday Short Oral Communication 4:12 PM USEFULNESS OF THYROID STIMULATING ANTIBODY AT THE TIME OF ANTITHYROID DRUG WITHDRAWAL IN PREDICTING RELAPSE OF GRAVES’ HYPERTHYROIDISM H. Kwon1, W. Kim1, E. jang2, M. Kim1, S. Park1, Y. Choi1, M. Jeon1, T. Kim1, Y. Shong1, W. Kim1 1 Asan Medical Center, Seoul, Korea (the Republic of); 2Dongnam Institute of Radiological and Medical Sciences, Busan, Korea (the Republic of)

Short Oral Communication 25 Autoimmunity Monday Short Oral Communication Translational 4:18 PM GWAS OF GRAVES’ ORBITOPATHY PATIENTS HIGHLIGHTS THE PRIMACY OF HLA IN AUTOIMMUNE THYROID DISEASE E. Webster1, R. Bahn3, X. Yin1, D. Rudifer1, Y. Tomer1,2, T.F. Davies1,2 1 Icahn School of Medicine at Mount Sinai, New York, NY; 2 James J Peters VA Medical Center, New York, NY; 3 Mayo Medical School, Rochester, MN A major issue in the genetics of autoimmune thyroid disease is the problem of clinical phenotype. In Graves’ disease, patients may

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present with advanced thyroid eye disease or almost no clinically discernable eye disease at all. The question of whether these represent genetically distinct disorders remains unanswered. Here we have analyzed, exclusively, patients with Graves’ orbitopathy subjected to orbital surgery thus defining a clear phenotype of patients with severe disease for genetic analysis. In total we analyzed 504 cases and 3,135 controls from two different cohorts (wave 1: 166 cases, 1,198 controls, wave 2: 338 cases, 1,937 controls) genotyped on different platforms. A meta-analysis on imputed dosages identified 52 SNPs reaching genome-wide significance (p-value < 5 · 10 - 8) of which 41 were in the HLA region and 9 were in a novel region on chromosome 10. Well known non-HLA implicated genes showed appropriate direction and effect sizes in this patient sample including CTLA-4, the TSHR, PTPN22 and FCRL3. These data continue to emphasize the importance of the HLA region in the genetic contribution to Graves’ disease and may suggest a specific contribution from chromosome 10 to Graves’ orbitopathy.

Short Oral Communication 26 Autoimmunity Monday Short Oral Communication Clinical 4:24 PM TRIPLE THERAPY (GLUCOCORTICOID + CICLOSPORIN + ORBITAL IRRADIATION) FOR DIPLOPIA (DIP) OF MODERATE-TO-SEVERE GRAVES’ ORBITOPATHY (MSGO). A PROSPECTIVE FOLLOW-UP STUDY P. Laurberg, D. Berman, I. Bu¨low Pedersen, S. Andersen, S. Malling, A. Carle´ Aalborg University Hospital, Aalborg, Denmark DIP is common and important for work disability in msGO; but quantitative data on DIP outcome are scarce. Double therapy (glucocorticoid + ciclosporin, or glucocorticoid + orbital radiation) has better effects on msGO than single therapy, and many msGO pts do not respond satisfactory to single therapy. We prospectively studied DIP outcomes after offering triple therapy (glucocorticoid + ciclosporin + orbital irradiation) to msGO pts. Some did not receive all 3 therapies because of contraindications (e.g diabetes or depression), or following patient wishes. In a sequential cohort of 216 pts with active msGO, fields of single eye motility and binocular single vision were plotted on diagrams and measured in % of expected fields by planimetry. Recordings were before therapy (t0) and at 3, 6, 12, 24, 36, 48, 60 mo. 158 pts had some degree of DIP at t0 caused by eye motility restriction, 150 were followed for ‡ 1 yr after therapy and were included (follow up 1/2/3/4/5 yrs: n = 9/7/6/9/119). 89.3 % received glucocorticoid. Before i.v. methylprednisolone (mpr) came into use, oral prednisolone was started with a mean dose of 32 mg/d. Later pts (n = 32) initially received mpr mean dose 2.5 g, and continued low dose oral prednisolone. Glucocorticoid mean duration was 17 mo (SD 9.7) Ciclosporin was started in 83.3% with mean 189 mg/d (SD 35.1) (2.7(0.7) mg/kg) and gradually reduced to be withdrawn after 21 (11) mo. Orbital irradiation given to 96.7% was 10 · 2 Gy. 78.7% patients received full triple therapy. Minor side-effects were common (weight gain, hypertension, reversible hypertricosis, need of bisfosfonate), no major sideeffects occurred. 2 developed myasthenia. 100 pts (66.7%) responded (R) with no need of eye muscle surgery. 50 pts (33.3%) had eye muscle surgery for persistent DIP. In multivariate models the only predictors of non-R were high t0 DIP % (p < 0.001) and high age (p = 0.01). After additional surgery end result was satisfactory even in non-R (figure). Triple therapy for msGO was tolerated and eye muscle surgery was not necessary in the majority of pts. In the minority that did not respond sufficiently, subsequent eye muscle surgery led to a satisfactory end result.

Short Oral Communication 27 Thyroid Hormone Metabolism & Regulation Monday Short Oral Communication Basic 4:00 PM DOT1L, THE H3K79 METHLTRANSFERASE, ACTS AS A NOVEL THYROID HORMONE RECEPTOR CO-ACTIVATOR L. Wen, Y. Shi National institutes of Health, Bethesda, MD Thyroid hormone is critical for postembryonic development in vertebrates. Frog metamorphosis resembles mammalian postembryonic development and is totally dependent on thyroid hormone. It offers as an excellent model to study postembryonic development due to the ability to manipulate this process. Thyroid hormone functions via it nuclear receptor (TR). TR and 9-cis retinoic acid receptor form a heterodimer, which binds to thyroid hormone respond element (TRE) and recruits co-repressor or co-activator complexes in absence or in presence of thyroid hormone, respectively our previous finding shows that Dot1L is a novel thyroid hormone direct targeted gene. Dot1L is the only H3K79 methltransferase, and the H3K79 methylation levels are up-regulated in thyroid hormone direct genes upon T3 treatment. We hypothesized that Dot1L may act as thyroid hormone receptor coactivator. We over-expressed Dot1L through transgenesis and knockdown endogenous Dot1L level through TALEN mediated mutagenesis. Overexpression of Dot1L increases the H3K79 methylation level in thyroid hormone targeted genes, and overexpression of Dot1L enhances T3 induced thyroid hormone direct targeted genes expression. more importantly overexpression of Dot1L accelarates thyroid hormone mediated tadpole methamorphosis. knockdow of Dot1L reduces H3K79 methylation and reduces T3 induced thyroid hormone direct targeted genes expression. Dot1L acts as a thyroid hormone receptor co-activator.

Short Oral Communication 28 Disorders of Thyroid Function Monday Short Oral Communication Basic 4:06 PM IODINE EXCESS EXPOSURE DURING PREGNANCY/ LACTATION IMPAIRS THYROID HORMONES PRODUCTION, METABOLISM AND TRANSPLACENTAL TRANSFER IN RAT DAMS C. Serrano-Nascimento1, R. Barrera Salgueiro1, T. Pantalea˜o2, V. Correa da Costa2, E. Bevilacqua3, M. Nunes1

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1

Department of Physiology and Biophysics, Institute of Biomedical Sciences, Sao Paulo, Brazil; 2Instituto de Biofı´sica Carlos Chagas Filho, Rio de Janeiro, Brazil; 3Department of Cell and Developmental Biology, Institute of Biomedical Sciences, Sao Paulo, Brazil Iodine is essential for thyroid hormones (TH) synthesis, which are important for normal placenta and fetal development. Moreover, maternal iodide transport through placenta is essential to guarantee fetal TH production that also plays an important role in embryonic development. Therefore, adequate iodine intake during pregnancy (P) and lactation (L) are required both for maternal and fetal TH synthesis. This study aimed to investigate the effects of rat dams’ exposure to iodine excess (IE) during P + L periods on TH production, metabolism and transplacental transfer. Female Wistar rats were treated with IE (0.6 or 6 mg/L) in drinking water throughout P + L. Hypothalamus, pituitary, thyroid and placenta gene expression were evaluated by qPCR and Western Blotting. TH/TSH serum levels were assessed by multiplex assays. Placenta histological analysis was also performed. Placenta labyrinth zone/juctional zone ratio and the number of pups were reduced in IE-exposed dams. Placental NIS and TH transporters expression were reduced in IE-treated rats, in a dosedependent manner. IE treatment also reduced TH and increased TSH serum levels. Indeed, rats exposure to IE increased TRH and TSH in the hypothalamus and pituitary, respectively. Pituitary expression of TRHR/D2 were increased and GH/prolactin were decreased in IEexposed dams. NIS, TSHR, TPO, Tg, Duox, Megalin, MCT8, TTF1 and Pax8 mRNA/protein thyroid expression were reduced in IEexposed dams, in both doses studied. Increased thyroid oxidative stress was also observed in IE-treated rats. Liver and kidney D1 activity/expression were reduced by IE treatment. Therefore, our study strongly suggests that IE exposure during P + L impairs maternal TH production/secretion/metabolism and TH placental transfer, which may induce deleterious effects on fetal development. Moreover, reduced placental NIS expression and altered placenta morphology suggest that maternal transfer of iodide and nutrients, as well as fetal TH production were impaired by IE treatment. Taken together, our data indicate that IE disrupts maternal thyroid function and may be as harmful as iodine deficiency to fetal/neonatal development. Financial Support: FAPESP.

Short Oral Communication 29 Disorders of Thyroid Function Monday Short Oral Communication Basic 4:12 PM A FULL-LENGTH MODEL OF THE THYROTROPIN RECEPTOR SUPPORTED BY EXPERIMENTAL DATA FROM MASS SPECTROMETRY AND TARGETED RECEPTOR MUTATION J. Schaarschmidt1, M. Nagel1,2, S. Huth1, H. Jaeschke1, S. Kalkof2, J. Meiler3, R. Paschke1 1 Department of Internal Medicine, University of Leipzig, Leipzig, Germany; 2Department of Proteomics, Helmholtz-Centre for Environmental Research, Leipzig, Germany; 3Center for Structural Biology, Vanderbilt University, Nashville, TN Little is known about the structural mechanism involved in activation of the TSHR, a key player in thyroid physiology. While the crystal structure of the entire follicle stimulating hormone receptor (FSHR) ectodomain (ECD) in complex with its ligand was a major step in understanding the activation mechanism of glycoprotein hormone receptors (GPHRs), it still didn’t provide details on how binding of the ligand to the extracellular domain triggers the conformational changes of the transmembrane domain (TMD) necessary for subsequent G protein activation.

Interdisciplinary approach of structural modeling and targeted experiments towards a full-length model of the TSHR in its activated and inactivated form. In order to gain insights into this process we have pursued an interdisciplinary approach of structural modeling, guided by experimental data from mass spectrometry and targeted mutation of the TSHR receptor. A soluble ECD of the TSHR was chemically crosslinked in the presence and absence of the hormone. The crosslinked product was then enzymatically digested and the fragments analyzed by mass spectrometry. In a second approach residues with reported constitutively activating mutations (CAMs) were specifically mutated and combined to TSHR single and double mutants. These were subsequently expressed in eukaryotic cells and tested for cell surface expression, G-protein signaling and ligand binding. The structural models were then generated with the Rosetta software suite. Chemical crosslinking yielded 18 different distance constraints, which were used to verify and refine homology models of the TSHRECD complex and the binding mode of its ligand TSH. The targeted mutation and functional characterization of S281, I486 and I568 suggests a close proximity of S281 and I486 in the TSHR with a change in their relative position being an important step of receptor activation. This experimentally verified contact of S281 located in the ECD and I486 located in the extracellular loop 1 (ECL1) of the TMD was utilized in docking models of the ECD to models of the TMD and generating a final set of full-length TSHR models. By combining experimental studies with structural modeling we have generated a set of full-length TSHR structures. These structures provide insights into likely key interactions during receptor activation, which can be tested by further experiments.

Short Oral Communication 30 Disorders of Thyroid Function Monday Short Oral Communication 4:18 PM HYPERTHYROID BUT NOT HYPOTHYROID PATIENTS ARE AT HIGHER RISK OF REHOSPITALISATION AND INCREASED CARDIOVASCULAR MORBIDITY-A MATCHED CASE-CONTROL STUDY B. Torlinska1, J. Franklyn1, J. Coleman2, K. Boelaert1 1 Centre for Endocrinology, Diabetes and Metabolism, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom; 2School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom Thyroid dysfunction (TD) often runs an indolent course and may be undiagnosed for prolonged periods. Most patients are treated as

A-14 outpatients and effects of TD on hospitalized patients are poorly studied. We set out to determine the prevalence of TD in a large cohort of inpatients and evaluated their comorbidities, reasons for hospitalization and rehospitalization rates. A case-control study was conducted using a computerized system of admissions (total number of patients N = 147,957) to a large tertiary center between 2007 and 2011. 673 (0.5%) hyperthyroid and 8,035 (5.4%) hypothyroid patients were identified based on ICD-10 coding and/or administration of thionamides or levothyroxine and matched with each other and with the general hospital population by age, gender and year of first admission. 673 matched triplets were analyzed. Hyperthyroid (lHr = 0.61 admissions per year; P < 0.001) but not hypothyroid inpatients (lHo = 0.47, lC = 0.44, NS) were more frequently re-admitted compared with controls. The total hospital stay duration was also higher in hyper- than hypothyroid and control patients (lHr = 5.1, lHo = 3.8, lC = 3.1 days per year; P < 0.001). The mean length of hospital stays was similar comparing hyper- and hypothyroid patients but was longer in those with TD than controls (lHr = 1.7, lHo = 1.7, lC = 1.4; p = 0.005). Hyperthyroid patients were more frequently admitted with cardiovascular disorders (CVD) compared with hypothyroid and control subjects (37.4%, 29.0%, 6.0% respectively; P < 0.001) while proportions of admissions for respiratory, nervous and digestive causes were not significantly different. Similarly, CVD were more frequently recorded in hyperthyroid subjects (67.0%, 61.4%, 57.1%; P = 0.01) who presented more frequently with atrial fibrillation (nHr = 195, nHo = 94, nC = 94; p < 0.001) and heart failure (nHr = 85, nHo = 61, nC = 46; p = 0.002). We demonstrate that inpatients with hyperthyroidism are at significantly increased risk of re-hospitalization and cardiovascular morbidity compared with hypothyroid and control subjects. The identification of these patients and institution of appropriate management and follow-up is likely to alleviate this significant health and financial burden.

Short Oral Communication 31 Disorders of Thyroid Function Monday Short Oral Communication Translational 4:24 PM DETECTION OF NOVEL GENE VARIATIONS IN CONGENITAL HYPOTHYROIDISM WITH TARGETED NEXT-GENERATION SEQUENCING C. Lo¨f1, K. Patyra1, T. Kuulasmaa2, G. Kleinau3, H. Ja¨schke1, H. Undeutsch1, A. Kero1, H. Krude3, J. Pursiheimo1, J. Ja¨a¨skela¨inen4, J. Toppari1, J. Ignatius5, M. Laakso4, J. Kero1 1 Department of Physiology, University of Turku, Turku, Finland; 2 Department of Medicine, University of Kuopio, Kuopio, Finland; 3 Institute of Experimental Pediatric Endocrinology, Berlin, Germany; 4Department of Medicine, University of Kuopio, Kuopio, Finland; 5Department of Genetics, Turku University Hospital, Turku, Finland Congenital hypothyroidism (CH) is a disease caused by the lack of thyroid hormones at birth. It can lead to severe mental and growth retardation, if not identified and treated promptly after birth. CH occurs in every 1:3000 newborns worldwide. Mutations in at least 15 different genes have been associated with this disease. While only up to 20% of all CH cases are hereditary, the majority (80–90%) of CH etiology is sporadic. Multigenic screening specifically of the hereditary forms of CH is required for identifying the exact etiology for the disease. Due to the high number of genes associated with CH, standard Sanger- sequencing would be very expensive and time consuming. In this study, we established a targeted next-generation sequencing (NGS) panel for a faster and more cost-effective genetic diagnosis of CH.

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FIGURE 1. Modified pedigrees of the study families with hereditary CH. The results of the thyroid function test and thyroid ultrasound (US) imaging are aligned below. The black color indicates patients with CH, gray the adult onset hypothyroidism and white subjects have no thyroid disease. Thyroid size evaluated by thyroid ultrasound if data available (n = normal thyroid size and location, + = goiter, a = athyreosis/no thyroid gland not detected, h = hypoplastic or small thyroid, n* = no clinical signs of goiter during the follow up). Serum thyroglobulin (TG) levels were measured at time of the participation to the study.(a = Patient had mild hypotonia, delay of development (speech and development) and abnormal hearing response, b = two other CH cases in the family, c = had abnormal hearing, d = was born in week 29 + 3, or = had agenesia renis.

Four CH patients with known gene mutations served as validation of our targeted NGS panel. Next, 28 CH patients were screened, including 15 with sporadic permanent CH and 12 from different families with hereditary form of CH. The NGS CH panel was designed to cover all the exons for the following genes: DUOX1, DUOX2, IYD, NKX2-5, PAX8, SLC26A4, SLC5A5, TG, TPO, TRH, TRHR, TSHB, TSHR and NKX2-1 (TTF1). Our targeted NGS panel identified all expected gene variants in 4 control patients with known mutations. Among the familial cases, 6 pathogenic mutations were found in the TPO, PAX8 and TSHR genes. Furthermore, pathogenic PAX8 and NKX2-1 mutations were also identified from several sporadic cases together with rare possible pathogenic variants in the TG, SLC5A5, SLC26A4 and DUOX2 genes. All identified novel pathogenic mutations were confirmed by Sanger-sequencing and characterized in silico or in vitro systems. Our study demonstrated that a targeted NGS panel of CH genes provides efficient multigenic screening for CH candidate genes with high coverage. Hence, this approach should be considered in the clinical management of patients with hereditary CH and in the selection of pedigrees for whole exome analysis.

Short Oral Communication 32 Thyroid Hormone Action Monday Short Oral Communication Clinical 4:00 PM RESISTANCE TO THYROID HORMONE (RTH) WITHOUT MUTATIONS IN THE THYROID HORMONE RECEPTOR BETA (THRB) GENE (NONTR-RTH): THE CHICAGO EXPERIENCE T. Pappa1, A. Dumitrescu1, R.E. Weiss2, S. Refetoff1 1 Department of Medicine, Thyroid Unit, The University of Chicago, Chicago, IL; 2Department of Medicine, University of Miami Miller School of Medicine, Miami, FL In 85% of the subjects with RTH phenotype a mutation in the THRB gene (RTHß) is found. However, 15% of subjects with identical

MONDAY, OCTOBER 19, 2015 phenotype have no mutation in the THRB gene (nonTR-RTH). We present demographic and biochemical data from 45 nonTR-RTH families studied over 34 years. Fourty five families (136 females and 90 males) were identified. The absence of THRB gene mutations was confirmed by sequencing (ß1 and ß2) and in sufficiently informative families, THRB gene involvement was excluded by linkage studies. History, clinical information and thyroid function testing (TFT) were obtained from all participating family members. Results were compared to subjects with RTHß. Based on TFT profiles, 36 females and 13 males were affected (F:M ratio 2.8:1 compared to 1.1:1 in the RTHb cohort). Mean age at diagnosis was 29 years. While in 9 families the presence of the thyroid phenotype in the offspring was documented, thus suggesting autosomal dominant inheritance, in 36 families the phenotype was observed only in one individual which can be consistent with putative recessive or de-novo defects. Ethnic origin was: European 52%, Asian 18%, African American 7%, Hispanic 2%, Jewish 1%, and unknown in 20% of the families. Reasons for thyroid testing were: tachycardia in 15, central nervous system/behavioral (anxiety, attention deficit disorder and hyperactivity) in 13, goiter in 10, routine testing in 3 and unknown reasons in 8 families. On average, serum free T4, free T3 and rT3 were 65, 45 and 66% above the upper limit of normal, respectively, and mean TSH was 11.7 mU/L. Thyroid autoantibodies were found in five individuals. Four received antithyroid drugs and 4 had gland ablation. These findings were similar to those previously reported by our laboratory for RTHb subjects. NonTR-RTH is identified more frequently in females compared to RTHß and inheritance of the defect is less often clearly dominant, while recessive defects cannot be excluded at this point. The ethnicity is variable, with white European dominance. There were no differences in clinical presentation or TFTs between nonTR-RTH and RTHß subjects. Studies using next generation sequencing are expected to identify the gene(s) associated with nonTRß-RTH.

Short Oral Communication 33 Thyroid Hormone Action Monday Short Oral Communication Clinical 4:06 PM COAGULATION AND FIBRINOLYSIS IN PATIENTS WITH RESISTANCE TO THYROID HORMONE DUE TO A THYROID HORMONE RECEPTOR b-GENE MUTATION L.P. Elbers1,2, C. Moran3, V.E. Gerdes1,2, B. van Zaane1,2, J.C. Meijers4,5, E. Endert6, G. Lyons3, K. Chatterjee3, P. Bisschop7, E. Fliers7 1 Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; 2Department of Internal Medicine, Slotervaart Hospital, Amsterdam, Netherlands; 3 University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom; 4Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; 5Department of Plasma Proteins, Sanquin Research, Amsterdam, Netherlands; 6Laboratory of Endocrinology and Radiochemistry, Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; 7Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands Hyperthyroidism is associated with a hypercoagulable state, but the underlying mechanism is unknown. Patients with resistance to thyroid hormone (RTH) due to defective thyroid hormone receptor b (TRb) exhibit elevated circulating thyroid hormones (TH) with refractoriness to TH action in TRb-expressing tissues. We tested the

A-15 hypothesis that the hypercoagulable state in hyperthyroidism results from a TRb-mediated effect of TH on coagulation factors. Our aim was to compare markers of coagulation and fibrinolysis between patients with RTH due to defective TRb, hyperthyroidism and euthyroid control subjects. In a cross sectional study, TH concentrations and markers of coagulation and fibrinolysis were measured in patients with RTH due to defective TRb (n = 18), hyperthyroidism (n = 16) and in euthyroid subjects (n = 18). Data are expressed as median [interquartile range]. Free thyroxine (FT4) levels were slightly higher in patients with hyperthyroidism than in RTH patients (53.9 [30.5-70.0] and 34.9 [28.4-42.2] pmol/l, respectively, P = 0.042). Both groups had raised FT4 levels compared to the euthyroid subjects (14.0 [13.0-15.8] pmol/l, P = 0.000). Levels of von Willebrand factor antigen (VWF:Ag), factor (F) VIII activity, fibrinogen and D-dimer were significantly higher in hyperthyroid patients than in RTH patients [VWF:Ag 231 [195-296] vs. 111 [82-140] %, FVIII 215 [192-228] vs. 145 [97-158] %, fibrinogen 3.6 [3.0-4.4] vs. 2.8 [2.5-3.2] g/L, Ddimer 0.41 [0.31-0.88] vs. 0.20 [0.17-0.26] mg/L, respectively, P £ 0.001 (P £ 0.010 after correcting for age and smoking status)], while there were no differences between RTH patients and euthyroid controls. Circulating parameters of coagulation and fibrinolysis were elevated in hyperthyroid patients compared to patients with RTH due to defective TRb, whereas these parameters were not different between euthyroid controls and RTH patients, despite elevated FT4 concentrations in RTH patients. This indicates that the procoagulant effects observed in hyperthyroidism are mediated via the TRb pathway.

Short Oral Communication 34 Thyroid Hormone Action Monday Short Oral Communication Translational 4:12 PM DECIPHERING THE POTENTIAL OF 3-IODOTHYROMINE (T1AM) IN REGULATING LIPID METABOLISM F. Assadi-Porter1, H. Reiland1, V. Carnicelli2, M. Sabatini2, M. Rogowski3, E. Selen1, M. Tonelli1, A. Saba2, L. Lorenzini2, S. Ghelardoni2, R. Zucchi2, G. Chiellini2 1 University of Wisconsin, Madison, WI; 2University of Pisa, Pisa, Italy; 3Texas Tech University, Lubbock, TX 3-iodothyronamine (T1AM) is a novel chemical messenger that has been reported to regulate energy metabolism and body weight. To better characterize its effects in a subacute model, we treated obese mice with two different dosages of T1AM for seven days, and analyzed plasma and tissue extracts using multidisciplinary approaches. Three groups of spontaneously obese female CD-1 mice (n = 6) were injected once a day i.p. with saline, 10 mg/Kg T1AM, or 25 mg/ kg T1AM. Blood was drawn on study days - 3, 4, and 7 and analyzed by 1H-NMR metabolomics. On day 7, animals were sacrificed and their organs collected for NMR-metabolomics and real-time qPCR targeted at major metabolic regulatory genes. Tissue T1AM concentration was determined by tandem mass spectrometry coupled to liquid chromatography. At both dosages, T1AM treatment produced a significant increase in plasma triglycerides (61.1 – 4.1 and 67.3 – 2.0 vs 49.0 – 2.4 mg/dL, P < 0.05) and a significant decrease in total plasma cholesterol (79.2 – 1.6 and 77.7 – 2.0 vs 90.8 – 3.7 mg/dL, P < 0.05), without any significant change in glycemia. 1H-NMR analysis of liver extracts showed that T1AM induced lipid mobilization and inhibited lipid synthesis and storage. Treatment with 10 mg/Kg T1AM increased glycerol, 3-hydroxybutyrate and acetone concentration, while at 25 mg/Kg glucogenic aminoacids, carnitine and acetate were also increased. In the liver, the highest T1AM dose stimulated the expression of sirtuin 6 and glucokinase, and inhibited the expression of

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sirtuin 4; in adipose tissue, only sirtuin 6 expression was increased. After treatment with 10 mg/kg/day, T1AM concentration increased over the baseline by about 3-fold in adipose tissue and by about 40fold in liver, while a 50 to 100-fold increase over the baseline was observed in both tissues in mice treated with 25 mg/Kg/day T1AM. Our multidisciplinary approaches provide evidence that treatment with exogenous T1AM affects lipid metabolism in a dose-dependent and tissue-specific manner. T1AM might play a physiological role in the regulation of metabolism and might provide a novel therapeutic tool for metabolic diseases.

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Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via b2-adrenoceptor (b2-AR) signaling. In a recent study, we showed that female mice with chronic sympathetic hyperactivity due to double knockout of adrenoceptors that negatively regulate norepinephrine release, a2A-AR and a2C-AR (a2A/a2CARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased bone formation. Furthermore, we found that these animals are resistant to the thyrotoxicosis-induced osteopenia. These findings suggest that b2AR is not the only adrenoceptor involved in bone mass regulation and show that a2-AR signaling may also mediate the SNS and thyroid hormone actions in the skeleton. AIMS: To investigate the participation of a2-ARs and their possible interaction with thyroid hormone in the regulation of bone mass A cohort of 30 day-old female congenic a2CAR-/- mice, in a C57BL6/J background, and their wild-type (WT) controls (n = 8/ group) were analyzed for 60 days. The bone phenotype of the femur and the vertebra (L6) were analyzed through micro computed tomography (lCT). Also, gene expression and culture cell were performed. Surprisingly, the lCT analysis showed that the trabecular bone volume (BV/TV) of the distal metaphysis of the femur and of the sixth lumbar vertebra (L6) were, respectively, 15%-45% lower and 31%-83% higher in a2C-AR-/- mice, when compared with WT animals (p < 0,05 for all). Furthermore, we showed a resistance of KO animals on the deleterious effects of thyroid hormone on bone, femur and vertebra. We also showed that isolated osteoclasts in culture are responsive to the selective a2CAR agonist UK14,304, which causes a decrease in RANKL-induced osteoclast differentiation. These findings suggest that a2C-AR mediates the effects of the SNS in the bone in a skeletal site specific manner; and that the actions of thyroid hormone on bone metabolism involves interactions with the SNS via a2C adrenergic receptors.

Thyroid Hormone Metabolism & Regulation Monday Short Oral Communication Basic 4:18 PM BISPHENOL-A IN RATS PRESENTS DIFFERENT THYROID HORMONE DISRUPTING PROFILES DEPENDING ON THE WINDOW OF EXPOSURE R.R. Conceic¸a˜o1, M.M. Kizys1, J.S. Souza1, K.C. Oliveira1, T. Kasamatsu1, R. Marino Romano2, G. Giannocco3,1, R.M. Maciel1, M.R. Dias da Silva1, M.A. Romano2, M.I. Chiamolera1 1 Laboratorio de Endocrinologia Molecular e Translacional, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; 2Laboratorio de Toxicologia Reprodutiva, Departmento de Farmacia, Universidade Estadual do Centro Oeste do Parana´, Guarapuava/Parana´, Brazil; 3 Departamento de Ciencias Biologicas, Universidade Federal de Sao Paulo, Diadema-Sao Paulo, Brazil Bisphenol A (BPA) is known as an endocrine disruptor. Either in vitro or in vivo experiments had showed that BPA might act as an antagonist to thyroid hormone receptors (THRs). The aim of the present study is to test BPA action on thyroid axis in vivo at different doses and in two different windows of exposure: peripubertal (PP) and perinatal (PN). In PP exposure, male Wistar rats were treated with zero, 5 and 25 mg/kg/day (C, T5 and T25) of BPA diluted in corn oil and administered per gavage, from postnatal day (PND) 23 to PND58, and euthanazed at PND102. In PN, pregnant females were exposed to zero, 0.5 or 5 mg/kg/day (C, T.5 and T5) of BPA by subcutaneous administration, from gestational day 18 to PND5. Male offspring were sacrificed at PND90. Serum concentrations of TSH, T3 and T4 were performed using commercial kits. In PP, pituitary and liver genes expression (Tshb, Mct8 and Dio1) were analyzed by RT-qPCR. PP animals presented an elevation of TSH (p < 0.01) and reduction of total T4 (p < 0.01 for T5 and p < 0.05 for T25), accompanied by a paradoxical increase of total T3 (p < 0.01 for T5). This apparent incongruence could be explained by the observed increase in liver Dio1 gene expression (p < 0.05 for T25) and the lower expression of Mct8 in pituitary (p < 0.01 for T5). The analysis of pituitary gene expression confirms the elevation of Tshb mRNA content (p < 0.01 for T5 and p < 0.001 for T25). In contrast, PN animals had a completely different thyroid hormone profile, with reduction in TSH concentration (p < 0.001 for T.5 and p < 0.01 for T5) and elevation in all treated groups for T3 (p < 0.001) and T4 (p < 0.05). Therefore, thyroid profiles of animals exposed to BPA are very distinct depending on when the exposition occurs. For PP animals the hormonal behavior resemble hypothyroid state, with a unique hormone profile similar to the one found in human with MCT8 mutation, which could be explained by the antagonistic action of BPA in THRs showed in former studies. Differently, PN exposure to BPA presented an adult animal with lower TSH levels, which data is supported from recent population studies demonstrating negative correlation between gestational urinary levels of BPA and newborn concentrations of TSH in humans.

Thyroid Hormone Action Monday Short Oral Communication 4:24 PM MICE WITH GENE INACTIVATION OF a2C-ADRENOCEPTOR ARE RESISTANT TO HYPERTHYROIDISMINDUCED BONE LOSS M.G. Teixeira1, G. Martins1, M. Miranda1, I. De Araujo1, P. Brum2, D. Novack3, C. Gouveia1 1 Anatomy, Institute of Biomedical Science, Sao Paulo, Brazil; 2 Physical Education and Sports School, Sao Paulo, Brazil; 3Medicine, Washington University in St. Luis, St Louis, MO

Short Oral Communication 37 Thyroid Cancer Monday Short Oral Communication Basic 4:00 PM IDENTIFICATION OF KIAA1217-RET AS A NOVEL FUSION GENE IN PAPILLARY THYROID CANCER O. Wang1, E. Chen1, L. Jin3,4, Y. Zhou1, W. Zhang1, Y. Cai1, S. Dong1, X. Zhang1, M. Xing2, X. Zhang1 1 Surgical Oncology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; 2Division of Endocrinology, Diabetes & Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD; 3Department of Breast and Thyroid Surgery, Shaoxing People’s Hospital, Shaoxing, China; 4Shaoxing Hospital of Zhejiang University, Zhejiang, China Fusion genes play an important oncogenic role in papillary thyroid cancer (PTC) as best exemplified by RET fusion genes consisting of the tyrosine kinase domain of the RET and the 5’ portion of a partner

MONDAY, OCTOBER 19, 2015 gene. We hypothesized that there could be novel RET fusion genes that remained to be identified in PTC. We performed a combined analysis of massive parallel wholetranscriptome sequencing of paired PTC tumor and normal tissues in 20 patients without history of familial cancer and radiation exposure. We found a novel fusion gene in one case of PTC (5%), the KIAA1217-RET fusion gene, with the chimeric protein product consisting of exons 1-11 of KIAA1217 and 8-19 of RET and the junction point being located between exon 11 of KIAA1217 and exon 8 of RET. Both genes were on chromosome 10. Sanger sequencing confirmed the fusion junction discovered in RNA-Seq. Abundant KIAA1217-RET protein was expressed in the PTC tumor, suggesting that expression of this gene was robustly driven by the upstream KIAA1217 promoter, typical of RET fusion genes. Immunofluorescent microscopy revealed diffuse distribution of the fusion protein surrounding the nuclear membrane in tumor cells. Decreased MAP kinase pathway were observed in the PTC cells harboring this fusion protein, suggesting a decreased ability of the cytoplasm RET tyrosine kinase to activate the classical MAP kinase pathway. Analysis using COILS and Paircoil2 revealed a coiled coil structure in the N-terminus of the KIAA1217-RET protein, suggesting that dimerization of this protein is an activating mechanism for the RET tyrosine kinase, which is typical of RET fusion genes. A molecular model of the tyrosine kinase domain of KIAA1217-RET was created using the SWISS-MODEL program to illustrate the potential regulatory tyrosine phosphorylation sites. We identified KIAA1217-RET as a novel fusion gene in PTC, which possesses similar properties of classical oncogenic RET fusion genes and is thus a new oncogene in PTC. Therapeutic treatment using RET tyrosine kinase inhibitors is likely effective in PTC harboring this fusion gene.

Short Oral Communication 38 Thyroid Cancer Monday Short Oral Communication Basic 4:06 PM P21-ACTIVATED KINASE 4 REGULATES PAPILLARY THYROID CANCER CELL PROLIFERATION, MIGRATION AND INVASION X. Xie1, Q. Guo2, X. Shi1, H. Guan1, Z. Shan1, W. Teng1 1 Endocrine department, Endocrine Institute, China Medical University, Shenyang, China; 2translational medicine, China medical university, Shenyang, China Papillary thyroid cancer (PTC) is a common endocrine malignancy. To improve survival, it is important to identify novel prognostic and therapeutic targets. P21-activated kinase 4 (PAK4) is involved in development of different tumor types, but its expression and function have not been investigated in PTC. We analyzed expression of PAK4 and its activated form, phosphorylated p-PAK4 Ser474, in papillary thyroid cancer samples and their matched normal tissue from 98 patients using immunohistochemistry. Effects of knockdown with small interfering RNA in PTC cell lines were evaluated in cell proliferation, migration and invasion. PAK4 signaling pathways were investigated in cells using immunoblot. In this study, we present a role for PAK4 in papillary thyroid cancer progression. We show a significant association between increased expression of PAK4 and p-PAK4 Ser474 with tumor size, extra thyroidal extension and tumor TNM stage. Stable knockdown of PAK4 in PTC cell lines retards cellular proliferation, migration and invasion. In addition, Neutralization of ROS inhibits PTC cellular proliferation, migration and invasion though down-regulating PAK4/ERK and PAK4/AKT pathways. TSH-mediated PTC cellular proliferation is dependent on cAMP/PKA/PAK4/CREB pathway.

A-17 Moreover, we demonstrated that activated PAK4 expression is correlated with the level of TSH in PTC patients serum and PKA expression in clinical PTC samples. These findings revealed a novel function of PAK4 in ROS- and TSH-mediated papillary thyroid cancer progression, which suggesting that PAK4 may become a promising diagnostic and therapeutic target for papillary thyroid cancer.

Short Oral Communication 39 Thyroid Cancer Monday Short Oral Communication Basic 4:12 PM METFORMIN INHIBITS THE PROLIFERATION OF THYROID CANCER STEM CELLS BY UP-REGULATING TUMOR SUPPRESSOR MIRNAS G. Chen, X. Li, S. Xu, C. Liu Endocrine and Diabetes Center, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, China Anaplastic thyroid carcinoma is one of the most aggressive and resistant human malignancies. Cancer stem cells (CSCs) are supposed to be the cellular basis for tumor metastasis, recurrence, and chemoresistance. This study investigated the effect of metformin on the proliferation of thyroid CSCs, in order to find out novel treatment strategy for the anaplastic thyroid carcinoma. HTh74 cell line was origin from human anaplastic thyroid carcinoma cells. Doxorubicin-resistant HTh74 cells (HTh74Rdox), which enriched with side population, were used as cell model for thyroid CSCs. HTh74Rdox cells were treated with metformin or miRNA mimics for different doses and time. Cell proliferation was detected by MTT. Cell cycle and apoptosis were detected by flow cytometry. The expression of tumor suppressor miRNAs was detected by realtime-PCR. In doxorubicin-resistant thyroid carcinoma cell line, the expression of tumor suppressor miRNAs as miRNA-34a, miRNA-101, miRNA-125b, and miRNA-138 were down-regulated when compared to the wide type, HTh74 cells. Metformin showed an antimitogenic effect by inhibition of cell cycle progression and induction of apoptosis in HTh74Rdox cells. Furthermore, the tumor suppressor miRNAs (miRNA-34a, miRNA-101, miRNA-125b, and miRNA138) were up-regulated by metformin in HTh74Rdox cells. Interestingly, miRNA-34a and miRNA-138 mimics caused a similar antiproliferative effect in HTh74Rdox cells, as found in metformin treated HTh74Rdox cells. Metformin exerts anti-motogenic effect in thyroid cancer stem cells through up-regulated tumor suppressor miRNAs, miRNA-34a and miRNA-138. Therefore, our results suggest this drug as adjuvant treatment for anaplastic thyroid cancer, especially combine with other chemotherapeutics.

Short Oral Communication 40 Thyroid Nodules & Goiter Monday Short Oral Communication Basic 4:18 PM LOSS OF XB130 CAUSES DYSHORMONOGENESIS ASSOCIATED WITH IODIDE ORGANIFICATION DEFECT AND THE DEVELOPMENT OF MULTINODULAR GOITER H. Cho1,2, H. Shimizu2, H. Toba2, X. Liao3, S. Refetoff3, S. Asa4, M. Liu1,2 1 Physiology, University of Toronto, Toronto, ON, Canada; 2Latner Thoracic Surgery Research Laboratories, University Health Network, Toronto, ON, Canada; 3Department of Medicine, University of Chicago, Chicago, IL; 4Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

A-18 The development of multinodular goiter (MNG) is a compensatory response to hypothyroidism caused by dyshormonogenesis. Xb130, predominantly expressed in human and mouse thyroid, is an adaptor protein for intracellular signal transduction. We have previously demonstrated that aged (17–20 month-old) Xb130 deficient mice develop a severe form of euthyroid MNG whereas younger adult (12month-old) mice have hypothyroid goiter. Here, we attempted to elucidate the mechanistic role of Xb130 in the growth of MNG. Thyroidal T4 and T3 levels were measured by radioimmunoassay. Thyroid function was determined via thyroidal uptake of I125 and perchlorate-induced discharge test. Aged Xb130 knockout (KO) mice had enlarged thyroids (42.1 – 4.4 mg) that were about 10-fold bigger than those (3.9 – 0.3 mg) of wild-type (Wt) mice. Aged KO mice showed a trend of euthyroidism with similar thyroidal and serum T4 and T3 levels compared to Wt mice. However, they showed significantly lower thyroidal T4 and T3 levels when normalized to protein content or thyroid weight. This indicates that aged Xb130 KO mice still have underactive thyroid function at the cellular level, but compensate their overall function by enlarging the tissue over time. Perchlorateinduced discharge test revealed that the amount of iodide organified was significantly lower in KO mice displaying 55% of iodide leakage, compared to 28% in Wt mice. Moreover, the protein level of iodinated thyroglobulin (TG) in the KO mice was abnormally lower, validating a defect in iodide organification. Xb130 is localized at the apical membrane of thyrocytes, where TG iodination/organification occurs. Among several organification-related proteins, the expression and localization of thyroid peroxidase (TPO) at the apical membrane in Xb130 KO mice were noticeably lower and patchy/ inconsistent. In our future study, we plan to compare TPO activity between Xb130 KO and Wt mice and to determine how Xb130 affects TPO localization and/or activity during the organification process. Xb130 plays a critical role in thyroid hormone biosynthesis. The loss of Xb130 leads to a defect in iodide organification, promoting the development of multinodular goiter as a form of maladaptation during aging.

Short Oral Communication 41 Thyroid Cancer Monday Short Oral Communication Basic 4:24 PM ETV5, AN ETS FAMILY TRANSCRIPTION FACTOR, IS A MARKER FOR RAS-DEPENDENT THYROID CANCER PROGRESSION O. Puli, B.P. Danysh, M. Hofmann Endocrine Neoplasia and Hormonal Disorders, M D Anderson Cancer Center, Houston, TX Oncogenic mutation of RET, RAS or BRAF serve as primary drivers of thyroid cancer. For papillary thyroid cancer (PTC) BRAF-V600E is the most prevalent mutation and thus a key therapeutic target. However, with targeted treatment (eg. Vemurafenib) patients eventually acquire resistance and the disease is invariably fatal. For many cancers, comprehensive molecular profiling of tumors has helped identify effectors of key clinical challenges such as tumor invasion and relapse. Analysis of NCBI GEO thyroid cancer datasets indicated that increased expression of the transcription factor ETV5 correlated with RAS pathway activation. Our hypothesis is that ETV5 is a downstream effector of altered RAS signaling, which drives proliferation and invasion, and may be a useful marker of tumor aggressiveness. All in vitro experiments were performed with the KTC1 cell line (human PTC), which harbors the BRAF-V600E mutation. We tested the role of ETV5 in cell proliferation and invasion using RNAi.

MONDAY, OCTOBER 19, 2015 Pharmacological inhibitors were used to define which signaling pathway(s) activate ETV5 expression. NCBI GEO dataset analysis indicated 1) an increased expression of ETV5 in thyroid cancer patients in comparison to normal controls, 2) a correlation between ETV5 expression level and RAS pathway alterations and tumor aggressiveness, 3) a subset of genes with an expression pattern similar to ETV5 (21%) with demonstrated roles in cell migration and EMT. In vitro studies revealed that knockdown of ETV5 in PTC cells causes a significant decrease in proliferation. Pathway analysis using pharmacological inhibitors demonstrated that only targeted downregulation of the RAS/MAPK/ERK pathway reduced ETV5 expression levels. Long-term exposure to vemurafenib (5 months) led to the development of drug resistance, which correlated with acquisition of a KRAS G12D activating mutation and a concomitant increase in ETV5 expression. ETV5 acts downstream of the RAS/RAF/MAPK pathway and plays a crucial role in PTC proliferation and possibly invasion. ETV5 could therefore serve as a marker of tumor aggressiveness linked to RAS mutations or RAS pathway alterations.

Short Oral Communication 42 Thyroid Cancer Monday Short Oral Communication Basic 4:00 PM INHIBITION OF MITOCHONDRIAL COMPLEX 4 INCREASES GLUCOSE CONSUMPTION IN THYROID CANCER CELLS K.E. Jensen1, A. Bikas2, J. Costello1, A. Patel1, K. Burman2, V.V. Vasko1 1 Pediatric Endocrinology, Uniformed Services University of the Health Sciences, Rockville, MD; 2Endocrinology, MedStar Washington Hospital Center, Washington, DC Metastatic thyroid cancer cells are characterized by increased glycolytic activity and aberrant expression of glucose transporters. We hypothesized that inhibition of mitochondrial protein synthesis in thyroid cancer cells would compromise oxidative respiration and result in compensatory over-expression of glycolytic genes. Our objective was to clarify the mechanisms of thyroid cancer cell adaptation to mitochondrial damage through characterizing the behavior of Cytochrome c oxidase 4 (COX4)-deficient cells. Human thyroid cancer cells (FTC133) were used to create COX4deficient cells by infection with lentiviral particles containing human COX4 specific shRNA. The efficiency of COX4 inhibition was confirmed by real-time PCR, Western blot and immunostaining. The effects of COX4 inhibition on mitochondrial membrane potential, cell proliferation, migration and glucose uptake were examined COX4 expression was inhibited without significant effects on expression of other mitochondrial molecules (NDUF, SDH, Cytochrome C and ATP5B synthase). The mitochondrial membrane potential was maintained in these cells, as detected by JC-1 staining. The rate of growth was higher in COX4-deficient cells as compared to the control cells, and expression of Cyclin D1 was increased. Neither expression of genes controlling epithelial-to-mesenchymal transition (Vimentin, E-Cadherin and Twist), nor cell migration was inhibited. The expression of glycolytic enzymes (Hexokinase 2, ALDOA, PKM1, PKM2, PFK and LDHA) was not significantly affected by COX4 knock-down. However, Glut1 expression was increased by 11 fold. Consistent with these observations, the rate of glucose consumption from the medium was increased in COX4deficient cells. This study demonstrates the dynamic nature of metabolic compensatory mechanisms in thyroid cancer cells. Thyroid cancer cells undergo metabolic reprograming and activate expression of genes controlling glucose uptake in response to COX4 inhibition. COX4-

MONDAY, OCTOBER 19, 2015 deficient thyroid cancer cells can be a useful model for analysis of the metabolic activity and development of new therapies for FDG-PET positive metastatic thyroid cancer.

Short Oral Communication 43 Thyroid Cancer Monday Short Oral Communication Basic 4:06 PM HIGHLY EXPRESSED PROTEIN FAM83F INCREASES RESISTANCE TO DOXORUBICIN IN PAPILLARY THYROID CANCER C.S. Fuziwara, K.C. Saito, E.T. Kimura Cell and Developmental Biology, University of Sao Paulo, Sao Paulo, Brazil Papillary thyroid cancer (PTC) molecular profiling shows high incidence of genetic alterations in the MAPKinase signaling pathway (i.e RET, RAS and BRAF genes). However, the understanding of additional molecular events associated with differential behavior within the same background tumors, leading to an aggressive outcome, is yet incomplete. Previously, our group has identified in the Human Genome Cancer Project (FAPESP/LICR) FAM83F gene (previous LOC113828) located at chromossome 22. The family of FAM83 is composed by eight members, from FAM83A to FAM83H, that share the conserved aminoterminal DUF1699 with unknown function. In recent studies, increased expression of FAM83A and FAM83B has been detected in other cancers such as breast and lung cancer in association with therapy refractoriness. Therefore, the aim of this study is to investigate the role of FAM83F in PTC. For that, we analyzed by imunohistochemistry the expression of FAM83F in human thyroid tumors and BRAF-transgenic mice PTC (Tg-BRAF). Moreover, we over-expressed FAM83F in PCCl3 cells (PCFAM83F) and analyzed cell viability by MTT, cell migration by transwell assay and resistance to doxorubicin by measuring cell apoptosis. We observed that FAM83F is highly expressed in PTC with predominantly cytoplasmic staining while faint expression is observed in normal thyroid tissue. Interestingly, goiter displays nuclear staining of FAM83F, while PTC from BRAF-transgenic mice (TgBRAF) exhibits high expression of FAM83F. FAM83F ectopic expression in PCCl3 cells (PC-FAM83F cells) increases cell viability in 15% and cell migration in more than 4-fold. Moreover, PC-FAM83F displays marked resistance to doxorubicin-induced apoptosis. We firstly reported the pro-oncogenic influence of FAM83F in thyroid cells that suggest a new role for this family of proteins in thyroid cancer biology. Financial support: Grants form FAPESP 2013/11019-4, CNPq, CAPES.

Short Oral Communication 44 Thyroid Cancer Monday Short Oral Communication Basic 4:12 PM TUMORIGENIC ROLE OF MICRORNA MIR-17-92 CLUSTER VIA DEREGULATION OF TGFb SIGNALING PATHWAY IN THYROID FOLLICULAR CELLS C.S. Fuziwara, E.T. Kimura Cell and Developmental Biology, University of Sao Paulo, Sao Paulo, Brazil MicroRNAs (miRNAs) are important regulators of physiological processes including cell proliferation and apoptosis, acting as posttranscriptional regulator of gene expression. TGFbeta (TGFb) antimitogenic signaling pathway is involved in high iodine anti-proliferative effect in thyroid follicular cells, and we have previously shown that the induction of miR-17-92 cluster of miRNAs by BRAF oncogene leads to resistance to TGFb-mediated cell cycle arrest. In this study, we aim to clarify the

A-19 role of miR-17-92 in the biology of normal thyroid follicular cell under the influence of TGFb signaling transduction. We used PCCl3-miR-17-92 cells that over-express miR-17-92 (pCDNA3.1-Neo-miR-17-92) and PCCl3-0 (empty plasmid) as control. TGFb signaling reporter assay was performed with 3TP-lux plasmid that contains responsive binding sites to TGFb signaling. MiR-17-92 expression was detected by real-time and protein expression of TGFb signaling components by Western-blotting (WB). Cell viability was measured by MTT assay, proliferation by cell counting, cell migration by transwell assay and resistance to doxorubicin by measuring cell apoptosis. We observed an impaired PCCl3-miR-17-92 response to TGFb at 1 and 2ng/mL, 0.53-fold and 0.45-fold, respectively, when compared to the PCCl3-0 in 3TP-lux assay. WB revealed reduced Tgfbr2, Smad4 and Smurf2 protein levels in PCCl3-miR-17-92 cells. In the cell cycle assay TGFb-treated PCCl3-miR-17-92 does not exhibit G1-arrest in the cells. Furthermore, PCCl3-miR-17-92 cells escape from the antiproliferative effect of high iodine concentration treatment (10 - 3M) and show resistance to doxorubicin-induced apoptosis. The enforced expression of miR-17-92 also increased the cell viability of PCCl3-miR17-92 cells in 18% and cell migration in more than 3-fold. The miR-17-92 over-expression enhances the PCCl3 proliferation, abrogating the anti-proliferative effect of high dose iodine and impairing the TGFb inhibitory signaling, by targeting components of TGFb pathway. Moreover, the miR-17-92 influence in the migration and resistance to chemotherapy suggest an important role of these miRNA in the tumorigenic behavior in thyroid follicular cells. Grants from FAPESP2014/50521-0 and NapmiR.

Short Oral Communication 45 Thyroid Cancer Monday Short Oral Communication Basic 4:18 PM THE INVITRO EFFECTS OF METFORMIN ON THYROID CANCER CELL LINES S. Kheder, K. Sisley, S. Hadad, S. Balasubramanian Oncology, University of Sheffield, Sheffield, United Kingdom Thyroid cancer is generally associated with an excellent prognosis, but there is significant long-term morbidity with standard treatment. Some sub-types however have a poor prognosis. Metformin, an oral anti-diabetic drug is shown to have anti-cancer effects in several types of cancer (breast, lung and ovarian cancer). Proposed mechanisms include activation of Adenosine Mono-phosphate-activated Protein Kinase (AMPK) pathway; inhibition of mTOR pathway; reduction in blood glucose and insulin levels by inhibiting hepatic gluconeogenesis and increasing peripheral glucose uptake. OCT1 (organic cation transporter 1) helps in the uptake of Metformin into liver cells. The effects of metformin on thyroid cancer cell lines (FTC-133, K1E7, RO82-W-1, 8305C and TT) and normal thyroid follicular cells (Nthy-ori 3-1) were investigated using the MTT (3-[4,5-dimethylthiazol2-yl]-2,5 diphenyl tetrazolium bromide) assay for cell proliferation; clonogenic assay; FACS analysis for apoptosis (using double staining with Annexin V-FITC stained early apoptotic cells and propidium idodide stained late apoptotic cells) and cell cycle (using propidium iodide staining); and H2A.X phosphorylation (cH2AX) assay for DNA repair. Also Immunocytochemistry was used to investigate OCT1 expression. Metformin inhibited cell proliferation and colony formation at a minimum concentration of 0.03mM and increased the percentage of apoptotic cells at concentrations of 0.1mM and above. Metformin also induced cell cycle arrest in G0/G1 phase at minimum concentration of 0.3mM. Unlike previous reports, no effect on DNA repair response was demonstrated. OCT1 expression was observed in all thyroid cancer cell lines, but no significant difference was observed in the proportion and intensity of OCT1 expression in metformin treated and non-treated cells.

A-20 Metformin suppresses thyroid cancer proliferation in vitro at concentrations in the therapeutic range for diabetic patients. Further work to determine the molecular mechanisms underlying observed effects and to investigate interaction with TSH and glucose is required.

Short Oral Communication 46 Thyroid Cancer Monday Short Oral Communication 4:24 PM INDUCTION OF THE ONCOTIC DEATH PATHWAY IN THYROID CANCER CELLS A. Bikas1,3, K.E. Jensen2, J. Costello2, A. Patel2, L. Wartofsky3, K. Burman3, V.V. Vasko2 1 Endocrinology, MedStar Health Research Institute, Washington, DC; 2Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD; 3Endocrinology, MedStar Washington Hospital Center, Washington, DC Anti-cancer therapy primarily acts by inducing cell death, and numerous studies have examined the mechanisms of apoptosis, autophagy and necrosis in thyroid cancer cells. Oncosis represents a distinct mode of programmed cell death that is induced by rapid decrease in ATP. However, very little is known about oncotic death in thyroid cancer cells. We hypothesized that inhibition of mitochondrial respiration in glucose-deprived thyroid cancer cells could be associated with induction of oncotic death. Our objective was to characterize morphological and molecular changes that occur in thyroid cancer cells undergoing oncosis and to analyze the effects of metformin. Thyroid cancer cells (FTC133) were cultured in low-glucose (5 mM) medium and subjected to treatment with mitochondrial complex I inhibitors (rotenone and metformin). Morphological changes in thyroid cancer cells were monitored by time lapse microscopy. Expression of molecular markers of oncosis (perforin) was examined by immunostaining, Western blot and real-time PCR. Time lapse microscopy revealed that constant motion is an intrinsic characteristic of thyroid cancer cells growing on adherent plates. Cellular division required temporary detachment from the extracellular matrix, followed by re-adherence. Treatment with metformin (5 mM) had no effect on cellular movement, but was associated with inhibition of cell division. In addition, metformin (5 mM) induced dynamic changes in cellular shape and size suggesting oncosis. Cellular swelling, followed by shrinkage and cell membrane blebbing were observed in metformin treated cells. Expression of perforin, a well characterized marker of oncotic cell death, was increased at the mRNA and protein level in metformin treated cells. In contrast, expression of apoptotic markers (cleaved caspase 3 and cleaved PARP) was not induced by metformin. Confocal microscopy revealed dynamic changes in perforin’s intracellular localization during the different stages of oncosis. This study provides morphological and molecular evidence indicating that oncosis represents a distinct mode of cell death in thyroid cancer cells, and that metformin administration plays a significant role in this process.

Short Oral Communication 47 Thyroid Cancer Monday Short Oral Communication Clinical 4:00 PM THE STRATIFICATION OF PATIENT’S RISK DEPENDING ON THE SIZE AND RATIO OF METASTATIC LYMPH NODES IN PAPILLARY THYROID CARCINOMA Y. Hong, H. Kim, Y. Eom, S. Lee, B. Chae, J. Bae Surgery, The Catholic University of Korea, Seoul, Korea (the Republic of) Regional neck lymph node (LN) metastasis is known as a predictive factor of recurrence in papillary thyroid carcinoma (PTC). The

MONDAY, OCTOBER 19, 2015 overall significance of size of the metastatic LN (m-LN) and lymph node ratio (LNR) has rarely been studied. Aim of this study is to identify the clinicopathologic significance according to the size of mLN and LNR in patients with PTC We analyzed 580 patients with PTC who underwent thyroidectomy with central LN dissection (CLND) or Modified radical neck dissection (MRND) and RAI ablation after surgery between 04. 2012 and 12. 2014. The patients were classified into Two groups (pN1mic : £ 0.2 cm, pN1mac : > 0.2 cm) by the m-LN size and were stratified three groups based on the m-LN size and m-LN ratio (cutoff : 0.4) (low, pN1mic and LNR £ 0.4; intermediate, pN1mic and LNR > 0.4 or pN1mac and LNR £ 0.4; and high, pN1mac and LNR > 0.4). We investigated the association of the classified groups and variable clinicopathologic factors. Among 580 patients (pN1mic : 205, pN1mac : 375), there were 171 males and 409 females. Extrathyroidal extension (ETE), tumor size and the Lateral LN metastasis were associated with larger m-LN size (P < 0.001, respectively). The more number of m-LNs, higher T stage, higher N stage (P < 0.001, respectively) and the higher m-LN ratio (P = 0.011) were significantly predictive factors in pN1mac. Mean stimulated Tg (sTg) after surgery was 1.29 ng/ml in pN1mic and 2.52 ng/ml in pN1mac, and there was statistical difference between two groups (P = 0.03). The sTg denoted a value which gradually increases for each group, had a statistically significant result (low:1.02 ng/ml, intermediate:2.14 ng/ml, high:3.30 ng/ml, p = 0.004). In the multivariate analysis, lateral LN metastasis, grossly ETE, and a larger number of m-LN had a significantly association with pN1mac Lateral LN metastasis and grossly ETE were the predictive factors of pN1mac. The larger m-LN size and intermediate or high risk patient groups were correlated with higher postoperative sTg level. Clinicians should consider the possibility of recurrence and decide to apply for RAI ablation according to the size of m-LN and risk groups of patient. We suggest the RAI ablation can be omitted in the low risk patient’s group.

Short Oral Communication 48 Thyroid Imaging Monday Short Oral Communication Clinical 4:06 PM SHEAR-WAVE ELASTOGRAPHY VS FINE-NEEDLE ASPIRATION BIOPSY FOR PREDICTING CANCER IN THYROID NODULES: NO CORRELATION IN PROSPECTIVE STUDY OF 5000 CONSECUTIVE PATIENTS I. Sleptsov, R. Chernikov, A. Semenov, V. Makarin, I. Chinchuk, U. Karelina, N. Timofeeva, K. Novokshonov, A. Bubnov, Y. Fedotov, E. Fedorov, A. Uspenskaya, Y. Malugov, S. Vorobjev, A. Kulyash, A. Belov Endocrine Surgery, North-Western Center of Endocrinology & Endocrine Surgery, St. Petersburg, Russian Federation The ‘‘gold standard’’ for cancer diagnostic in a patient with thyroid nodules is a fine-needle aspiration biopsy (FNA). In the last years ultrasound elastography was proposed as a possible thyroid cancer screening method. Shear-wave elastography was recognized by some studies as less operator-dependant technique than compressive elastography which gave hope for its possible use in thyroid nodules work-up. The aim of this study was to compare diagnostic results of FNA and SWE in thyroid nodules. This single-center study was performed in North-Western Center of Endocrinology & Endocrine Surgery (St. Petersburg, Russia). 5000 consecutive patients with thyroid nodules were prospectively included in this study between December, 2014 and April, 2015. All the patients had thyroid nodules revealed by thyroid ultrasound. Thyroid ultrasound and SWE were performed by a team of 9 highvolume endocrine surgeons with experience of not less than 10000 FNAs each using Supersonic Imagine Aixplorer scanner with SL10-2 linear probe. At first ultrasound features of the nodule (size, volume,

MONDAY, OCTOBER 19, 2015 echogenicity, halo-sign, margins, blood-flow, presence of cystic component) were collected. Then maximum, minimum, mean elasticity scores in the nodule and surrounding thyroid tissue were registered. After that FNA of the nodule was performed by 21-gauge needle (at least 2 punctures). Smears were prepared by May - Grunwald - Giemsa staining and analyzed by a team of dedicated pathologists. FNA results were expressed both in Bethesda system (2010) and local institutional system of reporting thyroid cytopathology. Statistical analysis of collected data revealed no correlation between SWE parameters (all of them) and FNA results (both in Bethesda and local systems). No correlations were revealed also in groups of nodules divided by their size. No operator-dependant correlations were found. After analysis of 5000 consecutive patients we found SWE useless in comparison with FNA in thyroid cancer diagnostics.

Short Oral Communication 49 Thyroid Cancer Monday Short Oral Communication Clinical 4:12 PM BETHESDA CATEGORIZATION OF THYROID NODULE CYTOLOGY & PREDICTION OF THYROID CANCER TYPE AND PROGNOSIS X. Liu1,2, M. Medici1, N. Kwong1, T.E. Angell1, E. Marqusee1, M.I. Kim1, P.R. Larsen1, J. Barletta3, J. Krane3, E.S. Cibas3, T. Yang2, E.K. Alexander1 1 Thyroid Unit, Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 2Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 3Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA Since inception, the Bethesda System for Reporting Thyroid Cytopathology (TBS) has been widely adopted. Each category conveys risk of malignancy and recommends next steps, though it is unclear if each category also predicts the type and extent of malignancy. If so, this would greatly expand the utility of TBS by providing prognostic information in addition to baseline malignancy prevalence. We performed a cohort analysis of all patients prospectively enrolled into our thyroid nodule database from 1995–2013 with histologicallyproven malignancy. We correlated primary UG-FNA cytology (AUS, FN, SUSP and M) with cancer type, and histological features known to impact prognosis and risk of recurrence including lymph node metastasis (LNM), lymphovascular invasion (LVI) and extrathyroidal extension (ETE). High risk malignancy was defined as all thyroid carcinoma except fvPTC, classical PTC, Warthin like PTC and minimally invasive FTC. 1,291 malignancies were identified, with primary cytology AUS in 130 cases, FN in 241 cases, SUSP in 411 cases, and M in 509 cases. AUS, SUSP, and M cytology were progressively associated with increasing risk of high-risk malignancy (p < 0.001), local LNM (p < 0.001), ETE (p < 0.001), and margin positivity (p < 0.001). Notably, 70% of malignancies with AUS cytology were fvPTC, in comparison to 62% with SUSP cytology, and only 20% with M cytology. In contrast, high-risk malignancies were diagnosed in only 4.6% of cases with AUS cytology, but increased to 10.7% with SUSP and 27.8% with M cytology. FN conveyed a significantly increased risk of FTC compared to all other types (27.8% vs. 1.9%; p < 0.001). A composite endpoint inclusive of local recurrence, distant metastases, and death increased linearly from 0.8%, 2.5%, 2.7%, to 7.1% with initial AUS, FN, SUSP and M cytology (p < 0.001). In addition to predicting thyroid cancer prevalence, TBS also imparts important prognostic information about the type, variant, and thyroid cancer extent and patient outcome when present. These data extend the utility of TBS classification beyond simply an assessment

A-21 of cancer likelihood by fostering improved understanding of the risk posed by such a malignancy if confirmed.

Short Oral Communication 50 Thyroid Cancer Monday Short Oral Communication Clinical 4:18 PM THE FREQUENCY OF HIGH RISK CHARACTERISTICS REQUIRING TOTAL THYROIDECTOMY FOR 1-4 CM WELL DIFFERENTIATED THYROID CANCER W.P. Kluijfhout1,2, J.D. Pasternak1,3, N. Seiser1, J. Lim1, J. Kwon1, C. Liu4, W.T. Shen1, J.E. Gosnell1, O.H. Clark1, I. Suh1, Q. Duh1 1 Endocrine Surgery, University California San Francisco Medical Center, San Francisco, CA; 2Endocrine and Oncological Surgery, University Medical Center Utrecht, Utrecht, Netherlands; 3General Surgery, University of Toronto, Toronto, ON, Canada; 4Endocrinology, University California San Francisco, San Francisco, CA Extent of thyroidectomy for low risk well differentiated thyroid cancer (WDTC) remains an area of controversy. Historically, total thyroidectomy (TT) has been recommended for WDTC ‡ 1 cm in size. However, recent NCCN and draft ATA guidelines recognize unilateral thyroid lobectomy as a viable alternative for 1-4 cm cancers due to their otherwise favorable prognosis, with TT remaining the preferred option for tumors with unfavorable pathological characteristics. We sought to determine how often a completion TT would be recommended based on these guidelines if lobectomy was initially performed in our patients with 1-4 cm WDTC without preoperatively known risk factors. We retrospectively reviewed our patients who underwent TT for 1-4 cm WDTC ( January 2000 to January 2010). We excluded patients with high risk characteristics, including gross extra-thyroidal extension on preoperative imaging, clinically apparent lymph node metastases, distant metastases, history of radiation and positive family history. We evaluated the pathology specimens from the cancer-containing lobe for features that would lead to a recommendation for TT based on current guidelines, including aggressive histology, vascular invasion, microscopic extra-thyroidal extension, positive margins and any positive lymph nodes within the specimen. Of 1000 consecutive patients operated for WDTC, 287 would have been eligible for lobectomy as the initial operation. The mean age in this cohort was 45 years, and 80% were women. Aggressive tall cell variant histology was found in 1 patient (0.5%), angio-invasion in 34 (12%), ETE in 48 (17%), positive margins in 51 (18%), and positive lymph nodes in 49 (18%). Completion TT would have been recommended in 122/287 (43%) patients. Even in those with 1-2 cm cancers, completion TT would have been recommended in 52/143 (36%). Nearly half of patients with 1-4 cm WDTC who are eligible for lobectomy under current guidelines would require completion TT based on pathological characteristics of the initial lobe. Surgeons, endocrinologists, and patients need to balance the relative benefits, risks, and costs of initial TT versus the possible need for reoperative completion TT.

Short Oral Communication 51 Thyroid Cancer Monday Short Oral Communication Clinical 4:24 PM THE IMPACT OF RET AND RAS MUTATION STATUS ON OVERALL SURVIVAL IN THE EXAM TRIAL, A PHASE 3 STUDY OF CABOZANTINIB (CABO) IN PATIENTS (PTS) WITH PROGRESSIVE, METASTATIC MEDULLARY THYROID CANCER (MTC) S.I. SHERMAN1, R. Elisei2, S. Mueller3, P. Scho¨ffski4, M.S. Brose5, M.H. Shah6, L. Licitra7, B. Jarzab8, V. Medvedev9, M. Kreissl10, B. Niederle11, E.E. Cohen12, L. Wirth13, H. Ali14, C. Hessel15, Y. Yaron15, D. Clary15, D. Ball16, B. Nelkin16, M. Schlumberger17

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1

University of Texas MD Anderson Cancer Center, Houston, TX; University of Pisa, Pisa, Italy; 3Universitatsklinikum Essen, Essen, Germany; 4UZ Leuven, Leuven, Belgium; 5University of Pennsylvania Health System, Philadelphia, PA; 6Ohio State University Medical Center, Columbus, OH; 7Istituto Nazionale dei Tumori, Milan, Italy; 8Instytut im. M. Sklodowskiej-Curie Oddzial w Gliwicach, Gliwicach, Poland; 9Medical Radiology Research Center of RAMS, Obninsk, Russian Federation; 10Universitatsklinikum Wurzburg, Wurzburg, Germany; 11Medizinische Universitat Wien, Vienna, Austria; 12University of California San Diego Moores Cancer Center, San Diego, CA; 13Massachusetts General Hospital, Boston, MA; 14Henry Ford Health System, Detroit, MI; 15Exelixis, Inc., South San Francisco, CA; 16Johns Hopkins University School of Medicine, Baltimore, MD; 17Institut Gustave Roussy, Villejuif, France 2

Cabo, a tyrosine kinase inhibitor, extended progression-free survival (PFS) in pts with progressive, locally advanced or metastatic MTC in the phase 3 EXAM study (hazard ratio [HR] = 0.28, p < 0.001) (Elisei et al, JCO, 2013). For the secondary endpoint of overall survival (OS), the estimated median OS was 26.6 mo for cabo vs 21.1 mo for placebo (P) (stratified HR = 0.85, 95% CI 0.64–1.12, p = 0.241; Schlumberger JCO 33, 2015; abstr 6012). 330 pts were randomized 2:1 to receive cabo (140 mg qd) or P. Pts were evaluated for the presence of RET and RAS mutations in blood and tumor samples using Sanger and next gen methods. Median duration of OS in genetic subgroups was estimated using the Kaplan-Meier method. No adjustments were made for multiple subgroup analyses. Results: RET mutational status was determined in 65% of pts. Of these, 79% had a RET mutation and 21% were RET mutation negative. 75% of RET mutations were M918T. For pts with RET mutations, median OS was 31.6 mo in the cabo arm vs 24.8 mo in the P arm (HR = 0.79, 95% CI 0.54–1.17, p = 0.240). For pts with RET M918T mutation, median OS increased 25.4 mo (44.3 mo for cabo vs 18.9 mo for P; HR = 0.60, 95% CI 0.38–0.94, p = 0.026). The subgroups of pts lacking RET mutations or lacking RET M918T showed no increase in OS, although improvements in PFS and objective response rate were observed. RAS mutations were identified in 16 pts, and a trend toward increased OS benefit was observed in this small subgroup (HR = 0.37, 95% CI 0.10–1.42, p = 0.131). The median duration of treatment was 10.8 mo for cabo and 3.5 mo for P. The most common serious adverse events ( ‡ 2%) on the cabo arm were pneumonia (4.2%), pulmonary embolism (3.3%), mucosal inflammation (2.8%), hypocalcemia (2.8%), hypertension, dysphagia, dehydration and lung abscess (2.3% each). Cabo treatment was associated with a non-significant 5.5 mo increase in median OS for the overall study population, while pts with RET M918T mutations showed a more than 2 year improvement in median OS. The safety profile of cabo has remained consistent with that observed at the time of the primary analysis for PFS.

Short Oral Communication 52 Thyroid Cancer Monday Short Oral Communication 4:00 PM COMPARISON OF EMPIRIC FIXED DOSING WITH A WHOLE BODY/BLOOD CLEARANCE DOSIMETRY BASED MANAGEMENT APPROACH TO RADIOACTIVE IODINE TREATMENT IN PATIENTS WITH RAI AVID DISTANT METASTASES FROM DIFFERENTIATED THYROID CANCER D. Deandreis4, H. Tala2, C. Rubino1, S. Leboulleux4, E. Baudin4, S. Larson3, M. Schlumberger4, R.M. Tuttle2 1 INSERM, Gustave Roussy, Villejuif, France; 2Endocrinology, MSKCC, New York, NY; 3Nuclear Medicine, MSKCC, New York, NY; 4Nuclear Medicine and Endocrine Oncology, Gustave Roussy, Villejuif, France

The aim of this study was to compare the outcome of metastatic patients with thyroid cancer (TC) who were treated with 131-I either with a standard activity (100 mCi) at Gustave Roussy (GR) or with a whole body (WB)/blood clearance (BC) dosimetric approach at Memorial Sloan Kettering Cancer Center (MSKCC). We retrospectively analyzed 352 TC patients (n = 231 at GR and n = 121 at MSKCC) treated with 131-I for RAI-avid distant metastases. At GR, a fixed activity of 100 mCi per treatment was given following thyroid hormone withdrawal (THW) while at MSKCC the administered activity per treatment varied between 75 and 503 mCi (following either THW or rhTSH stimulation) based on the results of the dosimetry calculations and individual clinico-pathologic characteristics. The primary endpoint was to compare Overall Survival (OS) in the two groups by log-rank test. Patients received a median of 4 treatments at GR and 3 at MSKCC for a median cumulated activity of 400 and 654 mCi (p < 0.0001). Patients had normal cross sectional imaging in 30% and 11%, micronodular lung lesions ( < 1 cm) or single bone lesion on cross sectional imaging in 29% and 35% and macronodular lung lesions or multiple bone lesions in 42% and 53% cases at GR and MSKCC respectively (p < 0.001). Median follow-up after the diagnosis of metastases was 7.1 ys (0.4 - 31). Five ys median OS was 86.8 % and 79.9% and 10 ys median OS was 73.2% and 53.1% for patients treated at GR and at MSKCC (p < 0.01). In multivariate analysis, there was no statistical difference in OS corrected for sex, age at diagnosis of metastases, metastases site and metastases extension between the two Centers (p = 0.22). Five ys OS was 96 % and 96% for patients 40 ys with macro or multiple metastases, 93% and 87% for patients 40 ys with micrometastases treated at GR and MSKCC (p = NS) (Figure 1). Routine use of WB/BC dosimetry studies provided no overall survival advantage when compared to empiric fixed RAI activity in the management of TC patients with RAI avid distant metastases.

Short Oral Communication 53 Thyroid Cancer Monday Short Oral Communication 4:06 PM SECOND PRIMARY MALIGNANCIES IN BELARUS, PATIENTS WITH POST-CHERNOBYL PAPILLARY THYROID CARCINOMA M. Fridman3, V. Drozd1,2, Y. Demidchik3, L. Levin5, D. Branovan1, N. Shiglik1, R. Schneider4, J. Biko4, C. Reiners4 1 Project Chernobyl, New York, United States, Brooklyn, NY; 2The International fund ‘‘Help for patients with radiation-induced thyroid cancer ‘‘Arnica’’, Minsk, Belarus; 3Oncology department, Belarusian Medical Academy for Postgraduate Education, Minsk, Belarus;

MONDAY, OCTOBER 19, 2015 4

Clinic and Policlinic of Nuclear Medicine, University of Wuerzburg, Wuerzburg, Germany; 5Belarusian Cancer-Registry, RSPC of Oncology and Medical Radiology named after NN Alexandrov, Minsk, Belarus

Based on data from European studies and the US SEER database, an increased risk of second primary malignancy (SPM) was found in thyroid cancer survivors. The aim of the our population-based study was to assess the prevalence and variation of SPM in patients treated for post-Chernobyl papillary thyroid cancer (PTC) in Belarus as children or young adults. The cohort consisted of Belarusian patients born in the years 1972–1986 diagnosed with PTC and treated between 1990–2015 (n = 4237). Patients were followed up until death or the end of the study period (March 31, 2015). In the study cohort, 41 (1%) patients developed SPM with the majority in women (28 or 68.3%). Mean age (SD) at surgery for thyroid carcinoma was 24 ( – 9.7) years, at presentation of SPM was 30 ( – 7.1) years. Twenty patients (48.8%) were treated with radioiodine (mean I-131 activity 7.47 GBq) and four with external beam irradiation (30 to 40 Gy). Solid tumors were detected in 32 (78.0%) patients. Integument malignancies were revealed in 11 patients. Of these breast carcinoma accounted for 4 cases, basal cell carcinoma for 2, melanoma for 3 and dermatofibrosarcoma protuberans for 2 cases. The genital and urinary tract was the primary site of SPM in further 11 patients. Cervical carcinoma accounted for 7 cases, (5 of these were carcinomas in situ, the kidney for 2 cases and the ovaries and the vulva for one carcinoma each. SPM of the digestive tract were found in 7 patients: colon carcinoma accounted for 4 cases, gastric carcinoma, pancreatic neuroendocrine carcinoma, and parotid gland mucoepidermoid carcinoma for 1 case each. Further, single cases of soft tissue and the respiratory tract were detected and one case of unknown primary malignancy. As for haematological malignancies, they were diagnosed in 9 patients (22%): acute leukemia accounted for 4 cases, non-Hodgkin lymphoma for 1 and Hodgkin’s lymphoma for 4. Nine patients (22.0%) died of SPM, (7 from solid carcinomas and two from acute lymphoblastic leukemia). The prevalence of SPM in this unique cohort of young adults treated for post-Chernobyl PTC during a follow-up of 15 years is 1%. Haematological malignancies, cervical, breast, and colon carcinomas were most frequently observed.

Short Oral Communication 54 Thyroid Nodules & Goiter Monday Short Oral Communication Clinical 4:12 PM SUB-CLASSIFICATION OF INDETERMINATE CATEGORIES OF THYROID CYTOPATHOLOGY IMPROVES RISK STRATIFICATION AND COULD BE USED TO SELECT AND INTERPRET THE RESULTS OF MOLECULAR MARKER TESTS P. Valderrabano1, M.E. Leon2, B.A. Centeno2, B. McIver1 1 Head and Neck, and Endocrine Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 2Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL In ATA words, ‘‘it is crucial to know the prevalence of malignancy (PoM) within each indeterminate cytological category at one’s institution’’ to appropriately select and interpret the results of molecular marker tests (MMT). MMT are deemed of little benefit for categories with very low or very high PoM, (Bethesda II, V or VI), but are often recommended for Bethesda III and IV. However, these two categories are heterogeneous. We hypothesized that further subclassification of these groups might identify a smaller subset of nodules that benefit from these tests.

A-23 A single pathologist blindly reviewed the cytology and histology of 97 thyroid nodules with indeterminate cytology (Bethesda III and IV) and histological confirmation. Cytological specimens were subclassified into 4 groups: Nuclear Atypia (NA); Follicular cell (FC); Hu¨rthle cell (HC); and Other. Twenty-five (26%) nodules were classified as Bethesda III and 72 (74%) as Bethesda IV. The overall PoM within these groups was 34%, similar to previously reported findings at our Institution in a larger series. Thirty-one (32%) nodules were identified to exhibit NA; 36 (37%) FC; 29 (30%) HC; and 1 (1%) exhibited other atypical features. The PoM was significantly higher (p < 0.01) for nodules exhibiting NA (77%) than those with FC, HC, or other features (11%, 17% and 0%, respectively). There was no significant difference between these PoM according to Bethesda group. Follicular variant of papillary carcinoma represented 82% (27/33) of the malignancies in this cohort, as described in other series. The finding of NA in Bethesda III or IV specimens, identifies a subset of thyroid nodules with high PoM, approaching that usually reported for Bethesda V. Applying any molecular marker tests to these samples might yield unreliable negative- and uninformative positive-predictive values, adding expense, but little value. In contrast, indeterminate cytology exhibiting FC, HC or other features of atypia may be more suited for the commercially available MMT. The presence of NA is a significant indicator of malignancy, and should be routinely reported on thyroid cytopathology.

Short Oral Communication 55 Thyroid Cancer Monday Short Oral Communication Clinical 4:18 PM OUTCOMES BY SITE OF METASTASIS FOR PATIENTS WITH RADIOIODINE-REFRACTORY DIFFERENTIATED THYROID CANCER TREATED WITH LENVATINIB VERSUS PLACEBO: RESULTS FROM A PHASE 3, RANDOMIZED TRIAL M.A. Habra1, J. Song2, P. Rietschel2 1 Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; 2Eisai Inc., Woodcliff Lake, NJ In the phase 3, randomized, double-blind study of patients (pts) with radioiodine-refractory differentiated thyroid cancer (RR-DTC), lenvatinib significantly improved median progression-free survival (PFS) vs placebo (18.3 vs 3.6 months, respectively; hazard ratio [HR] 0.21; 99% confidence interval [CI] 0.14–0.31; P < 0.001). This subanalysis examines patient efficacy outcomes based on baseline metastasis site. Pts with progressive RR-DTC were randomized 2:1 to lenvatinib 24 mg daily or placebo. Tumor assessments were performed at baseline and every 8 weeks from randomization, and were independently evaluated using the Response Evaluation Criteria in Solid Tumors (version 1.1). Of 392 pts, 388 (99.0%) had ‡ 1 metastatic site (1 site, n = 96; 2 sites, n = 134; 3 sites, n = 107, ‡ 4 sites, n = 51); 34% and 66% had follicular and papillary histologies, respectively. Median PFS for pts with 1, 2, 3, and ‡ 4 sites metastatic sites was not reached, 18.3, 16.5, and 11.0 months, respectively for pts on lenvatinib, and 3.7, 3.7, 3.6, and 2.0 months, respectively, for pts on placebo. Additionally, overall response rates for patients with specific metastatic sites were: brain 66.7% (6/9), bone 51.0% (53/104), liver 51.2% (22/43), lung 68.1% (154/226), and lymph node 65.2% (90/138); pts may have had ‡ 1 metastatic site. PFS by metastatic site are shown in the Table; differences were consistently observed between metastatic subgroups for lenvatinib and were less evident for placebo.

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For common sites of metastasis (brain, bone, liver, lung, lymph node), response rates were > 50% and a PFS benefit with lenvatinib was preserved in all but brain metastasis subgroup. These findings suggest a greater lenvatinib treatment benefit in pts with better prognosis, as defined by metastatic site.

Short Oral Communication 56 Thyroid Cancer Monday Short Oral Communication Basic 4:24 PM AMPK OVERACTIVATION IN BCPAP TUMOR CELLS INDUCES CELL DEATH THROUGH INCREASED REACTIVE OXYGEN SPECIES (ROS) R. Coelho, J. Cazarin, J.A. Albuquerque, A. Galina, B. Andrade, D.P. Carvalho UFRJ, Rio de Janeiro, Brazil AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that acts directly on cell proliferation and on transition from anaerobic to aerobic metabolic state. Our group showed that the

MONDAY, OCTOBER 19, 2015 activated form of AMPK (pAMPK) is overexpressed in papillary thyroid carcinoma (PTC) cases by immunohistochemistry. AMPK presents anti proliferative effects, so the biological meaning of AMPK activation in thyroid tumor cells and the consequences of its further activation on PTC metabolism is not known. We used the PTC-derived BCPAP cell line to analyze cellular responses to a further stimulation of AMPK with the pharmacological activator 5-aminoimidazole-4 carboxamide ribonucleoside (1 mM AICAR). Cell viability was measured by MTT, and apoptosis was analyzed by the expression of Annexin V by Muse cell analyser. ROS was measured by DCF-HD probe by FACS. Oxygen consumption was measured using high-resolution respirometry (Oroboros). Hexokinase (HK) tertiary structure was evaluated on a spectrofluorometer ( Jasco). BCPAP cells constitutively express high pAMPK levels, which correlates with the high glucose consumption rate (2 fold) and lactate production (2 fold), but lower oxygen consumption (30%) in these cells when compared to the non-tumoral NTHY-ori cell line. AICAR exposure further stimulated these metabolic parameters, but decreased BCPAP cell viability (4 fold), with increased (1.5 fold) production of reactive oxygen species (ROS). HK is an enzyme of the glycolysis pathway that, upon binding to mitochondria, protects against ROS. We observed an increase in HK activity (1.4 fold) produced by AICAR, but not in its association with HK-mitochondrial activity. Purified HK experiments confirmed that ROS (100 lM H2O2) alters the tertiary structure of HK decreasing its mitochondrial binding. The presence of NAC prevented cell death induced by AICAR treatment. Overall, these results suggest that, despite the up-regulation of glucose metabolism by AMPK, chronic activation of the enzyme with AICAR increases ROS levels promoting a negative regulation of HKmitochondrial binding. The further increase in ROS production induced by AICAR might play a role in the induction of tumor cell apoptosis.

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Tuesday, October 20, 2015 Oral 57 Thyroid Cancer Tuesday Oral Basic 9:45 AM ASSOCIATION BETWEEN TERT PROMOTER AND NRAS MUTATIONS AND THEIR COOPERATIVE UPREGULATION OF TERT EXPRESSION R. Liu, M. Xing Johns Hopkins University School of Medicine, Baltimore, MD The newly identified TERT promoter mutations and mutations in the PI3K/AKT pathway are frequently observed in follicular thyroid cancer (FTC), but their relationship and cooperative effects, if any, on the TERT gene are largely unknown. Mutations in the PI3K/AKT pathway and TERT promoter were analyzed by Sanger sequencing in FTC tumors and their relationship was analyzed. The functional relationship between the PI3K/AKT pathway and TERT gene, in the presence or absence of TERT promoter mutation, was investigated by examining the effects of transfected RAS mutant or AKT knockdown on TERT promoter activities in luciferase reporting assays and on TERT expression in thyroid cancer cells. In 67 FTC samples, TERT promoter mutations C228T and C250T were found in 8 (11.9%) cases. Mutations in NRAS, KRAS, HRAS, PTEN, and PIK3CA genes in the PI3K/AKT pathway were found in 12 (17.9%), 1 (1.5%), 0 (0%), 4 (6.0%), and 5 (7.5%) cases, respectively, and collectively in 19 (28.4%) cases. There was a significant association between TERT promoter mutations and NRAS mutations (P = 0.029), which was confirmed in our meta-analysis of published studies. The infrequency made it impossible to perform a similar relationship analysis on the remaining mutations. Compared with the wild-type NRAS, mutant NRAS could increase TERT promoter activities, particularly robustly when TERT promoter mutations were present, in luciferase reporting assays. Introduced expression of NRAS mutant in thyroid cancer cells harboring TERT promoter mutation increased TERT expression. In contrast, AKT knockdown by shRNA suppressed the PI3K/AKT signaling with correspondingly decreased TERT promoter activities in luciferase reporting assays and decreased expression of TERT in thyroid cancer cells. NRAS mutations are associated with TERT promoter mutations in FTC and, through activating the PI3K/AKT pathway, cooperate with TERT promoter mutations to upregulate the promoter activities and expression of the TERT gene. This represents a novel oncogenic mechanism in the tumorigenesis of FTC driven by NRAS and TERT promoter mutations, for which further exploratory research is currently ongoing in our lab.

Oral 58 Thyroid Cancer Tuesday Oral Basic 10:00 AM A NOVEL MECHANISM INVOLVING WIPF1 OVEREXPRESSION VIA PROMOTER HYPOMETHYLATION BY BRAF V600E IN THYROID TUMORIGENESIS T. Zhang, M. Xing Johns Hopkins University School of Medicine, Baltimore, MD BRAF V600E plays a fundamental role in the tumorigenesis of thyroid cancer. The WASp interacting protein family, member 1 (WIPF1) is involved in cellular activation, motility, migration and invasion. We hypothesized that WIPF1 might play an important role in thyroid tumorigenesis promoted by the BRAF V600E/MAP kinase pathway.

Using a variety of cellular and molecular approaches, such as RTPCR, DNA methylation PCR, Western blotting, shRNA knockdown, pharmacological drugs, and introduced gene expression, we investigated the role of BRAF V600E in the expression of WIPF1 and its promoter methylation and the role of WIPF1 in aggressive cellular functions of BRAF V600E mutation-harboring thyroid cancer cell lines K1 and OCUT1. The mRNA and protein levels of WIPF1 were profoundly downregulated in K1 and OCUT1 cells stably transfected with BRAF shRNA to silence BRAF V600E expression or treated with either BRAF V600E inhibitor PLX 4032 or MEK inhibitor AZD6244, suggesting that the BRAF V600E/MAP kinase pathway promotes the expression of WIPF1. Under these conditions, the WIPF1 promoter methylation was correspondingly increased, suggesting that the BRAF V600E/MAP kinase pathway normally maintains the WIPF1 at a hypomethylated state. WIPF1 expression was up-regulated in cells harboring BRAF shRNA after treatment with DNA demethylating agent 5¢-Azadeoxycytidine with resulting WIPF1 demethylation, demonstrating an important role of DNA methylation in the regulation of WIPF1 gene. Thus, the BRAF V600E/MAP kinase pathway promotes WIPF1 expression by inducing WIPF1 promoter hypomethylation. Knockdown of WIPF1 inhibited colony formation, migration, and invasion of thyroid cancer cells, demonstrating a direct role of WIPF1 in aggressive behaviors of thyroid cancer cells. Knockdown of BRAF similarly suppressed these cellular behaviors, which could be rescued by introduced expression of WIPF1 in the cells. This study uncovers a novel mechanism in BRAF V600E-promoted thyroid tumorigenesis, in which the BRAF V600E/MAP kinase pathway promotes WIPF1 overexpression by inducing hypomethylation of the WIPF1 promoter and the consequently overexpressed WIPF1 in turn promotes aggressive cellular behaviors of thyroid cancer cells.

Oral 59 Thyroid Cancer Tuesday Oral Translational 10:15 AM NEXT GENERATION SEQUENCING MUTATION PROFILING REVEALS NOVEL PUTATIVE TUMOR CANDIDATES IN ANAPLASTIC THYROID CARCINOMA S. Latteyer1, V. Tiedje1, K. Ko¨nig2, S. Ting3, L. Heukamp2, K.W. Schmid3, D. Fu¨hrer1, L.C. Moeller1 1 Endocrinology & Metabolism, University of Duisburg-Essen, Essen, Germany; 2Institute of Pathology, University Hospital Cologne, Cologne, Germany; 3Institute of Pathology, University of DuisburgEssen, Essen, Germany Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid malignancy with a median survival of 4–8 months. Identification of mutations contributing to aberrant activation of signaling cascades in ATC may provide novel opportunities for targeted therapy. DNA was extracted from paraffin-embedded tissues of 40 ATC samples. Next generation sequencing (NGS) was performed for ALK, NRAS, HRAS, KRAS, BRAF, PTPN11, TP53, and putative novel tumor suppressor genes NF1, ATRX. Sequence aberrations were compared to the COSMIC database. DNA was extracted from 40 ATC samples. Nine out of 40 samples could not be analyzed due to heterogeneous sequencing results. 46 distinct mutations were identified in the remaining 31 ATC samples.

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In 3 samples, no mutation was detected. Twenty eight tumors harbored a mutation in at least one of the studied genes: TP53 18/31, NF1 11/31, ALK 6/31, NRAS 4/31, ATRX 3/31, BRAF 2/31, HRAS 2/31, KRAS 1/31 and PTPN11 1/31. The most frequently mutated gene was TP53 (58%), followed by NF1 (35%). In 17 of 31 ATC (54%) mutations were found in 2 or more genes and a combination of RAS-like mutations was most frequent. Furthermore, some ATC showed 2 distinct somatic mutations within one gene (BRAF or NF1). 18/46 mutations (42%) identified in these ATC are listed in COSMIC as somatic mutations known in other cancer entities. TP53 was the most frequently mutated gene in our NGS panel. Surprisingly, one fourth of the ATC samples harbored mutations in NF1, which has not been associated with ATC before. Similarly, ATRX mutations, previously found in anaplastic glioma, have not been described in ATC to date. ALK mutations were detected in 19% of ATC and hence were more frequent than RAS or BRAF mutations. Of note almost half of ATC harbored mutations in two or more genes. These results contribute new candidates to the list of mutations present in ATC and support the idea that various genetic aberrations rather than a single driver mutation contribute to ATC aggressiveness, hence demanding a multitargeted treatment approach.

fibroblast cell lines NIH-3T3. We observed that the variant expressing cells ( + / - and - / - ) had higher number of foci and migration compared to the wt ( + / + ) suggesting a dominant negative tumor suppressive function. In conclusion, our data suggests that HABP2 is a susceptibility gene for FNMTC.

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New targeted therapies are needed for advanced thyroid cancer. Our lab has shown that Src is a key mediator of growth, invasion and metastasis in thyroid cancer cells.1–3 However, single-agent Src inhibitors have had limited efficacy in solid tumors.4 In order to more effectively target Src in the clinic, our lab has generated four thyroid cancer cell lines, 2 BRAF-mutant (BCPAP, SW1736) and 2 RAS-mutant (Cal62, C643), that are resistant to dasatinib (BMS-354,825) through gradual dose escalation. We have further tested two additional Src inhibitors and shown the dasatinib-resistant (DasRes) cells exhibit cross-resistance to saracatinib (AZD0530), but are sensitive to bosutinib (SKI-606), suggesting that unique off-targets of bosutinib play an important role in mediating sensitivity to bosutinib, and therefore resistance to dasatinib. To identify the potential targets of dasatinib versus bosutinib, we performed an unbiased compound centric chemical proteomics screen5 using the BCPAP-DasRes cell line as a model. Briefly, cell lysate was incubated with tagged dasatinib or bosutinib. Proteins that bound to the tagged inhibitors were isolated and identified by mass spectrometry. As expected, we identified Src family kinases as targets of both inhibitors, as well as 33 kinases that were pulled down with bosutinib, but not dasatinib. Using the STRING6 database to map proteinprotein interactions of the unique bosutinib targets, we identified a signaling axis containing 13 kinases, including MEK1/2, Focal Adhesion Kinase (FAK), Protein Tyrosine Kinase 2B (PYK2), and a

Thyroid Cancer Tuesday Oral Basic 10:30 AM HABP2 IS A NOVEL TUMOR SUPPRESSOR GENE THAT CAUSES FAMILIAL NONMEDULLARY THYROID CANCER S. Gara1, V. Neychev1, L. Jia3, M.J. Merino4, S. Agarwal2, L. Zhang1, M. Cam3, D. Patel1, E. Kebebew1 1 Endocrine Oncology Branch, National Cancer Institute, Bethesda, MD; 2Metabolic Diseases Branch, NIDDK, Bethesda, MD; 3CCR/ OD, NCI, Bethesda, MD; 4Laboratory of Pathology, NCI, Bethesda, MD Familial nonmedullary thyroid cancer (FNMTC) accounts for 3–9% of all thyroid cancer cases and has an autosomal dominant pattern of inheritance. FNMTC may be syndromic (e.g. Cowden’s, Carney complex), for which the susceptible genes are known but the majority of them are nonsyndromic, accounting for more than 95% of all cases. The susceptibility gene(s) for nonsyndromic FNMTC are not known. We performed whole exome sequencing on a large kindred with FNMTC to identify the cancer susceptible genes. We identified a germ line heterovariant, G534E, in the HABP2 gene that segregated with all affected members (7/7 cases) in a large kindred with FNMTC by whole-exome sequencing of their germline DNA. In addition, we identified 4 out of 96 unselected cases with thyroid cancer that had the same variant. One of the 4 carriers was found to have FNMTC on further pedigree analysis. An analysis of The Cancer Genome Atlas (TCGA) whole-exome sequencing data of germline DNA showed 20 of 423 (4.7%) patients with thyroid cancer had the G534E heterovariant. HABP2 mRNA and protein expression in thyroid tumor samples from G534E variant carriers was higher as compared to absent or low expression in adjacent normal thyroid tissue and sporadic thyroid cancer cases. Knock down of wild type (wt) HABP2 increased colony formation, cellular migration and invasion in thyroid cancer and HEK293 cell lines suggesting a tumor suppressive function of HABP2. Stably overexpression of the HABP2 G534E variant increased colony formation, cell migration and invasion whereas wt overexpression showed reduced colony formation, cell migration and invasion suggesting that the variant results in loss-of-function of the HABP2 protein. We then analyzed whether the HABP2 G534E variant can initiate malignant transformation by transiently overexpressing wt HABP2 ( + / + ), G534E ( - / - ) variant and equal amounts of both wt and G534E variant ( + / - ) in mouse

Oral 61 Thyroid Cancer Tuesday Oral Basic 10:45 AM A CHEMICAL PROTEOMICS APPROACH TO IDENTIFY MECHANISMS OF RESISTANCE TO THE SRC INHIBITOR, DASATINIB K. Mishall1, T.C. Beadnell1, B. Kuenzi2, B.E. Kessler1, J. Kim3, G. Superti-Furga4, U. Rix2, A. Tan3, R. Schweppe1 1 Endorcrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Denver, CO; 2Chemical Biology and Molecular Medicine, Moffitt Cancer Center & Research Institute, Tampa, FL; 3Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO; 4CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria

STRING analysis of the kinases pulled down with bosutinib. MEK1/2 (MAP2K1/2), FAK (PTK), PYK2 (PTK2B) and CaMKII (CaMK2D/G) are targets we have validated as key mediators of dasatinib resistance.

TUESDAY, OCTOBER 20, 2015 recently identified bosutinib target, Calcium/Calmodulin-dependent Protein Kinase II (CaMKII). We have previously shown inhibition of MEK overcomes dasatinib resistance. Here, we show that a CaMKII inhibitor, KN93, inhibits growth of control and DasRes cells (IC50 1.5–3lM) and increases apoptosis 2–7 fold. Additionally, dual inhibition of FAK/PYK2 with PF-562,271 can overcome resistance to dasatinib (IC50 0.5–1lM). Overall, these results have identified key mediators of Src inhibitor resistance, and provide important information on how to target these pathways alone or in combination with Src-directed therapies.

Oral 62 Iodine Uptake & Metabolism Tuesday Oral Translational 9:45 AM MESENCHYMAL STEM CELL-MEDIATED SODIUM IODIDE SYMPORTER (NIS) GENE DELIVERY IN A MOUSE MODEL OF PANCREATIC DUCTAL ADENOCARCINOMA USING NIS AS REPORTER GENE C. Schug1, A. Gupta2, K.A. Schmohl1, S. Hacker1, N. Schwenk1, M. Schwaiger3, J. Siveke2, P.J. Nelson4, C. Spitzweg1 1 Department of Internal Medicine II, University Hospital of Munich, Munich, Germany; 2Department of Internal Medicine II, University Hospital Klinikum rechts der Isar, Munich, Germany; 3Department of Nuclear Medicine, University Hospital Klinikum rechts der Isar, Munich, Germany; 4Biochemistry Group, Medizinische Klinik und Poliklinik IV, University Hospital of Munich, Munich, Germany The sodium iodide symporter (NIS) in its role as reporter and therapy gene allows noninvasive imaging of functional NIS expression by 123 I-scintigraphy and 124I-PET as well as therapeutic application of 131 I. We and others have investigated the capacity of NIS to induce radioiodine accumulation in non-thyroidal tumors using various gene delivery vehicles. Based on their excellent tumor-homing capacity, genetically engineered mesenchymal stem cells (eMSCs) show promising potential as tumor-selective gene delivery vehicles as shown in our previous studies. As a next step towards clinical application, tumor specificity and transduction efficacy of eMSCs were investigated in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC). Immortalized bone marrow-derived syngeneic mouse MSCs were stably transfected with a NIS expressing plasmid driven by the CMVpromoter (CMV-NIS-MSC). CMV-NIS-MSCs were characterized in vitro by analysis of functional NIS expression using iodide uptake assay, qPCR and Western blot. CMV-NIS-MSCs were injected systemically in PDAC mice and tumoral iodide uptake was monitored by 123I-scintigraphy. Resected tumors were further analyzed by NIS immunohistochemistry. Iodide uptake studies revealed a 20-fold increase in NIS-mediated perchlorate sensitive iodide uptake in CMV-NIS-MSCs compared to wild type MSCs based on functional NIS expression. A first set of in vivo experiments showed significant tumor-specific accumulation of 123I after i.v. application of CMV-NIS-MSCs in pancreatic tumors. Tumor-selective NIS protein expression was confirmed ex vivo in resected tumors by NIS-specific immunoreactivity. We have successfully established genetically engineered MSCs highly expressing NIS for the application as gene delivery vehicles in an advanced, more complex endogenous mouse model of PDAC. Preliminary in vivo studies demonstrate high stromal targeting of NIS by selective recruitment of NIS-expressing MSCs after systemic application. The high level of tumor-selective radionuclide accumulation after MSC-mediated gene delivery sets the stage for therapeutic application of MSC-mediated NIS radionuclide therapy in this clinically highly relevant PDAC mouse model.

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Oral 63 Iodine Uptake & Metabolism Tuesday Oral Translational 10:00 AM USING THE HYPOXIA RESPONSE NETWORK FOR TUMOUR-TARGETED 131I THERAPY OF ORTHOTOPIC HEPATOCELLULAR CARCINOMA (HCC) XENOGRAFTS AFTER MESENCHYMAL STEM CELL (MSC)-MEDIATED SODIUM IODIDE SYMPORTER (NIS) GENE DELIVERY A.M. Mueller1, K. Knoop1, K.A. Schmohl1, N. Schwenk1, D. Clevert2, J. Carlsen3, F. Gildehaus3, H. Niess4, E. Wagner5, P.J. Nelson6, C. Spitzweg1 1 Department of Internal Medicine II, University Hospital of Munich, Munich, Germany; 2Department of Clinical Radiology, University Hospital of Munich, Munich, Germany; 3Department of Nuclear Medicine, University Hospital of Munich, Munich, Germany; 4Department Of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Munich, Munich, Germany; 5Department of Pharmacy, Ludwig-Maximilian-University, Munich, Germany; 6Medical Clinic and Policlinic IV, University Hospital of Munich, Munich, Germany The tumour-homing property of mesenchymal stem cells (MSCs) has led to their use as delivery vehicles for therapeutic genes. The application of the sodium iodide symporter (NIS) as theranostic gene allows non-invasive imaging of MSC biodistribution, as well as therapeutic application of 131I. Solid tumours consist of large hypoxic areas as a result of increased metabolic rate, tissue inflammation and irregular angiogenesis. Hypoxia-inducible factor (HIF) is a key mediator of the cellular response to hypoxia and thus present at high levels in solid malignancies. Therefore we have investigated the feasibility of using a HIF-responsive promoter (HRP) for driving tumour stroma-targeted NIS expression and subsequent radioiodide accumulation after MSC-mediated delivery. Human MSCs were stably transfected with NIS, driven by a HRP (HIF-NIS-MSCs). Following in vitro characterisation of HIF-NIS-MSCs and demonstration of high levels of perchlorate-sensitive, HIF-responsive radioiodide accumulation in our previous studies in orthotopic HCC xenografts, established by injecting the HCC cell line HuH7 into the left liver lobe of nude mice, in the current study we evaluated the therapeutic efficacy of 131I after HIF-NIS-MSC-mediated NIS gene delivery. 131 I (55.5 MBq) was administered 48 h after three consecutive MSC applications given in two-day-intervals. This treatment cycle was repeated once followed by another MSC injection with a final 131 I application 48 h later. Monitoring of tumour growth by contrastenhanced sonography showed a tumour volume reduction of approx. 36% in the therapy group with significantly reduced tumour perfusion and increased necrotic areas as compared to the control group that was injected with NaCl instead of 131I. Survival was also significantly prolonged with 71% of therapy mice being still alive at day 24 post therapy as compared to only 17% control animals. Our results in an orthotopic HCC mouse model demonstrate the potential of HIF-NIS-MSC-mediated radioiodide therapy as a novel approach for the treatment of HCC patients.

Oral 64 Iodine Uptake & Metabolism Tuesday Oral Basic 10:15 AM ROLE AND MECHANISM OF TYPE 2 IODOTHYRONINE DEIODINASE UBIQUITINATION OF PITUITARY IN IODINE INDUCED TSH ELEVATION X. Zhang, Y. Jiang, W. Teng, W. Han, Z. Shan The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases, Department of Endocrinology and Metabolism, The First Hospital of China Medical University, Shenyang, China

A-28 Many epidemiological studies indicate that prolonged high iodine intake would lead to an elevation of serum thyrotrophin (TSH) level, but the mechanism is elusive. Type 2 iodothyronine deiodinase (D2) plays a crucial role in the regulation of hypothalamic-pituitary-thyroid axis (HPT axis). Our previous study has observed that activity of pituitary D2 was suppressed in Wistar rats fed with high iodine, suggesting a role for D2 in the iodine induced TSH increment. 200 Wistar rats were randomly divided into five groups and fed with different dosage of iodine, that is, normal iodine (NI), 3 fold iodine (3HI), 6 fold iodine (6HI), 10 fold iodine (10HI), 50 fold iodine (50HI). Rats were sacrificed at 4 weeks, 8 weeks, 12 weeks, 24 weeks after iodine administration. Pituitary weight, urinary iodine, serum thyroid function were measured. The mRNA and protein expression levels of pituitary D2, two D2-specific ubiquitin liagases: 1) WD repeat and SOCS box-containing protein 1 (WSB-1), 2) membrane associated ring finger(C3HC4) 6 (MARCH6 or TEB-4), two deubiquitinating enzymes: ubiquitin-specific proteases 20 (USP20) and USP33 were tested. We also measured the expression of USP19, a TEB-4 specific deubiquitinating enzyme. There was no difference of pituitary weight in different groups. Urinary iodine and serum TSH were significantly increased in high iodine group compared to normal iodine group. In 10HI and 50HI group, D2 protein level was decreased in 12 weeks and 24 weeks. But the mRNA level remained unchanged. These results indicated that suppressed D2 activity was due to the post-translation modification which is ubiquitination for D2. Prolonged iodine intake increased pituitary WSB-1 and TEB-4 both in mRNA and protein expression level in a dose and time dependent manner. High iodine intake had no discernible effects on USP20 and USP33 expression. We also observed an increase in USP19 mRNA and protein expression level. Our work indicates that the enzymes related to D2 ubiquitination change with prolonged high iodine intake. These results can serve as theoretical evidence for the role of D2 ubiquitination in iodine induced TSH elevation.

Oral 65 Thyroid Hormone Action Tuesday Oral Basic 10:30 AM THYROID HORMONE SIGNALING REGULATES ENDOGENOUS HYDROGEN SULFIDE PRODUCTION H. Kim1,4, P. Ramadoss1, C. Hine2, K. Bauerle5, J. Paulson8, W. Miyazaki6, J. Asara3, C. Hao1, M. Souza Matos7, J. Mitchell2, A. Hollenberg1 1 Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; 2 Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA; 3Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; 4 Division of Endocrinology, Diabetes and Metabolism, Eulji General Hospital, Eulji Medical School, Seoul, Korea, Seoul, Korea (the Republic of); 5Division of Endocrinology, Washington University, St. Louis, MO; 6Department of Public Health, Kumamoto University, Kumamoto, Japan; 7Pharmacy School of Federal University of Rio de Janeiro - UFRJ, Rio de Janeiro, Brazil; 8Division of Endocrinology, George Washington University, Washington, DC The regulation of genomic targets by thyroid hormone (TH) does not explain all of its effects. We hypothesize that TH regulates specific metabolite pathways that are critical for its actions. Recently, increased endogenous hydrogen sulfide (H2S), reported as a physiological vasodilator, has been linked to longevity in caloric restriction. Given the link between hypothyroidism and longevity in mice and humans we further explored the regulation by TH of the transsulfuration pathway (TSP) which produces H2S.

TUESDAY, OCTOBER 20, 2015 To gain further insight into novel pathways regulated by TH we used metabolite profiling. To measure H2S production we applied both in vivo and in vitro technology. To confirm the role of TH receptor (TR)b1 in metabolite production we performed in vivo studies using the liver-specific TH analog GC-1. Remarkably, we found that TH controls the TSP in the liver which regulates the production of cystathionine, cysteine and H2S. Using a variety of mouse models we demonstrate that hypothyroidism strongly induces H2S production in the liver by up-regulating the expression of cystathionine gamma-lyase (CTH) and cystathionine beta-synthase (CBS). This in turn leads to decreased cystathionine and increased cysteine. In contrast, TH directly down-regulates CTH and CBS leading to the suppression of H2S production in hyperthyroidism and an accumulation of cystathionine. Importantly, both CTH and CBS appear to be direct targets of TRb1 as hepatic H2S production is also regulated by the liver-specific TH analog GC-1 and both CTH and CBS have TH receptor binding sites within their regulatory regions. Finally, while the mTORC1 pathway has been linked to H2S regulation in caloric restriction studies in vivo, we show in a TH responsive hepatic cell line that the TSP is directly targeted by TH via the TR independently of mTORC1. Direct genomic signaling by TH via the TR does not explain all of the actions of TH. Here we have identified the production of endogenous H2S as being regulated in vivo by TH. Given the putative beneficial role of H2S including longevity it is tempting to speculate that H2S production plays a key role in TH action. Further studies on the role of H2S in TH action are needed.

Oral 66 Thyroid Hormone Action Tuesday Oral Basic 10:45 AM MEMBRANE-TRAVERSING MECHANISM FOR THYROID HORMONE TRANSPORT AT MCT8 J. Protze1, K.M. Hinz1, D. Braun2, U. Schweizer2, G. Krause1 1 Leibniz Institut fuer molekulare Pharmakologie (FMP), Berlin, Germany; 2Rheinische Friedrich-Wilhelms-Universita¨t, Bonn, Germany The molecular mechanisms how thyroid hormones are transferred across the membrane by different transporter proteins such as MCT8, OATP1C1 and LAT2 are unclear. Previous molecular models of thyroid hormone (TH) transporter MCT8 illustrated only the intracellular open conformation, based on the GlpT transporter crystal structure. Although mutational data indicated amino acid positions of MCT8 involved in T3 uptake, the translocation mechanism remained unsolved. Our goal was to create MCT8 models also in outward open conformation and reveal the complete molecular mechanism of TH-membrane-traversing. We generated two new MCT8 models built on a sequence homologous transporter, XylE, utilizing its two crystal structures of an inward (4AJ4) and a partly occluded outward open (4GBY) state. While the inward conformation was approximate to our previous model, the second new MCT8 model was not fully outward opened, hindering an extracellular entry or release of THs. Generating an entirely extracellular opened MCT8 model, we utilized the full outward open crystal structure of another 12-transmembrane-(TM)helix transporter FucP (3O7Q) and its identical structural arrangements in each of the respective two 6-TM-helix bundles like XylE. Structural alignment of the 6-TM subunits of both transportertemplates and computer assisted reciprocal tilting of the 6-TM subunits resulted finally in two new MCT8 models of fully outward and inward opened conformations. T3 docking studies from both sides revealed one central cavity for substrate recognitions (formed amongst others by previously identified H192, H415, R445, D498), which can be exposed to both faces of the protein. Mutagenesis of further residues supports this mechanism.

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We here identified a membrane-traversing mechanism for THs by MCT8 as the two banana shaped 6-TM-helix bundles are tilting around a central TH-interacting cavity with alternating extra- and intracellular accessibility of the TH recognition sensitive residues H192, H415, R445, D498. After extracellular recognition T3 adheres to these residues during MCT8-movement and is thus lifted through the central traversing channel and released towards the intracellular side and vice versa.

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This is the first study to show that maternal FT4 levels during early pregnancy are associated with gray matter and cortex volume of the offspring at the age of six years. High FT4 levels may have equally detrimental effects on brain development as low FT4 levels. Future studies are needed to investigate if these changes in gray matter and cortex volume mediate the clinical associations of maternal FT4 with child IQ and behavioral problems.

Oral 68 Oral 67 Thyroid & Development Tuesday Oral Clinical 9:45 AM MATERNAL THYROID FUNCTION DURING EARLY PREGNANCY IS ASSOCIATED WITH TOTAL CEREBRAL GRAY MATTER AND CORTEX VOLUME IN SCHOOL-AGE CHILDREN T.I. Korevaar1,3, R. Muetzel2, M. Medici1,3, L. Chaker1,3, T. White4, H. Tiemeier2, T. Visser1,3, R. Peeters1,3 1 Endocrinology, Erasmus University Medical Center, Rotterdam, Netherlands; 2Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, Netherlands; 3Rotterdam Thyroid Center, Rotterdam, Netherlands; 4Radiology, Erasmus University Medical Center, Rotterdam, Netherlands Thyroid hormone (TH) regulates brain development. Since the fetal thyroid is not fully functional until week 18-20 of pregnancy, critical early stages of intrauterine brain development predominantly depend on the supply of maternal TH. Already in the early 1970s, animal studies have suggested that both low and high levels of maternal TH during pregnancy have a detrimental effect on brain morphology via alterations of the migration, proliferation and differentiation of neuronal cells. However, there are no human studies on the association of maternal thyroid function over the entire range with child brain morphology. Maternal serum TSH and FT4 levels were determined in early pregnancy (9-18 wks) and child brain MRI scanning was performed at a median age of six years in 652 mother-child pairs from a large population-based prospective cohort study. All analyses were adjusted for gestational age at blood sampling, maternal age, BMI, child sex, birth weight, gestational age at birth, age at time of MRI and total brain volume and additionally for maternal hCG, TPOantibodies and child TSH and FT4 (at birth and at age of MRI). There was an independent, inverted U-shaped association of maternal FT4 with child total gray matter volume (P = 0.007; Fig 1A) and a similar association with child cortex volume (P = 0.001; Fig 1B). All analyses remained similar after adjustment for hCG, TPOAbs and child TSH and FT4. There was no association of maternal FT4 with total white matter, corpus callosum or hippocampal volume, and there was no association between TSH child brain MRI measurements.

Autoimmunity Tuesday Oral Translational 10:00 AM CLINICAL RELEVANCE OF THYROID STIMULATING ANTIBODIES IN HASHIMOTO’S THYROIDITIS AND ASSOCIATED ORBITOPATHY G.J. Kahaly, J. Glang, M. Kanitz, T. Diana Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany Thyroid-associated orbitopathy (TAO) rarely occurs in patients with Hashimotos’ thyroiditis (HT). Since TSH receptor (TSHR) stimulating autoantibodies (TSAb) play a putative role in the pathogenesis of TAO, we looked for the presence of TSAb in HT patients with and without TAO. TSAb was measured with a FDA-cleared bioassay that utilizes Chinese Hamster Ovary cells expressing a chimeric TSHR and a cAMP response element-dependent luciferase. All samples were diluted 1:11 in reaction buffer. Results of TSAb activity were reported as percentage of specimen-to-reference ratio (SRR %, cut-off >140%). A total of 1339 serum samples were collected from 706 HT patients with either overt TAO (n = 38/706, 5.4%, 33 female, mean age – SD 46 – 15.7 years) or without TAO (n = 668, 94.6%, 555 female, 35.2 – 18.3 years), as well as from 302 euthyroid healthy donors (155 female, 28 – 8 years). All controls were TSAb negative (SRR% 53 – 16). Compared to patients with HT only (SRR% 67 – 73.2), serum TSAb levels were markedly higher in HT + TAO (243.5 – 189.7, p < 0.001). TSAb were present in 83/121 (68.6%) and 90/1137 (7.9%, p < 0.001) serum samples of HT + TAO and HT patients, respectively. Serum TSAb titers highly correlated with both clinical activity and clinical severity of TAO (p < 0.001). Even TAO patients specifically treated with immunosuppressive drugs had markedly higher TSAb values compared to those with HT only (SRR% 222 – 185.2 vs. 63 – 66, p < 0.001). In smokers, serum TSAb levels were strongly higher in HT + TAO samples (205 – 152.7) versus HT only (72.6 – 96.6, p < 0.001). Serum TSAb levels were also higher (357 – 192) in hypothyroid (baseline serum TSH 37.12 – 43.1 mU/L) patients with HT + TAO compared to patients with HT only (105 – 111.5, p = 0.006). Finally, in samples with combined HT + TAO, serum TSAb titers correlated highly (r = 0.7, p < 0.001) with

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serum thyroid binding inhibitory immunoglobulins (TBII, automated binding ECLIA assay). Serum TSAb are highly prevalent in HT patients with overt TAO and, as with Graves’ disease, TSAb may be relevant in the pathophysiology of the associated orbital involvement.

Oral 69 Autoimmunity Tuesday Oral Clinical 10:15 AM THE NATURAL HISTORY OF SUBCLINICAL HYPERTHYROIDISM DUE TO GRAVES’ DISEASE - THE RULE OF THIRDS S. Zhyzhneuskaya1,2, C. Addison1, J. Weaver1,2, V. Tsatlidis1, S. Razvi1,2 1 Department of Endocrinology, Queen Elizabeth Hospital, Gateshead, United Kingdom; 2Newcastle University, Newcastleupon-Tyne, United Kingdom There is little information regarding the natural history of subclinical hyperthyroidism (SH) due to Graves’ disease (GD). The objectives of this study were to assess the natural course of individuals with SH due to GD over a prolonged period. We also investigated the factors contributing to the progression or remission in these patients. A prospective analysis of patients with SH due to GD between 2002 and 2013 who had at least 12 months of follow-up was performed. SH was diagnosed if serum TSH was below the laboratory reference range (0.4–4.0 mU/L) and when free thyroid hormones were normal. GD was confirmed by either a raised TSH receptor antibody level (TRAb) or uniform uptake on Technetium scan. Data regarding demographics, clinical and biochemical parameters were also collected. Forty four patients (89% female, 16% current smokers and 5% with active Graves’ orbitopathy) were diagnosed with SH due to GD. Over the follow-up period (mean 30 months), approximately one third (34%) of the cohort progressed to overt hyperthyroidism, one third (34%) normalised their thyroid function, slightly less than one third (30%) remained in the SH state while one person became hypothyroid. Multivariate Cox regression analysis showed that age had a positive association with risk of progression to overt hyperthyroidism: for each increase in age by a year HR of 1.04 (95% CI 1.00–1.08)], independent of other risk factors including current smoking, TRAb levels at diagnosis or gender. This study has shown for the first time to our knowledge - that a third each of patients with SH due to GD progress, normalise or remain in the SH state. Older people have a higher risk of progression of the disease. This seminal data needs to be verified and confirmed in larger cohorts and over longer period of follow-up.

Oral 70 Disorders of Thyroid Function Tuesday Oral Clinical 10:30 AM EFFECTS OF LEVOTHYROXINE THERAPY ON PREGNANCY OUTCOMES IN WOMEN WITH SUBCLINICAL HYPOTHYROIDISM S. Maraka1,2, N. Singh Ospina1,2, D.T. O’Keeffe1, A. Espinosa De Ycaza1, R. Rodriguez Gutierrez2, V. Montori1,2, C. Coddington3, M. Stan1 1 Division of Endocrinology, Mayo Clinic, Rochester, MN; 2 Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, MN; 3Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN Subclinical hypothyroidism (SCH) has been associated with an increased risk of adverse pregnancy outcomes in some, but not all, studies. Uncertainty remains regarding the impact of levothyroxine (LT4) therapy on improving health outcomes in pregnant women

with SCH. Our aim was to assess the potential benefits of LT4 therapy in pregnant women with SCH. We retrospectively reviewed the electronic medical records of women evaluated at Mayo Clinic, Rochester, from January 2011 to December 2013, who met the criteria for SCH during pregnancy (TSH > 2.5 mIU/L for 1st trimester or > 3 mIU/L for 2nd and 3rd trimester but £ 10 mIU/L). Women were divided into two groups: group A women had been started on LT4, whereas group B had not. Women were followed until pregnancy loss or post-partum visit. We excluded subjects with twin pregnancy or use of medications affecting thyroid function. We compared the rate of pregnancy loss (primary outcome) and other prespecified adverse outcomes between group A and group B. There were 79 women in group A and 285 in group B. The groups were not different regarding age, history of pregnancy loss or smoking status. Group A had higher body mass index compared to group B (p = 0.02) and higher TSH level (p < 0.0001).There was a clinically but not statistically significant decrease in pregnancy loss in group A (5.1%) vs. group B (8.8%). There was a significant decrease in frequency of low birth weight ( < 2500g) in group A vs. group B (1.3% vs. 10% p = 0.02) and Apgar score £ 7 at 5 min (0% vs. 6.9% p = 0.02). There was no significant difference between the two groups among the other 11 maternal and neonatal outcomes (Table 1). This is the largest cohort reporting pregnancy outcomes of women with SCH who were treated with LT4 therapy compared to those who remained untreated. Our study found an association of LT4 therapy with decrease in low birth weight and low Apgar score, however no difference in pregnancy loss and other maternal and neonatal outcomes. This association awaits confirmation in randomized trials before the widespread use of LT4 therapy in pregnant women with SCH.

Oral 71 Disorders of Thyroid Function Tuesday Oral Clinical 10:45 AM THYROID HORMONE LEVELS IN NORMAL PREGNANT WOMEN: THE INFLUENCE OF BODY MASS INDEX L. Mosso1, A. Martinez1, G. Latorre2, C. Campusano1 1 Endocrinology, Pontificia Universidad Catolica De Chile, Santiago, Chile; 2Medicine, Pontificia Universidad Catolica Chile, Santiago, Chile

TUESDAY, OCTOBER 20, 2015

Thyroid hormone levels are related to BMI but it is not included as a variable in the determination of normal TSH in pregnancy. Our aim was to evaluate relationship between thyroid function and BMI in pregnant population in order to define TSH reference values. We also explore obstetric and neonatal outcomes. We included healthy pregnant women. TSH, total T4, free T4 (fT4) and anti-thyroid peroxidase antibodies (TPOAb) were measured. Normal reference population included normal weight patients without TPOAb, TSH < 10 lUI/mL and TSH, total T4 or fT4 mathematical outliers. Subclinical hypothyroidism was defined as FT4 within normal range and TSH over percentile 97.5 and under 10 lUI/ mL. Hypothyroidism was define as FT4 below the normal range with TSH < 10 lUI/mL or TSH > 10. The cohort was followed until delivery. All patients with TSH over the laboratory normal values (4.2 lUI/ml) or FT4 below the normal range were treated. We included 720 pregnant women. Mean age was 25.4 y (CI 95%; 25.0–25.9), gestational age 8.8 weeks (CI 95%; 8.6–8.9), mean BMI 26.3 (CI 95%; 25.9–26.7). 220 were overweight (30.6%) 145 were obese (20.1%). 73 had positive TPOAb (10.1%). Median TSH increased and fT4 decreased according to BMI (Figure). 270 subjects meets our normal reference population criteria: TSH 1.88 lUI/mL (0.05–5.63), T4: 9.6 ug/dl (6.88–14.22), freeT4: 1.15 ng/dl (0.91–1.57). We found 1,4% of overt and a 3.3% of subclinical hypothyroidism respectively. If we had using TSH 2.5 uUI/ml as higher normal value, the prevalence would have reached 37.6%. Preterm delivery (22.7 vs 5.7%), newborn obstetrical complication (8.7 vs 1.4%) or newborn disease (21.7 vs 9.5 %) were significantly correlated to subclinical hypothyroidism but not to treated clinical hypothyroidism. We found that TSH increases and fT4 decreases according to the increase in BMI. We propose a new TSH reference range for first trimester excluding abnormal BMI, which is higher than the internationally proposed value. We confirm that treated hypothyroidism and hypothyroxinemia has no obstetrical and neonatal complication but untreated subclinical hypothyroidism was correlated to important complications.

Oral 72 Thyroid Cancer Tuesday Oral Clinical 9:45 AM OUTCOMES IN RESPONSE TO AGGRESSIVE MULTIMODAL THERAPY IN ANAPLASTIC THYROID CANCER: THE MAYO CLINIC EXPERIENCE A. Kumar6, N. Prasongsook1, J. Kasperbauer4, R.C. Smallridge5, J.R. Molina2, J. Morris6, I. Hay6, G. Thompson4, C. Grant4, M. Richards4, V. Fatourechi6, B. McIver3, V.J. Suman9, L. Ricardo10, T. Sebo7, R. Foote8, K.C. Bible2 1 Phramongkutklao Hospital, Bangkok, Thailand; 2Division of Medical Oncology, Mayo Clinic, Rochester, MN; 3Moffitt Cancer Center, Tampa, FL; 4Department of Surgery, Mayo Clinic, Rochester, MN; 5Division of Endocrinology, Mayo Clinic, Jacksonville, FL; 6Division of Endocrinology, Mayo Clinic, Rochester, MN; 7 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; 8Department of Radiation Oncology, Mayo Clinic, Rochester, MN; 9Department of Health Sciences Research, Mayo Clinic, Rochester, MN; 10Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI

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Historical outcomes in anaplastic thyroid carcinoma (ATC) are dire; median overall survival (OS) is *5 months. However, we observed apparently improved survival in association with aggressive multimodal therapy in a small series of ATC patients with locoregionallyconfined disease; median Kaplan Meier (KM) OS in our pilot series was 60 months; 1 and 2 year KM OS was 70% and 60% respectively. We now report outcomes in an expanded series of 29 ATC patients treated with aggressive multimodal therapy regardless of stage. In this IRB-approved study, we reviewed the records of all ATC patients evaluated at Mayo Clinic Rochester between January 2003 and May 2015. Of 56 unique patients (pathologically confirmed ATC), 3 (5%) were excluded (1 due to active therapy, 2 due to refusal for record review). The 29 patients (52%) deemed suitable for, and who elected, aggressive multimodality therapy not participating in therapeutic clinical trials were included in this intention-to-treat analysis. Median age was 60 years (72% males); 2 patients were stage IVA (7%), 20 IVB (69%) and 7 IVC (24%) at diagnosis. Surgery was undertaken in 93%; R0 (no residual tumor) and R1 (microscopic residual tumor) resection was achieved in 24% and 52% patients respectively. All patients received chemotherapy: 24 (83%) taxanes, 19 (66%) docetaxel/doxorubicin (our standard of care, administered if deemed tolerable). All patients received definitive-intention locoregional radiation (median: 66 Gy, Range: 46–70 Gy; median fractions = 33); 24 (83%) completed, while 5 (17%) did not complete treatment [due to toxicity (4) or death (1)]. Ten patients (34%) are still alive [median follow up 24.5 months (range- 6.8 months- 8.5 years)]. Median KM OS was 22.4 months. One, 3 and 5 year KM OS was 61, 48 and 43%. Death was attributed to distant metastases in 14 (74%) or to both distant and locoregional disease in 2 (10%). OS was not significantly different by AJCC stage (P = 0.07), extent of surgery (p = 0.81) or age above or below 60 years (P = 0.36). Although limited by a small number of patients, our experience suggests that aggressive multimodality therapy has potential to result in longer-term survival in ATC patients, especially in lower stage disease.

Oral 73 Thyroid Cancer Tuesday Oral Clinical 10:00 AM CABOZANTINIB IN PATIENTS WITH RADIOIODINEREFRACTORY DIFFERENTIATED THYROID CANCER WHO PROGRESSED ON PRIOR VEGFR-TARGETED THERAPY: RESULTS OF NCI- AND ITOG-SPONSORED MULTICENTER PHASE II CLINICAL TRIAL M.H. Shah1, J. de souza2, L. Wirth3, M.E. Menefee4, S. Liu5, S. Geyer6, J. Wright7, M. Villalona1, M. Cabanillas8 1 Division of Medical Oncology, The Ohio State University, Columbus, OH; 2University of Chicago, Chicago, IL; 3Mass General Hospital, Boston, MA; 4Mayo Clinic, Jacksonville, FL; 5Georgetown

A-32 University, Washington, DC; 6University of South Florida, Tampa, FL; 7National Cancer Institute, Bethesda, MD; 8The University of Texas M. D. Anderson Cancer Center, Houston, TX Sorafenib and lenvatinib are oral multikinase inhibitors (MKI) targeting VEGFR and approved for radioiodine (RAI) refractory advanced differentiated thyroid cancer (DTC) in a first line setting. However, there are no approved 2nd or 3rd line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral MKI targeting MET and VEGFR that is approved for progressive medullary thyroid cancer. In a phase 1 study of cabozantinib, 5 of 8 DTC patients treated with one prior MKI targeting VEGFR had an objective response. RAI-refractory DTC pts with measurable disease who had evidence of RECIST progression on one or two VEGFR targeted therapy were enrolled on this study. Cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient failed to achieve a response. Subjects underwent tumor assessments by RECIST v1.1 every 8 weeks. Study required a maximum of 25 response-evaluable patients, defined as those who received at least one dose of cabozantinib, and had at least 90% power to reject the null hypothesis if the true objective response was at least 30% and a Type I error constraint of 0.10. Under this design, if at least 5 patients had an objective response, we would consider that cabozantinib is a promising agent in this patient population. In this National Cancer Institute- and International Thyroid Oncology Group-sponsored multicenter trial, 25 patients were enrolled. The median age was 64 years and 64% were men. Twenty patients had one line and five patients had two lines of prior VEGFR targeted therapies. The most common prior VEGFR targeted therapies were sorafenib (52%) and pazopanib (28%). The most common related adverse events were fatigue, hand-foot skin reaction, anorexia, nausea, mucositis, weight loss, diarrhea, and hypertension. Of the 25 patients, 9 (36%; 95% CI: 18% to 57%) had confirmed partial response, 13 (52%) had stable disease, and 1 (4%) had progressive disease as best response to therapy. The median progression-free survival was 12.9 months. Cabozantinib demonstrated clinically- and statistically-significant activity in DTC patients who have progressed on prior VEGFR targeted therapies.

TUESDAY, OCTOBER 20, 2015

Oral 74 Thyroid Cancer Tuesday Oral Clinical 10:15 AM RECENT CHANGES IN THE CLINICAL OUTCOME OF PAPILLARY THYROID CARCINOMA WITH CERVICAL LYMPH NODE METASTASIS M. Jeon1, W. Kim1, Y. Choi1, H. Kwon1, D. Song2, Y. Lee3, T. Sung3, J. Yoon3, S. Hong3, J. Baek4, J. Lee4, J. Ryu5, T. Kim1, Y. Shong1, K. Chung3, W. Kim1 1 Internal Medicine, Asan Medical Center, Seoul, Korea (the Republic of); 2Pathology, Asan Medical Center, Seoul, Korea (the Republic of); 3Surgery, Asan Medical Center, Seoul, Korea (the Republic of); 4Radiology, Asan Medical Center, Seoul, Korea (the Republic of); 5Nuclear Medicine, Asan Medical Center, Seoul, Korea (the Republic of) The prognosis of papillary thyroid cancer (PTC) with cervical lymph node (LN) metastasis has changed with increased detection of subclinical metastatic LNs. The number and size of metastatic LNs were proposed as new prognostic factors in PTC with cervical LN metastasis (N1). The aim of study is to evaluate changes in N1 PTC characteristics and clinical outcome over time and to confirm the prognostic value of the number and size of metastatic LNs. This study included 1,815 N1 PTC patients diagnosed between 1997 and 2011. Patients were classified into three risk groups according to the number and size of metastatic LNs: very low risk, £5 and 5. Metastatic LNs became smaller and the ratio of metastatic LNs, which represents the extent of LN involvement and the completeness of surgery, decreased significantly over time. The proportion of patients with excellent response significantly increased from 33% to 67% over time (P < .001). These improvements were more evident in the low- and high-risk groups than in the very low-risk group. The DFS 5 years after initial surgery was also significantly increased from 73% to 91% over time (P < .001). The new LN classification was strongly associated with outcome. Patients in the very low-risk group had longer DFS than those in the low- and high-risk groups during the study period. The clinical outcome of N1 PTC has significantly improved over time with decreased extent of LN involvement, improved diagnostics and more complete surgical neck dissection. The number and size of metastatic LNs are important prognostic factors of recurrence in N1 PTC.

Oral 75

Waterfall plot for Best Response.

Thyroid Nodules & Goiter Tuesday Oral 10:30 AM LONG-TERM OUTCOME OF LOCALIZED THYROID MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA: RETROSPECTIVE ANALYSIS OF 106 CONSECUTIVE CASES N. Watanabe, J.Y. Noh, A. Yoshihara, K. Iwaku, Y. Kunii, M. Matsumoto, M. Suzuki, N. Suzuki, K. Endo, R. Suzuki, N. Hattori, H. Ohye, K. Mukasa, K. Ito Ito Hospital, Tokyo, Japan

TUESDAY, OCTOBER 20, 2015 This study was conducted to evaluate the long-term outcomes in patients with stage IE and IIE thyroid mucosa-associated lymphoid tissue (MALT) lymphoma. Between 1990 and 2009, 106 patients were diagnosed as stage I (n = 43) and II (n = 63) thyroid MALT lymphoma at Ito Hospital, and were retrospectively analyzed. The median age of patients was 68 years (range, 28–88 years) with a female predominance (4:1). Except for one (1%) patient whose treatment was unknown, 55 (52%) patients received radiation therapy (RT) alone with a median dose of 40 Gy (range, 30–50 Gy) and 49 (46%) received chemotherapy and RT with a median dose of 36 Gy (range, 21–45 Gy) (combined modality therapy: CMT), one (1%) patient received chemotherapy alone. The median follow-up time was 7.6 years (range, 0.1–24 years). Complete/partial response was noted in 105 (99%) patients. The 10-year event-free survival rate was 89%, the overall survival rate was 90%, and the cause-specific survival rate was 99%. These 10year survival rates were not significantly different between the patients with RT alone and CMT. Among those patients who achieved complete/ partial response, 3 patients (3%) developed disease recurrence, chiefly in distant site (n = 1) or contra-lateral-thyroid lobe (n = 2). At the time of disease recurrence, one patient had transformed to diffuse large B-cell lymphoma. One patient died of lymphoma. Stage, elevated lactate dehydrogenase, soluble interleukin-2 receptor, or autoimmune disease did not influence the prognosis. Patients with localized thyroid MALT lymphomas showed excellent clinical outcome. Despite disease recurrence, the disease often maintained an indolent course and the overall survival remains favorable in these patients.

Oral 76 Thyroid Cancer Tuesday Oral Clinical 10:45 AM TREATMENT OF CHILDHOOD AND ADOLESCENT THYROID CANCER IN FUKUSHIMA AFTER FUKUSHIMA DAIICHI NUCLEAR POWER PLANT ACCIDENT ON MARCH 11, 2011 S. Suzuki1, I. Nakamura1, T. Fukushima1, C. Ookouchi1, K. Nakano1, S. Suzuki1, S. Suzuki1, H. Shimura2, H. Mizunuma1, S. Takenoshita3, S. Yamashita4 1 Fukushima Medical University School of Medicine, Fukushima Medical University, Fukushima, Japan; 2Department of Laboratory Medicine, Fukushima Medical University School of Medicine, Fukushima, Japan; 3Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan; 4 Radiation Medical Science Center for the Fukushima Health Management Survey, Fukushima Medical University, Fukushima, Japan After the Fukushima Daiichi Nuclear Power Plant accident that followed the Great East Japan Earthquake and Tsunami on March 11, 2011, residents in Fukushima Prefecture faced the problem of low-dose radiation exposure-caused health effects. Therefore, thyroid ultrasound examinations were as started in the same year for people aged 18 years or younger at the time of the disaster. Thyroid cancer cases were diagnosed by fine needle aspiration cytology (FNAC). We report this cancer, which was without clinical symptoms and found by large scale and sophisticated ultrasound screening, in comparison to childhood thyroid cancer with clinical symptoms reported before the disaster. In the preliminary baseline survey, 299,543 subjects (participation rate: 81.5%) were screened by March 31, 2015. Among them, 2,279 subjects were recommended to undergo a second screening, in which 112 subjects were diagnosed with malignancy or suspected of malignancy by FNAC following precise ultrasound examination. A second survey was completed by 148,027 subjects (participation rate: 67.5%), among whom 15 were also diagnosed with malignancy by FNAC.

A-33 Among the 127 subjects with malignancy or suspected malignancy, 104 underwent surgery, and in which one benign nodule and 103 thyroid cancers were confirmed. Twelve subjects are still waiting for surgical treatment and eleven others selected nonsurgical observation. Of the 103 thyroid cancer cases, 97 underwent surgery at our department, on which we report for clinicopathological study after surgical treatment. Among them, 94 papillary thyroid carcinomas and three poorly differentiated thyroid carcinomas were confirmed postoperatively. Mean age at diagnosis was 17.4 years, and mean tumor size was 15 mm. Postoperative lymph node metastasis, extrathyroidal invasion, and pulmonary metastasis were positive in 73, 38 and two cases, respectively. Total thyroidectomy was performed in only six cases. Thyroid microcarcinoma was detected in 29 cases. There were no postoperative complications. Causes of these thyroid cancers might not be associated with the radiation exposure from the Fukushima nuclear accident.

Short Oral Communication 77 Autoimmunity Tuesday Short Oral Communication Clinical 1:00 PM ASSOCIATIONS OF POLYMORPHISMS IN GENE ENCODING PRI-MIR-125A AND THE MATURE MIR-125A EXPRESSION WITH THE PROGNOSIS OF AUTOIMMUNE THYROID DISEASES M. WATANABE1, Y. Inoue1, N. Inoue1, T. Kagawa1, S. Shibutani1, H. Otsu1, M. Saeki1, Y. Takuse1, Y. Hidaka2, Y. Iwatani1 1 Department of Biomedical Informatics, Osaka University Graduate School of Medicine, Suita, Japan; 2Department of Laboratory Medicine, Osaka University Graduate School of Medicine, Suita, Japan It is important to search the biomarker to predict the development and prognosis of autoimmune thyroid diseases, such as Hashimoto’s disease and Graves’ disease. MicroRNA (miR) directly bind to the 3’ untranslated region of specific target mRNAs to suppress the expression of proteins, promote the degradation of target mRNAs and regulate immune response. miR-125a is known to be a negative regulator of RANTES, IL-6 and TGF-b, however, its association with autoimmune thyroid diseases remains unknown. To clarify the association between autoimmune thyroid diseases and miR-125a, we genotyped the rs12976445 C/T, rs10404453 A/G and rs12975333 G/T polymorphisms in the MIR125A gene, which encodes miR-125a, using direct sequencing and PCR-RFLP methods in 155 patients with Graves’ disease, 151 patients with Hashimoto’s disease and 118 healthy volunteers. We also examined the expression of miR-125a in peripheral blood mnonuclear cells from 55 patients with Graves’ disease, 79 patients with Hashimoto’s disease and 38 healthy volunteers using quantitative real-time PCR methods.

PBMC miR-125a expression in study groups. The PBMC miR125a expression level in patients with AITDs and control subjects (A), with different prognoses of GD (B) and HD (C). A Student’s ttest was used to compare the expression level of miR-125a between two groups and Dunnett’s test was used between three groups.

A-34 We determined that the CC genotype and C allele of the rs12976445 C/T polymorphism were significantly more frequent in patients with Hashimoto’s disease compared with control subjects (p < 0.05) and in intractable Graves’ disease compared with Graves’ disease in remission (p < 0.05). The expression of miR-125a was negatively correlated with age (p = 0.0010) and downregulated in patients with Graves’ disease compared with control subjects (p = 0.0249). MiR-125a expression in peripheral blood mnonuclear cells and the rs12976445 C/T polymorphism were associated with development and prognosis of autoimmune thyroid diseases. The expression of miR-125a was negatively correlated with age.

Short Oral Communication 78 Autoimmunity Tuesday Short Oral Communication Clinical 1:06 PM CXCL10, CXCL9, AND CXCL11 a-CHEMOKINES CIRCULATING LEVELS ARE INCREASED IN GRAVES’ OPHTHALMOPATHY PATIENTS, AND REDUCED BY CORTICOSTEROIDS TREATMENT S. Ferrari, P. Fallahi, U. Politti, I. Ruffilli, A. Antonelli Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy CXC a-chemokines CXCL10, CXCL9 and CXCL11 play an important role in the initial phases of Graves’ ophthalmopathy (GO). Orbital cells in primary culture produce large amounts of CXCL10, CXCL9 and CXCL11 when stimulated by IFNc and TNFa. Serum CXCL10, CXCL9 and CXCL11 were measured in 60 consecutive patients with Graves’ disease (GD), 60 age- and sexmatched patients with GO (with active or inactive GO after reaching euthyroidism), 60 controls. In GO patients treated with corticosteroids serum CXCL10, CXCL9 and CXCL11 were measured also at the end of the treatment. Serum CXCL10, CXCL9 and CXCL11 were higher (p < 0.0001) in GD and GO than in age- and sex-matched euthyroid controls. Among GO patients, serum CXCL10 were significantly higher in those with active disease than with inactive disease (p < 0.003). In GO patients treated with corticosteroids serum CXCL10, CXCL9 and CXCL11 decreased significantly at the end of the treatment (p < 0.01), reaching near normal values; the decrease was higher in patients with a better clinical response to treatment (p < 0.05). We conclude that in Graves’ ophthalmopathy serum CXCL10, CXCL9, and CXCL11 are higher in the active phase of the disease, and are useful in monitoring the effect of corticosteroids therapy.

Short Oral Communication 79 Autoimmunity Tuesday Short Oral Communication Clinical 1:12 PM GLUCOCORTICOID RECEPTOR, NF-KB, AND AP-1 EXPRESSION IN ORBITAL FAT AND EXTRAOCULAR MUSCLE IN PATIENTS WITH GRAVES’ ORBITOPATHY A.N. Cury1, I.L. Romero-Kusabara2, M.R. Melo3, N.M. Scalissi1, J. Vital2, K.C. Melo3, G. Demartino3, C.A. Longui3 1 Medicine - Endocrinology, Santa Casa Medical Faculty, Sao Paulo, Brazil; 2Department of Ophthalmology, Santa Casa of Sa˜o Paulo, Sa˜o Paulo, Brazil; 3Molecular Medicine Laboratory, Santa Casa of Sa˜o Paulo, Sa˜o Paulo, Brazil Graves’ orbitopathy (GO) is an organ-specific autoimmune disease, characterized by increased extraocular musculature and adipose tissue. GO is caused by inflammation in the orbital tissues and fibroblast proliferation secondary to abnormal cellular autoimmune responses and

TUESDAY, OCTOBER 20, 2015 excessive IL-1, IL-6, IL-8, interferon-c, and TNF-a. There are phenotypic and functional differences between fibroblasts and fat of the orbit. Thus, based on the inflammation profile, orbital disease is categorized as having a muscle or fat predominance. Therefore, other immune factors should be involved, such as glucocorticoid receptors (GRs), nuclear transcription factor-kB (NF-kB), inhibitor of kB (IjB), inhibitor of kappaB kinase (IKK), and activator protein-1 (AP-1), which mediate proinflammatory responses, cell growth and proliferation. A prospective study of 34 patients and 38 healthy controls. GO individuals with CAS £ 2 were subdivided into subtype 1-predominantly lipogenic and subtype 2-predominantly myogenic. Orbital fat (OF) was harvested from 33 patients during surgical decompression and 27 controls. Extraocular muscle (EOM) biopsy was obtained from 32 patients with GO and 18 controls. Samples were examined by real-time PCR for mRNA expression of IKK1, IjB, c-Fos (AP-1), NF-kB, and 11b-HSD1. The GRa were higher in GO patients [median 213 (96-376)] vs control muscle [78 (34-138)] (p < 0.001), as was NF-kB expression in muscle [223 (31-520)] vs control [8 (6-31)] (p < 0.001).The 11b-HSD1 expression was higher in EOM vs control EOM [0.78 (0.47-2.01) and 0.22 (0.09-0.51), respectively] (p < 0.001). IKK1 [115 (20-223)], IjB [111 (54-299)], and c-Fos [0,11 (0,03-0,19)] levels rose in EOM compared with controls [5.8 (2-13), 21 (5-52), and 0.05 (0.001-0.03), respectively] (p < 0.001). However, in OF samples, GRa, IKK1, IjB, c-Fos (AP-1), NF-kB and 11b-HSD1 mRNA levels were similar between groups. NF-kB is disproportionally elevated compared with GRa, indicative of local persistent proinflammatory profile. The expression of GR and 11b-HSD1 rises, but NF-jB activation predominates. A chronic inflammation of the orbit may be involved in role of new onset GO after radioiodine or active GO in moments that was expected to be a calm, fibrotic, phase.

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Short Oral Communication 80

Vitamin-D supplementation in AITD may have a beneficial effect on autoimmunity as evidence by significant reductions in TPO-Ab titers.

Autoimmunity Tuesday Short Oral Communication Clinical 1:18 PM VITAMIN-D SUPPLEMENTATION REDUCES THYROID PEROXIDASE ANTIBODY LEVELS IN PATIENTS WITH AUTOIMMUNE THYROID DISEASE: AN OPEN LABELED RANDOMIZED CONTROLLED TRIAL S. chaudhary1, M. Kumar1, D. Dutta2, S.A. Mondal3, S. Chowdhury1, S. Mukhopadhyay1 1 ENDOCRINOLOGY, IPGME&R, Kolkata, India; 2 ENDOCRINOLOGY, Post Graduate Institute of Medical Education & Research & Dr. Ram Manohar Lohia Hospital, New Delhi, India; 3 Biochemistry, IPGME&R, Kolkata, India Although vitamin-D deficiency has been linked to autoimmune thyroid disorders (AITD), the impact of vitamin-D supplementation on thyroid autoimmunity is not known. This study aimed to evaluate impact of vitamin-D supplementation on thyroid autoimmunity (thyroid peroxidase antibody [TPO-Ab] titers) in patients with newly diagnosed AITD in a randomized controlled trial (RCT). 100 patients with newly diagnosed AITD (TPO-Ab > 34kIU/L and/ or sonographic evidence of thyroiditis), selected from 981 screened patients, were randomized into GROUP-1(intervention group) and GROUP-2 (control group). Group-1 received cholecalciferol 60,000 IU weekly and calcium 500mg/day for 8 weeks; GROUP-2 received calcium 500mg/day for 8 weeks. Responders were defined as ‡ 25% fall in TPO-Ab titers. Individuals with at least 3-months follow-up were analyzed. Serum 25OHD was estimated using radioimmunoassay (RIA) (Diasorin, MN; analytical sensitivity 4ng/ml;range 5-100ng/ml; intra-assay and inter-assayCV 4.5% and 11.3% respectively). Estimation of fT4, TSH, TPOAB and i-PTH were performed using CLIA (Immulite-1000, Gwynedd,UK). The trial was registered with the Clinical Trial Registry of India (CTRI/2015/04/005713). AITD patients (n = 100) (68 with TSH £ 10mIU/L,38 with TSH >10mIU/L), with 93% having vitamin-D insufficiency were analyzed. TPO-Ab titers were highest among patients in lowest quartile of 25 hydroxy-vitamin-D (P = 0.084). At 3 months follow-up, there was significant fall in TPOAb in Group-1 ( - 46.73%) as compared to Group-2 ( - 16.6%) (P = 0.028). Sixty-eight percent patients in Group-1 were responders compared to 44% in Group-2 (P = 0.015). Sub-group analysis revealed significantly greater reduction in TPO-Ab titers in subclinical hypothyroidism, but not in overt primary hypothyroidism. Cox-regression revealed vitamin-D supplementation (Group-1) followed by baseline TPO-Ab and fT4 levels to be good predictor of response to therapy (P = 0.042, 0.069 and 0.074 respectively).

Short Oral Communication 81 Autoimmunity Tuesday Short Oral Communication Clinical 1:24 PM SYSTEMATIC ASSESSMENT OF NONENDOCRINE AUTOIMMUNE DISORDERS IN A LARGE COHORT OF CONSECUTIVE PATIENTS WITH AUTOIMMUNE THYROIDITIS C. Virili1, M. Santaguida1, S. Capriello1, M. Cellini2, N. Brusca2, L. Gargano2, M. Centanni1,2 1 Medico-surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; 2Endocrine Unit, AUSL Latina, Latina, Italy The association of autoimmune thyroiditis (AIT) with nonendocrine autoimmune disorders (NEAD) has been classified as a variant of type 2 polyglandular autoimmune syndrome (PAS2). However, this association is far more frequent than classic PAS 2 and systematic studies on this field are scanty. In a cohort of 9,415 consecutive outpatients, AIT was diagnosed in 2884 (30.6%). If suspected on clinical and/or immunological ground, the presence of further autoimmune disorders was screened on the basis of guidelines for each disease. Histological diagnosis was obtained in all gastroenterological diseases. The association AIT + NEAD was observed in 358 patients (12.8%) (315W/43M; median age = 39 years). Of these, 34 patients (10.5%) had more than one autoimmune disorder associated with AIT. The most frequent associated disease was chronic atrophic gastritis (CAG) (30.4%), followed by nonsegmental vitiligo (19.9%), celiac disease (11,8%), and multiple sclerosis (7.2%). The juvenile form ( < 30 yrs) accounted for 14.5% of the whole sample and was characterized by a high frequence of celiac disease (44.2%) associated with thyroiditis, followed by vitiligo (13.4%), while CAG was less observed (7.7%). Patients with AIT + NEAD showed peculiar clinical features. In fact, thyroxine malabsorption was higher than in patients with isolated thyroid diseases (34.6 vs 8.1%; p < 0.0001; OR = 5.953). Unexplained anemia was also significantly higher in euthyroid patients with AIT + NEAD (23.2 vs 6.8%; p < 0.0001; OR = 4.105) than in euthyroid patients with isolated AIT. Recurrent pregnancy loss was also clearly increased (6.9% vs 1.7%; p < 0.0001; OR = 4.06) in patients with AIT + NEAD as compared with isolated AIT. a) Further autoimmune disorders may be diagnosed in 1/8 patients with AIT and 1/10 of them is younger than 30 years; b) atrophic gastritis, vitiligo and celiac diseases are the most frequent autoimmune disorders associated with AIT, being their prevalence age-related; c) the presence of thyroxine malabsorption, chronic unexplained anemia and recurrent pregnancy loss in patients with AIT warrants to further diagnostic workup for additional autoimmune disorders.

Short Oral Communication 82 Thyroid & Development Tuesday Short Oral Communication Basic 1:00 PM MULTIPLE TRANSDUCTION PATHWAYS MEDIATE TSH RECEPTOR SIGNALING IN BONE A. Boutin, S. Neumann, M. Gershengorn Laboratory of Endocrinology and Receptor Biology, NIH/NIDDK, Bethesda, MD Adult bone constantly undergoes remodeling carried out by boneforming osteoblasts and bone-resorbing osteoclasts. Recently evidence has emerged showing an anti-osteoporotic action of TSH. We

A-36 and others have shown that TSH receptor (TSHR) couples to a number of different signaling pathways in bone although the GscAMP-protein kinase A (PKA) pathway has been considered the primary. Herein we investigated the signaling pathways involved in the bone differentiating effects of TSH. We measured bone marker mRNA and protein expression in pre-osteoblast-like U2OS cells stably over-expressing TSHRs. We determined which signaling cascades are involved in the regulation of interleukin-11 (IL-11), alkaline phosphatase (ALP), and osteopontin (OPN) expression using pathway specific activators and inhibitors and siRNA silencing. We demonstrated that TSH stimulated a rapid upregulation of IL11. IL-11 was upregulated by forskolin (FSK), an adenylylcyclase activator, inhibited by PKA inhibitors H-89 and KT5720, and by silencing of Gas. Therefore, TSH-induced upregulation of IL-11 is mediated via the Gs pathway. On the contrary, FSK-stimulated cAMP production inhibited upregulation of ALP by TSH whereas knockdown of Gas resulted in an increase in the basal level of ALP. Mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors and silencing of extracellular signal-regulated kinases (ERK1/2) demonstrated that ALP upregulation is, at least in part, mediated by ERK1/2. Osteopontin (OPN) levels were not affected by either FSK or PKA inhibitors but its upregulation was inhibited by the p38a MAPK inhibitor LY2228820 and siRNA knockdown of p38a, as well as by TSHR/Gi-uncoupling by pertussis toxin. These observations allowed us to conclude that OPN upregulation by TSH was cAMPindependent and in part mediated by p38a and Gi. We showed that TSH induces expression of differentiated bone markers via several distinct pathways. This knowledge is of particular importance for screening for ligands with biased signaling properties that may lead to the development of a drug to treat osteoporosis.

Short Oral Communication 83 Thyroid & Development Tuesday Short Oral Communication 1:06 PM THE THR92ALA SUBSTITUTION IN COMBINATION WITH LOW-NORMAL THYROID FUNCTION IS ASSOCIATED WITH INCREASED ODDS OF A SUB-OPTIMAL IQ SCORE IN CHILDREN P.N. Taylor1, C. Hales1, A. Sayers2, L. Zhang1, K. Northstone2, D. Shillabeer1, M. Draman1, W. Woltersdorf3, A. Taylor4, E. Pearce5, S. Ring2, S. Channon1, J. Gregory1, J. Lazarus1, A. Rees1, O. Okosieme1, M.E. Ludgate1, G. Davey-Smith2, N. Timpson2, C.M. Dayan1 1 Cardiff University, Cardiff, United Kingdom; 2University of Bristol, Bristol, United Kingdom; 3Amedes MVZ fu¨r Laboratoriumsmedizin, Mikrobiologie und Humangenetik Halle, Leipzig GmbH Leipziger Chaussee, Halle, Germany; 4RUH, Bath, United Kingdom; 5Boston Medical Center, Boston, MA Common genetic variation (Thr92Ala substitution) in deiodonase-2 might predispose individuals with low thyroid hormone levels to adverse outcomes. We explored whether individuals with free thyroxine (FT4) in the lowest quartile and homozygous for the Thr92Ala substitution had higher odds of a lower IQ. We studied 3,043 children who participated in the Avon Longitudinal Study of Parents and Children (ALSPAC) who had full thyroid function measured at age 7, cognitive assessments performed at age 8 and had genetic data available. To assess the effect of in utero exposure to lower thyroid function we also studied a subset of 222 children in the Controlled Antenatal Thyroid Study II (CATS II), with maternal thyroid function measured before 16 weeks gestation, child genotype available and with IQ measured at ages 7-9 years.

TUESDAY, OCTOBER 20, 2015 Low IQ was defined as total IQ < 85. Analyses were adjusted for age, sex, thyroid hormone parameters, markers of social class and early life environment including household cohesion and finances. In ALSPAC children homozygous for Thr92Ala with FT4 in the lowest quartile had higher odds of an IQ < 85 (OR = 2.50 95% CI 1.31, 4.77 p = 0.002) with evidence of interaction between FT4 in the lowest quartile and the Thr92AlaD2 substitution in their relationship with IQ (p = 0.005). In CATS II, children homozygous for Thr92Ala whose mothers had FT4 in the lowest quartile during pregnancy also had increased odds of an IQ < 85 OR = 4.30 (95% CI 0.75, 24.7) p = 0.10 than the rest of the study population. Higher odds ratios were observed at both lower FT4 thresholds and lower IQ scores. Metaanalysis identified that children homozygous for Thr92Ala in combination to exposure to FT4 in the lowest quartile had increased odds of an IQ < 85 OR = 2.69 (95% CI 1.46, 4.89) p = 0.002 than the other children. Common genetic variation in the intracellular thyroid hormone pathway appears to substantially modify the effect of low-normal serum thyroid hormone levels in childhood and pregnancy. These data suggests that targeted thyroid hormone replacement in a genotype dependent manner may improve patient outcomes in borderline hypothyroidism.

Short Oral Communication 84 Thyroid & Development Tuesday Short Oral Communication Clinical 1:12 PM BIRTH DEFECTS, AGRANULOCYTOSIS AND LIVER FAILURE ASSOCIATED WITH THE USE OF ANTITHYROID DRUGS IN THE POPULATION IN GENERAL AND IN PREGNANCY: A DANISH NATIONWIDE STUDY S.L. Andersen1,2, J. Olsen3, P. Laurberg1,4 1 Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 2Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark; 3Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark; 4 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark Methimazole (MMI) and Propylthiouracil (PTU) are both associated with birth defects, and both drugs may also rarely be associated with agranulocytosis and liver failure. However, the frequency of these side effects when antithyroid drugs (ATD) are used in the population in general and in pregnancy remains to be elucidated. All individuals registered as the parent of a live-born child in Denmark, 1973-2008, were identified in nationwide registers (n = 2,299,952; 51% female) and studied from 1995–2010 (median age 34 years 1.1.1995) for the use of ATD and hospital diagnosis of agranulocytosis, liver failure and birth defects. To specifically evaluate the frequency of these side effects associated with the use of ATD in pregnancy, all pregnancies (n = 830,680) leading to birth of a live-born child (n = 848,022), 1996–2008, were identified in a subanalysis. In the general population; 28,998 individuals (82% female) redeemed prescriptions of ATD from 1995–2010 (MMI n = 23,103/ PTU n = 1,717/MMI&PTU n = 4,178): 45 cases (MMI n = 29/PTU n = 16) of agranulocytosis, 10 cases (MMI n = 7/PTU n = 3) of liver failure and 75 cases of birth defects (MMI n = 48/PTU n = 27) associated with the use of ATD were observed. In the general population, birth defects and agranulocytosis were the most common side effects (see Table) and 4 times more frequent than liver failure (44 and 41 vs. 11 cases/5 mill inhab/10 years). In a total of 2,115 pregnancies, the mother redeemed prescriptions of ATD (MMI n = 1,012/ PTU n = 768/MMI&PTU n = 335): one case of ATD associated agranulocytosis (PTU) and one case of liver failure (PTU) were

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A-37 on apoptosis. Porreca et al. (2012) has demonstrated that bcl2l in zebrafish is expressed on thyroid primordium and it is essential for thyroid cell survival, and its expression is modulated by pax2a, nkx2.1a and hhex. No mutations were found in classical genes related to thyroid development (NKX2-1, NKX2-5, FOXE1, PAX8, TSHR, and HHEX), including their paralogs. We first describe two coding variations on BCL2L12 gene in 4/26 thyroid agenesis patients. The mutation p.Arg144* can result on impairment of cell survival towards vanishing thyroid tissue. Other BCL2L12 alterations may affect splice processing, therefore generating non-functional transcripts and contributing to apoptosis of thyroid primordial cells.

observed, and 3.4% of 2,204 exposed children (n = 75) had birth defects associated with maternal use of ATD in the pregnancy. Birth defects were the dominant side effect in pregnancy (see Table) and 75 times more frequent than agranulocytosis and liver failure (44 vs. 0.6 cases/5 mill inhab/10 years). In general, birth defects and agranulocytosis had similar frequencies and were more common than liver failure. For the use of ATD in pregnancy, birth defects were dominant. In the population, the burden of side effects to the use of ATD can be considerably reduced by restricting the use of ATD in the teratogenic period of early pregnancy.

Short Oral Communication 85 Thyroid & Development Tuesday Short Oral Communication Translational 1:18 PM MUTATIONS IN THE ANTI-APOPTOTIC FACTOR BCL2L12 IN PATIENTS WITH THYROID AGENESIS M.M. Kizys1, S. Nesi-Franc¸a2, I.S. Kunii1, G.K. Furuzawa1, M. Mitne-Neto3,4, M.R. Dias-da-Silva1, R.M. Maciel1 1 Medicine, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; 2 Pediatrics, Universidade Federal do Parana, Cuitiba, Brazil; 3Research and Development, Fleury Group, Sao Paulo, Brazil; 4Human Genome and Stem Cell Research Center, Universidade de Sao Paulo, Sao Paulo, Brazil The main causes of Congenital Hypothyroidism (CH) are derived from alterations occurred during thyroid embryogenesis, collectively known as Thyroid Dysgenesis (TD). Agenesis is characterized by complete absence of thyroid gland and comprises up to 40% of TD cases. The use of Whole Exome Sequencing (WES) molecular strategy could contribute to disclose new causative genes related to TD. Objective: To perform WES in patients with agenesis, and after identification of potential genes, to expand the screening to a larger cohort by Sanger sequencing. Total DNA was isolated from peripheral blood samples from 5 sporadic patients with agenesis for WES. We applied SeqCap EZ Human Exome v3 kit and Illumina HiSeq2000 for exon enrichment, capture and sequencing. Mapping, alignment and variant calling were performed using the CLC Genomic Workbench 6.5. Thereafter, a bioinformatics pipeline of coverage, heritage pattern, prediction effect on protein, and minor allele frequency (MAF) for filtering variants were applied accordingly. In 1 out of 5 patients who undergone WES was found a stop codon mutation p.Arg144* on BCL2L12 gene. Searching for mutations on additional 26 patients showed the same mutation in other sporadic case and the missense mutation p.Gly47Val (MAF 0.051) in other 2 cases. Intronic variations were also identified: c.1-61T > C (in 13), c.1-141A > G (1), C.1-154A > G (4) and c.120-77G > C (1). BCL2L12 is a new member of BCL2 gene family, which plays a role

Short Oral Communication 86 Thyroid & Development Tuesday Short Oral Communication Translational 1:24 PM WHOLE EXOME SEQUENCING ANALYSIS OF PATIENTS WITH CONGENITAL HYPOTHYROIDISM DUE TO HYPOPLASIA REVEALS MUTATIONS ON HOXA2 GENE M.M. Kizys1, S. Nesi-Franc¸a2, R. Doto1, M.C. Melo1, I.S. Kunii1, G.K. Furuzawa1, M. Mitne-Neto3,4, M.R. Dias-da-Silva1, R.M. Maciel1 1 Medicine, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; 2 Pediatrics, Universidade Federal do Parana, Curitiba, Brazil; 3Research and Development, Fleury Group, Sao Paulo, Brazil; 4Human Genome and Stem Cell Research Center, Universidade de Sao Paulo, Sao Paulo, Brazil Thyroid Dysgenesis (TD) comprises embryonic alterations along the gland development that may cause Congenital Hypothyroidism (CH). Among TD types, thyroid hypoplasia (TH) is characterized by a topic but diminished tissue. TH occurs in 5% of TD cases. Until now, gene mutations were identified in only 2% besides copy number variations (CNVs) in 8.75% of TD patients. Next Generation Sequencing (NGS) could help clarify TD molecular etiology. Objective: To perform Whole Exome Sequencing (WES) in patients with TH and correlate the findings with in silico functional analysis and clinical phenotype. Through salting-out protocol, peripheral blood DNA was isolated from 3 sporadic TH patients to perform WES. Whole exons were enriched and captured by using SeqCap EZ Human Exome v3 kit, then parallel sequenced by Illumina HiSeq2000 technology. WES findings were sequenced by Sanger Method for confirmation. For alignment, mapping and variant calling, we have used the CLC Genomic Workbench 6.5. Fleury bioinformatics pipeline for coverage, prediction of effect, heritage pattern and minor allele frequency (MAF) £ 0.05 were used. We started WES analysis searching for variations on genes related to thyroid development and their paralogs and receptors. The average of variations found per patient was 813. The majority was located on non-codifying regions such as introns, 5’ and 3’ UTR. After applying subsequent filters, 45 variants were exclusively to TH. Among scrutiny analysis of these variants, we were able to find mutation in 2 out 3 TH patients on HOXA2 gene: p.His286Tyr (new missense mutation) and p.Val327Ile (MAF < 0.01). HOX family genes are involved in palate formation and its disruption leads to alterations on neural crest specification. Knockout models for its paralog Hoxa3, present TH and absence of thymus and parathyroid. An additional TH sporadic cohort is under screening for HOXA2 mutations. No variations were identified on NKX2-1, NKX2-5, TSHR, HHEX, FOXE1 and PAX8 coding regions. Patients with TH presented mutation on HOXA2 coding region. These missense mutations could impair thyroid primordial cells proliferation leading to hypoplasia.

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Short Oral Communication 87 Thyroid Hormone Metabolism & Regulation Tuesday Short Oral Communication Translational 1:00 PM PARADOXICAL D1 ALONG WITH BRAIN-PROTECTIVE D2 EFFECTS OF THYROTOXIC T4 CONCENTRATIONS ON HUMAN THYROID HORMONE REGULATION DYNAMICS J. DiStefano1, R. Shao2, A.P. Chen2, P.R. Larsen3 1 Computer Science and Medicine, UCLA, Los Angeles, CA; 2 Computer Science, UCLA, Los Angeles, CA; 3Medicine, Harvard Medical School, Boston, MA Little is known about how excess T4 affects pathways of T3 production & metabolism when plasma T4 is markedly elevated in humans. Both are secreted in excess in hyperthyroidism & in euthyroid humans *80% of T3 is produced via Types 1 and 2 deiodinases (D1, D2) in roughly equal amounts. In vitro & animal studies show T3 paradoxically induces D1 mRNA & protein in liver, kidney & thyroid, while both T4 & T3 reduce D2 expression in muscle & brain. Under all conditions, circulating T4 & T3 exchange rapidly with liver & kidney (fast) & slowly with muscle & brain etc, complicating the question further. We embedded these mechanistic assumptions into a wellvalidated whole-body dynamic system model of TH regulation & requantified it using T3 & T4 serum response kinetic data over 7 days following 3000 lg oral dosing with T4. The new model has adjusted binding dynamics & augmented positive D1 & negative D2 feedback pathways embedded in fast & slow tissue compartments. It fits the in vivo T4 & T3 serum kinetic data exceptionally well (top left & right graphs). Quantified T3 & T4 inter-compartment exchange rates are altered substantially in the new model (not shown) (10 · T4 to liver, 0.2 · to muscle etc). All support presence of the proposed in vitro mechanisms in vivo, with e.g. more than double T3 production from T4 via D1 in fast & * none in slow compartments. Note the large early spikes in T4 & T3 (top) (with 50% increase in free hormone fractions), & the unusual biphasic serum T3 temporal response - also reflected in the response from simulated fast T3 model compartments (middle right). These are all consistent with a severalfold D1 up-regulation by T3 in liver & kidney - as shown in the simulated D1 response perturbation (middle right inset). The transient fall & then rise in T3 in the slow muscle + brain compartments (bottom right) is accompanied an abrupt D2-down regulation (to *0 T3 production) in muscle & brain due to excess T4. These results show peripheral T3 production in hyperthyroid patients is likely all D1-mediated, accounting for its susceptibility to inhibition by PTU, & further justifying use of PTU in thyroid storm. Simulated 7-day human overt-hyperthyroid T4 and T3 dynamic responses in serum, fast (liver + kidney), slow (muscle, brain + ) and

TUESDAY, OCTOBER 20, 2015 deiodinase D1 compartments in response to 3000 micrograms oral T4. Model fits in vivo serum TH data (top) exceptionally well. Predictions consistent with paradoxically D1-mediated high T3 production.

Short Oral Communication 88 Disorders of Thyroid Function Tuesday Short Oral Communication 1:06 PM IMMUNE THERAPIES TARGETING THE THYROID: NEW INSIGHTS FROM A COMPREHENSIVE REVIEW OF PEMBROLIZUMAB-INDUCED THYROIDITIS CASES AT MAYO CLINIC D. Delivanis1, M.M. Merten1, L. Kottschade2, M. Ryder1 1 Endocrinology, Mayo Clinic Rochester, Rochester, MN; 2 Oncology, Mayo Clinic, Rochester, Rochester, MN Immune checkpoint inhibitors ipilimumab, pembrolizumab and nivolumab induce potent anti-tumor responses and immune-related adverse effects (irAEs). Understanding irAEs is required to improve patient care and to enhance our knowledge of both rare and common autoimmune diseases, such as lymphocytic hypophysitis and Hashimoto’s thyroiditis. The goal of this study was to comprehensively characterize pembrolizumab-induced thyroid dysfunction and examine its potential pathophysiology. We performed a retrospective review of cancer patients receiving pembrolizumab at Mayo Clinic from April 2014 till January 2015. Cases with abnormal thyroid function tests (TFTs) were further examined to determine etiology, incidence and clinical presentation of thyroid disorders. Of 92 patients receiving pembrolizumab (61% male, 39 % female), 13 (14%) developed abnormal TFTs with a median onset of 4 weeks. Of these, 10 (11%) represented new onset acute thyroiditis (n = 6, 2 female) and/or new hypothyroidism (n = 4, 1 female) while 3 (all female) represented recurrent hypothyroidism on thyroid hormone replacement. Nearly all patients (n = 12) received ipilimumab. Anti-thyroid peroxidase antibodies (anti-TPO), available in 10 cases, were elevated in 0 cases of thyroiditis, 2 cases of new onset hypothyroidism and 3 cases of recurrent hypothyroidism. On PET/CT, new thyroid fluorodeoxyglucose (FDG) uptake was identified in 6 of 13 cases with no correlation to anti-TPO status. Resolution of thyroiditis occurred in 2, progressed to hypothyroidism in 3 and was persistent in 1. One new onset hypothyroid patient had spontaneous thyroid function recovery. Combination immune checkpoint blockade enhances the incidence of thyroiditis/hypothyroidism compared to ipilimumab alone. Only 50% of patients developed elevated anti-TPO antibodies, suggesting autoantibody dependent and independent mechanisms. Ongoing studies are underway to better understand its pathophysiology in order to improve clinical care. Paradoxically, this knowledge may be used to induce anti-thyroid responses in patients with therapeutically refractory metastatic differentiated thyroid cancer.

Short Oral Communication 89 Disorders of Thyroid Function Tuesday Short Oral Communication Clinical 1:12 PM AUTOIMMUNE THYROID DISEASES AND THYROID DYSFUNCTION IN HIROSHIMA AND NAGASAKI ATOMIC-BOMB SURVIVORS EXPOSED IN CHILDHOOD M. Imaizumi1,2, W. Ohishi1, E. Nakashima3, N. Sera4, K. Neriishi5, M. Yamada1, Y. Tatsukawa1, I. Takahashi1, S. Fujiwara6, K. Sugino7, T. Ando2, T. Usa8, A. Kawakami2, M. Akahoshi1, A. Hida1 1 Department of Clinical Studies, Radiation Effects Research Foundation, Nagasaki and Hiroshima, Japan; 2Graduate School of

TUESDAY, OCTOBER 20, 2015 Biomedical Sciences, Nagasaki University, Nagasaki, Japan; 3Department of Statistics, Radiation Effects Research Foundation, Hiroshima, Japan; 4Department of Metabolism/Diabetes and Clinical Nutrition, Nagasaki University Hospital, Nagasaki, Japan; 5Yachiyo Hospital, Hiroshima, Japan; 6Hiroshima Atomic Bomb Casualty Council, Hiroshima, Japan; 7Nakajima Tsuchiya Clinic, Hiroshima, Japan; 8International Hibakusha Medical Center, Nagasaki University Hospital, Nagasaki, Japan It is well known that high-dose radiation exposure (several tens of gray) to the thyroid induces hypothyroidism. However, influences of radiation exposure by low to moderate doses on autoimmune thyroid diseases and thyroid dysfunction have been debated. Furthermore, a few studies evaluated radiation dose-response relationships among adults exposed to radiation in childhood when radiation sensitivity is thought to be high. The purpose of this study is to evaluate radiation dose-responses for the prevalences of autoimmune thyroid diseases and thyroid dysfunction in atomic-bomb survivors exposed in childhood. We conducted a survey study comprising 3,087 Hiroshima and Nagasaki atomic-bomb survivors who were younger than 10 years old at exposure. We measured free T4, TSH, anti-TPO antibody, and anti-Tg antibody between October 2007 and October 2011. Data from 2,668 participants (mean age 68.2 years, 1,213 men and 1,455 women) with known atomic-bomb thyroid radiation doses (mean dose 0.182 Gy, median dose 0.018 Gy, and dose range 0–4.040 Gy) were analyzed. The prevalences of positive for anti-TPO and/or anti-Tg antibodies, hypothyroidism, hyperthyroidism were 21.5% (573 cases), 4.8 % (129 cases), and 1.2% (32 cases), respectively. All hyperthyroidism cases were Graves disease. The prevalences of anti-thyroid antibodies positive hypothyroidism and negative hypothyroidism were 2.1% and 2.7%, respectively. In the analyses for radiation doseresponses, no diseases were associated with thyroid radiation dose (P > 0.1). In further analyses using alternative definitions of hypothyroidism and hyperthyroidism, we failed to detect significant doseresponses. Associations between atomic-bomb radiation exposure and autoimmune thyroid diseases and thyroid dysfunction were not found in atomic-bomb survivors more than 60 years after their exposure in childhood.

Short Oral Communication 90 Iodine Uptake & Metabolism Tuesday Short Oral Communication Basic 1:18 PM NF-jB P65 S-NITROSYLATION INHIBITS TSH-INDUCED NA + /I- SYMPORTER EXPRESSION J.P. Nicola1, V. Peyret1, M. Nazar1, J.M. Romero2, A.M. Lucero1, M. Montesinos1, C.G. Pellizas1, A.M. Masini-Repiso1 1 Departamento de Bioquı´mica Clı´nica, Facultad de Ciencias Quı´micas, Universidad Nacional de Co´rdoba, Co´rdoba, Argentina; 2 Departamento de Quı´mica Biolo´gica, Facultad de Ciencias Quı´micas, Universidad Nacional de Co´rdoba, Co´rdoba, Argentina Nitric oxide (NO) is a ubiquitous signaling molecule involved in a wide variety of cellular physiological processes. In thyroid cells, NOsynthase III-endogenously produced NO reduces thyrotropin (TSH)stimulated thyroid specific gene expression, suggesting a potential autocrine role of NO in modulating thyroid function. Further studies indicate that NO induces thyroid dedifferentiation, since NO donors repress TSH-stimulated I- uptake. Here, we investigated the molecular mechanism underlying the NO-inhibited Na + /I- Symporter (NIS)-mediated I- uptake in thyroid cells.

A-39 FRTL-5 cells, a line of highly differentiated rat thyroid-derived cells, were incubated with different NO donors (sodium nitroprusside, S-nitrosoglutathione, Spermine NONOate). NIS function was measured using 125I- transport assays, and NIS expression was evaluated through western blot, RT/qPCR, and gene reporter assays. NIS post-transcriptional modifications were evaluated in FRTL-5 cells stably expressing N-terminal HA-tagged NIS. NO donors reduced I- uptake in a concentration-dependent manner, which correlated with decreased NIS protein expression. NOreduced I- uptake resulted from transcriptional repression of NIS gene rather than post-transcriptional modifications impairing functional NIS expression at the plasma membrane. We observed that NO donors repress TSH-induced NIS gene expression by reducing the NF-jB subunit p65-dependent transcriptional activity rather than affecting Pax8 expression or transcriptional activity. NO-promoted Cys-38 p65 S-nitrosylation reduces p65-mediated transactivation of the NIS promoter in response to TSH stimulation. We demonstrated that exogenous NO-induced p65 S-nitrosylation repressed TSH-stimulated NIS gene transcription, thus leading to a subsequent reduction of NIS-mediated I- uptake in rat thyrocytes. These findings support the participation of NO as an inhibitory signal molecule to counterbalance TSH-stimulated NF-jB activation, thus modulating TSH-induced thyroid specific gene expression.

Short Oral Communication 91 Iodine Uptake & Metabolism Tuesday Short Oral Communication Clinical 1:24 PM THE EFFECT OF IODINE STATUS ON PAPILLARY THYROID CARCINOMA - A META-ANALYSIS J. Lee1, Y. Hwang2, J. Yi3, R. Song3, H. Yu3, J. Jung1, H. Kwon3, S. Kim3, Y. Chai4, J. Choi1, S.K. Park2, K. Lee3 1 Endocrine Surgery, Seoul National University Bundang Hospital, Seongnam, Korea (the Republic of); 2Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea (the Republic of); 3Endocrine Surgery, Seoul National University Hospital, Seoul, Korea (the Republic of); 4Endocrine Surgery, Seoul National University Boramae Medical Center, Seoul, Korea (the Republic of) Previous publications have demonstrated the association between iodine status and papillary thyroid carcinoma (PTC). Although many studies focus on the dietary differences among geographic locations, others compare the iodine status before and after universal salt iodization (USI). This meta-analysis assessed the occurrence of PTC in all comparative studies between high and low iodine exposed groups published after 2000. We searched Pubmed, EMBASE, and Cochrane database, for observational, cross-sectional, and cohort studies evaluating PTC occurrence in high and low iodine exposed groups. Keywords ‘‘Thyroid neoplasm’’, ‘‘Thyroid cancer’’, ‘‘iodine’’ or ‘‘iodide’’ were searched. Studies published after the year 2000 were selected because the increased diagnostic accuracy around that time is believed to better reflect true. Iodine status was dichotomized into high and low exposure groups in all studies according to urinary iodine level, consumption of iodine rich food, geographical location of known iodine status, and pre/post USI status. The odds ratio (OR) with 95% confidence intervals (95% CI) was calculated to synthesize the association. Subgroup analyses were done within studies assessing USI effect and in other studies. Random-effect model was used to interpret the synthetic effect size in all groups. Among the 9279 studies searched from the keywords, 14 were eligible. The PTC occurrence of the high iodine exposure group was associated with a total effect size OR of 1.430 with 95% CI ranging from 1.039 to 1.969. In subgroup analyses, 4 studies which evaluated

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TUESDAY, OCTOBER 20, 2015 the specific TAAR1 antagonist EPPTB was used (5-10 nM). In wild type EC slices exposed to EPPTB (5–10 nM for 10 minutes, starting 5 minutes before the high frequency stimulation), LTP was impaired, and the protective effect produced by T1AM vs Ab toxicity was abolished. Finally the assay of EC homogenates by mass spectrometry coupled to HPLC revealed the presence of endogenous T1AM, whose average concentration was in the pmol/g range. Our results suggest that T1AM plays a neuroprotective effect, rescuing Ab-induced neuronal dysfunction. This effect may implicate the interaction with TAAR1. Further insight into the physiological, pathophysiological or pharmacological role of T1AM and TAAR1 might open new perspectives in the study of AD.

Short Oral Communication 93 Total effect size of 14 selected studies. the effect of USI demonstrated an effect size of 1.664 with 95% CI ranging from 0.836 to 3.232. In the subgroup of 9 studies not dealing with USI, the OR was 1.326 with 95% CI from 0.923 to 1.904. The total effect size demonstrates statistically significant positive relationship between high iodine exposure and PTC occurrence. Subgroup analyses, however were closely shy of statistical significance. The small number of studies may be the reason for the lack of statistical power. Our research demonstrates the positive association between PTC occurrence and iodine status. More studies are required to strengthen the statistical power in subgroup analyses.

Short Oral Communication 92 Thyroid Hormone Action Tuesday Short Oral Communication Translational 1:00 PM 3-IODOTHYRONAMINE EFFECT ON LONG-TERM POTENTIATION: RESCUING b-AMYLOID-INDUCED NEURONAL DYSFUNCTION A. Accorroni1,2, C. Criscuolo3, M. Sabatini1, R. Donzelli1, A. Saba1, N. Origlia3, R. Zucchi1 1 University of Pisa, Pisa, Italy; 2Scuola Superiore S. Anna, Pisa, Italy; 3Institute of Neuroscience, CNR, Pisa, Italy It has been suggested that brain thyroid hormone metabolism may be altered in Alzheimer’s disease (AD), while acute administration of the thyroid hormone derivative 3-iodothyronamine (T1AM) has been shown to stimulate memory acquisition in mouse. Long-term potentiation (LTP) is one of the basic mechanisms of memory. LTP is inhibited by beta-Amyloid oligomers (Ab), and in the early stage of AD it is selectively impaired in the entorhinal cortex (EC). Therefore we investigated if administration of exogenous T1AM has any effect on LTP in EC of wild type mice exposed to Ab and in a transgenic model of AD (hAPP-J20 mouse). Extracellular in vitro recordings were performed in EC slices: field potentials were evoked in layer II after stimulation of the same layer and LTP was elicited by high frequency stimulation, consisting of three trains of 100 pulses at 100 Hz. T1AM (5 lM) was administered for 10 minutes, starting 5 minutes before the delivery of high frequency stimulation. In some experiments, Ab was infused at 200 nM concentration. In wild type EC, T1AM that did not affect either basal synaptic transmission or LTP induction and maintenance. Exposure to Ab inhibited LTP, but T1AM perfusion restored LTP in Ab-treated EC (123 – 10% vs 98 – 6%, P < 0.05). In EC from 2 month-old APP-J20 mice LTP could not be elicited, but it was rescued in the presence of T1AM (120 – 9% vs 90 – 7%, P < 0.05). To evaluate the role of trace amine-associated receptor (TAAR1), the putative T1AM receptor,

Thyroid Hormone Action Tuesday Short Oral Communication Basic 1:06 PM TR SUMOYLATION INFLUENCES PREADIPOCYTE PROLIFERATION VIA G1 PHASE CELL CYCLE REGULATORS Y. Liu, J. Jiang, J. Li, G.A. Brent Medicine, UCLA/VA Healthcare System, Los Angeles, CA In humans, about 10% of adipocytes are replaced each year from differentiated preadipocytes. Preadipocytes proliferate in order to maintain a stem cell population for adipose tissue renewal. Cell proliferation is controlled by cell cycle regulators. Thyroid hormone and its receptors (a and b) play an important role in the regulation of cell proliferation and differentiation, depending on cell type and stage of development. We previously reported that SUMO modification of thyroid hormone receptor is required for differentiation and proliferation of human subcutaneous preadipocytes. TRa contains two sumoylation sites, lysine 283/lysineK288 (interchangeable site) and lysine 389. We generate the TRa K283Q/K288R mutant to study the transition, G0/G1 to S1, which is the limiting phase for the cell cycle. Human preadipocytes were transfected with control (empty vector), TRa and TRaK283Q/K288R (TRa sumoylation mutant). Cells were synchronized at G0 phase by serum starvation for 48 hours, and then released into G1 phase by supplementation with 10% serum for 8 hours. Cells were analyzed for G1 phase progression. When cells re-enter the cell cycle from a quiescent state, cyclinD1 is increased and degraded rapidly, forming a cyclinD-CDK4/6 complex stabilized cyclinD. CyclinD-CDK4 then forms a complex with CDK inhibitors P21cip or P27kip to enter the nucleus. In the nucleus, CDK4 phosphorylate retinoblastoma protein (Rb) to release Rb/HDAC’s inhibitory effects and activate E2F/DP1 for downstream transcription. In TRa mutant-transfected cells, nuclear CDK4, but not cytoplasmic CDK4, was significantly reduced compared to control and TRa-transfected cells. As a consequence, unphosphorylated Rb/HDAC1 was retained bound to E2F/DP1 and blocked transcription. We also found that P27kip was significantly reduced in the nucleus of cells expressing the TRa sumoylation mutant, compared to control cells, suggesting that cyclinD-CDK4 nuclear import was limited by P27kip. Our data demonstrate that TRa sumoylation influences G1 phase regulators in human preadipocytes.

Short Oral Communication 94 Thyroid Hormone Action Tuesday Short Oral Communication Basic 1:12 PM ABSENCE OF UCP3 BLUNTS THE STIMULATORY EFFECT OF TRIIODOTHYRONINE ON ENERGY EXPENDITURE IN HYPOTHYROID MICE A. Lombardi1, R.A. Busiello2, S. Savarese3, F. Goglia2 1 Biologia, Universita` di Napoli ‘‘Federico II’’, Napoli, Italy; 2 Scienze e Tecnologie, Universita` del Sannio, Benevento, Italy;

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Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Seconda Universita` di Napoli, Caserta, Italy Thyroid hormone (T3), by influencing the metabolism of most mammalian tissues, plays a crucial role in metabolic rate (MR). T3 greatly affects mitochondrial oxidative capacity as well as phosphorylation efficiency, with mitochondrial Uncoupling Proteins (UCPs) being a target. In hypothyroid rats, we showed that UCP3 (the isoform expressed in skeletal muscle, heart and brown adipose) is one of the molecular determinants for the stimulatory effect of T3 on resting MR. On the other hand, in mice, the absence of UCP3 does not seem fundamental for the effect of T3 on MR. Thus, further studies are needed to clarify this aspect of thyroid physiology. As animal models we used WT and UCP3 KO mice, made hypothyroid and housed at thermoneutrality. Hypothyroidism was induced by a simultaneous treatment with Propylthiouracil and Iopanoic acid for 6 weeks. The effect of hypothyroidism and of a single administration of T3 (25 lg/100 g bw) into hypothyroid mice on whole animal resting energy expenditure (EE) and UCP3 levels have been evaluated. EE and UCP3 levels have been detected by indirect calorimetry and Western Blot, respectively. When compared to WT controls, KO mice showed a reduced EE. Induction of hypothyroidism lead to a significant decrease of EE in WT mice that was associated to a reduction of UCP3 mitochondrial levels in skeletal muscle, heart but not in brown adipose tissue. Induction of hypothyroidism did not influence EE in KO mice. The presence of UCP3 significantly increased T3’s stimulatory effect on EE in hypothyroid mice. Indeed, in WT mice the induction of EE by T3 was long-lasting and almost doubled compared to that of KO mice, in addition it was associated with a significant increase in skeletal muscle, heart and brown adipose tissue mitochondrial UCP3 levels. The results of this study demonstrate that UCP3 is a crucial factor for the stimulatory effect of T3 on EE.

Short Oral Communication 95 Thyroid Hormone Action Tuesday Short Oral Communication Basic 1:18 PM 3,5-DIIODO-L-THYRONINE (T2) AND NOT 3,5,3’-TRIIODOL-THYRONINE (T3) REDUCES LIPOGENIC SIGNALING PATHWAYS IN RATS RECEIVING A HIGH-FAT DIET P. de Lange, R. Senese, C. Leanza, L. Iannucci, A. Lanni Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Seconda Universita` degli Studi di Napoli, Caserta, Italy The increased incidence of fatty liver disease (NAFLD) is of global concern. Thyroid hormones are known modulators of hepatic lipid synthesis and b-oxidation. 3,5-diiodo-L thyronine (T2) effectively inhibits hepatic lipogenesis by activating the sirtuin-deacetylase family member SIRT1, which deacetylates sterol regulatory element binding protein 1-c (SREBP-1c), inhibiting its activity and transcription and that of its target genes. These genes all contain thyroid hormone response elements (TREs) and T3 is known to up-regulate their expression in various cell systems. We wanted to compare the effects of T2 versus T3 on gene expression involved in the modulation of hepatic lipogenesis in high-fat-fed rats. Male Wistar rats (aged 8 wk) were fed a standard diet or a high-fat diet (HFD) (21% carbohydrates, 29% proteins, and 50% fat, J/J), with 2 subgroups (HFD-T2 and HFD-T3) intraperitoneally receiving T2 (25 lg/100 g BW) or T3 (2.5 lg/100 g BW). Animals were killed after 1 week. Liver lipid content was determined using Oil Red O, gene expression was assessed by real time PCR. Both T2 and T3 prevented high-fat diet-induced lipid accumulation. T2 and T3 both decreased the expression of SREBP-1c, but only T2 decreased the expression of the SREBP-1c-target genes acetyl-CoA

A-41 carboxylase (ACC), fatty acid synthase (FAS), and ‘‘spot 14’’ (S14). Another TRE-containing key regulator of hepatic lipogenesis, carbohydrate-response element-binding protein (ChREBP) was strongly downregulated by T2 and much less so by T3. Using the given doses, both T2 and T3 are able to prevent fatty liver, but do so, at least in part, through different mechanisms since in the case of T2, thyroid hormone receptorTRE-mediated effects on lipogenic gene transcription are avoided. T2 may be more effective than T3 in inhibiting hepatic steatosis since on the longer term the antisteatotic effect of T3 may be counteracted by the activation of lipogenic pathways, which does not occur in the case of T2.

Short Oral Communication 96 Thyroid Hormone Action Tuesday Short Oral Communication Basic 1:24 PM PUTATIVE ROLE OF HEPATOCYTE NUCLEAR FACTOR4a (HNF4a) IN THE 3,5-DIIODOTHYRONINE-DRIVEN CHOLESTEROL REDUCTION IN LDL RECEPTOR KNOCK-OUT MICE (LDLR - / - ) M. Moreno1, M. Coppola1, E. Silvestri1, J. Ehrenkranz2, I. Goldberg3, F. Goglia1 1 Science and Technologies, University of Sannio, Benevento, Italy; 2 Medicine, Intermountain Healthcare, Murray, UT; 3Medicine, Columbia U. College of Physicians and Surgeons, New York, NY High doses of 3,5-diiodo-L-thyronine (T2), when administered to LDLr-knockout (Ldlr - / - ) mice, dramatically reduce VLDL/LDL cholesterol as well as circulating levels and liver production of ApoB. The goal of the following study was to determine proteomic changes in the livers of Ldlr - / - mice to investigate the mechanisms responsible for the T2-driven cholesterol reduction. Ldlr - / - mice were placed on a western diet one week prior to receive T2 (12.5 mg/kg BW ) or T3 (0.75 mg/Kg BW), by oral gavages for 1 week. Proteins of interest were measured by 2D-E and Western blot analysis. Comparative studies using T3 were performed. Following hepatic proteome analysis, we in silico identified HNF4a as the highest-scoring node involved in the hypocholesterolemic effect of T2 in Ldlr - / - mice. Both T2 and T3 administration to Ldlr - / - mice significantly reduced nuclear HNF4a protein levels. An interrelationship of HNF4a with its coactivator PGC-1a in the regulation of lipoprotein metabolism has been characterized. Specifically T2, but not T3, significantly reduced expression levels of PGC-1a, hence suggesting decreased PGC-1a - HNF4a-dependent signalling in the reduction of hepatic production of ApoB associated with the hypocholesterolemic effect of T2. The HNF4a modulation by T2 was consistent with altered expression of key liver HNF4atarget proteins such as ApoE, ApoB48, ApoB100, FABP, GK: all of which are involved in intrahepatic lipid metabolism. Although our study was not meant to investigate the use of T2 as a therapeutic agent, it opened new perspectives in individuating new nonLDLr pathways involved in cholesterol handling. In particular, reduction of the PGC-1a - HNF4a signalling pathway may provide a useful mechanism to manage cholesterol levels in the absence of LDL receptor.

Short Oral Communication 97 Thyroid Cancer Tuesday Short Oral Communication Basic 1:00 PM MICRORNA-146B MEDIATES PTEN SILENCING PROMOTING PI3K/AKT PATHWAY HYPERACTIVATION LEADING TO THYROID CANCER PROGRESSION L. Wert-Lamas, J. Ramirez-Moya, P. Santisteban Endocrine Physiopathology, Biomedical Researh Institute ‘‘Alberto Sols’’, Madrid, Spain

A-42 Recent studies have shown that the microRNA (mir)-146b is the most upregulated mir in thyroid cancer and it has been shown to play a fundamental role in thyroid cancer progression. Using bioinformatic predictions based on miRanda algorithm, we have identified the tumor suppressor PTEN as a target of miR-146b. Because the PI3K pathway constitutive hyperactivation is the second more frequent driver event in thyroid carcinomas, in the present study we investigated the underlying mechanisms by which tumoral overexpression of mir-146b enhances proliferation, survival, migration and invasion. For this purpose, we used the human Nthy-ori and the rat PCCl3 thyroid cells to generate stable cell lines constitutively overexpressing mir-146b. PTEN and Luciferase construct plasmids were transiently transfected. The mRNA and protein levels were determined by RT-qPCR and Western blot/Immunofluorescence respectively. Functional assays including proliferation, survival, migration and invasion assays were carried out. The results showed that both constitutive overexpression of RAS and treatment with PI3K pathway effector IGF-1 resulted in increased expression of mir-146b in thyroid follicular cells. Conversely, overexpression of mir-146b dramatically decreased PTEN mRNA and protein levels by direct binding to its 3‘UTR promoting tumoral hyperactivation of PI3K/AKT pathway. Additionally, mir-146b overexpressing cells showed decreased FOXO1 and p27 nuclear levels, an increase of BCL-2/p53 ratio, and silencing of ECadherin expression, that led to an increased proliferation, survival and migration/invasion respectively. Furthermore, overexpression of PTEN reverted mir-146b-induced p27, FOXO1, BCL-2, p53 and Ecadherin aberrant expression and rescued normal phenotype in proliferation, survival, migration and invasion assays in constitutively overexpressing mir-146b cell lines. In summary, our results demonstrate that miR-146b causes an exacerbated hyperactivation of PI3K/AKT pathway via PTEN suppression, leading to a more aggressive tumoral behavior. Altogether, our results suggest that targeting miR-146b may provide a new therapeutic strategy against thyroid cancer.

Short Oral Communication 98 Thyroid Cancer Tuesday Short Oral Communication Basic 1:06 PM AUTOPHAGY INHIBITION SENSITIZES BRAF-MUTANT THYROID CANCER TO VEMURAFENIB W. Wang1,2, I. Min1, Y. Zhao1, B. Wyrwas1, R. Zarnegar1, L. Teng2, T. Fahey1 1 Department of Surgery, Weill Medical College of Cornell University, New York, NY; 2Department of Surgical Oncology, First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China The RAF inhibitor vemurafenib has been shown to increase survival in patients with BRAF-mutant metastatic melanoma. However, it is relatively ineffective in BRAF-mutant thyroid cancer cells, and the reason for this disparity remains unclear. Autophagy is a highly conserved catabolic process that can induce adaptive drug resistance in a variety of cancer types and treatments. Here we looked to determine if autophagy is active in BRAF-mutant thyroid cancer, and whether autophagy inhibition improves the treatment efficacy of vemurafenib. Cell proliferation in response to vemurafenib was assessed in five thyroid cancer cell lines by an MTT assay. To determine the level of autophagy, Western blot assay and transmission electron microscopy were used to measure the expression of LC3 and the number of autophagosomes. The combined effects of autophagy inhibitor hydroxychloroquine (HCQ) and vemurafenib were analyzed by an MTT assay and a clonogenic assay.

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i. Vemurafenib induced autophagy in both a dose and time dependent manner. FRO cells were incubated with indicated concentration of vemurafenib for 48 hours or incubated with 5lM vemurafenib for the indicated intervals. HCQ was used to block autophagic degradation. ii. Autophagosome number increased upon vemurafenib treatment. Electron microscopy of FRO cells exposed to vemurafenib for 48 hours. Typical autophagosomes (white arrow) were observed in vemurafenib treated groups (D and E, higher resolution in F). iii. HCQ augmented the anti-proliferative effect when combined with vemurafenib in thyroid cells. FRO and BCPAP were treated with increasing doses of vemurafenib in medium with or without HCQ for 72 hours and MTT assays were performed. IV. Vemurafenib induced autophagy by suppression of the Akt/mTOR pathways. Western blot for phospho-Akt and P70S6K in FRO and BCPAP cells, which were incubated with 5lM vemurafenib for the indicated intervals. All BRAF-mutant thyroid cell lines tested here were refractory to vemurafenib (IC 50s ‡ 1000nmol/L). Autophagy levels in thyroid cancer cells were highly induced upon vemurafenib treatment in both a dose and time dependent manner: higher dose of vemurafenib triggered higher level of LC3II and this effect was most pronounced after 48 hours’ incubation of vemurafenib. The number of autophagosomes which is another hallmark of autophagy increased significantly in the vemurafenib treated groups by at least five fold when compared to the untreated group. Combination of HCQ and vemurafenib treatments significantly augmented growth inhibition induced by vemurafenib in FRO and BCPAP cells. The long-term colony formation assay further confirmed that the combination of vemurafenib and HCQ was the most effective way to reduce colony numbers. The autophagy induction by vemurafenib is, in part, through suppression of the Akt/mTOR signaling pathways. Our data demonstrate that inhibition of autophagy augments the anti-cancer effects of vemurafenib in BRAF-mutant thyroid cell lines. Autophagy inhibition may be a beneficial strategy to overcome RAF inhibitor (vemurafenib) resistance in thyroid cancer.

Short Oral Communication 99 Thyroid Cancer Tuesday Short Oral Communication Basic 1:12 PM A SPONTANEOUS KRAS (G12D) MUTATION FOLLOWING LONG-TERM VEMURAFENIB TREATMENT DRIVES ACQUIRED BRAF INHIBITOR (BRAFI) RESISTANCE IN A BRAF (V600E) PTC CELL LINE B.P. Danysh, M. Cabanillas, M. Hofmann Endocrine Neoplasia and Hormonal Disorders, MD Anderson Cancer Center, Houston, TX

TUESDAY, OCTOBER 20, 2015 Activating mutations in BRAF (V600E) are commonly observed in PTC and result in a functional dependence upon the constitutively active MAPK pathway. While targeted inhibitors are initially effective, inevitably cells develop alternative mechanisms of pathway activation. Mechanisms of primary resistance have been described in thyroid cancer cell lines, however acquired resistance has not. Our study investigates these adaptive mechanisms of BRAF (V600E) inhibitor resistance and accompanying metastatic phenotypes in PTC cells following long-term vemurafenib exposure. KTC1 sub-cell lines (PTC cells, BRAFV600E) were developed following treatment with either 0.25 or 1.0 lM of vemurafenib (BRAFi) for > 20 passages. RPPA, Western blot, and qRT-PCR, were used to assess EMT marker expression and pathway activation. 3D Matrigel invasion, immunofluorescence microscopy, and direct cell count growth assays were used to assess inhibitor resistance and metastatic phenotypes. Sequenom was used to detect acquired mutations. A vemurafenib resistant (VR) subline of KTC1 cells was derived following long-term treatment with the drug. Resistance coincided with spontaneous acquisition of a KRAS (G12D) activating mutation. No resistance was observed in the control and another treated subline (vemurafenib sensitive, VS). Increases in activated AKT, ERK, and EGFR were observed in the VR subline. In the VS subline, increases in activated AKT and HER3 in the presence of vemurafenib were observed. The VR/KRAS mutant line was less susceptible to combinations of ERK (GDC0994) and PI3K (LY29002) inhibitors. Increased expression of distinct EMT markers was observed in both treated sublines; however only the KRAS mutant line demonstrated increased invasive properties. Our results suggest an acquired KRAS mutation confers BRAF (V600E) inhibitor resistance and a more aggressive metastatic phenotype in vitro. This is supported by studies associating the presence of an activating KRAS mutation and more aggressive PTC variants.

Short Oral Communication 100 Thyroid Cancer Tuesday Short Oral Communication Basic 1:18 PM PAPILLARY THYROID CANCER-DRIVING ONCOGENE BRAFV600E INDUCES TOLL-LIKE RECEPTOR 4 OVEREXPRESSION V. Peyret1, M. Nazar1, J.P. Nicola1, C.S. Fuziwara2, M. Montesinos1, C.G. Pellizas1, E.T. Kimura2, A.M. Masini-Repiso1 1 Departamento de Bioquı´mica Clı´nica, Facultad de Ciencias Quı´micas, Universidad Nacional de Co´rdoba, Centro de Investigaciones en Bioquı´mica Clı´nica e Inmunologı´a - Consejo Nacional de Investigaciones Cientı´ficas y Te´cnicas, Co´rdoba, Argentina; 2Departamento de Biologia Celular e do Desenvolvimento., Instituto de Cieˆncias Biome´dicas. Universidade de Sa˜o Paulo., Sa˜o Paulo., Brazil Toll like receptors (TLRs) comprise a family of transmembrane proteins related to the Interleukin-1 receptor. Emerging evidence suggests that deregulated TLRs expression in tumor tissue promotes tumor survival signals, thus favoring tumor progression. Recently, aberrant TLR4 overexpression was demonstrated in papillary thyroid cancer (PTC). Aim: To study the mechanisms underlying TLR4 overexpression in PTC harboring the BRAFV600E mutation. TLR4 expression was evaluated in thyroid tissue derived from human PTCs and transgenic mice expressing BRAFV600E in thyrocytes (Tg-BRAFV600E mice) (immunohistochemistry and RT/ qPCR). PCCl3 cells expressing BRAFV600E in response to doxycycline (PC-BRAFV600E) and BRAFV600E-positive PTC cell line BCPAP were used to study BRAFV600E-driven TLR4 expression (western blot, RT/qPCR, and gene reporter assays).

A-43 Immunohistochemistry analysis showed TLR4 overexpression in primary and metastatic human PTCs compared to normal thyroid tissue. Moreover, TLR4 expression was increased in thyroid tissue from TgBRAFV600E mice compared to littermate controls. Stimulation of doxycycline-treated PC-BRAFV600E and BCPAP cells with the TLR4 agonist lipopolysacharide induced the activation of the transcription factor NF-jB (5X NFjB-Luciferase reporter), suggesting functional TLR4 signaling. Doxycycline-induced BRAFV600E expression in PCBRAFV600E cells upregulated TLR4 protein levels. BRAFV600E increased TLR4 expression at transcriptional level by stimulating TLR4 promoter activity. Deletion analysis of the TLR4 promoter revealed a distal mitogen-activated protein kinase (MAPK)-sensitive ETS bindingsite critical for BRAFV600E-induced TLR4 expression. Consistently, pharmacological inhibition of BRAFV600E and MEK/ERK signaling reduced TLR4 mRNA expression in the BRAFV600E-positive PTC cell line BCPAP. Our findings revealed that the oncogene BRAFV600E induces functional TLR4 overexpression in thyroid cancer involving a MEK/ ERK-dependent TLR4 gene transcriptional activation. Altogether, these data raise an intriguing question regarding the role of TLR4 signaling in the development and progression of PTC, opening new possibilities for the design of therapeutic approaches.

Short Oral Communication 101 Thyroid Cancer Tuesday Short Oral Communication Basic 1:24 PM A NOVEL MODULATOR OF CELLULAR INVASION AND METASTASIS IN THYROID CANCER W. Imruetaicharoenchoke1, R. Watkins1, N. Sharma1, E. Gentillin2, E. Bosseboeuf1, K. Perkin1, R. Fletcher1, H. Mehanna1, K. Boelaert1, M. Read1, J. Watkinson1, V. Smith1, C. McCabe1 1 Centre for Endocrinology, Diabetes and Metabolism, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom; 2University of Ferrara, Ferrara, Italy Metastasis is responsible for the majority of poor oncological outcomes, especially cancer deaths. The cortical actin binding protein cortactin is central to the recruitment of actin fibres at the periphery of the cell, promoting cellular movement. A precise understanding of cortactin’s mechanisms of action is required to fully comprehend metastatic cell activity. We used mass spectrometry to identify protein binding partners and determined co-localisation and protein:protein interaction through immunofluorescence, Proximity Ligation Assays and coimmunoprecipitations (Co-IP). Boyden chamber assays were applied to examine cellular invasion. Western blotting and real-time PCR were used to characterise levels of gene expression in human papillary thyroid cancers (PTC). We identify the proto-oncogene PBF as a new functional binding partner of cortactin. PBF has recently been correlated with thyroid and breast cancer metastasis, and with decreased disease specific survival in thyroid cancer. Cortactin and PBF co-localised preferentially at the leading edge of migrating cells. Oncogenic overexpression of PBF induced potent cell invasion and migration in thyroid ( p = 0.01) and breast ( p < 0.001) cancer cells, which was completely abolished by simultaneous cortactin knockdown. In 43 matched PTC, cortactin was significantly upregulated at the mRNA ( p = 0.022) and protein ( p = 0.045) levels, particularly in more aggressive tumours, and significantly correlated with PBF expression. Cortactin and PBF specifically interacted in vitro. Co-IP assays demonstrated that mutation of PBF’s endocytosis motif resulted in plasma membrane retention, increased avidity of cortactin binding, and an absolute block of cellular invasion.

A-44 Overall, we determine a new modulator of cortactin activity, and demonstrate for the first time that cortactin is over-expressed in thyroid cancer. Modification of PBF subcellular localisation may present a novel mechanism of addressing thyroid cancer cell invasion and migration.

Short Oral Communication 102 Thyroid Cancer Tuesday Short Oral Communication Translational 1:00 PM PROMISING ROLE OF CIRCULATING MICRORNAS IN THE DIFFERENTIAL DIAGNOSIS OF THYROID NODULES PARTICULARLY WITH INDETERMINATE CYTOLOGY T. Pilli1, S. Cantara1, G. Busonero1, S. Cardinale1, G. cevenini2, G. Sebastiani3, F. Dotta1, F. Pacini1 1 Department of Clinical&Surgical Sciences and Neuroscience, University of Siena, Siena, Italy; 2Department of Medical Biotechnologies, University of Siena, Siena, Italy; 3Fondazione Umberto Di Maio ONLUS, Toscana Life Sciences, Siena, Italy Recently, we have identified in the serum of patients, with benign nodular goiter (n = 80) and papillary thyroid cancer (PTC: n = 79), 2 miRNAs ( - 190 and - 95) that in combination allow the differential diagnosis of thyroid nodules with great accuracy. A total of 473 patients have been enrolled in our study (159 patients retrospectively and 314 prospectively). All patients underwent fine needle aspiration cytology at our Institute and 300 out of 473 patients were treated surgically and the histology is available. We calculated the probability of malignancy (pmiRNA), by entering serum mir - 190 and - 95 in a mathematical formula, with a cut-off value of 0.5 above which the patient was at high risk of malignancy. Diagnostic accuracy of pmiRNA and cytology were similar but the combination of two methods increased the sensitivity and negative predictive values to 99.1% and to 99.2% respectively. In a subgroup of patients, with a known mutational status, pmiRNA showed a similar or better accuracy than molecular biology in the diagnosis of nodules classified as inadequate or indeterminate at cytology. Also, we determined pmiRNA in different serum samples of 36 patients (17 PTC and 19 benign) over 65 months before surgery. In 26/36 patients pmiRNA were consistent in all determinations for each patient. Finally, in a subgroup of patients we determined pmiRNA after surgery (3 patients with benign disease and 8 PTC patients). Post-surgical pmiRNA seems to be consistent with the disease status particularly cancer remission or persistence. PmiRNA showed a high sensitivity (92.3%), specificity (93.6%) and diagnostic accuracy (94.9%) in PTC diagnosis, confirming that may be useful as non-invasive tool for the differential diagnosis of thyroid nodules, particularly in case of indeterminate lesions. Potential role of pmiRNA as marker of disease, like thyroglobulin, will be investigated in future studies.

TUESDAY, OCTOBER 20, 2015 R. Donehower14,2, P. LoRusso15,2, M. Millward16,2, A.V. Chintakuntlawar1,2, A. Kumar4, B.R. Kipp8, J.S. Voss8, K.M. Rumilla8, P. Ivy9, P. Harris9, P. Haluska1,2, C. Erlichman1,2 1 Oncology, Mayo Clinic, Rochester, MN; 2Mayo Phase 2 Consortium, Rochester, MN; 3Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN; 4Endocrinology, Mayo Clinic, Jacksonville, FL; 5Oncology, University of Wisconsin, Madison, WI; 6 Oncology, Minnesota Oncology Hematology, Minneapolis, MN; 7 Oncology, National University Hospital, Singapore, Kent Ridge, Singapore; 8Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; 9CTEP, National Cancer Institute, Bethesda, MD; 10 Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; 11Oncology, University of Colorado, Denver, CO; 12 Oncology, Mayo Clinic, Scottsdale, AZ; 13Oncology, Washington University, St. Louis, MO; 14Oncology, Johns Hopkins, Baltimore, MD; 15Oncology, Wayne State University, Detroit, MI; 16Oncology, University of Western Australia, Perth, WA, Australia Kinase inhibitors, including lenvatinib, sorafenib, vandetanib, sunitinib, axitinib and pazopanib, have demonstrated disease-modifying activity in patients with advanced radioactive iodine-refractory (RAIR) differentiated thyroid cancers (DTC). This prospective therapeutic clinical trial intended independent evaluation of the clinical effects of pazopanib in a large cohort of patients with progressive, RAIR-DTC, with parallel assessment of potential correlations between response to therapy and associated changes in serum thyroglobulin (Tg). A one-stage phase II trial was conducted to primarily assess any association between therapy-associated Tg changes and pazopanib anti-tumor activity in RAIR-DTC patients lacking Tg antibodies. With a sample size of 68 patients (assuming 23 attaining PR), a onesided a = 0.10 two sample test of proportions would have a 90% chance of detecting a difference of ‡ 30% when the proportion of patients with stable/progressive disease whose Tg values decrease by ‡ 50% is £ 50%. From May 1, 2009 to December 31, 2011, 60 individuals were treated and evaluated; 91.7% had previously received systemic therapy in addition to radioiodine. Adverse events were consistent with expectation; no deaths were attributed to study therapy. Twenty two confirmed partial RECIST responses were observed (36.7% PR, 95%CI: 24.6- 50.1%). Although Tg change after cycle 1 (4 weeks) did not differ by response, Tg nadir was greater among the 20 patients attaining PR (median: - 86.8%; IQR: - 90.7 to - 70.9%) compared to the 28 who at best maintained disease stability (median: - 69.0%; IQR: - 78.1 to - 27.7%, Wilcoxon rank-sum test: p = 0.002). BRAF, p53, JAK3 and/or HRAS mutations were identified in 11 of 16 assessed patient cancers but were not found correlated with treatment

Short Oral Communication 103 Thyroid Cancer Tuesday Short Oral Communication Translational 1:06 PM PAZOPANIB IN PATIENTS WITH PROGRESSIVE, RADIOACTIVE IODINE-REFRACTORY, METASTATIC DIFFERENTIATED THYROID CANCER LACKING THYROGLOBULIN ANTIBODIES: MAYO PHASE 2 CONSORTIUM STUDY RESULTS K.C. Bible1,2, V.J. Suman3,2, J.R. Molina1,2, R.C. Smallridge4,2, W.J. Maples1,2, M.E. Menefee1,2, J. Rubin1,2, K. Sideras1,2, J.C. Morris4, B. McIver4, J.K. Burton1,2, I. Hay4, V. Fatourechi4, K.P. Webster1,2, C. Bieber1, A.M. Traynor5,2, P.J. Flynn6,2, B.C. Goh7,2, C. Lin10,2, M. Kane11,2, N. Karlin12,2, D. Adkins13,2,

Maximal RECIST Tumor Response (% Control, ‘‘Waterfall’’ Plot).

TUESDAY, OCTOBER 20, 2015 response. Moreover, response to pazopanib therapy was not correlated with prior therapy. Pazopanib was confirmed to have significant clinical activity in progressive, RAI-refractory DTC. Response to therapy, however, was not well forecast by early associated changes in Tg, by tumor mutational status or by prior therapy. Support: NCI CA15083 and CM62205.

Short Oral Communication 104 Thyroid Cancer Tuesday Short Oral Communication Translational 1:12 PM A 6 BP IN FRAME GERMLINE DELETION IN EXON 7 OF THE RET GENE LEADS TO INCREASED RET PHOSPHORYLATION, MAPK/ERK AND PI3K ACTIVATION AND MEN2A S. Latteyer1, L. Klein-Hitpass2, C. Khandanpour1, D. Zwanziger1, T.D. Po¨ppel3, K.W. Schmid4, D. Fu¨hrer1, L.C. Moeller1 1 Endocrinology & Metabolism, University of Duisburg-Essen, Essen, Germany; 2Center for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany; 3Department of Nuclear Medicine, University of Duisburg-Essen, Essen, Germany; 4Institute of Pathology, University of Duisburg-Essen, Essen, Germany Multiple endocrine neoplasia (MEN) 2 includes medullary thyroid cancer (MTC), pheochromocytoma and less frequently primary hyperparathyroidism. MEN2 is usually caused by missense mutations in hot spot regions of the proto-oncogene RET, leading to constitutive activation of the tyrosine kinase receptor RET. We identified a novel and uncommon RET mutation in a female caucasian patient who was diagnosed with bilateral pheochromocytoma at age 32 and subsequently developed MTC (T1aN0M0) at age 37. Exome and Sanger sequencing was performed from leukocyte DNA and compared to COSMIC. Constructs with mutant or wild-

FIGURE 1. The RET9 p.505_506del mutation increases autophosphorylation and activation of downstream signaling pathways. 10 lg protein lysate from HEK293 transfected cells with RET9 WT, C634R (common MEN2 mutation, positive control), p505_506del or non-transfected HEK293 cells were separated on SDS-page and transferred on a PVDF membrane (n = 4). PVDF membranes were stained with antibodies against RET (A), pRET (B), pERK (C) or pAkt (E) (a-tubulin (D) and b-Actin (F) serve as loading controls).

A-45 type RET9 were transfected in HEK293. Phosphorylation and activation of MAPK/ERK and PI3K/AKT was analyzed by Western blotting and luciferase assay and effect on cell proliferation was tested in a colony forming assay. Exome sequencing revealed a 6 nucleotide/2 amino acid in frame deletion in exon 7 (c.1512_1517delGGAGGG, p.505_506del) of RET. In vitro expression showed that phosphorylation of the crucial tyrosine 905 in the tyrosine kinase domain is much stronger in the p.505_506del RET mutant compared to wild type RET (Fig. 1), indicating ligand-independent autophosphorylation. Furthermore, the p.505_506del RET mutant induces a strong activation of the MAPK/ ERK pathway (pERK1/2) and, to a lesser degree, the PI3K pathway (Fig. 1). Consequently, transfection of the p.505_506del RET mutant into HEK293 cells increases colony formation fourfold compared to cells transfected with RET WT (P < 0.0001). The finding of bilateral pheochromocytoma and MTC in our patient was highly suspicious of a RET mutation, yet sequencing of the RET exons commonly associated with MEN2 failed to detect a mutation. Exome sequencing finally revealed a 6 bp deletion in exon 7 of RET, an exon that has not yet been associated with MEN2. In vitro, increased ligand-independent phosphorylation of the novel p.505_506del RET mutant, increased activation of downstream pathways and promotion of cell proliferation demonstrated the pathogenic nature of the mutation. We, therefore, recommend to screen the whole sequence of RET in MTC and pheochromocytoma patients with red flags for a genetic cause.

Short Oral Communication 105 Thyroid Cancer Tuesday Short Oral Communication Translational 1:18 PM C-MET-MEDIATED REACTIVATION OF PI3K/AKT SIGNALING CONTRIBUTES TO DRUG INSENSITIVITY AND EPITHELIAL-MESENCHYMAL TRANSITION OF BRAF(V600E) MUTANT THYROID CANCER TO BRAF INHIBITION H. Byeon, H. Na, Y. Yang, E. Choi, Y. Koh Otrhinolaryngology, Yonsei University College of Medicine, Seoul, Korea (the Republic of) BRAF (V600E) mutation is the most commonly detected genetic alteration in thyroid cancer. Unlike its high treatment response to selective BRAF inhibitor (PLX4032) in metastatic melanoma, the treatment response in thyroid cancer is reported to be low. The purpose of this study is to investigate the acquired resistance mechanism responsible for this low treatment response to BRAF inhibitor in order to maximize the effect of targeted therapy. We examined the expression of feedback regulation mechanisms and alterations in the upper signal transduction pathway in thyroid cancer cell lines harboring BRAF mutation. Also we investigated the effect of dual inhibition from combinatorial therapy. Two thyroid cancer cell lines, 8505C (anaplastic thyroid cancer) and BCPAP (papillary thyroid cancer) were selected and treated with PLX4032 and its drug sensitivity were examined and compared. Further investigation on the changes in signals responsible for the different treatment response to PLX4032 was carried out and the same experiment was performed on orthotopic xenograft mouse models. Unlike BCPAP cells, 8505C cells presented drug resistance to PLX4032 treatment and this was mainly due to increased expression of c-Met. Furthermore, epithelial-mesenchymal transition (EMT) was increased in 8505C cells after PLX4032 treatment. Effective inhibitions of c-Met, p-AKT, and p-ERK were achieved after dual treatment with BRAF inhibitor (PLX4032) and c-Met inhibitor (PHA665752). EMT markers such as vimentin, n-cadherin, CD44 were also effectively inhibited following dual treatment. Similar results were confirmed by in vivo study with orthotopic xenograft mouse model.

A-46 c-Met-mediated reactivation of the PI3K/AKT pathway and MAPK pathway contributes to the relative drug insensitivity and EMT of BRAF (V600E) mutant ATC cells to PLX4032. Dual inhibition of BRAF and c-Met leads to sustained treatment response.

Short Oral Communication 106 Thyroid Cancer Tuesday Short Oral Communication Translational 1:24 PM COMBINATORIAL TARGETING WITH ANTI-BRAFV600E AND ANTI-ANGIOGENESIS THERAPY ENHANCES CELL DEATH AND SUPPRESSES CELL MIGRATION IN METASTATIC PAPILLARY THYROID CARCINOMA J. Sisms, Z. Antonello, C. Nucera Pathology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA BRAFV600E exerts an essential oncogenic function in many tumors, including papillary thyroid carcinoma (PTC). These tumors are resistance to radioiodine treatment and have high rates of recurrence and metastases and low survival rates. Furthermore, BRAFV600E-PTC cells up-regulate tyrosine kinases (TKs)-dependent angiogenic signaling in the tumor microenvironment. Although BRAFV600E and TK inhibitors are available, lack of response has been frequently observed. Aims: (i) to unravel underlying resistance mechanisms to BRAFV600E and pro-angiogenic TKs and (ii) to assess the effects of combinatorial therapy vemurafenib plus sorafenib in patient-derived metastatic BRAFV600E-PTC cells. We used cell cultures of human metastatic/recurrent BRAFV600EPTC and tested the effects of vemurafenib (selective inhibitor of BRAFV600E) versus sorafenib (anti-angiogenesis/TKs inhibitor) used as single agents or in combination. We also performed dynamic assays (i.e. cell cycle analysis and wound-healing/migration) and molecular characterization of angiogenic signaling in PTC cells harboring BRAFV600E or with BRAFWT in vitro. We found that metastatic BRAFV600E-PTC cells express TKs such as VEGFR2 and PDGFRb which elicit resistance to vemurafenibor sorafenib-induced inhibition of cell viability. Vemurafenib or sorafenib treatments partially suppressed BRAFV600E-downstream targets, e.g. phospho(p)-ERK1/2 and pPDGFRb. Importantly, the combinatorial therapy (vemurafenib + sorafenib) led to apoptosis, altered cell cycle distribution, and inhibited migration of BRAFV600E-PTC cells resistant to the single agent treatment. Mechanistically, this combined therapy strongly reduced pERK1/2 and pPDGFRb protein levels in BRAFV600E-PTC cells vs. vehicle-treated or single agent treated cells. No functional effects of vemurafenib were found in BRAFWT-PTC cells. In contrast, sorafenib decreased migration of BRAFWT-PTC cells vs. vehicle-treated cells. Our results indicate for the first time that PTC cells express VEGFR2 and dual treatment with anti-BRAFV600E and anti-angiogenesis therapy improves therapeutic response in metastatic BRAFV600EPTC cells by directly reducing cell survival and migratory capacities via pERK1/2 and pPDGFRb down-regulation.

Short Oral Communication 107 Thyroid Nodules & Goiter Tuesday Short Oral Communication Clinical 1:00 PM EXAMINING THE ROLE OF PREOPERATIVE POSITRON EMISSION TOMOGRAPHY (PET)/COMPUTERIZED TOMOGRAPHY (CT) IN DISCRIMINATING BENIGN FROM MALIGNANT THYROID NODULES DEFINED CYTOLOGICALLY AS INDETERMINATE M.M. Merten1, M. Castro1, J. Zhang2, M. Ryder1 1 Endocrinology, Mayo Clinic, Rochester, MN; 2Laboratory Medicine/Pathology, Mayo Clinic, Rochester, MN

TUESDAY, OCTOBER 20, 2015 Cytologically defined indeterminate thyroid nodules are a diagnostic challenge. Surgical lobectomy remains the gold standard for definitive diagnosis. However, 70–85% of these nodules are benign on surgical histopathology. In published studies, PET/CT has demonstrated 57–100% negative predictive value (NPV) in discriminating benign from malignant nodules. The purpose of our study was to evaluate the preoperative role of PET/CT in risk stratifying indeterminate nodules within our institution. We performed a retrospective chart review of patients with indeterminate thyroid nodules (suspicious for Hurthle cell [HCN] or follicular neoplasm [FN]) at Mayo Clinic between 2000–13 who had a PET/CT (usually done for other reasons) within 1 year of FNA and had undergone definitive diagnostic lobectomy. Of 51 indeterminate nodules with PET/CT, 45 (88%) were PET positive and 6 (12%) were PET negative. On final histopathology, 1 PET negative and 9 PET positive nodules proved malignant (NPV 83%). The single false negative PET case represented a papillary microcarcinoma which was likely below the resolution of PET detection. Excluding the microcarcinoma, the NPV improved to 100%, consistent with published data. With widespread use of ultrasound (US) and US-guided FNAs, the number of cytologically defined indeterminate thyroid nodules has risen sharply, leading to an increased rate of diagnostic lobectomies. The majority, however, are benign on final histopathology. Molecular markers may be useful to risk stratify these nodules but efficacy across different sites, including ours, has been discordant. PET/CT may represent a promising noninvasive tool for discrimination of indeterminate nodules >1 cm with the potential to reduce the number of diagnostic lobectomies by *40%. Larger prospective studies are needed to validate this data.

Short Oral Communication 108 Thyroid Nodules & Goiter Tuesday Short Oral Communication Clinical 1:06 PM TREATMENT OF BENIGN CYSTIC THYROID NODULES BY ETHANOL ABLATION: COMPARISON OF ETHANOL RETENTION AND ASPIRATION H. Park1, J. Baek1, E. Ha2, J. Lee1, Y. Shong3, W. Kim3, T. Kim3 1 Radiology, Asan Medical Center, Seoul, Korea (the Republic of); 2 Radiology, Ajou University, Seoul, Korea (the Republic of); 3Internal Medicine, Asan Medical Center, Seoul, Korea (the Republic of) Retention of injected ethanol could induce leakage causing pain and perithyroidal fibrosis. If aspiration of injected ethanol shows noninferior efficacy compared with retention, injected ethanol should be aspirated because of its drawback. This study prospectively compared the efficacy of ethanol aspiration and retention group for treating benign cystic thyroid nodules. This noninferiority study prospectively enrolled 120 patients with ethanol retention from January 2011 to January 2012 and then compared with retrospectively enrolled 120 patients with ethanol aspiration from February 2009 to February 2011. Primary end point was VRR at last follow-up; the noninferiority margin was chosen as - 8% (ethanol aspiration minus retention). Secondary end points included improvement of symptoms and cosmetic problems, vascularity, pain and presence of major complication. A one-sided 95% confidence interval (CI) for the mean difference in VRR at last follow-up was calculated to test for noninferiority. All demographic data of both groups showed no differences, except vascularity (P = .013). The mean VRR was 83.2% in ethanol retention group and 86.1% in ethanol aspiration group (difference, 2.858%; 95% CI, - 4.156 to 9.873%), thus demonstrating the noninferiority of ethanol aspiration to retention. Mean symptom and cosmetic scores showed no significant difference in either groups

TUESDAY, OCTOBER 20, 2015

(P = .677 and P = .277). Pain was significantly higher in retention group (P = .001). There were no major complication (P > .99). VRR of ethanol aspiration group was noninferior to that of retention; however pain was significant in retention group. Therefore, aspiration is preferred for treating benign cystic thyroid nodules.

A-47 distinguish progressive from stable disease ( p = 0.009). Calcitonin levels higher than 4020 pg/mL ( p = 0.0004), CEA levels higher than 26.8 ng/mL ( p = 0.04) and calcitonin doubling time shorter than 24.1 months ( p = 0.015) were associated with progressive disease in our cohort. The proportion of variance explained analysis (PVE) that predicted progressive disease was 64.9% for calcitonin cutoff of 4020 pg/mL, 32% for 18F-FDG uptake, 27.1% for calcitonin doubling time of 24.1 months and 24.8% for CEA cutoff of 26.8 ng/mL. When we considered the combination between theses predictors, the PVE was 64.9% for calcitonin plus 18-F-FDG PET/CT, 44.3% for calcitonin plus doubling time and 41.2% for doubling time plus 18 F-FDG PET/CT. 18 F-FDG uptake was able to distinguish progressive from stable disease. This tool should not replace the role of the validated calcitonin doubling time, but the combined informations could improve the clinical reassessment and better provide identification of patients who deserves a more careful surveillance.

Short Oral Communication 110 Short Oral Communication 109

W RA HD IT W

Several prognostic markers are established in medullary thyroid cancer (MTC), as age at diagnosis, lymph node involvement, tumor staging and calcitonin/CEA doubling times. As 18F-FDG PET/CT shows increasing detection rate of metastases with high blood tumor marker levels in several cancers, higher rate of positive cases in MTC might be observed in patients with shorter calcitonin/CEA doubling times. The aim of this study is to analyse the ability of 18F-FDG PET/ CT alone and in combination with established predictive parameters in the determination of prognosis in the follow-up of patients with MTC. Medical records of 17 patients with MTC who performed 18FFDG PET/CT were analysed retrospectively. All patients were classified in 2 groups: stable disease or progressive disease. Eight patients presented progressive disease, and all showed 18FFDG uptake (100%), compared to only 3 out 9 patients who presented stable condition (33%). 18F-FDG PET/CT results were able to

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Thyroid Imaging Tuesday Short Oral Communication Clinical 1:12 PM PROGNOSTIC VALUES IN MEDULLARY THYROID CARCINOMA: CLINICAL UTILITY OF 18F-FDG PET/CT J.H. YANG1, C.P. Camacho1, D. Andreoni1, L. Yamaga2, J. Wagner2, R.M. Biscolla1, R.M. Maciel1 1 ˜ O PAULO, Sao MEDICINA, UNIVERSIDADE FEDERAL DE SA Paulo, Brazil; 2HOSPITAL ISRAELITA ALBERT EINSTEIN, Sa˜o paulo, Brazil

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Short Oral Communication 111 Thyroid Cancer Tuesday Short Oral Communication Clinical 1:24 PM THERMAL ABLATION THERAPY FOR PMTC WITH CAREFUL OBSERVATION COULD BE THE ALTERNATIVE TO THYROID SURGERY? T. Nishikawa, N. Fukunari, M. Nakano, S. Aida Surgery, Showa University Yokohama Northern Hospital, Yokohama, Japan The management of papillary thyroid microcarcinomas (PTMC) has been controversial and only observation without surgery has been advocated for the low-risk PTMC. Radio-frequency ablation (RFA) has been applied to thyroid nodule, which shows safe and useful results for benign thyroid nodules. In our institution, not only benign nodules, but thyroid malignancies have been attempted to be therapeutic objectives by RFA. The aim of this study is to evaluate the efficacy of RFA for primary PTMC. Objectives: Eighty-nine cases were treated by RFA from 2007 in our institution, which consisted of 55 hyperplastic nodules, 9 AFTNs, 5 local recurrences of papillary carcinomas, 11 metastatic LNs and 9 primary PMTCs. All of 9 patients with PTMC were initial cases without the history of previous thyroid surgery or irradiation, and refused the surgery because of cosmetic and private reasons. Methods: RFA has carried out under general or local anesthesia and under careful US imaging guidance. The equipment of 17-18G needle electrodes were applied to thyroid RFA: STARmed RF electrode (STARmed, Korea) As an intra-operative assessment for the estimation of extent of ablated area, gray-scale US, color-Doppler imaging, Elastography and contrast enhanced US were applied to judge the satisfactory ablation. Results: All cases showed no side effect or thermal damage, and discharged after one night observation. The efficacy of RFA has been verified with both imaging diagnosis and repeated FNA. Post therapeutic FNA revealed no cancer cells remained in 8 of 9 PTMC cases. Conclusions: The efficacy of RFA has shown satisfactory results and a possibility to be one of alternative treatments for PMTC. Longtime follow-up and careful attention for thermal damage to surrounding tissues are required.

Short Oral Communication 112 Thyroid Cancer Tuesday Short Oral Communication Translational 1:00 PM INVESTIGATING THE ROLE OF POLYMORPHISM RS2910164 IN MIR146A IN CANCER PREDISPOSITION T.P. McVeigh1,2, P.W. Owens1,3, R. Mulligan1, C. Guerin6, N. Miller1, F. Sebag6, D. Quill3, M. Bell4, A.J. Lowery1,3, J.B. Weidhaas5, M.J. Kerin1,3 1 Discipline of Surgery, National University of Ireland Galway, Galway, Ireland; 2Department of Clinical Genetics, Our Lady’s Children’s Hospital, Crumlin (OLCHC), Dublin, Ireland; 3Department of Surgery, University Hospital Galway, Galway, Ireland; 4 Department of Endocrinology, University Hospital Galway, Galway, Ireland; 5Department of Radiation Oncology, University of California, Los Angeles, CA; 6Department of Endocrine Surgery, Hopital de la Timone, Marseilles, France Micro(mi) RNAs are non-coding RNA molecules that bind with cis-regulatory regions in target messenger(m)RNA to exert post-

TUESDAY, OCTOBER 20, 2015 transcriptional effects on gene expression, influencing a host of physiological and pathological processes. Polymorphisms in genes encoding miRNAs, or in miRNA-mRNA binding sites have been associated with cancer risk. MiR146a has a role in inflammation and is postulated to be a tumor suppressor miRNA. The aim of this study was to investigate the frequency and impact of polymorphism rs2910164 in HSA-pre-miR146a in a cohort of patients with breast and thyroid cancer compared to cancer free controls. The study group comprised Irish patients with breast cancer and French and Irish patients with non-medullary differentiated thyroid cancer (DTC), as well as cancer free controls. DNA from study participants was genotyped using a Taqman-based platform. Data was analysed using SPSS v22 and the Online Encyclopedia for Genetic Epidemiology studies. The study group included 1,250 patients, including 637 controls, 524 breast and 179 DTC cases. The variant was detected with a minor allele frequency (MAF) of 0.18 in controls, 0.21 in breast, and 0.28 in DTC cases. The variant conferred per allele odds ratio of 1.22 (1–1.5, p = 0.05, X2) for breast, and 1.7 (1.31–2.25, p < 0.0001) for DTC. An allele dosage effect was observed for both cancers, with rare homozygous genotype conferring greater risk than heterozygous for both cancer types. A common variant in pre-miR146a is associated with breast and thyroid cancer predisposition. Further work is required to fully elucidate how this finding can translated into clinical use.

Short Oral Communication 113 Thyroid Nodules & Goiter Tuesday Short Oral Communication Clinical 1:06 PM ANALYSIS OF 40696 FNAB OF THYROID NODULES PERFORMED IN ONE CENTER V. Makarin, A. Bubnov, Y. Fedotov, R. Chernikov, I. Sleptsov, A. Semenov, I. Chinchuk, N. Timofeeva, K. Novokshonov, U. Karelina, A. Uspenskaya, A. Kulash, S. Vorobyev Endocrine Surgery, Saint Petersburg State University, Saint-Petersburg, Russian Federation Fine needle aspiration biopsy is generally acknowledged as a «gold standard» for diagnostics of thyroid malignancies. However data on FNAB vary considerably in publications from different centers. In this study we have analyzed the results of more than 40.000 FNAB of thyroid nodules performed in North-West Regional Endocrine Center during 2010–2012 years. Indication for FNAB was a thyroid nodule of ‡ 1 cm, and a nodule less than 1 cm with clinical and ultrasound signs suspicious for malignancy. In case of multinodular goiter each nodule was examined separately. Female-male ratio was 10:1. Mean age for women was 56,0 – 13,7 years, for men - 54,7 – 14,8 years. Cytological results were as follows according to the Bethesda system: noninformative - 8%, benign nodules - 81,9% (colloid nodules 71,6%, Hashimoto’s thyroditis - 10,2%, subacute thyroditis and others - 0,02%), follicular lesion - 7,2% (follicular neoplasm 7,1%, follicular lesion of inderterminate significance - 0,1%), suspicious for malignancy - 0,02%; malignant tumours - 3%, among the latter 93,0% were papillary carcinomas. When comparing the cytological and histological results in 3004 patients, submitted to surgical treatment, false-positive and false-negative results were detected in 0,2% and 1,5% of cases, accordingly. The presented results based on analysis of more than 40000 FNAB confirm that this method is highly informative in detection of thyroid malignancies. Application of FNAB significantly increases number of patients submitted to surgery due to a malignant tumour, and decreases quantity of diagnostic operations. Only 12.5% operations

TUESDAY, OCTOBER 20, 2015 in 2004 were performed in our clinics in patients with malignancies but in 2012 its percentage increases up to 53%.

Short Oral Communication 114 Thyroid Nodules & Goiter Tuesday Short Oral Communication Clinical 1:12 PM AUTOIMMUNE THYROIDITIS AND DIFFERENTIATED THYROID CARCINOMA DO NOT AFFECT SERUM CT LEVELS IN PATIENTS WITH NODULAR DISEASE M.G. Castagna, F. Maino, S. Memmo, G. Busonero, M. Franci, B. Lucani, F. Pacini Department of Medical, Surgical, and Neurological Sciences, University of Siena, Siena, Italy The association between hypercalcitoninemia and autoimmune thyroiditis (AIT) or differentiated thyroid carcinoma (DTC) has been addressed, with conflicting results. To evaluate the influence of AIT and DTC on serum calcitonin (CT) levels, we retrospectively evaluated 2446 patients undergoing fine needle aspiration cytology for thyroid nodules. Patients with medullary thyroid carcinoma were excluded. CT was undetectable ( < 1.5 pg/ml, und-CT) in 1001/2446 (40.9%) and detectable ( > 1.5 pg/ml; det-CT) in the remaining 1445/2446 (59.1%) patients. In patients with det-CT the mean value of CT was 5.1 – 4.0 pg/ml (range 1.5–57.9 pg/ml). Based on the clinical diagnosis, patients were divided in two groups: nodular AIT (N-AIT, 15.6%) and nodular goiter (NG, 84.4%). The rate of und-CT was not different between N-AIT and NG, both in males (35.3% vs 23.9% p = 0.15) and females (47.7% vs 44.6% p = 0.31). The mean values of det-CT was not different between N-AIT and NG, both in females (4.6 – 2.7 pg/ml (range 1.5–13.4 pg/ml) vs 4.4 – 3.0 pg/ml (range 1.5– 25.4 pg/ml); p = 0.53) and males (8.4 – 5.4 pg/ml (range 2.9–24.3 pg/ ml) vs 6.7 – 5.6 pg/ml (range 1.5–57.9 pg/ml), p = 0.19). In particular, N-AIT was not associated with significant ipercalcitoninemia. Based on cytological results, patients were divided in two groups: Thy2 (93%) and Thy4/5 (7%). The rate of und-CT was not different between Thy2 and Thy4/5, both in males (23.8% vs 29.3% p = 0.45) and females (45.3% vs 45.1% p > 0.99). The mean values of det-CT was not different between Thy2 and Thy4/5 group, both in females (4.4 – 2.8 pg/ml (range 1.5–21.9 pg/ml) vs 4.7 – 3.5 pg/ml (range 1.5– 21 pg/ml); p = 0.87) and males (6.7 – 5.6 pg/ml (range 1.5–57.9 pg/ ml) versus 8.1 – 7.8 pg/ml (range 1.7–37.9 pg/ml), p = 0.62). In particular, Th4/Thy5 nodules were not associated with significant ipercalcitoninemia. In conclusion no differences in serum CT values were observed in nodular thyroid disease with or without autoimmunity and between nodules with benign or suspicious/malignant cytologies.

Short Oral Communication 115 Thyroid Nodules & Goiter Tuesday Short Oral Communication Clinical 1:18 PM THYROIDECTOMY DURING PREGNANCY: AN ANALYSIS OF THE AMERICAN COLLEGE OF SURGEONS NATIONAL SURGICAL QUALITY IMPROVEMENT PROGRAM (ACS NSQIP) DATASET M.B. Albuja Cruz, D.A. Hirth, P. Hosokawa, A. Paniccia, C.D. Raeburn, R.C. McIntyre GI, Tumor and Endocrine Surgery, University of Colorado School of Medicine, Aurora, CO Thyroid surgery is often required in women of child bearing age, but there is a paucity of data regarding the perioperative risk for pregnant patients.

A-49 The ACS NSQIP database from 2006–2012 was queried to obtain all female patients aged 12–50 years with CPT codes corresponding to thyroid lobectomy, thyroidectomy, or thyroidectomy with lymph node dissection. Preoperative, intra-operative, post-operative (including complications), and discharge variables were collected and compared. 17,142 patients were identified, 109 (0.6%) of which were pregnant. 6426 underwent lobectomy including 31 pregnant patients, 8693 patients underwent thyroidectomy including 51 pregnant patients, and 2023 patients underwent thyroidectomy with neck dissection, including 27 pregnant patients. Preoperative variables were similar. Pregnant patients were more likely than non-pregnant patients to undergo thyroidectomy for hyperthyroidism (43% vs 16%, p < .0001). A subgroup analysis of patients undergoing thyroidectomy for hyperthyroidism found that the pregnant patients had a significantly greater length of surgical stay (2.38 vs 1.35 days, p = .03). The rates of parathyroid auto-transplantation, neuro-monitoring and operative times were not significantly different in this group. There were no other significant differences in length of stay for any other groups. No complications were recorded for any of the pregnant patients, however, NSQIP does not record thyroidectomy specific complications (i.e. hypocalcemia and laryngeal nerve injury) or fetal outcomes. Post-thyroidectomy outcomes recorded in ACS NSQIP are similar for pregnant and non-pregnant patients. The only identified difference was increased length of surgical stay for pregnant patients undergoing thyroidectomy for hyperthyroidism. It is unclear from the NSQIP database whether this is due to post-thyroidectomy specific complications, complications of the pregnancy, or merely heightened monitoring.

Short Oral Communication 116 Thyroid Imaging Tuesday Short Oral Communication Clinical 1:24 PM INTRATHYROIDAL ECTOPIC THYMIC TISSUE MIMICKING THYROID CANCER IN CHILDREN H. Cho1, H. Song2, Y. Choi1, J. Park1, Y. Kim1, J. Cheon1, W. Kim1, I. Kim1 1 Radiology, Seoul National University Hospital, Seoul, Korea (the Republic of); 2Emergency Medicine, Wonkwang University Sanbon Hospital, Seoul, Korea (the Republic of) Ectopic intrathyroidal thymic tissue is thought to be a rare entity. It is due to aberrant thymic migration during embryogenesis, and when discovered incidentally in children, it can be mistaken for malignant thyroid nodule and may lead to unnecessary invasive procedures or surgery. However, the thymus has a unique appearance on ultrasonography (US) and ectopic thymic tissue can be easily identified. The US hallmark of intrathyroid thymic tissue is a hypoechoic lesion with linear or punctate internal echoes, the so-called ‘‘starry sky

A-50 appearance’’. These lesions have been shown to involute with growth and do not require treatment. The purpose of this study is to increase awareness of the important differential diagnosis between intrathyroidal ectopic thymic tissue and thyroid cancer when performing neck US in pediatric patients. We report 12 cases of intrathyroidal thymic tissues that were initially referred as possible thyroid nodules (n = 4), cervical lymphadenopathy (n = 1), thyroiditis (n = 2) or hypothyroidism (n = 5). Fine needle aspiration (FNA) was performed in 1 patient. US findings and cytologic feature of 1 case are described, and the distinguishing US characteristics of intrathyroidal thymic tissue versus papillary thyroid cancer (PTC) are discussed. Twelve pediatric patients who underwent thyroid or neck US were diagnosed with thyroid nodule including PTC in 1 patient and in-

TUESDAY, OCTOBER 20, 2015 trathyroidal thymic tissue in 11 patients. All lesions exhibited an echo texture identical to the normal thymus gland. Several US features may help to distinguish intrathyroidal thymic tissue from an PTC. FNA of the suspected nodule revealed polymorphous lymphoid cells in our study. Six patients (50%) underwent follow-up US imaging 3 months to 3 years later that showed stability of the intrathyroidal lesions. The increasing use of thyroid US in children may result in an increased detection of intrathyroidal thymic tissue, and it can be mistaken for thyroid cancer as both conditions have similar US features. This awareness is especially important in the current era of commonplace screening US. Close US surveillance in selected cases may help to avoid unnecessary invasive investigations and surgery in children.

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Monday, October 19–Tuesday, October 20, 2015 Poster 117 Autoimmunity Monday & Tuesday Poster 9:00 AM THE INFLUENCE OF GASTROINTESTINAL AUTOIMMUNE DISORDERS ON LEVOTHYROXINE REQUIREMENTS IN PATIENTS WITH HASHIMOTO’S THYROIDITIS N. Rella1,2, M.L. Garcı´a3, G. Szuman4, M. Scioscia1 1 Endocrinology, Sanatorio Dr Julio Me´ndez., Buenos Aires, Argentina; 2Endocrinology, Hospital Brita´nico, Buenos Aires, Argentina; 3Endocrinology, Sanatorio Dr Julio Me´ndez, Buenos Aires, Argentina; 4Endocrinology, Sanatorio Dr Julio Mendez, Buenos Aires, Argentina Positive parietal cells antibodies (PCA) have been reported in 20% of patients with autoimmune thyroid disease (ATD) and in 40% of patients with high requirements of levothyroxine (LT) (the dose per kg correlates with the severity of the gastric mucosal damage). Celiac disease (CD) is present in 2–5% of ATD. IgA anti-tissue transglutaminase (TTG) is a highly sensitive screening test. Ig A deficiency (IgAD), more common in patients with CD, determines false negative results. We report two cases of association of ATD + CD + chronic atrophic gastritis (CAG). Case 1: 41-year-old female with Hashimoto’s thyroiditis (HT) and progressive increase in her daily LT requirements. LT intake was correct without any food or medication interference. Positive PCA and a gastric biopsy confirmed the diagnosis of CAG. IgA antigliadin (AG), antiendomysial (EMAs), TTG levels and total IgA were low. LT administration with citrus juice (CT) led to a reduction of the LT daily dosage. IgG AG, EMA and TTG were elevated, duodenal biopsy showed lymphocytic infiltration in intestinal epithelium (MARSH 1) and HLA typing showed DQ8 genotype. Gluten-free diet (GFD) led to an additional reduction in LT daily dose. Case 2: 55-year-old woman with chronic anemia started treatment with LT after being diagnosed with grade III autoimmune hypothyroidism. She had secondary hyperparathyroidism due to vitamin D deficiency and osteoporosis. IgA TTG was negative but she had IgAD. IgG PCA and TTG were positive and duodenal biopsy confirmed the diagnosis of CD. GFD led to a small improvement of the anemia but LT requirements remained high. CT led to a reduction in LT requirements and a greater improvement of the anemia. Conclusions: 1) In patients with increased LT requirements, it is essential to rule out malabsorption, which may be secondary to more than one gastrointestinal autoimmune disorders. 2) In the presence of ATD, we should always consider the potential appearance of other immune-mediated diseases. The association between HT, CAG and CD is well known,but this triad in one patient is infrequent. 3) The recognition of multiorganic autoimmune subclinical disease is the best way to minimize the morbidity and mortality in these patients.

Poster 118 Autoimmunity Monday & Tuesday Poster 9:00 AM CHRONIC LYMPHOCYTIC THYROIDITIS IS ASSOCIATED WITH INVASIVE CHARACTERISTICS OF DIFFERENTIATED THYROID CARCINOMA IN CHILDREN AND ADOLESCENT G. Effraimidis1, P. Iliadou2, K. Michalakis2, G. Panagiotou2, P. Mitsakis2, F. Patakiouta3, K. Pazaitou-Panayiotou2 1 Internal Medicine Department, Endocrinology Section, Nykøbing Falster Hospital, Nykøbing Falster, Denmark; 2Department of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, Greece;

3

Department of Pathology, Theagenio Cancer Hospital, Thessaloniki, Greece

The association between chronic lymphocytic thyroiditis (CLT) and thyroid cancer is an interesting topic. The aim of the present study was to evaluate the differences in the demographic and histological characteristics and in the long-term outcome of thyroid cancer between children and adolescents with and without CLT. The medical records of children and adolescents ( £ 21 years old) were reviewed. The following data were recording: gender, year and age at diagnosis, family history of thyroid cancer, history of external radiation therapy, histological type (papillary and variants, follicular and variants), tumour size, multifocality, infiltration of thyroid parenchyma or surrounding soft tissues, vascular invasion, presence of lymph node, distant metastases and the presence of TgAb and TPOAb. One hundred eight children and adolescents (median age 19.0, interquartile range 4.0 years) were diagnosed with DTC. Thirty one patients (28.7%) presented histological characteristics compatible with CLT. Infiltration of thyroid parenchyma was more frequent in patients with CLT compared to patients without (74.2% versus 48.1% respectively, p = 0.024). Familial PTC was more frequent in patients with CLT compared to those without CLT (20.7 vs 2.8% respectively, p = 0.009). There was no better outcome with respect to the presence of CLT or not. Children and adolescents with CLT present more frequently familial PTC as well as thyroid cancer with invasive characteristics.

Poster 119 Autoimmunity Monday & Tuesday Poster 9:00 AM NEW ONSET GRAVES’ DISEASE MASQUERADING AS PREECLAMPSIA AND PULMONARY HYPERTENSION IN PREGNANCY I. Parody1, L.S. Chertman1, A.J. Manzano2, A. Hernandez1 1 Internal Medicine, Mount Sinai Medical Center, Sunny Isles Beach, FL; 2Mount Sinai Medical Center, Miami Beach, FL Graves’ disease is an autoimmune disorder causing hyperthyroidism with multisystem involvement that can resemble normal physiologic changes in pregnancy, requiring a high index of suspicion. The rare triad of hyperemesis gravidarum, preeclampsia, and pulmonary hypertension is an important clue. A 20 year old gravida 1 female presented at 30 weeks gestation with 3 days of palpitations, dyspnea and edema, with hyperemesis gravidarum, hair loss and inability to gain weight during the 1st trimester. She was hypertensive, tachycardic, and had alopecia, left eye proptosis, enlarged non-tender thyroid, intentional tremor and non-pitting edema. TSH 0.01, FT4 3.58, FT3 3.58, thyroid stimulating immunoglobulin 342 and thyrotropin binding inhibitory immunoglobulin 69 confirmed thyrotoxicosis caused by Graves’ disease. 2D echo showed ejection fraction > 70% and pulmonary hypertension with RVSP 48 which improved 1 week after starting methimazole and labetalol, and overt proteinuria of preeclampsia resolved. Pregnancy was managed conservatively until she returned at 37 weeks with preeclampsia and underwent C-section. The 2.7 kg male, Apgar 9/9, developed transient tachypnea and passed the newborn endocrinology screen. Graves’ disease in pregnancy presents non-specifically and is associated with maternal, fetal and neonatal adverse events. Hyperemesis gravidarum, with high hCG levels causing increased estrogen-mediated nausea, can be associated with gestational transient thyrotoxicosis and rarely, Graves’ disease in 0.1–1% of pregnancies. There is a known association between pulmonary hypertension and Graves’ disease, via

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increased catecholamine sensitivity and altered vascular smooth muscle and endothelial cell function, but only a few documented cases occurring during pregnancy. Hyperthyroid patients with dyspnea should be screened for pulmonary hypertension, and patients with pulmonary hypertension should be screened for hyperthyroidism. Prompt diagnosis and treatment of Graves’ disease during pregnancy is important to mitigate adverse events in the patient and fetus including possible antibody transfer. Concurrent preeclampsia and pulmonary hypertension should prompt investigation for underlying Graves’ disease.

1

Poster 120 Thyroid Cancer Monday & Tuesday Poster 9:00 AM THYROID NODULES AND ACROMEGALY: AN UNHAPPY COMBINATION L.S. Chertman1, M.M. Chertman2,3 1 Internal Medicine - Medical Teaching Service, Mount Sinai Medical Center, Miami Beach, FL; 2Endocrinology Private Practice, University of Miami Hospital, Miami, FL; 3Clinical Preceptorship, University of Miami Miller School of Medicine, Miami, FL Increased IGF-1 in acromegaly stimulates the thyroid follicles leading to higher incidence of goiter (20–80%) than the general population. Acromegaly has a 1.5–4 fold increased risk of neoplasms, with the prevalence of DTC ranging from 5–10%. A 74 year old man had bilateral complex cold thyroid nodules, benign by UG-FNA, measuring 2.6 cm for which surgery was recommended but refused by the patient. For the last 20 years he had sausage-like fingers, thick lips, wide nose, and increased shoe size. High IGF-1 and failure to suppress GH with glucose load confirmed acromegaly and his pituitary micro-adenoma was treated with gamma knife. For the next 4 years thyroid ultrasound was unchanged, until he developed compressive symptoms and enlarging nodules. Repeat UGFNA was negative (right) and non-diagnostic (left). Gene Expression Classifier was requested but not done. CT neck showed bilateral lung nodules, confirmed as metastatic follicular cancer on biopsy. Pathology of total thyroidectomy showed follicular thyroid cancer (FTC) with lymphovascular and capsular invasion, pT3NxM1. 150 mCi I-131 was given and post I-131 scan had intense accumulation in the thyroid and lungs, with thyroglobulin (TG) 11,352 ng/mL. On soranefib he developed hand-foot syndrome, and 4 months later I-131 total body scan had no abnormal accumulation, TG was 588.6 ng/mL, and PET/CT scan was negative. Octreotide was started after increased IGF-1 confirmed active acromegaly but discontinued after he developed cholecystitis. The 2nd treatment of 150 mCi I-131 was given and surprisingly, post therapy scan became positive (accumulation in both lungs). DTC in the setting of acromegaly is mostly papillary and in females. Our case is a rare combination of FTC in a male. DTC likely results from IGF-1 stimulation of cellular proliferation and angiogenesis plus anti-apoptotic effects, but there’s no correlation between DTC risk and IGF-1 levels or duration of acromegaly. Prior radiotherapy and BRAF mutations may play a role. Sorafenib, a multikinase inhibitor, is an option for I-131 resistant metastases. Guidelines on acromegaly should recommend surveillance with periodic thyroid US and surgery for suspicious nodules even with negative UG-FNA.

Poster 121 Autoimmunity Monday & Tuesday Poster 9:00 AM ORBITAL LYMPHATICS IN THYROID EYE DISEASE L. Wong1, G. Lee2,3, D. Bielenberg4, D. Amarnani1, S.K. Freitag2,3, P.A. D’Amore2,1, L.A. Kim2,1

Schepens Eye Research Institute, Boston, MA; 2Ophthalmology, Harvard Medical School, Boston, MA; 3Ophthalmic Plastic Surgery, Massachusetts Eye and Ear Infirmary, Boston, MA; 4Surgery, Harvard Medical School, Boston, MA Graves’ Disease is often associated with an ophthalmic manifestation known as Thyroid Eye Disease (TED). In TED, fat and muscle in the orbit are preferentially involved in inflammation and tissue expansion while the rest of the body is generally spared. These changes can cause compressive optic neuropathy and potential blindness. Our research focuses on identifying what makes the orbit a unique environment that is susceptible to excessive edema, cytokines, and auto-antigens. It is believed that the orbit is one of the few locations in the body where no lymphatics exist. TED typically has an active phase and a chronic phase. The active phase is characterized by severe inflammation and edema while the chronic phase is thought to primarily involve fibrosis. In order to understand the preferential involvement of the orbit, we propose to characterize the orbital vasculature in patients with TED. Orbital fat specimens from twenty patients with TED as well as five age and gender matched controls were examined using immunohistochemistry for vascular and lymphatic endothelial cell markers. One of the most specific lymphatic markers, podoplanin, was consistently negative in patients in the chronic stage of thyroid eye disease. Interestingly, a small subset of active phase patients stained positive for podoplanin and had lymphatic capillaries invested in the adipose tissue. Another less-specific marker, LYVE-1, was positive in active and chronic TED patients, highlighting macrophage infiltration. CD31, a pan-endothelial vascular marker, was markedly increased in TED specimens compared with controls. In TED, there is active blood vessel infiltration as part of the inflammatory response. Lymphatic vessels may have the ability to form during the active phase of the disease, however, the absence of positive staining during the chronic stage suggests their eventual regression. These findings are consistent with a disproportionate fluid exudation compared to lymphatic drainage.

Poster 122 Autoimmunity Monday & Tuesday Poster Basic 9:00 AM CD40 SIGNALING IN THYROID CELLS IS MEDIATED THROUGH NF-KB2 ACTIVATION: IMPLICATIONS TO THYROID AUTOIMMUNITY H.J. Lee, M. Stefan, A. Lombardi, C. Li, E. Concepcion, Y. Tomer Endocrinology, Diabetes, and Bone Disease, Icahn School of Medicine at Mount Sinai, New York City, NY CD40, a TNF-receptor expressed primarily on antigen presenting cells but also on thyrocytes, is emerging as a pivotal susceptibility gene for Graves’ disease (GD) and autoimmunity in general. The interaction between CD40 and its ligand provides costimulatory signals essential for the adaptive immune response. Augmented CD40-CD40 ligand interaction has been implicated in autoimmune diseases, and our lab has previously shown that thyroidal CD40 expression plays a key role in the etiology of GD. Furthermore, we showed that a 5’UTR SNP in CD40 is associated with GD via increased CD40 surface expression. The exact molecular mechanisms, however, by which thyroidal CD40 expression triggers thyroid autoimmunity are unknown. We hypothesized that the effector functions of thyroidal CD40 occur via both the canonical NF-KB1 and the noncanonical NF-KB2 pathways. To delineate the molecular events that follow CD40 activation in thyrocytes, we transfected a human thyroid cell line (ML-1) to overexpress and over-stimulate CD40. We also exposed primary

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 human thyrocytes, cultured from both normal and GD thyroids, to G28.5, a CD40-stimulating mAb. CD40-overexpressing ML-1 cells and CD40-stimulated primary thyrocytes demonstrated significant increases in the mRNA and protein levels, measured by RT-PCR and Luminex respectively, of both NF-KB1 (IL-6, IL-8, TNFa) and NF-KB2 (BAFF, CCL21) cytokines. Western blot analysis of the primary thyrocytes showed that p65, a transcription factor unique to NF-KB1, appeared to be constitutively expressed with marked upregulation in the setting of GD. In contrast, p52, the transcription factor specific to NF-KB2, was induced only after CD40 stimulation in both normal and GD thyrocytes. These results suggest that thyroidal NF-KB activation is key to the pathogenesis of GD and that thyroidal CD40’s effects in GD may be mediated more by the NFKB2 pathway. Our data suggest that new therapies for GD could target thyroidspecific, downstream signal cascades and cytokines triggered by the thyroidal NF-KB2 signaling pathway.

Poster 123 Autoimmunity Monday & Tuesday Poster Basic 9:00 AM THE ROLE OF THYROID CD8 + T REGULATORY CELLS IN THYROID EYE DISEASE (TED) F. Al-Ansari, H. Lahooti, J.R. Wall Academic Medicine, Sydney Medical School, Nepean, The University of Sydney, Bankstown, NSW, Australia Thyroid Eye Disease (TED) is an autoimmune disease involving the inflammation of the extra-ocular muscles and the surrounding connective tissue. It is usually associated with thyroid autoimmunity and occurs in approximately 50% of Graves’ Disease (GD) and 25% of Hashimoto’s Thyroiditis patients. The link between the autoimmune reactions in the thyroid and the eye in TED is unclear. A proposed link is the presence of a thyroid and orbital tissue shared antigen that becomes target of immune cells. As in other autoimmune diseases, the pathogenesis of this disease may be related to a lack of the normal regulation of immune reactions. These regulations are mainly induced by T regulatory cells. Most of the studies addressing T regulatory cells so far has focused on CD4 + T regulatory cells. However, recent research has shown that a lack in the number and/or function of CD8 + T regulatory cells may equivalently lead to the development of various autoimmune conditions. We hypothesise that the development of TED may be related to a reduction in the number of CD8 + T regulatory cells within the thyroid tissue that allows the over activation of the thyroid and orbital tissue shared antigen specific T cells. These activated cells entre the blood stream and find their way into the orbit where they initiate the autoimmune reactions and therefore inflammation. We obtain fresh thyroid specimen after thyroidectomy from GD patients. The tissues are processed immediately to isolate mononuclear cells which are labelled with flurochrome conjugated antibodies for CD8 + T regulatory and CD8 + T effector cell markers. The number of CD8 + T regulatory and CD8 + T effector cells are compared to their number in the peripheral blood. These numbers are correlated to the presence/absence of TED. So far, our data shows some decrease in the number of CD8 + T regulatory cells in the thyroid of TED patients compared to GD patients without the eye disease. These data will help in understanding the link between thyroid autoimmune reactions and the development of TED. It will also aid in understanding the relevance of CD8 + T regulatory cells to the development of autoimmune diseases, and in the development of future immunotherapy for TED.

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Poster 124 Autoimmunity Monday & Tuesday Poster 9:00 AM A CASE OF SERONEGATIVE GRAVES’ DISEASE IN A PATIENT WITH IGG DEFICIENCY R. Asghar Internal medicine -Endocrine, University of Texas Medical Branch Galveston, Galveston, TX There is a paradoxical relationship between immunodeficiency disease and autoimmunity. Defects within particular components of immune response carry a higher risk for autoimmune disease than others. This is a rare case of seronegative Graves’ disease in a patient with IGG deficiency. A 58 year old Caucasian female presented for evaluation of hyperthyroidism. Her symptoms included weight loss, anxiety, heat intolerance, palpitations, sweating, tremor, blurry vision over 2 months. Her past medical history was significant for recurrent respiratory infections including pneumonia, otitis media and rhinosinusitis. Patient had been diagnosed with hypogammaglobulinemia recently and was started on immunoglobulin G (IVIG) infusion therapy a few months prior to presentation. Her physical exam showed tachycardia, warm skin, fine finger tremors, hyperreflexia. Thyroid exam revealed diffuse goiter with thyroid bruit. Ophthalmologic exam revealed failure of convergence, mild exophthalmos and lid lag. Laboratory data revealed TSH < 0.015uIU/ml (0.45– 4.70), Free T4 3.29 ng/dl (0.78–2.20) and total T3 353.00 ng/dl (97.00–170.00), TSI 102 (122%) and TRAB < 0.90 (1.75 IU/L). Patient was started on Methimazole 10 mg PO TID and Propranolol. Three months later, she had clinical improvement in her symptoms including goiter and ophthalmopathy. Subsequent Laboratory data showed TSH < 0.01uIU/ml, Free T4 1.45 ng/dl and Total T3 192 ng/dl Seronegative Graves’ disease is very rare which is secondary to low titer of antibodies in blood. Immunodeficiency can lead to autoimmune disorders which is a well known factor. Association of immunodeficiency states is rarely described with Graves’ disease in literature. This is a rare case of IGG deficiency presenting with Graves’ disease after initiation of IGG therapy. IGG therapy has been used to treat Graves’ disease however this patient developed Graves’ disease after starting IGG infusion that is very unusual. Seronegativity of Graves’ disease is also an unusual finding in this case.

Poster 125 Autoimmunity Monday & Tuesday Poster 9:00 AM SUCCESSFUL TREATMENT OF CHRONIC IDIOPATHIC URTICARIA AND ANGIOEDEMA IN A PATIENT WITH SUBCLINICAL HYPERTHYROIDISM ASSOCIATED WITH TRIPLE POSITIVE ANTIBODIES D. Abushanab, A.A. Achira, W. Taha Endocrinology and Metabolism, Wayne State University, Dearborn, MI An association between chronic idiopathic urticaria (CIU) and autoimmune thyroid disease (ATD) has been reported. However, coexisting Graves’ disease or subclinical hyperthyroidism has only rarely been observed. A 30-year-old woman presented with a 9-month history of daily CIU and did not respond to regular antihistamine therapy (dephenhydramine up to 300 mg daily) and only partially responded to systemic steroids (up to 50 mg daily of prednisone). The patient was seen by an Immunologist and was started on one omalizumab injection every month but with only partial improvement. The patient complained of anxiety and palpitation, so a thyroid function test was

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done. Test results showed normal levels of free thyroxine 3 (free-T3) and free thyroxine 4 (free-T4), but markedly depressed levels of thyrotropin (TSH). Subsequent tests revealed positive antithyroid peroxidase antibodies (anti-TPO = 1200), antithyroglobulin antibodies (anti-TG); most importantly, thyroid-stimulating immunoglogulin (TSI = 196) was also high. Radioactive thyroid uptake scan showed 36.6% uptake confirming hyperthyroid state. Patient was started on Methimazole 10 mg daily and her CIU and angioedema improved significantly once the thyroid levels normalized. There is a well-known relationship between CIU and thyroid autoimmunity. The pathophysiology of the association is not well understood, but patients with CIU and ATD present a greater risk of angioedema. Most reported cases of ATD with CIU are associated with high levels of anti-TPO antibodies and Hashimoto’s hypothyroidism. Only a few hyperthyroidism and CIU cases have been described. The presence of angioedema in our case makes it even more rare and interesting. Clinicians should exclude hyperthyroidism if CIU and angioedema respond poorly to conventional treatments, as prompt treatment of hyperthyroidism significantly improves urticaria and angioedema.

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Poster 126 Autoimmunity Monday & Tuesday Poster 9:00 AM A RARE CASE OF POLYGLANDULAR AUTOIMMUNE DISEASE TYPE IIIB R. Roy, M.K. PANDYA, M. Raghuwanshi Endocrinology, Rutgers University-NJMS, Newark, NJ Polyglandular Autoimmune Syndrome is an underdiagnosed endocrine disorder that involves at least two endocrine gland insufficiencies associated with autoimmune, organ-specific, endocrine and non-endocrine diseases. PAS Type IIIb, characterized by autoimmune thyroiditis and pernicious anemia, is more prevalent in middle-aged women. We present a rare case of Polyglandular syndrome, Type III B in a previously healthy young man. A 39 year old man with a history of asthma presented with worsening shortness of breath and abdominal pain over the past 2 months. He also reported 15 pound weight gain, fatigue, hair loss, brittle nails, and hand paresthesia over the past 1 year. Physical exam was significant for atrophic glossitis. He was found to have severe macrocytic anemia secondary to vitamin B12 deficiency with positive intrinsic factor antibodies. His thyroid function tests revealed hypothyroidism with positive anti-thyroglobulin and thyroid peroxidase antibodies. He was treated with blood transfusion and intramuscular Vitamin B12 for his pernicious anemia and levothyroxine replacement for hypothyroidism. Patient was discharged after resolution of anemia with improvement of his symptoms. PAS type 3 is characterized by autoimmune thyroid disease associated with other autoimmune disease in the absence of Addison’s disease and/or hypoparathyroidism. The patient’s anti-thyroid peroxidase and thyroglobulin antibodies confirmed Hashimoto’s thyroiditis. Type IIIb is associated with pernicious anemia resulting from autoimmune atrophic gastritis characterized by fundic gland atrophy and/or auto-antibodies against secretory products of parietal cells. Due to our patient’s intrinsic factor antibodies, he developed vitamin B12 malabsorption, leading to symptomatic macrocytic anemia, hand paresthesia, and atrophic glossitis. PAS type III is typically limited to 2-3 glands, but involvement of up to 7 autoimmune diseases with auto-antibodies has been documented. Thus, this patient will require screening for other glandular involvement. This case emphasizes the need to consider multiple gland involvement in autoimmune endocrine disease.

Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM CLINICAL FEATURES OF HASHIMOTO’S THYROIDITIS WITH ELEVATED SERUM IMMUNOGLOBULIN G4 LEVELS IN JAPAN K. Takeshima, H. Ariyasu, I. Hidefumi, Y. Inagaki, H. Yamaoka, Y. Furukawa, A. Doi, H. Furuta, M. Nishi, T. Akamizu Wakayama Medical University, Wakayama, Japan Immunoglobulin G4-related disease (IgG4-RD) is characterized by elevated serum IgG4 levels, IgG4-positive plasmacytes, and lymphocyte infiltration into multiple organs. IgG4 thyroiditis is a subset of patients with Hashimoto’s thyroiditis (HT) who exhibited histopathological features of IgG4-RD; its source of serum IgG4 is suggested to be the thyroid gland. Although a relationship between IgG4-RD and IgG4 thyroiditis has been reported, the meaning of serum IgG4 in HT is uncertain. In this report, we prospectively evaluated serum IgG4 levels and clinical features of patients with HT. A total of 149 patients with HT were prospectively recruited into this study. According to the comprehensive diagnostic criteria of IgG4-RD, patients were divided into two groups: elevated IgG4 ( > 135 mg/dL) and non-elevated IgG4 ( £ 135 mg/dL). Median serum IgG4 levels of HT patients were 32.0 mg/dL (interquartile range, 20.0–65.0), with a unimodal non-normal distribution. Six patients (4.0%) had elevated serum IgG4 levels above 135 mg/dL. The elevated IgG4 group was older and exhibited enlarged hypoechoic areas in the thyroid gland, as revealed by ultrasonography, relative to the non-elevated IgG4 group. Levothyroxine (L-T4) replacement doses, titers of anti-thyroid antibodies and antinuclear antibodies did not differ significantly between the two groups. Two out of six HT patients with elevated serum IgG4 levels had extra-thyroid organ involvement as seen in IgG4-RD. In conclusion, HT patients with elevated serum IgG4 levels shared clinical features with both IgG4-RD and IgG4 thyroiditis. Longer follow-up periods and histopathological assessments are needed to further understand the meaning of elevated serum IgG4 levels in HT.

Poster 128 Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM LIVER ENZYME CHANGES AND TREATMENT OF HYPERTHYROIDISM IN GRAVES’ DISEASE: IS COMMON BELIEF INCORRECT? A. Hsieh1,2, S. Adelstein3,2, S. McLennan1,2, P.F. Williams1,2, S.M. Twigg1,2, E. Chua1,2 1 Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia; 2Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; 3Department of Clinical Immunology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia Abnormal liver function tests (LFT) are often noted at the time of initial presentation of Graves’ disease (GD). Earlier studies postulated the changes were due to an excess of circulating thyroid hormones. However, a recent study{ reported TSH receptor antibody (TRAb) level was the main factor associated with abnormal LFT. We performed a review and analysis of the Royal Prince Alfred Hospital Adult Thyroid Clinic database from 2000 to 2012 inclusive to determine the liver enzyme profiles in adults with GD at baseline and after therapy. Of the 146 patients who had FT4, FT3, LFT and TRAb results available prior to commencement of anti-thyroid medications, the mean age at diagnosis was 35 years; 82% were female; 39% had

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family history of thyroid disorders. Among the 146 patients, 69 (46%) had abnormal LFT. GGT was most frequently abnormal in 79% of patients, followed by ALT (56.5%), ALP (39.1%) and AST (29%). Following medical therapy, 75% of the LFT normalised, 13% were persistently abnormal, and 12% were lost to follow up. In light of the non-linear correlation of TRAb, FT3 & FT4 results at high levels, we categorised TRAb level (IU/l) into mild (TRAb £ 10), moderate (TRAb 10.1–20) and severe (TRAb > 20) elevations; FT3 by multiples of the upper limit of normal (ULN), i.e. FT3 £ 2.5xULN, 2.5–5xULN, or > 5xULN, and FT4 by £ 2xULN, 2.1–3xULN, or > 3 xULN. By logistic regression analyses, high TRAb was significantly associated with instances of abnormal LFT (P = 0.008, OR 1.33– 6.92) but not related to the levels of individual liver enzyme. TRAb levels were significantly associated with FT3 and FT4 elevation. Multivariate regression of TRAB, FT3 and FT4 demonstrated the elevation in liver enzymes was associated more strongly with FT3 & FT4 than TRAb. However, in the subgroup with persistently abnormal LFT, the initial FT3 and FT4 levels were not associated with the occurrence of initial LFT abnormality. Our data demonstrates that GD is most commonly associated with abnormal levels of GGT and that abnormal LFT is more directly linked to the degree of thyrotoxicosis than levels of TRAB. { He K et al. Hepatic dysfunction related to thyrotropin receptor antibody. Exp Clin Endocrinol Diabetes 2014.

Frequency of KIR2DS1( + )HLA-CwLys( + ) was significantly lower in the GD patients than in the controls (5.93% vs 17.59%, p < 0.01). The CD69 expression, a NK activation marker, remarkably decreased in NK cells of GD patients (53.86% – 22.42% vs 67.86% – 15.42%, p < 0.01). Our data suggest that KIR/HLA-C may correlate with the pathogenesis of GD, and the activity of NK cells in GD are impaired. The deficiency of KIR2DS1( + )HLA-CwLys( + ) may contribute to the defection of NK cell in GD.

Poster 129 Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM POLYMORPHISM OF KILLER CELL IMMUNOGLOBULIN RECEPTORS (KIRS) AND HLA IN GRAVES’ DISEASE H. Zhang1,2, C. Guo1, J. LI1, J. Zhao1,2 1 Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; 2Shandong Clinical Medical Center of Endocrinology and Metabolism, Jinan, China Graves’ disease (GD) is one of organ-specific autoimmune diseases. The defect of immunosuppression plays an important role in the initial stage, and the pathogenesis is not elucidated. Natural Killer (NK) cell is a kind of important immune regulator. Several abnormalities of NK cell activity in GD patients have been described, but the results were controversial. Interactions between killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands regulate the activity of NK cell. The aim of this study is to determine whether certain KIR/HLA genotype combinations play a role in the pathogenesis of GD, and to investigate the activity of NK cell in GD patients. 118 unrelated GD patients and 108 random healthy individuals were enrolled in a case-control study. Peripheral blood was collected for DNA extraction. Genotyping KIR genes and HLA-C alleles were acquired by polymerase chain reaction with sequence specific primers (PCR-SSP), followed by electrophoresis on an agarose gel.95 Graves’ disease patients and 83 healthy controls were enrolled to detect the surface molecules of peripheral blood mononuclear cell, including CD3, CD56 and CD69, using flowcytometry.

Poster 130 Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM SINGLE DOSE TRANSCUTANEOUS INJECTION OF TRIAMCINOLONE ACETONIDE FOR EYELID SWELLING AND RETRACTION ASSOCIATED WITH GRAVES’ DISEASE C. Funaki, R. Inoue, T. Inoue Olympia Eye Hospital, Shibuya-ku, Japan To determine the effectiveness of Triamcinolone Acetonide (TA) injection transcutaneously, but not sub-conjunctively as previously reported, for Graves’ Disease (GD)-related eyelid swelling and retraction. To monitor the side effects of TA, such as change of intraocular pressure (IOP), and adrenal cortex function etc. Thirty eyes with eye lid swelling and 26 eyes with eyelid retraction were enrolled in this study. An injection of 0.5 ml of TA (40 mg/ml) was performed into the region. Within 6 months after the injection, improvement of eyelid swelling and retraction was determined by digital photography analysis. IOP was measured individually before and 1 month after the injection. Sixteen patients with both eyelid injections were tested serum cortisol and ACTH. Eyelid retraction improvement was found in 25 of total 26 eyelids within 1 to 4 months’ time, only 1 eyelid without prominent change by the end of the 6 months observation period. Eyelid swelling improved in all patients. No IOP elevation was detected after the procedure (pre-injection IOP average 14.7 mmHg, post-injection IOP average 15.1mmHg, p = 0.10). Nine of 16 patients had the normal range serum cortisol and ACTH, while the other 7 had lower level of cortisol and/or ACTH after 1 month of the injection. This study suggests that a single dose injection of TA transcutaneously, but not sub-conjunctively, is an effective treatment for GDrelated eyelid swelling and retraction. No elevation of IOP is found, which usually considered the side effect of TA. However there is possibility that injection of TA could suppress the function of the adrenal cortex, especially when repeated procedure is required in the long term.

Poster 131 Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM AN ANALYSIS OF 10 JAPANESE PATIENTS WITH RIEDEL’S THYROIDITIS ASSOCIATED WITH IGG4-RELATED DISEASE H. Ariyasu1, K. Takeshima1, Y. Furukawa1, H. Furuta1, M. Nishi1, M. Hirokawa2, A. Yoshida3, R. Imai4, T. Akamizu1 1 The first department of internal medicine, Wakayama medical university, Wakayama, Japan; 2Kuma Hospital, Kobe, Japan; 3Kanagawa Cancer Center, Yokohama, Japan; 4KKR sapporo Medical center, Sapporo, Japan Riedel’s thyroiditis (RT) is a rare chronic fibrosing disorder characterized by a hard, infiltrative lesion in the thyroid gland, which is often associated with multifocal fibrosclerosis. Immunoglobulin G4-

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related disease (IgG4-RD) is typified by infiltration of IgG4-positive plasma cells into multiple organs, resulting in tissue fibrosis and organ dysfunction. In order to evaluate the clinicopathological features of RT and its relationship with IgG4-RD, we performed a Japanese literature search using the keywords ‘‘Riedel’’ and ‘‘Riedel’s thyroiditis.’’ We used the electronic databases Medline and Igaku Chuo Zasshi, the latter of which is the largest medical literature database in Japan. The diagnosis of RT was based on the presence of a fibroinflammatory process with extension into surrounding tissues. Only 10 patients in Japan fulfilled RT diagnostic criteria during the 26-year period between 1988 and 2013. Two patients with confirmed IgG4/IgG immunohistochemical findings demonstrated 43 and 13 IgG4-positive plasma cells per high-power field, respectively, and the IgG4-positive/IgG-positive plasma cell ratios of 20% and less than 5%. Of the 10 patients with RT, two received glucocorticoids, one of whom experienced marked shrinkage of the thyroid lesion. One patient had extra-thyroid involvement in the form of retroperitoneal fibrosis. Although the clinicopathological features of RT suggest that IgG4-RD may be the underlying condition in some cases, further investigation is needed to clarify the etiology of RT in relation to IgG4-RD.

Poster 133

Poster 132 Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM SERUM SELENIUM AND SELENOPROTEIN P LEVELS IN GRAVES’ DISEASE, GRAVES‘ OPHTHALMOPATHY AND HASHIMOTO’S THYROIDITIS PATIENTS: A SAMPLE OF THE BRAZILIAN POPULATION M.A. Federige2, A.P. Milkos2, M. Koike2, K. Takei2, E.S. Portes2, J.H. Romaldini1 1 Endocrinology, PUC-CAMPINAS, HSPE-IMASPE, Sao Paulo, Brazil; 2Endocrinology, IAMSPE, Sao Paulo, Brazil Selenium (Se), selenoprotein P (SePP) has an antioxidant function. SePP is responsible for transporting Se and Se has been used to avoid progression of Graves’ ophthalmopathy (GO) and reducing thyroid antibodies levels. Therefore, it is important to measure Se levels before therapeutic administration. In this study, we aimed to investigate Se and SePP levels in patients with Graves’ disease (GD) with and without GO, Hashimoto‘s thyroiditis (HT) and compared with controls (C). We studied 65 patients; 44 with GD; 21 with active GO; 33 with HT and 27 C. Se values was measured using graphite furnace atomic absorption spectrophotometry. Serum SePP levels were measured by an ELISA method. Data were shown as medians and interquartile ranges. Groups were compared using Kruskal-Wallis Anova on ranks complemented by Dunn test. Serum Se levels was similar among groups. GD: 53.9 (46.5– 67.9 lg/L); GO: 53.6 (43.5–60.0 lg/L); HT: 54.2 (43.9–60.0 lg/L) patients and C group: 56.0 (52.4–61.5 lg/L), P = 0.393. However, serum SePP was lower in GO: 0.30 (0.15-1.05 mg/L) and in HT: 0.45 (0.17–1.39 mg/L) compared to C group: 1.00 (0.56–4.21 mg/L) as well as to GD: 1.10 (0.28–2.44 mg/L) patients, P = 0.017. Regression analysis identified antithyroglobulin antibodies (r = 0.252; P = 0.035) as predictor of Se level and Free T3 (r = 0.281; P = 0.019) as predictor of SePP level. In conclusion, the inflammatory reactions in HT and GO may be the main reason for the lowest concentration of SePP found in these patients. An increase in consumption of Se-dependent proteins, as an attempt to reduce production of free radicals generated by the immunological attack, may explain these findings.

Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM EFFECTS OF SELENIUM SUPPLEMENTATION ON SERUM THYROID PEROXIDASE ANTIBODY LEVELS IN PATIENTS WITH AUTOIMMUNE THYROIDITIS J.R. Neto, A.A. Nogueira de Pontes Endocrinology, Federal University of Campina Grande, Campina Grande, Brazil Selenium (Se) is a precursor of many important selenoenzymes, most of then involved with the regulation of thyroid, notably the glutathione peroxidase (GPx) which eliminates free radicals during the formation of thyroid hormones, and deiodinases, responsible for the conversion of FT4 in T3. Deficiency of this mineral leads to worsening of autoimmune conditions such as autoimmune thyroiditis (AIT) enhancing the formation of antibodies like the Thyroid Peroxidase Antibody (TPOAb). We performed single-blind controlled trial to primary evaluate the effects of Se supplementation on the levels of TPOAb and the clinical implications that this supplementation can bring in AIT patients, by assessing the levels of TSH and FT4. Fifty-two patients aged between 21 and 74 years (mean 47.9 years) with AIT and TPOAb levels higher than 100 IU/dL were recruited and underwent supplementation during sixty days with chelated Selenium (60 lcg). The mean levels of TPOAb initially 520.4 IU/dl ( – 450.8) compared with post-treatment 312.1 IU/dl ( – 354.7) showed an average reduction of 208, 2 IU/dl ( – 160.5) in absolute values and percentage of 51.3% ( – 22.4) compared to the control group( p < 0,01). None statistically significant changes between the initial and final levels of TSH and FT4 were demonstrated. This is the first South American study to analyses these effects of Se and the first to demonstrate that a significant reduction of TPOAb levels can be achieved with a physiologic supplementation, and not only with a daily dose much greater than that required by the body, as many authors suggested. In addition, most of them assessed the effects of a 3 to 9 months supplementation.We showed that a similar response is also possible with 2 months.The absence of changes in TSH and FT4 levels suggests that the activation of deiodinases is only compromised by severe deficiency of Se, contrary to GPx, that rely on optimal concentration of it This trial showed that is possible to achieve significant reductions in the levels of TPOAb with a physiologic Selenium supplementation (60lcg/day) for a 2 months period in patients with autoimmune thyroiditis.

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Poster 134 Autoimmunity Monday & Tuesday Poster 9:00 AM EVOLUTION AND TREATMENT OF A CASE WITH MODERATE SEVERE GRAVES’ ORBITHOPATHY WITH LATE REACTIVATION M. Simescu1, C. Podia Igna2, L. Parlog Cristian3 1 Endocrinology, SC SIMEDIS CONSULT SRL, Bucharest, Romania; 2Endocrinology, Policlinica Astra, Sibiu, Romania; 3 Endocrinology, Medlife, Bucharest, Romania Graves’ orbithopathy (GO) rarely becomes active again once it had become quiescent. We present the evolution and treatment of a 64 y.o. women, nonsmoker, with moderate severe GO (MS GO) with late reactivation (LR) at 10 years and 15 years after the onset of the disease. In 2000 she developed GO 10 months after hyperthyroidism, NOSPECS 2b4c, CAS 4, treated with i.v. and oral methylprednisolone (MP) (7, 5 g) and orbital radiotherapy (20 Gy). After 18 months of recovery she had a relapse of hyperthyroidism and GO NOSPECS 2b4c5b6a, CAS 5, treated with i.v. and oral MP (9 g). Methotrexate (MTX) was associated after 1 month, 15 mg/week for 8 months with restoration of orbital changes to normal at the end of the treatment. She had first LR of GO 10 years (7 years of quiescent GO disease) and a second LR 15 years after the onset of the disease, with extraocular muscle involvement (EOMI), diplopia grade IV, CAS 4 (no drive, no read). The first LR GO was associated with euthyroidism; the second LR developed after the relapse of hyperthyroidism. Both episodes of LR GO were treated with Methotrexate 15 mg/week combined with i.m. MP for the first 4 months (7 g and 5 g respectively) with complete recovery of diplopia and EOMI. The markers of thyroid autoimmunity (TSHRAb and anti-TPO) were not detectable. The thyroid ultrasound revealed a small gland with intense vascularization. Hyperthyroidism was treated with ATS. The state of euthyroidism was repeatedly controlled. The last MRI showed edematous infiltration - prolonged T2 relaxation time- of 6 EOM and partial T1 signal of other 4 EOM. There is no evidence of thyroid autoimmunity markers at the LR GO. The first LR GO was associated with euthyroidism. Complete recovery of diplopia and EOMI with restoration of normal vision was obtained with this therapeutic formula, MTX up to 1 year combined with corticotherapy in the first months.

Poster 135 Autoimmunity Monday & Tuesday Poster 9:00 AM ACID GLYCOPROTEIN-POSITIVE CELLS IN THE THYROID OF SUBACUTE THYROIDITIS H. Fukazawa2,1, N. Ohtani3, Y. Ohsaki1, K. Yoshida4, H. Ohtani3 1 Internal Medicine, KKR Suifu Hospital, Mito, Japan; 2Division of Health Care Center, Mito Kyodo General Hospital, Mito, Japan; 3 Department of Pathology, Mito Saiseikai Hospital, Mito, Japan; 4 KKR Tohoku Kousai Hospital, Sendai, Japan Immunosuppressive acidic protein (IAP) is a major acute phase protein that has been reported in the sera of cancer patients, as well as those with collagen diseases and certain inflammatory diseases. We previously reported that IAP, a type of a1-acid glycoprotein (AGP), is elevated during the acute phase of subacute thyroiditis (SAT) ( JCEM 71:193, 1990). We also reported that serum concentrations of IAP in patients with SAT are significantly higher than in those with hyperthyroid Graves’ disease (GD), chronic thyroiditis and silent thyroiditis. As no IAP antibody is currently available, AGP antibody was used in the present study. Tissue culture studies have shown that AGP is mainly produced by hepatic cells, but extrahepatic expression

A-57 has been reported in other tissues (e.g., human endothelial cells and cultured human monocytes). However, no studies have examined AGP expression in the thyroid of patients with SAT. We therefore investigated the histological expression of AGP in the thyroid of a patient with SAT. Subjects: A 58-year-old woman (reported at 14th International Thyroid Congress, Paris, 2010) with high TSH receptor antibody (TRAb) and increased thyroidal radioactive iodine uptake (RAIU) was diagnosed with GD, and near total thyroidectomy was performed due to side effects of methimazole. Histological examination unexpectedly revealed marked granulomatous inflammation in the thyroid. Granulomas consisted of epithelioid cells, multinucleated giant cells and lymphocytes without caseous necrosis. The pathological diagnosis was SAT. Immunohistochemically, expression of AGP was observed in the thyroid follicular epithelium, epithelioid cells and mononuclear cells. Double staining confirmed that AGP-positive mononuclear cells comprised CD3-positive T-lymphocytes and some CD68positive macrophages. We previously reported that serum IAP, a type of AGP, is elevated during the acute phase of SAT. To the best of our knowledge, this is the first case, in which AGP-positive cells were confirmed in the thyroid tissue in patients with SAT. Further studies may clarify the principal mechanisms responsible for these AGP-positive cells.

Poster 136 Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM TOTAL THYROIDECTOMY IN PATIENTS WITH HASHIMOTOS DISEASE LEADS TO ELIMINATION OF ANTI-THYROIDPEROXIDASE (ANTI-TPO) LEVELS AND TO ELIMINATION OF SEVERE ACCOMPANYING AILMENTS I. Guldvog1, A. Lauzike1, L. Reitsma1, T. Bernklev1, H. Søiland2 1 Surgical Department, Telemark Central Hospital, Porsgrunn, Norway; 2Surgical Department, University Hospital, Stavanger, Stavanger, Norway Introduction: Substitution with thyroxin eliminates only a few symptoms by Hashimoto. Especially serious exhaustion, pain and stiffness in musculature and joints are correlated with elevated titres of anti-TPO. In a pilot study and in an interim analysis in a randomized study the antibodies and the symptoms disappeared in parallel when the thyroid gland was completely removed. Patients/methods: In 97 consecutive Hashimoto patients operated from 01.06.04–30.06.09 antibodies have been measured preoperatively and up to 96 months after surgery. The first patients consisted of tumours as indication for operation but were combined with elevated antibodies and thyroiditis histology. More and more as we gained experience a clean Hashimoto group emerged with high anti-TPO titres, need for thyroxin supplement and typical symptoms not ameliorated by thyroxin. The symptoms were registered by a survey by phone, the patients being asked to estimate on a Numeric Rating Scale (NRS) from 1-5 the change in the severity of the autoimmune symptoms before and after surgery. They were also asked if they would recommend the operation to others. The randomized study was commenced in February 2012, and an interim analysis undertaken with 75 patients included and followed 18 months. The quality of life was measured every 6 months by 5 different QofL scemes. Results: In the pilot study all but 2 patients had their antibodies eliminated or reduced more than 70% during the follow up time. These 2 patients were the only ones who did not have symptom relief and would not recommend the operation to others. The randomization study was almost a copy of the pilot study, and all QofL schemes showed a highly significant difference between surgical and medical

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treatment. The complications were few, 0 hypocalcemia > 4 months (0 %) and recurrence nerve influence in 4/194 (2,0%) nerves at risk. Conclusion: The results stimulate the hypothesis that Hashimoto is a surgical condition. There is no other treatment alternative. We have now included all 150 patients planned for the randomized study, and we are in the middle of the follw up time observing that the antbodies are falling in all patients.

1

Poster 137 Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM EPIDEMIOLOGICAL CHARACTERISTICS OF 726 PATIENTS WITH DYSTHYROID ORBITOPATHY SEEN BETWEEN 1995 AND 2013 IN A MULTIDISCIPLINARY THYROID-EYE CONSULTATION IN TOULOUSE (FRANCE) M. El Alaoui1, P. Imbert2, S. Grunenwald1, S. Huo Yung Kai3, M. Valet3, F. Boutault4, P. Caron1 1 ENDOCRINOLOGY, CHU LARREY, TOULOUSE, Toulouse, France; 2Ophthalmology, Clinique du Parc, Toulouse, France; 3 EPIDEMIOLOGY, CHU TOULOUSE, Toulouse, France; 4 MAXILLOFACIAL SURGERY, CHU PURPAN, Toulouse, France Context: Dysthyroid orbitopathy (DO) is the most frequent extrathyroidal manifestation of Graves’ disease, but it may be observed in patients with Hashimoto’s thyroiditis, and even in patients with no thyroid dysfunction. Oral or intravenous corticosteroids with or without orbital radiotherapy are indicated in active DO whereas rehabilitative surgery may be required depending on DO sequelae. In order to improve the diagnosis and treatment of DO patients, a multidisciplinary and outpatient thyroid-eye consultation was developed in 1995 in Toulouse (France). Results: 726 consecutive patients were seen between 1995 and 2013, and 50 new patients/year were seen during the last 5 years. Mean (SD) age was 48.5 (13.2) years and DO was more frequent in women (82.2%) and in patients with Graves’ disease (89.6%). Patients were treated with anti-thyroid drugs (33.9%), total thyroidectomy (8.6%), radioiodine therapy (2.1%) or variable combined therapies. An episode of hypothyroidism was present in 19.2% of patients. The prevalence of active smokers was 39.9%. DO was observed before (11.8%), concomitantly (38.3%) or after (49.9%) the onset of hyperthyroidism. The most frequent signs of DO were upper lid retraction (82.5%), exophthalmos (72.7%), or diplopia (42.6%). DO was mild (43.2%), moderate (27.1%) and severe (29.7%) with sight-threatening forms in 30 patients. Severity of DO was significantly related to age (p = 0.022), male sex (p < 0.001), radioiodine therapy (p < 0.001) and episode of hypothyroidism (p = 0.049) while no association was found with cigarette smoking. Only radioiodine therapy in women (OR = 5.07; 95% CI = 2.79–9.21) was significantly associated to DO severity after multivariate logistic regression. Conclusion: We report the epidemiological characteristics of a large cohort of consecutive DO patients seen in Toulouse (France) during the last two decades. Further studies should evaluate the modalities of treatment during the inflammatory/active phase and surgical results in patients with inactive DO.

Poster 138 Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM FATIGUE IN PATIENTS WITH SYSTEMIC SCLEROSIS AND HYPOTHYROIDISM S. Ferrari1, P. Fallahi1, G. Elia1, F. Ragusa1, F. Di Bari2, M. Colaci3, D. Giuggioli3, C. Ferri3, A. Antonelli1

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 2Department of Clinical and Experimental Medicine, Section of Endocrinology, University of Messina, Messina, Italy; 3Department of Medical, Surgical, Maternal, Pediatric and Adult Sciences, University of Modena & Reggio Emilia, Modena, Italy

Persistent fatigue, defined as ongoing exhaustion, disproportionate to exertion and not adequately alleviated by rest, reduces health-related quality of life in patients with Systemic sclerosis (SSc), and is associated with a reduced capacity to carry out daily activities, work disability and impaired physical function. Clinical studies demonstrated a high prevalence of hypothyroidism in patients with SSc, and hypothyroidism and the associated fatigue symptoms could be cured by L-thyroxine (L-T4) substititutive therapy. For these reasons, we evaluated the evolution of fatigue symptoms in SSc hypothyroid patients treated with substitutive therapy. We treated 10 clinical hypothyroid and 23 subclinical hypothyroid female SSc (all with diffuse scleroderma) patients (mean age 54 – 11) with L-T4 substitutive therapy. After 2 months a first control of TSH, FT3, FT4 was made, the dosage of the therapy was adjusted, and patients were re-evaluated at 4 months. SSc patients completed the General Fatigue Index (GFI) of the Multidimensional Fatigue Inventory at baseline, and at 4 months. Mean baseline GFI scores in hypothyroid SSc (15.7 – 5.1) were significantly higher (greater fatigue; P < 0.05) than in the same patients after reaching euthyroidism at 4 months (10.6 – 4.1). The abovementioned data indicate that female SSc patients could be screened for thyroid function, particularly in the presence of fatigue symptoms, and that an appropriate L-T4 subtitutive therapy could be useful to mitigate these symptoms. In order to confirm these data, further studies are necessary in larger samples of hypothyroid patients with SSc. Moreover, longitudinal studies could evalute if L-T4 therapy could be useful in alleviating complications of SSc (such as skin thickness, pulmonary hypertension, etc).

Poster 139 Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM A QUESTIONNAIRE ON QUALITY OF LIFE IDENTIFIES GRAVES’ OPHTHALMOPATHY PATIENTS WHO DESERVE MORE ATTENTION D. Villagelin1,2, R.B. Santos1, A. Sandrin1, J. Giovanetti1, H. Nogueira1, L. Campos1, R. Carbinatto1, N.E. Bufalo2, L.S. Ward2, J.H. Romaldini1,3 1 Endocrinology & Metabolism, School of Medicine, Pontifical University Catholic of Campinas, Campinas, Brazil; 2Laboratory of Cancer Molecular Genetics, School of Medicine Sciences, University of Campinas (UNICAMP), Campinas, Brazil; 3Endocrinology, Hospital Servidor Pu´blico Estado de Sa˜o Paulo, IAMSPE, Sao Paulo, Brazil Graves’ ophthalmopathy (GO) is an inflammatory disease of the orbit that occurs in association with Graves’ disease (GD). The eye injury caused by the disease originates from minor changes to visible deformities on the face, compromising the visual capacity and the aesthetics of the patient. These consequences affect the quality of life in both the biological and emotional. Currently there are questionnaires to evaluate the patient’s health, quality of life and their relationship with a specific disease. The use of these questionnaires is recommended to improve the quality of care and, mainly, to identify patients who are in need of psychological support.

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 140 consecutive patients with GD, these patients were investigated according to the severity of ophthalmopathy, (Clinical Activity Score), and quality of life, according to the questionnaire on quality of life in Graves’ ophthalmopathy (GO-QoL) 140 patients were separate in two groups according the initial CAS. Group 1 (CAS 0 or 1), n = 108, group 2 (CAS ‡ 2), n = 32.There were no differences in age, duration of disease and gender between the groups. Group 1 had better results regarding Score Total on Visual Functioning (p = 0.0048) and Score Total on Appearance (p < 0.0001). Patients in group 2 are more affected with simple tasks as Moving Around the House, Walking Outdoors, Reading, Watching TV, p = 0.0179, p = 0.0022, p = 0.0319 and p = 0.0048, respectivelly. Also this group had more influence on your self-confidence (p < 0.0001) and felt hindered from something that wanted to do because of the thyroid eye disease (p = 0.0298). GO significantly affects the quality of life. The use of questionnaire are important to identify these patients. The choice of Graves’ disease treatment in these patients must be carefully evaluated.

Poster 140 Autoimmunity Monday & Tuesday Poster 9:00 AM OXIDATIVE STRESS ASSESSED BY MALONDIALDEHYDE AND NITRIC OXIDE SERUM VALUES IN PATIENTS WITH AUTOIMMUNE THYROID DISEASE R. Cano1, M. Agostini2, G. Carzo1, S. Linares1, R. An˜ez1 1 Centro de Investigaciones Endocrino-Metabo´licas Dr. Fe´lix Go´mez, Maracaibo, Venezuela, Bolivarian Republic of; 2Hospital Universitario De Caracas, Maracaibo, Venezuela, Bolivarian Republic of Autoimmune thyroid disease (AITD) are a group of diseases characterized by the presence of autoantibodies directed against thyroglobulin, thyroperoxidase or thyroid-stimulating hormone receptor, which are pivotal thyroid-specific molecules for the production of thyroid hormones. A chronic inflammatory milieu, can lead to local and systemic ROS accumulation and in patients with thyroid autoimmunity increased ROS levels, have been demonstrated. So, our objective was to assess oxidative stress in patients diagnosed with AITD: Hashimoto’s thyroiditis or Grave’s disease. We evaluated a total of 40 patients, over the age of 18 years, that attended the Centro de Investigaciones Endocrino-metabo´licas ‘‘Dr. Fe´lix Go´mez’’, in Maracaibo, Venezuela, from March 2015 until June 2015. Thyroid antibodies (AbTPO and AbTgB) serum levels were quantified in all patients, and so was MDA (malondialdehyde) and NO (nitric oxide). Variables with non-normal distribution were presented as median values (percentile 25-percentile 75). Spearman correlation test was used to evaluate correlation among quantitative variables. Mean age of the group studied was 43,0 (33,0–48,0) years old. Oxidative profile showed a mean MDA value of 0,6 (0,5–1,0) lM and NO 26 (21,5–31,5) lM. A 90,3% of patients had lower than normal NO values and only 9,7% had values within normal range. MDA was elevated only in 9,7% of patients. Thyroid hormones (fT3, fT4) and TSH were within normal range. A positive correlation was found among NO and MDA (r: - 438; p: 0,005). Thyroid hormones (TH) exert a multitude of physiological effects, and plasma membrane, endoplasmic reticulum and mitochondria have been considered potential cellular sites of action. Our group of patients with AITD and elevated AbTPO and AbTgB were euthyroid, which could explain by we found normal MDA and NO serum levels. Thus, maintaining normal TH values in patients with AITD help prevent oxidative stress.

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Poster 141 Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM POSTMENOPAUSAL WOMEN WITH A HEALTHY THYROID GLAND HAVE SIMILAR SEX HORMONE LEVELS AS EUTHYROID POSTMENOPAUSAL WOMEN WITH HASHIMOTO’S THYROIDITIS K. Bajuk Studen1, S. Gaberscek1,2, A. Bicek1, A. Oblak1, E. Pirnat1, K. Zaletel1 1 Department of Nuclear Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia; 2Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Hashimoto’s thyroiditis (HT) is predominantly a genetically caused disease. However, the prevalence of thyroid peroxidase antibodies (TPOAb) was shown to be significantly higher in women than in men and increased with age, especially after the age of 50. Therefore, the role of sex hormones in the occurrence of HT has been postulated but not evaluated yet. Estrogens were shown to increase, and testosterone and progesterone to decrease various immune responses. Our aim was to evaluate possible role of sex hormones in the development of HT. In this prospective clinical study in postmenopausal women we included 19 healthy subjects (HS) and 32 women with euthyroid HT (EuHT). Levels of thyrotropin (TSH), thyroid antibodies, folliclestimulating hormone (FSH), estradiol (E2), free testosterone (FT), and progesterone (P) were measured. The E2/FT and E2/P ratios were calculated. HS were negative and EuHT positive for TPOAb and/or thyroglobulin antibodies. HS and EuHT did not differ with respect to age (median (range), 60 (53–67) and 60 (53–67), respectively, p = 0.619), FSH level (median (range), 57.4 (23.8–133.0) and 60.7 (20.6–122.0), respectively, p = 0.852), and TSH level (median (range) 3.1 (1.1–4.5) and 2.8 (1.3–4.5) mU/L, respectively, p = 0.777). Levels of E2 were similar in both groups (median (range) 0.108 (0.07–0.198) and 0.089 (0.07–0.309) nmol/L, respectively, p = 0.379). Also levels of FT were similar in HS and in EuHT (median (range), 6.2 (5.8–17.4) and 6.2 (5.6–39.1) pmol/L, respectively, p = 0.765). HS and EuHT did not differ with respect to P levels (median (range), 0.64 (0.64–0.916) and 0.64 (0.64–1.02) nmol/), respectively, p = 0.109). The E2/FT ratio was similar in HS and in EuHT (median (range), 11.9 (10.8–30.3) and 12.7 (5.0–48.3), respectively, p = 0.654). Also the E2/P ratio was similar in HS and in EuHT (median (range), 0.14 (0.10–0.31) and 0.14 (0.11–0.31), respectively, p = 0.554). According to this study, postmenopausal women with a healthy thyroid gland have similar levels of sex hormones as euthyroid women with HT. Our results do not confirm the hypothesis of possible role of sex hormones in the development of HT.

Poster 142 Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM EUTHYROID POSTMENOPAUSAL WOMEN WITH HASHIMOTO’S THYROIDITIS DID NOT DIFFER FROM HYPOTHYROID POSTMENOPAUSAL WOMEN WITH HASHIMOTO’S THYROIDITIS WITH RESPECT TO SEX HORMONE LEVELS K. Bajuk Studen1, S. Gaberscek1,2, A. Bicek1, A. Oblak1, E. Pirnat1, K. Zaletel1 1 Department of Nuclear Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia; 2Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia The role of sex hormones in the severity of Hashimoto’s thyroiditis (HT) was postulated but not yet proven. Estrogens were shown to increase, whereas testosterone and progesterone tend to decrease the

A-60 immune response. Higher estrogen/testosterone and estrogen/ progesterone ratio could be associated with the more severe form of HT. Our aim was to establish the impact of sex hormones on severity of HT. In this prospective clinical study we included 32 postmenopausal women with euthyroid HT (EuHT) and 23 women with hypothyroid HT (HypoHT). Levels of thyrotropin (TSH), thyroid antibodies, follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), estradiol (E2), free testosterone (FT), and progesterone (P) were measured. The E2/FT and E2/P ratios were calculated. Women with EuHT and HypoHT did not differ with respect to age (median (range), 60 (53–67), and 59 (52–72), respectively, p = 0.715) and FSH level (median (range), 60.7 (20.6–122.0), and 55.4 (24.2– 129.0), respectively, p = 0.976). Level of TSH was significantly lower in EuHT than in HypoHt (median (range) 2.84 (1.28–4.52) and 9.69 (5.35–96.6) mU/L, respectively, p < .001). Level of SHBG was similar in both groups (median (range), 51.4 (16.8–110.0) and 45.4 (13.6–74.1) nmol/L, respectively, p = 0.274). Level of E2 was similar in both groups (median (range) 0.089 (0.07–0.309) and 0.07 (0.07– 0.32) nmol/L, respectively, p = 0.629). Level of FT was significantly lower in EuHT than in HypoHT (median (range), 6.2 (5.6–39.1) and 6.4 (6.0–21.7) pmol/L, respectively, p = 0.001). EuHT and HypoHT did not differ with respect to P level (median (range), 0.64 (0.64– 1.02) and 0.64 (0.64–1.8) nmol/), respectively, p = 0.144). The E2/FT ratio was significantly higher in EuHT than in HypoHT (median (range), 12.7 (5.0–48.3) and 11.4 (8.1–38.6), respectively, p = 0.036). The E2/P ratio was similar in both groups (median (range), 0.14 (0.11–0.31) and 0.11 (0.11–0.38), respectively, p = 0.147). Postmenopausal women with EuHT have similar levels of sex hormones as women with HypoHT with the exception of FT. Therefore, our results do not confirm the hypothesis of possible role of sex hormones in the severity of HT.

Poster 143 Autoimmunity Monday & Tuesday Poster Translational 9:00 AM A NOVEL MURINE MODEL OF ORBITAL INFLAMMATION N.G. Lee1,2, L. Wong3, D. Amarnani3, S.K. Freitag1,2, D. Bielenberg4,5, P.A. D’Amore3,1, L.A. Kim1,3 1 Ophthalmology, Harvard Medical School, Boston, MA; 2 Ophthalmic Plastic Surgery, Massachusetts Eye and Ear Infirmary, Boston, MA; 3Schepens Eye Research Institute, Boston, MA; 4 Surgery, Harvard Medical School, Boston, MA; 5Boston Children’s Hospital, Boston, MA Orbital inflammation secondary to Graves’ disease or nonspecific orbital inflammation can cause devastating compressive optic neuropathy. Treatment for these cases have centered on decreasing the inflammation with steroids or surgically decompressing the orbit. However, current therapeutic options may not be sufficient to resolve the optic neuropathy. To our knowledge, there are no animal models of acute orbital inflammation that can be used to explore novel treatment modalities. We have developed an animal protocol to induce inflammation in the murine orbit with the use of a skin sensitizer, oxazolone. 8-week-old female BALB/c mice were sensitized with a topical application of 2% oxazolone (4-ethoxymethylene-2-phenyl-2oxazolone-5-one; Sigma-Aldrich) solution in olive oil/acetone (2:1 vol/vol) to the shaved abdomen. Five days after sensitization ( = day 0), the right eye was challenged with an orbital injection of 2% oxazolone solution. The left eye, serving as a control, received a sham injection of the vehicle alone. Mice then underwent magnetic resonance imaging (MRI) on day 1 to day 3. They were euthanized at various time points and their exenterated orbits were examined histologically.

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A) Injection into the orbit of oxazolone or vehicle only B) Rightsided proptosis and dermatitis C) MRI demonstrating right facial inflammation and orbital edema D) Exenterated right orbit with focus of acute inflammation 1 day after injection Twenty-four hours following the orbital challenge, mice were observed to demonstrate the phenotypic changes of mild proptosis and dermatitis with secondary ptosis. MRI on day 1 confirmed the findings of exophthalmos as well as retrobulbar inflammation and periorbital edema. On day 3, there was relative reduction of edema and proptosis compared to day 1. Histopathologic examination of the mouse orbit from day 1 to day 5 corroborated the MRI findings of intense, periocular and intraocular inflammation consisting of neutrophils with a transition to chronic inflammation with lymphocytes by day 3 and early fibrosis on day 5. We present a novel animal model of acute orbital inflammation utilizing a type 4 hypersensitivity reaction. Through this model, we may be better able to understand why the orbit is preferentially affected with inflammation and edema in conditions like Graves’ disease. In addition, this model may provide a way to evaluate potential alternatives to steroid and surgical treatment.

Poster 144 Autoimmunity Monday & Tuesday Poster 9:00 AM ABERRANT LEVELS OF HEMATOPOIETIC/NEURONAL GROWTH AND DIFFERENTIATION FACTORS IN EUTHYROID WOMEN AT RISK FOR AUTOIMMUNE THYROID DISEASE E.T. Massolt1,2, G. Effraimidis3, T.I. Korevaar1,2, W.M. Wiersinga4, E. Visser1,2, R. Peeters1,2, H.A. Drexhage5 1 Internal medicine, Erasmus MC, Rotterdam, Netherlands; 2Rotterdam Thyroid Center, Erasmus MC, Rotterdam, Netherlands; 3Endocrinology, Nykøbing Falster Hospital, Nykøbing Falster, Denmark; 4Endocrinology, Academic Medical Center, Amsterdam, Netherlands; 5Immunology, Erasmus MC, Rotterdam, Netherlands Subjects at risk for mood disorders have a higher risk to develop autoimmune thyroiditis (AITD) and vice-versa. This implies a shared pathogenesis of AITD and mood disorders. In mood disorder patients, an abnormal profile of hematopoietic/neuronal growth factors (e.g. Brain-Derived Neurotrophic Factor (BDNF), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF), IL-7, Granulocyte-macrophage Colony-Stimulating Factor (GM-CSF) and IL-3) is observed, suggesting that growth and/or differentiation abnormalities of neuronal/ myeloid cell lineages may predispose to mood disorders. Interestingly

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A-61 tively. Urinary iodine concentration (UIC), thyroid hormones, TSH, Tg, TgAb and TPOAb in serum were determined. Compared to median of maternal UIC of control group, that in pregnancy showed no significant differences, but which in lactation presented a ordinal decrease (P < 0.05 in the late lactation). Serum FT3, FT4, TT3, TT4, TSH and Tg level in pregnancy and lactation showed hypothyroid characters, and which was more obvious in lactation. There was no significant difference of TgAb, and TPOAb among all groups. Maternal thyroid function alterations associated with different trimester of pregnancy in Wistar rats are similar to human, but maternal thyroid function does not recover until the late lactation. No significant changes are found in thyroid autoantibodies. Whether rat should be used for research of human in pregnancy and lactation is decided by the objective.

animal autoimmune models show growth and differentiation abnormalities in hematopoietic cell lineages as well. The aim of our study was to investigate whether an aberrant profile of hematopoietic/neuronal growth factors, similar to that of mood disorder patients, can be found in subjects at risk to develop AITD. We studied 64 euthyroid TPO-Ab-negative females with at least 1 first- or second-degree relative with AITD, of whom 32 did and 32 did not seroconvert to TPO-Ab positivity in 5 year follow-up. Subjects were selected to be not different regarding age, current smoking behavior, Body Mass Index, current estrogen use and thyroid function and were compared to 32 age and gender matched healthy controls (HC). We measured serum levels of above listed growth factors at baseline. BDNF was significantly lower in subjects than in HC (8.2 vs 18.9 ng/ ml, P < 0.001). EGF was significantly higher in subjects than in HC (506.9 vs 307.6 pg/ml, P = 0.003) as well as IGFBP-2 (388.3 vs 188.5 ng/ml, P = 0.028). Seroconverters had significantly higher levels of SCF than non-seroconverters (26.5 vs 16.7 pg/ml, P = 0.017). Subjects at risk for AITD, show serum changes in several hematopoietic/neuronal growth factors, similar to those found in mood disorder patients. Shared growth and differentiation defects in both the hematopoietic and neuronal system may underlie the relation between thyroid autoimmunity and mood disorders.

Poster 145 Disorders of Thyroid Function Monday & Tuesday Poster Basic 9:00 AM STUDY OF CHANGES IN THYROID FUNCTION AND AUTOANTIBODIES DURING PREGNANCY AND LACTATION OF WISTAR RATS L. Lin1, Y. Yan1, Y. Zhang2, Y. Sun1, Y. Li1, X. Qiao3 1 Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China; 2Department of Physiology and Pathophysiology, School of Basic Medicine, Tianjin Medical University, Tianjin, China; 3Tianjin Medical University, Tianjin, China Thyroid function in pregnancy and lactation is different from that in normal condition. So this research is aimed to observe the changes of thyroid function and autoantibodies in each trimester of pregnancy and lactation in Wistar rats, and provide animal experimental data for studies on thyroid diseases of human. One hundred and eleven healthy female adult SPF/VAF weaning Wistar rats were randomly divided into 7 groups: control group, the early pregnancy group, the mid pregnancy group, the late lactation group, the early lactation group, the mid lactation group and the late lactation group, with 16 rats in each group. Maternal urine and blood samples were collected at the 7th, 14th and 20th day of their pregnancy and at the 7th, 14th and 20th day of their lactation, respec-

Poster 146 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM NT-PROBNP AS A MARKER OF MYOCARDIAL DYSFUNCTION OF THE LEFT VENTRICLE IN PATIENTS WITH GRAVES’ DISEASE AND CHRONIC HEART FAILURE IN DYNAMICS DURING THE TREATMENT A.V. Frolova, T.I. Rodionova Endocrinological, Saratov State Medical University named V.I. Razumovsky, Saratov, Russian Federation The aim of the study is to estimate myocardial dysfunction of the left ventricle in patients with GD and chronic heart failure (CHF) in dynamics during thyrostatic therapy with investigation of N-terminal fragment of brain natriuretic peptide (NT-proBNP). The study included 50 patients free of any cardiovascular disorders with GD, the diagnosis is confirmed by investigation of plasma levels of TSH, thyroid hormones, thyrotropin-receptor antibodies. All patients had symptoms of heart failure diagnosed by NYHA classification. The control group - 15 healthy volunteers, matched for age and sex with the patient. In both groups, determined the level of NT-proBNP at the beginning of treatment and when patients had an euthyroid state. 11 Mens (22%) and 39 Women (78%), aged between 18 and 50 years old with GD were examined. CHF functional classes (FC): I - 23 patients (46%), II - 15 patients (30%), III- 10 patients (20%) and IV two patients (4%). At the beginning the median of NT-proBNP was significantly higher in patients with CHF and GD (392.4 pg/ml [272.0, 566.2] (p < 0.001)) compared with the control group. Increasing the concentration of NT-proBNP was associated with an increase of CHF FC (r = 0,9). After reaching an euthyroid state NT-proBNP concentration was statistically significant reduced in patients with CHF I FC (p < 0.001), and there were not significant differences for this indicator in patients with CHF II-IV FC (p > 0.05). CHF associated with GD leads to increase NT-proBNP level. After restoration of euthyroid state level of NT-proBNP remains elevated in patients with CHF II-IV FC. This indicates a continuing left ventricular dysfunction, therefore NT-proBNP should be considered in the assessment of the cardiovascular system state in patients with GD.

Poster 147 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM TSH RECEPTOR STIMULATING IMMUNOGLOBULINS: PERFORMANCES OF A NOVEL FULLY AUTOMATED ASSAY D. Gruson, B. Ferracin Laboratory Medicine, Cliniques Universitaires Saint Luc, Brussels, Belgium

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Measurement of TSH receptor auto-antibodies (TRAb) is important for the diagnosis and monitoring of Grave’s disease (GD). Several automated methods for testing are available but are not standardized and not specific of TSH receptor stimulating immunoglobulin (TSI). Our objective was to determine the performances of a novel automated assay with enhanced specificity for TSI. We evaluated the IMMULITE TSI assay (Siemens), a fully automated chemiluminescent immunoassay based on a pair of recombinant hTSHR and engineered to be clearly more specific of TSI. Assay‘s imprecision was assessed with two levels of control materials and linearity through a eight points dilution test of high titer samples. Reference values were determined with samples from 50 healthy volunteers free of thyroid diseases and medications. Method comparison was performed with a second-generation TRAb enzyme immunoassay Medizym (Medipan) with 70 patients’ samples (46 with active or treated GD and 24 without GD). Between-run coefficients of variation were 6.5 and 4.7% for concentrations of 1.0 and 22.6 IU/L, respectively. The dilution test covered a range of concentrations ranging from 40 to 0.32 IU/L and the mean recovery was 108 %, confirming assay’s linearity. The TSI levels in healthy volunteers were below 0.10 IU/L. TSI and TRAb assays were significantly correlated (r = 0.95, p < 0.01) but clearly not commutable. In patients without GD, all results obtained with TSI assay were < 0.5 IU/L (manufacturer’s cut-point) with a mean concentration of 0.17 IU/L (range: 0.1–0.42) in contrast to 3 falsely positive results with the TRAb assay (mean: 1.45 IU/L, 0.46–4.49; institutional cut-off: 2.5). In patients with GD, the mean TSI and TRAb concentrations were 8.5 IU/L (range: 0.351 – > 40) and 11.8 IU/L (1.5 – > 40), respectively. Five GD patients with biologically confirm hyperthyroidism were positive with the TSI assay and negative with the TRAb method. Our preliminary data showed excellent analytical and clinical performances for this novel fully automated assay with enhanced specificity for stimulating antibodies. However, the performances will need to be confirmed by comparison to a bioassay.

An inhibitory dose-response effect of DE-71 on TSH stimulated thyrocytes was found (n = 13 cell cultures). Maximal inhibition were found in cells exposed to 50 lg/mL where the Tg level were reduced by 71.9 % (range: 8.5–98.7%, n = 7 cell cultures), and the mean cAMP-level was reduced by 95.1% (range: 91.5–98.8%, n = 6 cell cultures) compared to controls. Ranges of controls were 16.7– 2399.3 ng/mL and 32–1786 pmol/mL for Tg an cAMP respectively. DE-71 inhibits the thyroid cell function on a molecular level. This is relevant in the elucidating process regarding the specific effect of flame retardants. Further experiments are needed to confirm or disprove a direct causative influence of DE-71 on thyrocytes.

Poster 148 Disorders of Thyroid Function Monday & Tuesday Poster Basic 9:00 AM THE FLAME RETARDANT DE-71 INHIBITS HUMAN THYROID CELL FUNCTION ˚ .K. Rasmussen1, L. Ramhøj2, T.M. Kronborg1, J.F. Hansen1, A U. Feldt-Rasmussen1 1 Department of Medical Endocrinology, Rigshospitalet, Copenhagen, Denmark; 2National Food Institute, Technical University of Denmark, Søborg, Denmark Endocrine disrupting chemicals (EDCs) affect thyroid function, which is essential for general growth and metabolism. Flame retardants are a group of EDC’s containing polybrominated diphenyl ethers (PBDE’s), used worldwide to reduce flammability in e.g. upholstery and electronic equipment. Production is banned, but there will be a continuous release from existing products for many years. There seems to be an influence on the thyroid homeostasis, and the aim of this study was to investigate a possible direct effect of the flame retardant mixture DE-71 on human thyroid cell function in vitro. Primary human thyroid cells were obtained as paraadenomatous tissue from thyroidectomies. The tissue was cut into small pieces and cells extracted by incubation with collagenase I/dipase II. The cells were starved for TSH in 3 days before addition of DE-71 (0.01, 0.1, 1, 5, 10 and 50 lg/mL) for 72 h in presence of TSH. Cell supernatants were harvested and centrifuged before analysis of cyclic adenosine monophosphate (cAMP) (competitive protein binding assay) and thyroglobulin (Tg) (ELISA).

Poster 149 Thyroid Cancer Monday & Tuesday Poster Translational 9:00 AM EGFR AND HER2 EXPRESSION IN PAPILLARY THYROID CARCINOMA J. Kim Surgery, Catholic University Uijeongbu St. Mary’s Hospital, Uijeongbu City, Korea (the Republic of) The epidermal growth factor receptor (EGFR) family plays a crucial role in the growth of malignant tumors. Among these genes, EGFR and human epidermal growth factor receptor 2 (HER2) overexpression and amplification are associated with an unfavorable prognosis and are important therapeutic targets in breast cancer. However, HER2 expression in papillary thyroid carcinoma (PTC) has rarely been studied. The aim of this study was to evaluate the relationship between EGFR and HER2 expression and clinicopathological factors of PTC in a single institution. One hundred and twenty nine consecutive patients with PTC were enrolled in this study and underwent thyroid surgery at Uijeongbu St. Mary’s Hospital between October 2013 and February 2015. EGFR and HER2 protein expressions were evaluated in the 129 primary tumors by immunohistochemistry, and the results were compared with clinicopathological features. The degree of HER2 staining was scored as 0, 1, 2 or 3 according to the breast cancer criteria because no criteria for papillary thyroid carcinoma have been established. The cancer tissues that received scores of 2 or 3 were defined as positive for HER2 expression. Of the 129 tumors (papillary thyroid carcinoma), 112 (86.8%) were HER2 negative and 17 (13.2%) were HER2 positive. EGFR positivity was observed in 111 (86%) tumors. The mean age of the patients was 46.3 – 11.9 years (range 20–74 years). The mean tumor size was 1.08 – 0.75 cm (range 0.2–3.5 cm). cervical lymph node metastases were present in 47 (36.4%) patients. Tumor size, extrathyroidal extension, histologic type, and TNM stage were not significantly associated with HER2 expression. However,, HER2 expression was significantly associated with younger age ( £ 45 years) and cervical lymph node metastasis. High Ki-67 was significantly associated with EGFR expression (p = 0.002). Also, Ki-67 was higher in HER2 expression group although not of statistical significance. Based on our data, it is not clear EGFR expression is associated with tumor aggressiveness in PTC. But HER2 expression is associated with lymph node metastases in PTC. To identify the prognostic value of HER2 expression, a long-term follow-up study will be needed.

Poster 150 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM DI-(2-ETHYLHEXYL) PHTHALATE HAS LIMITED INFLUENCE ON HUMAN DIFFERENTIATED THYROID CELL FUNCTIONS IN VITRO J.F. Hansen1, M. Boas2, K. Main2, H. Frederiksen2, ˚ .K. Rasmussen1, U. Feldt-Rasmussen1 J. Hofman-Bang1, A

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Laboratory of Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 2Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Phthalates are suspected to influence thyroid function in epidemiologic and experimental in vivo studies. Aim of this study was to investigate if the differentiated function of primary human thyroid cell cultures was influenced by di-(2-ethylhexyl) phthalate (DEHP). Human thyrocytes obtained from thyroidectomies and cultured to monolayers were exposed for 72 hours to DEHP (0.001 to 100 lM) in presence of thyroid stimulating hormone (TSH) (1 IU/l). Thyroglobulin (Tg) and cyclic AMP (cAMP) were quantified in cell supernatants (ELISA and competitive protein binding method, respectively). Gene expression of thyroid peroxidase (TPO), sodium iodine symporter (NIS), TSH receptor (TSHr) and Tg were quantified by real-time quantitative polymerase chain reaction (RT-qPCR). Two-way ANOVA and Tukey’s post-hoc analysis was used for statistics (SAS-institute). A significant influence on cAMP-secretion, the second messenger of TSH, was demonstrated (p = 0.0006, n = nine cultures in single determination). Post-hoc analysis demonstrated an inhibiting influence by 10 lM DEHP compared to control, 1, 0.1 and 0.01 lM DEHP. The estimated ratio (95% CI) of 10 lM DEHP compared to control, 1, 0.1 or 0.01 lM DEHP was 0.73 (0.58; 0.92), 0.76 (0.60; 0.96), 0.75 (0.60; 0.95) and 0.75 (0.59; 0.94), respectively. Neither Tg-secretion nor gene-expression of TPO, NIS, TSHr and Tg were influenced by DEHP (p = 0.76, 0.47, 0.59, 0.76 and 0.92, respectively). Although a high concentration of DEHP inhibited cAMP secretion in human thyroid cells, no influence on Tg-secretion or geneexpression of differentiated thyrocyte function was found. Furthermore the influence on cAMP secretion was not dose-dependent. Thus, the influence on the thyroid axis suggested in other studies does not seem to be caused by a DEHP-mediated effect on the thyroid gland itself.

Poster 151 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM RESEMBLANCE AND DIVERSITY OF THE ACTIVITY OF GRAVES’ DISEASE SEEN IN MONOZYGOTIC FEMALE TWINS OVER THE COURSE OF 20 YEARS N. Momotani, S. Iwama-Carlson Endocrinology, Tokyo Health Service Association, Tokyo, Japan Twin studies suggest that the development of Graves’ disease (GD) is not determined only genetically, but environmental factors play a role. We report on a 20 year observation of GD in female twins, suggesting a significant contribution of environmental factors to the activity of GD. The twins (T1 and T2) were born in 1989 at 34 weeks of gestation. T1 had lower birth weight (2002g vs. 2500g). Their mother had been treated with methimazole (MMI) for GD, and the twins suffered from transient hyperthyroidism after birth. At 5 years of age, GD developed in T1, and MMI was initiated. TRAb values changed greatly and abruptly elevated from 13.9% to 85% (normal&10%) in 1998, when GD developed in T2. T2 was treated with iodine because skin eruption occurred after the initiation of MMI. Her TRAb reached 88%. Their TRAb values became normal almost simultaneously in 2001. MMI in T1 and iodine in T2 were discontinued. After that, transient hyperthyroidism developed once every year for three years in both of them. They became thyrotoxic once again in 2004, and it was due to GD in T1 and painless thyroiditis in T2. After that event, they took quite a different course. In T1, the TRAb value became extremely high and she underwent a total thyroidectomy in 2011. The TRAb got to an undetectable level and she gave birth to a healthy baby in 2014. T2 remained in remission status until in 2012. It was

A-63 when she got a job and moved to an area far from her family that GD relapsed, and iodine was initiated again. TRAb value reached as high as around 90% in 2014. Long-term follow up of Graves’ disease in monozygotic twins may be valuable because it may elucidate how the environmental factors contribute to the development or the activation of Graves’ disease. If we had taken notice of the event that the twins encountered, we could have learned more about it. The eventful course of GD seen in the monozygotic twins suggests that the timing of the development or the activity of GD is attributed to changing in magnitude of the contribution of environmental factors.

Poster 152 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM WEEKLY INTRAMUSCULAR INJECTION OF LEVOTHYROXINE FOLLOWING MYXOEDEMA: A PRACTICAL SOLUTION TO AN OLD CRISIS P.N. Taylor1, A. Tabasum2, G. Sanki2, D. Burberry2, B. Tennant2, A. Aldridge2, O. Okosieme2,1, G. Das2 1 Cardiff University, Cardiff, United Kingdom; 2Prince Charles Hospital, Cardiff, United Kingdom Myxoedema Coma is rare complication of hypothyroidism. Data on optimal management are limited given the limited number of case series. An 82 year-old female with known hypothyroidism was admitted to hospital after being found on the floor. On examination, she was unkempt, confused, bradycardic, hypothermic and barely arousable. Her initial biochemistry revealed a thyroid stimulating hormone (TSH) of >100 mU/L, free thyroxine (FT4) of 1.5 pmol/L which supported a diagnosis of myxoedema coma. She was resuscitated and commenced on liothyronine, levothyroxine and hydrocortisone. Unfortunately she developed pulmonary oedema consequent to an acute coronary syndrome and needed diuresis, ionotropic support and assisted ventilation. She was stepped down to the ward where her thyroid function tests improved on a combination of oral levothyroxine and intravenous liothyronine and her free tri-iodothyronine (FT3) was maintained in the lower half of the reference range. However it became apparent she was pouching and spitting out her oral levothyroxine as a result of impaired cognitive function. She was therefore maintained on IV liothyronine for longer than originally intended. Given the need for prompt alternative control we sought advice from international experts where intramuscular levothyroxine was recommended. She was therefore managed from day 50 onwards

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on intramuscular levothyroxine 200mcg once weekly, which was subsequently increased to 500mcg. She made continual cognitive and physical progress with stabilisation of her thyroid function and she was discharged to a rehabilitation hospital. Following continued improvement she was subsequently restarted on oral levothyroxine, with a plan for discharge home and close monitoring of her thyroid function in primary care. This report highlights the potential to use intramuscular levothyroxine in individuals with poor absorption or compliance even in severe hypothyroidism.

TSH-secreting adenomas are rare tumors, accounting for less than 2% of all pituitary tumors, and an even more rare cause of thyrotoxicosis. A 32 year old female was diagnosed with an incidental pituitary macroadenoma measuring 3.4 · 2.9 · 3.0 cm with local invasion on MRI brain performed for numbness and tingling of her left upper extremity. At the time she also reported worsening daily headaches, photophobia and tunnel vision causing inability to drive or read. She denied any symptoms of thyrotoxicosis. Physical exam revealed normal vital signs and no goiter. Formal visual field testing revealed bitemporal hemianopsia with decreased visual acuity and color vision. Initial labs revealed a TSH of 4.89uIU/mL (Reference range 0.47 to 4.68 uIU/mL), Free T4 2.38ng/dL (Ref range 0.78 to 2.19ng/ dL), and Free T3 is 8.5pg/dL (Ref range 2.4 to 4.2pg/dL). Remaining pituitary axis including AM cortisol, ACTH, prolactin and IGF1 were within normal limits. Glycoprotein alpha subunit was 0.8 ng/mL (0.0–1.4) giving an alpha subunit to TSH molar ratio of 2.5 suggesting TSH secreting tumor. CT Angiogram of the head revealed left carotid cave and bilateral para-ophthalmic aneurysms arising from the tumor margins, making her a poor surgical candidate. Monthly long acting octreotide was initiated. Within 4 months of follow-up she noticed an improvement in vision and she was able to read and drive again. Her tumor remained stable in size on follow-up MRI brain. 12 month follow-up labs showed Free T4 normal at 1.26 ng/dL, Free T3 normal at 3.9pg/dL with a corresponding TSH of 1.85 uIU/mL. Although trans-sphenoidal surgery remains the first-line treatment for TSH secreting adenomas, medical therapy is frequently required for invasive tumors. Given that native somatostatin inhibits TSH secretion, treatment with somatostatin analogues has been used with unresectable tumors or after surgery. Octreotide not only decreases TSH secretion by the tumor but can also cause shrinkage of tumor, restoration of euthyroid state, decreased goiter size and vision improvement. Somatostatin analogs represent a useful tool for long-term treatment of inoperable TSH secreting pituitary tumors.

Poster 153 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM MEDICALLY REFRACTORY HYPERTHYROIDISM IN A PATIENT WITH GRAVE’S DISEASE E. Cousin-Peterson1, L. Rivera Robles2, A. Hodes1 1 Surgery, University of South Florida, Tampa, FL; 2Endocrinology, Tampa General Hospital, Tampa, FL Hyperthyroidism affects 0.5% of the US population, resulting in a physiologic syndrome of thyrotoxicosis. Euthyroidism can generally be achieved with medical therapy alone or in conjunction with surgery, limiting the risk of perioperative thyroid storm. There are rare cases that medical management can’t bring a patient to euthyroidism, in which more extreme treatment protocols must be used. We discuss a case of resistant thyrotoxicosis, the resulting treatments, and other medical options used in refractory cases. A 39 year old woman presented with tremors, palpitations, anxiety, and a visible goiter. She was diagnosed with hyperthyroidism following initial work-up. The patient was started on methimazole and propranolol. Her symptoms improved initially, but her thyrotoxicosis subsequently worsened despite maximum dose of methimazole. Her medication regimen was transitioned to increasing doses of propylthiouracil as well as propranolol. Despite this, she remained symptomatic, with progressive worsening of her thyroid function tests. Due to her resistant disease, she was admitted to the hospital for urgent total thyroidectomy. Pre-operatively, she was continued on PTU, propranolol, and started on SSKI and dexamethasone. The patient improved, displaying only mild tachycardia and shrinking of her thyroid goiter. She was near euthyroid pre-operatively. She underwent an uncomplicated total thyroidectomy and post-operative course. Surgical management of medically refractory hyperthyroidism is a widely accepted standard for definitive therapy. Refractory hyperthyroidism may be secondary to persistent Grave’s disease, toxic nodular goiter, Amiodarone use, or Iodine-containing contrast. There exists the challenge of achieving a state of euthyroidism prior to urgent surgery in order to limit the risk of thyroid storm. We discuss adjunct medical therapies and more advanced modalities such as therapeutic plasma exchange and single-pass albumin dialysis that may represent options for rapid preparation of patients prior to surgery. Medically refractory thyrotoxicosis is a rare complication of hyperthyroidism. Non-traditional treatment options are utilized to ensure patient safety in the process of attaining definitive cure.

Poster 154 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM NOT YOUR REGULAR THYROTOXICOSIS! MEDICAL TREATMENT OF TSH SECRETING PITUITARY ADENOMA F. Dojki, D. Elson Endocrinology, University of Wisconsin-Madison, Madison, WI

Poster 155 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM A CASE OF RESISTANCE TO THYROID HORMONE IN A FAMILY WITH HYPOTHYROIDISM AND ADHD T. Jaber1, D. Rodriguez- Buritica2, S. Nader-Eftekhari1 1 Endocrinology, Diabetes, and Metabolism, The University of Texas Health Science Center at Houston, Houston, TX; 2Medical Genetics, The University of Texas Health Science Center at Houston, Houston, TX Resistance to thyroid hormone (RTH) is a rare disease characterized by thyroid hormone resistance in target tissues. Mutations in THRB, which encodes the thyroid hormone receptor beta, is the most frequent cause of RTH, affecting around 1000 individuals who belong to some 300 families. Clinicians should have a high index of suspicion for RTH when the clinical picture consists of elevated thyroid hormones with unsuppressed TSH along with a family history of thyroid disease and ADHD. Our patient is an 18 year-old female who was referred for evaluation of abnormal TFTs. She initially presented to her gynecologist for irregular menstrual cycles. Hormonal work up revealed a normal prolactin, negative pregnancy test, and a normal TSH with elevated free T4 and free T3 levels. A thyroid ultrasound was consistent with goiter. She was clinically euthyroid and had no signs of pituitary dysfunction. Family history was remarkable for hypothyroidism in her maternal aunts and ADHD in her brother.

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A-65 dL (6–14) and normal TSH of 4.6 microIU/mL (0.2–4.9). No FT4 was available initially; albumin was 3.8 mg/dL (3.3–4.3). In order to find out if the thyroid lab abnormality was associated with her plasmapharesis, repeat thyroid function testing was done before and after the next plasmapharesis session. Before plasmapharesis, her TSH was 4.8 microIU/ml (0.2–4.9), FT4 1.2 ng/dL (0.8–1.8), FT3 2.7 pg/mL (1.4–4.4), TT4 8.3 mcg/dL (6–14), and TT3 72 ng/dL (60–180). Immediately post plasmapharesis, TSH was 3.6 microIU/ml (0.2–4.9), FT4 1.0 ng/dL (0.8– 1.8), TT4 2.8 mcg/dL (6–14), and TT3 was 53 ng/dL (60–180). In this patient, plasmapharesis resulted in decreased TT4 and TT3 which is likely related to the removal of the binding proteins. Although in our patient the free Thyroxine levels were normal, plasmapharesis has been reported to decrease free thyroxine in patients with thyrotoxicosis. Plasmapharesis therapy can be associated with thyroid function abnormalities. Understanding the mechanisms by which plasmapharesis operates can help in the interpretation of these values.

FIGURE 1. Three-generational Pedigree

Upon evaluation in the endocrinology clinic, repeat TFTs were obtained which again showed normal TSH at 2.57 (0.50–4.30 MIU/ L), elevated free T4 at 1.9 (0.9–1.4 ng/dl) and elevated free T3 at 5.3 (2.9–4.6 pg/ml). Total T4 and T3 levels were also obtained to rule out a protein binding effect, both of which were elevated at 17.2 (4.5–12 mcg/dL) and 201 (76–181 ng/dl), respectively. Autoimmune disease was ruled out with negative thyroid peroxidase antibodies and thyroid stimulating immunoglobulins. Central etiology was ruled out by the normal alpha subunit level at 0.2 (0.1–0.6 ng/ml). Given her family history, she was referred to and evaluated by the genetics department. An assessment of her family pedigree warranted genetic testing which showed a mutation in exon 9 of the THRB gene, with replacement of arginine by cysteine at position 320 (p.Arg320Cys), an autosomal dominant mutation. It is important to have a high clinical suspicion for RTH as an identifiable mutation can have implications not only for family members but also for the affected individual. DNA testing could save the affected individual multiple rounds of testing, unnecessary brain imaging and inappropriate treatment.

Poster 156 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM ALTERATION IN THYROID FUNCTION IN A PATIENT ON PLASMAPHARESIS FOR MYASTHENIA GRAVIS M. Alhusseini Internal Medicine, Detroit Medical Center/Wayne State University, Dearborn, MI Plasmapharesis is a therapeutic procedure in which plasma components are extracted from the blood. Most thyroid hormone is bound to plasma proteins which are good candidates for removal by plasmapharesis. This procedure has been reported to cause alterations in thyroid hormone levels. We describe a patient with underlying hypothyroidism receiving plasmapharesis for myasthenia gravis who exhibited thyroid function abnormality. A 42 year old female with history of myasthenia gravis and hashimoto’s thyroiditis diagnosed at the age of 27 (on levothyroxine 200 mcg daily) presented to the hospital with difficulty swallowing and underwent plasmapharesis for myasthenia gravis crisis. Review of systems and physical examination suggested euthyroidism. The endocrinology service was consulted because of low TT4 of 3.0 mcg/

Poster 157 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM RADIOIODINE ABLATION-INDUCED GRAVES’ DISEASE J. Furst, A.P. Kuker, S.A. Ebner Division of Endocrinology, Columbia University College of Physicians and Surgeons, New York, NY We describe the case of a patient with congestive heart failure and toxic multinodular goiter (TMNG) with subclinical hyperthyroidism who developed Graves’-like hyperthyroidism after I-131 ablation. A 67-year-old woman with CHF, T2D, HTN, and TMNG with low but detectable TSH (0.04–0.84, nl range 0.32–4.05mIU/L) and normal fT4, TT4, TT3 from 2011 through 2014 had negative TPO, antithyroglobulin and TSI antibodies prior to ablation. Her thyroid US showed a 1.7 · 1.3 · 1.2cm solid, hypoechoic nodule in the right lobe and a 4.4 · 2.9 · 3.6cm complex, cystic nodule in the left lobe. 123I uptake and scan was notable for mild heterogeneous uptake, with overall uptake of 19.8%. Given subclinical hyperthyroidism with TSH < 0.1 mIU/L in a woman with CHF, we recommended ablation with 30mCi of I-131. Two weeks post-ablation, she complained of anterior neck pain and had TSH < 0.03 with normal fT4, TT4, TT3. She received ibuprofen for presumed ablation-induced thyroiditis. TSH levels rose over the following weeks. However, four months post-ablation, she developed clinical and biochemical overt hyperthyroidism with TSH < 0.03, fT4 1.66 (0.70–1.24ng/dL), TT4 10.25 (5.41–11.66ug/dL), and TT3 192 (58–159ng/dL). Her thyroid antibodies were now positive [TPO 66 (0–34IU/mL), TSI 381 ( £ 122%), TSH receptor antibody 8.54 ( £ 1.75IU/L)]. There are reports of patients with TMNG developing Graves’-like hyperthyroidism after I-131 ablation. It may be more likely to occur in those with pre-ablation uptake patterns characterized by disseminated autonomy. In a review of patients with TMNG, 11% had relapsed hyperthyroidism 3–6 months after treatment with I-131. Of these, 35% developed positive TSH receptor antibodies, perhaps due to release of thyroid antigens from destroyed follicular cells. Alternately, subclinical Graves’ disease may be unmasked by I-131 therapy due to increased production of stimulating antibodies following release of thyroid antigens. While our patient had negative antibodies pre-ablation, she developed Graves-like hyperthyroidism after I-131 ablation with positive TPO, TSI and TSH receptor antibodies. She remains on methimazole with positive antibodies almost one year later.

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Poster 158 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM A CASE OF HYPOTHYROIDISM IN A CAT OWNER WITH METHIMAZOLE USE FOR THE TREATMENT OF FELINE HYPERTHYROIDISM: I.K. Dardi1, K. Gourneni2, E.B. Ruby1 1 Division of Endocrinology, Thomas Jefferson University Hospital, Philadelphia, PA; 2Department of Medicine, Mercy Catholic Medical Center, Darby, PA Hyperthyroidism is the most common endocrine disorder in middle aged and older feline patients. The three treatment options available for hyperthyroid cats include pharmacologic treatment, radioactive iodine or surgical intervention.Due to high rate of adverse reactions, propylthiouracil is no longer recommended in feline patients, thus leaving methimazole (oral felimazole or topical formulations) as the most commonly used medication for the treatment of this condition. We present a case of 76 year old female with history of diabetes with good control seen in Endocrine office for a routine follow up when she was noted to have mild diffuse enlargement of her thyroid gland with no prior history of thyroid disease. Lab evaluation showed TSH of 6.12 uIU/mL (normal range 0.45 to 4.5uIU/ml) and negative thyroid peroxidase and thyroglobulin antibodies. During the clinical encounter, patient mentioned that it was coincidental that her cat was diagnosed with hyperthyroidism this year requiring methimazole (transdermal gel) treatment for past two months which the patient had been applying for her cat without wearing gloves or washing hands.Patient was advised to take appropriate precautions by wearing gloves to avoid skin contamination or accidental ingestion of any drug residue on her hands and have thyroid function tests repeated in 6 to 8 weeks. Patient did start wearing gloves but returned after 4 months with repeat labs including TSH of 1.98 uIU/mL with free T4 of 1.32 ng/dL (normal range 0.82–1.77ng/dL) in addition to clinical resolution of her thyroid gland enlargement. USA has about 36 million households with cats as pets. Since feline hyperthyroidism is a common condition requiring long term methimazole use as one of the treatment options, it is crucial to inform pet owners regarding the potential dangers associated with casual human handling of this drug in any form. Also methimazole crosses the placenta and is transferred in breast milk as well, so it is an additional important safety concern in pregnant and lactating women involved in the care of hyperthyroid cats. In summary, we believe this to be the first reported case of human hypothyroidism related to feline methimazole administration.

Poster 159 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM YI KANG WAN (A HERBAL MEDICINE PILLS) CAUSE SERIOUS LIVER DAMAGE: A CASE REPORT Y. Guan, M. Zhang Department of Nuclear Medicine, The First Affiliated Hostipal of Nanchang University, Nanchang, China Yi Kang Wan is a usually used antithyroid herbal medicine pill when radioactivity iodine (131I) therapy for Grave’s hyperthyroidism. It can relieve hyperthyroidism symptoms of eye, sweating, heart palpitations and limbs tremor, etc, but It caused serious liver damage in a very few case and decreaed 131I thyroid uptake rates in no case. We described a 50 years old hyperthyroidism woman patient with mildly increased direct bilirubin, Who developed serious liver damage and had lower 131I thyroid uptake rates in 3 time tests after using Yi Kang Wan for 3 months. who’s liver function was back to

original lower level and have obvious increase of 131I thyroid uptake rate without Yi Kang Wan for 2 months. Yi Kang Wan may induce serious liver damage and decreae 131I thyroid uptake rates of Grave’s hyperthyroidism patient. Huang Yao Zi (a saponins plant, containing iodine:14.3mg/kg) is one of the most important components of Yi Kang Wan. Modern pharmacological research confirms that Huang Yao Zi can regulating thyroid function, treatment of iodine deficient goiter, but can cause liver damage because of hard distinguish active and toxic ingredients, therapeutic and toxic dose, So we consider that this side effect of Yi Kang Wan is related with Huang Yao Zi. We should take a reasonable, short-term use of small doses of Yi Kang Wan and regular liver function monitoring during 131I therapy of Hyperthyroidism, and not use it if hyperthyroidism patient with mild hepatic disfuntion.

Poster 160 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM THYROTOXICOSIS FACTITIA IN BODYBUILDERS USING PERFORMANCE ENHANCING DRUGS: A REPORT OF TWO CASES G. Rothberger, S.P. Klek, M. Mikhail Winthrop-University Hospital, Mineola, NY Thyrotoxicosis factitia (TF) is intentional or accidental ingestion of excessive thyroid hormone (TH) and is often a result of an attempt to lose weight. Thyroid hormone is often used in small quantities by bodybuilders to enhance muscle definition. We report two cases of thyrotoxicosis factitia in bodybuilders using performance enhancing drugs. Case 1: A 27 year old man was hospitalized for leg weakness, palpitations, tremor and weight loss. He had recently competed in a bodybuilding competition and used anabolic steroids and a weight loss supplement provided by his trainer. He was found with a suppressed TSH, free T4 3.61 ng/dL (0.87–1.76 ) and total T3 0.92 ng/dL (0.82–1.47). 24 hour thyroid uptake was 0.6% and thyroglobulin was 9.0 ng/dL, consistent with TF. He improved over several days without treatment. Case 2: A 30 year old man was hospitalized for tachycardia, fevers, and diaphoresis. He used anabolic steroids intermittently for several years. He purchased liothyronine 25 mcg tablets from an unregulated online pharmacy two weeks prior, and took one tablet daily for one week and two tablets daily for the next week. He was found to have a suppressed TSH, a free T4 level > 10 ng/dL and total T3 15.2 ng/mL (0.82–1.47). 24 hour thyroid uptake was 1.7% and thyroglobulin was 1.6 ng/mL, consistent with TF. He improved with beta blockade and cholestyramine. TF is often seen as a consequence of weight loss supplementation or accidental ingestion of TH. There are no reported cases as far as we know of TF caused by performance enhancing drugs in a bodybuilder. Thyrotoxicosis is undesirable to bodybuilders as it can induce muscle catabolism, so TF would likely result from accidental

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overdose. The first patient was not aware he was taking thyroid hormone, and the second patient was likely taking large doses of Lthyroxine unknowingly. TF can result from use of performance enhancing drugs in a bodybuilder and should be considered in the evaluation of thyrotoxicosis in these patients.

Thyrotoxicosis results in increased bone turnover, shortening of the bone remodeling cycle, and reduced bone mineral density (BMD). Treatment of thyrotoxicosis can normalize BMD in in males and premenopausal females, but there have been few reports on changes in the BMD of postmenopausal hyperthyroid patients in response to treatment. We performed a prospective observational study that focused on the BMD and bone turnover markers of postmenopausal hyperthyroid patients. Eighty-five postmenopausal patients newly diagnosed with Graves’ disease (GD) were the subjects of this study. The BMD of their lumbar vertebrae, both femurs, and left distal forearm was measured by dual-energy X-ray absorptiometry. Body height, body weight, BMD, serum thyroid hormone levels, and bone turnover marker levels were evaluated before treatment, and at 6, 12, 18, 24 months after a euthyroid state had been achieved with antithyroid drugs (ATDs). The BMD data before treatment were normal in 19 patients (22.3%) but indicated osteopenia in 27 patients (31.8%), and osteoporosis in 39 patients (45.9%). The group with osteoporosis was significantly older and had significantly lower body mass index (BMI) and higher serum alkaline phosphatase (ALP), bone ALP, and serum type I collagen cross-linked N-telopeptide values than the normal-BMD group. There were no significant differences between the serum thyroid hormone and TRAb titer levels of these two groups. One year after achieving a euthyroid state with ATDs, the BMD of one third of the osteoporotic patients had improved to the osteopenia level. Two years after achieving a euthyroid state, the BMD of half of the osteoporotic patients had improved to the osteopenia level, and the BMD of one patient had become normal. No fractures occurred in any of the patients during this study. In this study 77% of the postmenopausal GD patients had low BMD in the hyperthyroid state. A low BMI and high serum ALP level are good indications for measuring BMD. The BMD of the hyperthyroid patients with osteoporosis had increased after being maintained in a euthyroid state with ATDs for two years.

Poster 161 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM THYROID DYSFUNCTION AND ANTI-THYROID ANTIBODIES IN PREGNANT WOMEN ATTENDING TERTIARY CARE HOSPITAL IN BANGLADESH F. Akter1, M. Fariduddin2, M. Hasanat2 1 Medicine, Chittagong Medical College, Chittagong, Bangladesh; 2 Endocrinology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh Thyroid dysfunction and antithyroid antibodies in pregnany has deleterious effects on both mother and fetus.Study on this topic is scarce in Bangladesh. So this study aimed to see the frequency of thyroid dysfunction according to American Thyroid Association defined pregnancy reference value as well as comparison with nonpregnant reference value and anti-thyroid antibody status in 1st trimester of pregnancy. This cross sectional study done in Bangabandhu Sheikh Mujib Medical University, Bangladesh encompassed 200 pregnant women of first trimester at their first antenatal visit for study of thyroid dysfunction (FT4,TSH) and status of anti-thyroid antibodies (antiTPO, anti-TG) according to ATA. All patients were interviewed by structured questionnaire. Age (mean – SD) of subjects was 25 – 4.8 yrs, median gestational age: 9.0 wks. Among them according to ATA pregnancy range, subclinical hypothyroid were 21%, overt hyperthyroid 5%, overt hypothyroid 0.5%, euthyroid 17.5%, euthyroid hyperthyroxinaemia 56%. Goiter detected in 46 subjects mostly in euthyroid hyperthyroxinaemia (29/46), followed by subclinical hypothyroidism (9/46). Frequency of dysfunction was not statistically different either between subjects with or without goiter (P = 0.806). 25 subjects detected as euthyroid and 17 subjects as subclinical hyperthyroidism by non-pregnant reference value, fell into subclinical hypothyroidism and euthyroid hyperthyroxinaemia respectively in pregnancy reference value. There was statistically significant disparity for functional status defined by these two references cut off value (P < 0.001). Dysfunction was higher in subjects with abortion (79.6%). Significant difference was found between ATA defined subgroups for status of antibody (p < 0.001). Subjects having positive antibody status mostly (90%) showed dysfunction. A good number of pregnant mother in our society shows thyroid dysfunction during first trimester of pregnancy.Positive antibody status mostly associated with dysfunction. So universal screening for thyroid dysfunction in pregnancy should be considered.

Poster 162 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM CHANGES IN BONE MINERAL DENSITY AND BONE TURNOVER MARKERS IN POSTMENOPAUSAL PATIENTS WITH GRAVES’ DISEASE AFTER NORMALIZATION OF THYROID HORMONE LEVELS A. Yoshihara, J. Yoshimura Noh, N. Watanabe, K. Mukasa, Y. Kunii, M. Suzuki, N. Suzuki, H. Ohye, M. Matsumoto, K. Iwaku, S. Kobayashi, K. Ito Ito Hospital, Tokyo, Japan

Poster 163 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM PREVENTION OF HYPERTHYROIDISM EXACERBATION DURING RADIOACTIVE IODINE THERAPY IN A PATIENT WITH GRAVES’ DISEASE AND A HUGE GOITER J.Y. Noh1, A. Yoshihara1, N. Watanabe1, S. Kobayashi2, K. Ito1 1 Ito Hospital, Tokyo, Japan; 2Keio University, Tokyo, Japan Withdrawal of MMI during radioactive iodine (RI) therapy for Graves’ disease is needed but could exacerbate hyperthyroidism. Patients with Graves’ disease and a huge goiter have significant thyroid dysfunction and can develop atrial fibrillation and cardiac failure, especially the elderly, if MMI is withdrawn. We report a case of Graves’ disease in an elderly patient with a huge goiter who was safely treated with RI therapy. An 85-year-old man with Graves’ disease had been receiving MMI since 50 years of age. MMI was maintained at 7.5–15 mg/day and controlled the disease. Recently, he was referred to our hospital because the goiter became enlarged and the disease became uncontrollable despite 10mg/day MMI. The estimated thyroid weight on ultrasonography was 194 g. The FT3 and FT4 levels were 10.8 pg/mL and 2.76 ng/dL, respectively. The MMI dose was increased every 3–4 weeks from 15 to 60 mg/day and combined with LT4 at 50 mg/day. Iodine intake was discontinued 7 days before the RI therapy. MMI was withdrawn 4 days before and resumed 4 days after the RI therapy (at 30 mg/day and then decreased thereafter). The RI therapy dose was 1110 MBq (104 Gy; 24-h RAIU 63%; half-life 6.1 days). The following FT3 and FT4 values indicated changes in thyroid function: 5.1 pg/mL and 1.14 ng/dL at the time of MMI withdrawal;

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4.9 pg/mL and 0.59 ng/dL during RI therapy; and 7.4 pg/mL and 0.59 ng/dL at 4 days after RI therapy. For 3 months of follow-up, the patient received MMI at 20 mg/day and LT4 at 50 lg/day, and showed FT3, FT4, and TSH values of 2.4 pg/mL, 0.47 ng/dL, and 0.19, respectively. No atrial fibrillation or cardiac failure occurred during the clinical course. The method described herein prevented hyperthyroidism exacerbation during RI therapy in a patient with Graves’ disease and a huge goiter. We consider it to be especially useful for patients with concurrent diseases that are affected by exacerbated hyperthyroidism.

investigated using multivariable Cox models adjusted for age, race/ ethnicity, smoking status, diabetes, and history of cardiovascular disease. We also examined the relationship between FT4 levels (low normal or high normal) and prevalence of MetS by logistic regression analysis adjusted for the covariates listed above. A total of 913 subjects (509 males and 404 females) was analyzed. Low normal FT4 (compared to high normal) was associated with an increased risk of MetS in the multiple regression analysis (Odds ratio(OR) = 1.9, P = 0.02). Adjusted all-cause or cardiovascular mortality rate was not significantly different between high normal FT4 and low normal FT4 subjects (all-cause: Hazard ratio(HR) = 0.88, P = 0.54; cardiovascular: HR = 1.1, P = 0.88). MetS itself was well known as a risk factor of cardiovascular disease. Although we identified an increased risk of MetS among low normal FT4 subjects as previous studies showed, no association was observed between FT4 levels and mortality. No association was observed between low normal thyroid function and overall or cardiovascular mortality.

Poster 164 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM ASSOCIATION BETWEEN LOW NORMAL THYROID FUNCTION AND MORTALITY K. Inoue1, T. Tsujimoto2, J. Saito1, T. Sugiyama3,4 1 Division of Endocrinology & Metabolism, Department of Medicine, Yokohama Rosai Hospital, Kanagawa, Japan; 2Department of Diabetes, Endocrinology, and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan; 3Department of Clinical Study and Informatics, Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan; 4 Department of Public Health/Health Policy, the University of Tokyo, Tokyo, Japan Some studies suggest the association between thyroid function and risk of metabolic syndrome (MetS) in euthyroid subjects. However, it is still unclear whether low normal thyroid function is associated with increased overall or cardiovascular mortality. A prospective cohort study was conducted using the National Health and Nutrition Examination Survey 2001–2002 and its mortality data through December 2011. Participants aged 20 years and older with TSH and free T4 (FT4) levels within normal range (0.45– 4.49 mIU/L and 0.6–1.6 ng/dL, respectively) were included. We excluded subjects with history of thyroid disease, thyroid functionaltering medication and other hormone medications use, cancer and pregnancy. Subjects were categorized into two groups according to their FT4 concentration (high normal: 0.9–1.6 ng/dL, low normal: 0.6–0.8 ng/dL). Associations between thyroidal condition measured by FT4 levels and mortality (all-cause or cardiovascular death) were

Kaplan-Meier estimates of all-cause mortality and Prevalence of metabolic syndrome (MetS). Analyses were adjusted for age, race/ethnicity, smoking status, diabetes, and history of cardiovascular disease.

Poster 165 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM TSH STABILITY IN HYPOTHYROID PATIENTS ASSUMING LIQUID LEVOTHYROXINE THIRTY MINUTES BEFORE OR AT BREAKFAST: RESULTS OF A MULTICENTER ITALIAN STUDY I. Pirola1, D. Brancato2, R. Negro3, E. Puxeddu5, A. Antonelli4, A. Delbarba1, S. Morelli5, A. Scorsone2, C. Cappelli1 1 Department of Medical and Surgical Sciences, Endocrine and Metabolic Unit, University of Brescia; Clinica Medica - 2^ Medicina Spedali Civili di Brescia, Brescia, Italy; 2Centro Regionale di Riferimento per la Diabetologi e l’Impianto dei Microinfusori, UOC Medicina Interna, PO Civico di Partinico., Partinico, Italy; 3Division of Endocrinology., ‘‘V. Fazzi’’ Hospital. 73100. Lecce, Lecce, Italy; 4 Department of Clinical and Experimental Medicine, University of Pisa, Italy, Pisa, Italy; 5Dipartimento di Medicina, Universita` degli Studi di Perugia, Perugia, Italy Levothyroxine (L-T4) is the treatment of choice for millions of hypothyroid patients and a limited serum TSH concentration represents the best marker to assess a successful treatment. Current guidelines recommend that L-T4 tablets should be taken in a fasting state, but this prescription is often cause of poor compliance to the therapy. Over the last few years, pharmaceutical companies have introduced in a few countries new, non-tablet L-T4 formulations, such as liquid and soft gel capsules. Few reports, in small series of patients, showed that liquid L-T4 could be assumed at breakfast. Aim of the present study was to compare TSH levels of hypothyroid patients treated with liquid L-T4 thirty minutes before or at breakfast. We enrolled hypothyroid patients in stable euthyroidism on liquid LT4 (Tirosint fiala monouso, IBSA Farmaceutici Italia) treatment assumed half an hour before breakfast. The patients were invited to assume L-T4 with breakfast for 8-wks. Individual L-T4 doses titrated during the first sequence period did not change during the second sequence. At the end of the second period TSH was re-checked. 478 patients (401/77 female/male, age 40.2 – 12.8 years) were enrolled in the study. 415 patients were in replacement therapy for Hashimoto thyroiditis and 63 after thyroidectomy for the removal of histologically proven benign goiter. No difference of TSH levels was observed whether L-T4 was assumed at breakfast or half an hour before in a fasting state [2.74 – 2.36 vs. 2.51 – 1.78 (mIU/L), p = 0.086]. A sub-analysis was performed on 102 patients assuming a concomitant drug treatment (including proton pump inhibitors, calcium or iron supplements) or using fiber and soy milk products at

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 breakfast. Again, no difference of TSH levels was observed [2.81 – 2.4 vs. 2.59 – 2.23(mIU/L), p = 0.498]. The present study indicates that a liquid L-T4 formulation can be assumed directly at breakfast, thus potentially improving therapeutic compliance.

Poster 166 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM ARE TSH TRIMESTER SPECIFIC REFERENCE VALUES FOR DIAGNOSE OF HYPOTHYROIDISM IN PREGNANCY BEING USED? P.A. Tavares, G. Rocha, A. Sousa, S. Monteiro, M. Barbosa, A. Ta´vora, M.M. Oliveira Endocrinology, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal There is a controversy among scientific guidelines regarding the recommendation to screen for thyroid dysfunction during pregnancy. In 2012, The Endocrine Society Task Force could not reach agreement: some recommended screening while others advocated aggressive case finding in high risk women. American Thyroid Association proposed that if trimester-specific reference ranges for TSH are not available, the following reference ranges are recommended: first 0.12.5mIU/L; second 0.2-3.0mIU/L; third 0.3-3.0mIU/L. Our objective was to determine the screening and hypothyroidism frequency in pregnancy using that trimester specific reference ranges for TSH and if it resumed post-delivery. Retrospective study with 1419 pregnant women with a first obstetrics consult in our hospital between January and May 2013. TSH was obtained in 334 women at least in one pregnancy trimester and hypothyroidism was diagnosed. Subclinical hypothyroidism using trimester specific reference ranges was present in 113 (33,8%) women. Prior to pregnancy 22 had thyroid disease with 18 being medicated with LT4. 52 of the 113 patients were sent to our endocrinology clinics. 44 patients had L-thyroxine during pregnancy and 21 remained medicated after delivery. Persistent thyroid dysfunction was newly diagnosed in 11 (9,7%) patients. Using our laboratory reference interval (0.27–4.2 mIU/L) only 38 (11,4%) of the 334 pregnant women had subclinical hypothyroidism. Women were more likely to be referenced to our endocrinology clinic if the laboratory reference interval was used to diagnose hypothyroidism instead of the trimester specific reference (70% vs 33,7% referenced hypothyroid women). Women who were referenced had higher average TSH (8,7 mIU/L vs 3,6 mIU/L, p = 0,012). Obstetrics complications were similar in patients with or without hypothyroidism (p = 0,69). In our hospital thyroid dysfunction screening is low. The general population reference range to diagnose hypothyroidism instead of the trimester specific reference values is still more used during pregnancy to reference pregnant women to the endocrinology expert. Postdelivery thyroid function evaluation is crucial for distinguish transient from persistent subclinical hypothyroidism.

Poster 167 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM PRE-OPERATIVE THYROID FUNCTION AND ANTIBODY LEVELS NOT PREDICTIVE OF TREATMENT FAILURE FOLLOWING SUBTOTAL THYROIDECTOMY FOR GRAVES’ DISEASE J. Teh1, C. Tay1, Y. Gwee2, J. Hu3, K. Ngiam1, R. Parameswaran1, C. Tan1, W. Cheah3,1, A. Rauff1, W. Tan1

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Department of Surgery, National University Health System, Singapore, Singapore; 2Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 3Department of General Surgery, Alexandra Hospital, Singapore, Singapore Surgical options in Graves’ disease (GD) include total thyroidectomy (TT) and subtotal thyroidectomy (ST). Proponents of ST cite lower risk of morbidity and an anticipated postoperative euthyroid state, but at the cost of higher recurrence. In fact, majority of patients undergoing ST still end up hypothyroid on long term follow-up. Several factors have been proposed to affect thyroid function postST, with size of thyroid remnant the most powerful predictor of relapse. The effect of preoperative thyroid function and antibody levels on recurrence remains unclear, with some studies suggesting TSH-binding inhibitory immunoglobulin to be predictive of postoperative hyperthyroidism. We aim to elucidate factors predisposing to treatment failure (TF) after ST in GD. In particular, we sought to identify preoperative biochemical markers predictive of TF, which may aid in selection of surgical approach. Data of all patients who underwent ST for GD in a single tertiary care centre over a period of 20 years from 1991–2010 was retrospectively reviewed. The main outcomes analyzed were preoperative thyroid function, TRAB, anti-TPO and anti-TG levels between TF and non-TF groups. TF includes cases of relapse and persistent disease post-ST. 79 patients underwent ST for GD at our centre over the given time period. 85.5% were female with a mean age of 31.7 years and majority were Chinese (86.3%). The median length of follow-up was 129 months, with at least 1 year for all cases. TF occurred in 24.1% (19/79) of patients - 3 were persistent disease and 16 were relapses. Only 26.6% (21/79) remained euthyroid on long term follow-up. Levels of preoperative TSH, T4, TRAB, anti-TPO and anti-TG were not significantly different between the patients who developed relapse compared to those who did not. Our results suggest that higher preoperative levels of thyroid hormone and thyroid antibodies do not predispose to TF post-ST. Besides the size of thyroid remnant, there is still no reliable predictor of TF preoperatively. ST has a high rate of TF and only a limited number of patients achieve a euthyroid state.

Poster 168 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM SPECIFIC SYMPTOMS OF THYROID DYSFUNCTION IN JAPANESE: REEVALUATION OF CLASSICAL SYMPTOMS IN MODERN THYROID FUNCTION TESTS T. Tagami, M. Tsuiki, M. Kakita, H. Umakoshi, T. Ogasawara, K. Hiroshima, T. Usui, M. Naruse, A. Shimatsu Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Kyoto, Japan Medical interviews of patients can yield clues for the detection of thyroid dysfunction. However, symptoms of thyroid dysfunction as described in textbooks are based on Western populations. The aim of this study is to elucidate specific symptoms of thyroid dysfunction in Japanese. For one year, consecutive patients who visited us for their first medical examination were asked to complete an original questionnaire about their overall complaints (prospective study). Excluding patients who were already being treated for thyroid dysfunction, 533 subjects were analyzed: 105 overt hyperthyroid patients (T), 34 with subclinical hyperthyroidism (ST), 12 hypothyroid patients (H), 46 with subclinical hypothyroidism (SH), and 336 euthyroid subjects (E). Eight symptoms in T, five in ST, two in

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SH, and six in H were cited by more than 60% of the patients. However, more than 60% of the subjects in E also cited ‘easy fatigability’, ‘heat intolerance’, and ‘cold intolerance’, indicating that these are considered as nonspecific and indefinite complaints to detect thyroid dysfunction. The mean severity of 13 symptoms in T, 3 in ST, 1 in SH and 6 in H was significantly higher than in E, after adjustment for age and sex. ROC analysis was moderately accurate in four symptoms of ‘palpitation’, ‘shortness of breath’, ‘body weight loss’, and ‘tremor’ at distinguishing T from E and in four symptoms of ‘easy fatigability’, ‘general malaise’, ‘lethargy’, and ‘muscle weakness’ at distinguishing H from E. Four symptoms - ‘palpitation’, ‘shortness of breath’, ‘body weight loss’, and ‘tremor’ - are thought be the most useful for efficiently detecting thyrotoxicosis (OR = 15.3). On the other hand, four symptoms - ‘easy fatigability’, ‘general malaise’, ‘lethargy’, and ‘muscle weakness’ - are useful for hypothyroidism (OR = 7.8).

Poster 169 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM FACTORS AFFECTING LEVOTHYROXINE THERAPY AND DOSING RESULTS OF THE CONTROL SURVEILLANCE PROJECT M.S. McMillan1, K. Vora2, L. Thevathasan3 1 Administration, McMillan Survey Research & Statistical Consulting, Cordova, TN; 2Akrimax Pharmaceuticals, Cranford, NJ; 3 LT Associates Ltd, Paris, France Factors that affect levothyroxine efficacy and tolerability include: 1. concomitant GI conditions 2.GI medications, and 3. food allergies. The CONTROL Surveillance Project is a patient-based survey conducted with hypothyroid patients undergoing levothyroxine treatment. The primary objective of this study was to quantify the prevalence of key factors adversely affecting levothyroxine therapy. Eligible participants selected from a large proprietary database completed a 21-question survey online. Of the 1000 eligible patients, 925 (92.5%) were being treated with levothyroxine monotherapy. Mean age was 60.4 years; 755 (81.6%) were female, and 168 (18.2%) male. While most patients had been on levothyroxine for years (94.1% for ‡ 3 years), many (31.4%) reported a change of levothyroxine dose within the past year, with 8.0% reporting ‡ 2 dose changes. Overall, 435/925 (47.0%) patients reported having concomitant GI conditions that adversely affect levothyroxine absorption. Among patients with GI co-morbidities, 10.6% (46/435) had ‡ 2 levothyroxine dose changes in the past year vs. 5.7% (28/490) of those without such conditions (P < 0.01).

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Overall, 37.1% (343/925) of patients reported taking GI medications that could adversely affect levothyroxine absorption. Of patients taking those medications, 9.0% (31/343) had ‡ 2 levothyroxine dose changes in the past year vs. 7.4% (43/582) of all other patients (P > 0.05). Overall, 15.2% (141/925) of patients reported allergies to foods that can affect levothyroxine. For those respondents, 14.2% (20/141) had ‡ 2 levothyroxine dose changes in the past year, vs. 6.9% (54/784) of those without such allergies (P < 0.01). CONTROL Surveillance helps quantify the prevalence of factors known to affect levothyroxine. Frequent dose changes ( ‡ 2/year) may indicate suboptimal therapeutic response, as a function of comorbid GI conditions, medications used to treat those conditions, or food allergies. Better initial workup and ongoing surveillance of patients, focusing on identification of relevant GI co-morbidities, medications, and allergies, may lead to improved performance of levothyroxine.

Poster 170 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM FACTORS AFFECTING LEVOTHYROXINE THERAPY: CONCOMITANT GI MEDICATIONS RESULTS OF THE CONTROL SURVEILLANCE PROJECT M.S. McMillan1, K. Vora2, L. Thevathasan3 1 Administration, McMillan Survey Research & Statistical Consulting, Cordova, TN; 2Akrimax Pharmaceuticals, Cranford, NJ; 3 LT Associates Ltd, Paris, France Levothyroxine therapy for hypothyroidism can be adversely affected by certain concomitant medications, particularly those taken for the relief of gastrointestinal symptoms. These medications may contribute directly or indirectly to the failure of therapy, by limiting the absorption of levothyroxine, and can adversely affect the satisfaction of both patients and clinicians. The CONTROL Surveillance Project is one of the most comprehensive patient-based surveys ever conducted with hypothyroid patients undergoing levothyroxine treatment. The primary objective of this study was to quantify the prevalence of key GI factors adversely affecting levothyroxine therapy.

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Eligible participants selected from a large proprietary database completed a 21-question survey online. Of the 1000 eligible hypothyroid patients, 925 (92.5%) were being treated with levothyroxine monotherapy. Mean age was 60.4 years; 755 (81.6%) were female, and 168 (18.2%) male. Overall, 37.1% of patients receiving levothyroxine reported taking medications that could adversely affect its absorption - proton pump inhibitors, histamine-receptor antagonists, and OTC antacids. Significant relationships were shown between use of these medications, symptom control, and satisfaction with therapy. Half as many respondents who were taking these medications vs. those who were not (30.3% vs 56.3%, P < 0.001), indicated control of their hypothyroid symptoms (disagreed or slightly agreed with the statement ‘‘It’s hard to control my hypothyroid symptoms’’). Similarly, half as many respondents taking GI medications vs. those who were not (27.5% vs 53.0%, P < 0.001) reported being satisfied with their hypothyroid therapy. The results of CONTROL Surveillance help to quantify the prevalence of factors known to affect levothyroxine efficacy and tolerability. Better initial workup and ongoing surveillance of patients, focusing on identification of relevant concomitant medications, may lead to improved performance of levothyroxine.

Poster 171 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM EARLY PREDICTION OF POST-THYROIDECTOMY HYPOCALCEMIA USING INTRAOPERATIVE PARATHYROID HORMONE ASSAY D.S. Kim, A.E. Barber, R. Wang Division of Otolaryngology-Head and Neck Surgery, University of Nevada School of Medicine, Las Vegas, NV Hypocalcemia is the most common postoperative complication of total thyroidectomy. The etiology of post-thyroidectomy hypocalcemia is iatrogenic hypoparathyroidism secondary to an inadvertent removal of parathyroid glands, direct gland injury, or disrupted blood supply to the glands. Parathyroid hormone (PTH) is a principal regulator of serum calcium and is also an ideal real-time marker for parathyroid gland function due to its short half-life (1-4 minutes). The objectives of this study are to establish a correlation between intraoperative PTH (iPTH) and postoperative calcium levels and to devise iPTH-based numerical criteria for same-day discharge following total thyroidectomy. Seventy patients undergoing total thyroidectomy were prospectively enrolled in the study. iPTH levels were measured at two time points: pre-incision (following anesthesia induction but prior to skin incision) and post-excision (at 20 minutes after complete removal of thyroid gland). Total and ionized calcium levels were measured at 6 and 12 hours postoperatively. Significant hypocalcemia was defined

A-71 as total Ca £ 7.5 mg/dL or iCa < 0.9 mmol/L. Absolute iPTH and changes in iPTH were correlated with postoperative calcium levels. PTH increased in response to anesthesia induction. Preoperative and pre-incision PTH showed no correlation with postoperative calcium levels. 14 patients (20.0%) developed significant hypocalcemia while 2 patients (2.9%) developed permanent hypoparathyroidism. Post-excision PTH was significantly lower in those with hypocalcemia compared to the normocalcemic group (9.6 vs 57.0 pg/ mL; p < 0.01). iPTH reductions were higher in the hypocalcemic group (94.5 vs 61.8%; p < 0.01). The post-excision PTH threshold of 25 pg/mL or greater would keep all high-risk patients in hospital while discharging 82% of low-risk patients on the same day, whereas an iPTH reduction of less than 95% as a threshold would allow for same-day discharge of all of low-risk patients while keeping half of high-risk patients in hospital. Intraoperative PTH assay has a predictive value for postoperative hypocalcemia. Using iPTH criteria, low-risk patients can be safely discharged on the same day while minimizing unnecessary tests and hospital stay.

Poster 172 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM SURGICAL MANAGEMENT OF GRAVES’ DISEASE OVER A 25-YEAR PERIOD: A SOUTH-EAST ASIAN PERSPECTIVE C. Tay1, J. Teh1, Y. Gwee2, J. Hu3, K. Ngiam1, R. Parameswaran1, C. Tan1, W. Cheah3,1, A. Rauff1, W. Tan1 1 Department of Surgery, National University Health System, Singapore, Singapore; 2Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 3Department of General Surgery, Alexandra Hospital, Singapore, Singapore Graves’ disease (GD) is the most common cause of hyperthyroidism. Current treatment options include antithyroid medication, radioactive iodine (RAI) or thyroidectomy. The preferred first line treatment is dependent on place of practice, commonly it is RAI in the USA as compared to medication in Asia & Europe. Surgery is often offered as second line treatment when drug therapy fails or is contraindicated. However, the extent of resection remains a controversial topic. Total thyroidectomy (TT) has been shown to lower recurrence rate, but subtotal thyroidectomy (ST) is presumed to have a lower risk of complications and postoperative hypothyroidism. Several studies have so far refuted this claim, and we seek to compare the long term outcomes of TT vs ST in a South-East Asian population. A retrospective review of prospectively collected data of all patients who underwent surgery for GD in a single tertiary care centre over a period of 25 years from 1991–2015 was performed. The main outcomes compared between ST and TT groups were: length of stay (LOS), recurrence rate, temporary and permanent hypocalcemia, and recurrent laryngeal nerve palsy. 130 patients underwent surgery for GD at our centre over 25 years. 13 patients were excluded due to lack of follow-up data postoperatively (n = 117). 85.5% were female with mean age of 33.3 years and most were Chinese (86.3%). TT comprised of 32.5% (38/117) of cases, most performed within the past decade. The median length of follow up was 102 months. TT was associated with a significantly lower rate of recurrent hyperthyroidism (TT 0% vs ST 20.3%; p = 0.001). There was no difference in the rate of temporary and permanent hypocalcemia, transient recurrent laryngeal nerve palsy and mean LOS. There was no permanent recurrent laryngeal nerve palsy in both groups. 3 cases had persistent disease post-ST. The rate of hypothyroidism requiring hormone replacement post-ST is 63.3% (50/79).

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Poster 174 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM THYROID DYSFUNCTION & TYPE 2 DIABETES MELLITUS IN ASIAN INDIAN SUBJECTS S.R. Joshi1,2, S.S. Joshi1, P. Agarwal1, M. Shah1 1 Joshi Clinic, Mumbai, India; 2Endocrinology, Lilavati Hospital, Mumbai, India

Long-term results of surgery for GD in a South-east Asian population are similar to current literature. TT prevents recurrence and has a similar safety profile to ST in GD. TT should be made the surgery of choice for GD if reliable access to thyroid replacement is available.

Poster 173 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM THYROID PATHOLOGY PREVENTION IN SCHOOL AGE: PROSPECTIVE STATISTICAL ANALYSIS IN THE NEW ETHNIC REALITIES A. Di Paolo***, C. De Santis***, F. Culasso*, S. Chiarini**, S. Federici*, C.D’Ercole***, P. Grilli*** *UNIVERSITY OF ROME - LA SAPIENZA **UNIVERSITY OF CHIETI - G. D’ANNUNZIO ***ROME ONLUS BUTTERFLY MEMBERS G. Paola2,1, C. Stella1, D. Arianna2 1 UNIVERSITY, Rome, Italy; 2Onlus Butterfly, Rome, Italy Thyroid pathology has been increasing in adults and young people during these last years.Related to this, we’ve decided to prevent, to diagnostic and take care of these thyroid pathologies in young age. The project purpose has been beginning with a prospective epidemiological analysis on young people and early locate any alterations in order to avoid the evolution. From 2013 at today in 12^ - 13^ school year kids have been analyzed in Rome schools. We’ve spread a symptoms template survey in order to calculate all the symptoms and value them statistically for discoverying, with the echography, which eventual morphological alterations they could have. We have make an analysis consists by dedicated medical staff that going to the schools to examine each child and submit him to a thyroid echography with color-doppler. We reported quantitative data and qualitative data such as absolute frequency and relative for different variables. For the quantitative variables have been executed the ‘‘t’’di Student e Mann-Whitney for valuing the meaningfulness of the differences of the variables got in different groups. For the qualitative variables have been considered the independence among two variables with the test ‘‘x2’’ and the difference between the frequencies with the test ‘‘z’’ For the different test there is a probability, indicated with ‘‘a’’, which is under 5% and it’s considered statistically significant. We’ve noticed either a significant difference (p < 0,01) in the results coming from the echography among the class 13 of two different schools. Furthermore we’ve been noticed in these two specific classes there is also a crucial difference (p < 0,05) among the frequency of negative results at the echography. Our results underline that children in the 12 classes manifest thyroid pathology symptoms less than classes 13 id est in that age between 11 and 12 years old and in particular for females, in pre-menarche, the physic-ormonal stress can induce the pathology and we can prevent it before it happens. Therefore, we believe that our study deserve to be expanded with the collection of data in order to identify what are the factors that, at the same age.

The Type 2 diabetes prevalence in India is second highest in the world. However, the prevalence of thyroid dysfunction (Hypothyroidism) in these patients has not been investigated systematically. We decided to prospectively investigate prevalence of thyroid dysfunction in Type 2 Diabetic Indian patients in a tertiary referral endocrine center in India. This prospective study was conducted at the Tertiary Care Endocrine Center in Mumbai, India between July 2014 and April 2015. A group of 1215 consecutive type 2 diabetic patients (T2DM) were screened for thyroid dysfunction.They all underwent investigations for thyroid functions; total thyroxine (TT4), Total tri-iodothyronine (TT3) and thyroid stimulating hormone (TSH) and thyroid peroxidase antibodies (antiTPOab). All associated autoimmune disorders were excluded from the analysis.Lipid profile and Glycosylated hemoglobin also was measured in all cases.Type 1 and other types of diabetes were excluded. 66.58% (809) cases were female. 16.95% (206) of Type 2 diabetic patients were known to have primary hypothyroidism. The number of new primary hypothyroidism cases diagnosed were 11.68% (142) of the cohort. The diagnosis of new cases was based on screening and were asymptomatic. The prevalence of positive Anti- TPO antibody was found in 24.44%(297) of Type 2 Diabetic patients. Despite of tertiary endocrine care referral bias (clinic based) the prevalence of both new as well as thyroid autoimmunity was high in Type 2 diabetes was high. This study suggests that Type 2 diabetic patients should be screened for asymptomatic thyroid dysfunction. Due to high prevalence of both asymptomatic new cases as well as autoimmunity in this population a proper epidemiological study needs to be planned to unearth prevalence of primary hypothyroidism in Type 2 diabetes and the factors which may contribute to this.

Poster 175 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM INTERPRETING UNUSUAL THYROID FUNCTION TESTS: HEREDITARY TBG DEFICIENCY AND GRAVES’ DISEASE H.R. Berger1,2, A. Kargi2,1 1 Endocrinology, Jackson Memorial Hospital, Miami Shores, FL; 2 Endocrinology, University of Miami Hospital, Miami, FL Thyroxine-binding globulin (TBG) deficiency has been described in families. An X-linked mode of inheritance has been reported and the prevalence is thought to be 1:2500. In euthyroid patients, total T4 is low and TSH normal. Secondary TBG deficiency due to hypermetabolic condition in hyperthyroid patients is often encountered and TBG levels should recover when hyperthyroidism is treated. In hereditary TBG deficiency associated with hyperthyroidism, TBG will not recover when euthyroid state is achieved. Hereditary TBG deficiency together with hyperthyroidism has rarely been reported. 33 year old Indian male presents with abnormal labs on routine physical exam. His TSH was found to be 0.01(0.40-4.50miU/L). On further testing, total T4 3.0 (4.5–12.0mcg/dL), free T4 2.0 (0.81.8ng/dL), free T3 3.6 (2.3–4.2 pg/mL). Thyroid stimulating immunoglobulins were markedly elevated at more than 55% baseline. Patient denied weight changes, heat or cold intolerance, tremors, palpitations, or changes in appearance of his eyes. Physical exam was unremarkable. Patient was diagnosed with Graves’ disease and

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started on methimazole 5mg PO daily. Repeat labs one month later show TSH 0.02, Free T4 1.5, Total T4 2.1, Thyroxine binding globulin < 3.5 (12.7–25.1 mcg/mL). Three months later, after normalization of thyroid function tests with TSH 0.81, free T4 1.6, TBG remained undetectable at < 3.5. Our patient was diagnosed with Graves’ disease. Considering his suppressed TSH, low total T4, and undetectable TBG levels, he likely has familial thyroglobulin binding deficiency in addition to Graves’ disease. Genetic testing has not been completed yet. Our patient is of Indian ethnicity, and thyroid hormone binding protein abnormalities are more often reported in Indian and Japanese populations. Graves’ disease co-existing with TBG deficiency is rare but has been described. Patients with TBG deficiency and Graves’ disease will have unusual thyroid function tests. Total T4 will be normal or low and if patient has this finding with suppressed TSH, TBG levels should be evaluated to identify TBG hereditary abnormalities. This will allow for more clear interpretation of thyroid function tests.

statistically significant in terms of their distribution in the two groups. There is no statistically significant difference in the echocardiographic findings related to the cause of hyperthyroidism, also, neither the etiology represents a risk factor for representative echocardiographic changes.

Poster 176 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM PREVALENCE OF ECHOCARDIOGRAPHIC CHANGES DEPENDENT OF THE CAUSES OF HYPERTHYROIDISM P.R. Rangel2, A.S. Caballero1 1 Endocrinologia, Instituto Mexicano del Seguro Social, Distrito Federal, Mexico; 2Endocrinologia, Instituto Mexicano del Seguro Social. Centro Me´dico Nacional La Raza, Distrito Federal, Mexico Cardiovascular abnormalities that can be found in patients with hyperthyroidism. Hyperthyroidism affects global left ventricular function, the total volume of plasma, heart rate and contractility increased while reducing afterload. Observational, retrospective and prospective, transversal, descriptive and open study, from December 2014 to May 2015. Patients > 18 with hyperthyroidism (diffuse toxic goiter or toxic nodular goiter) uncontrolled. Pearson correlation coefficient, Chi square were applied and percentages, means and standard deviations were calculated.76 patients were selected, classified according to the cause of hyperthyroidism. Echocardiography Doppler, M-mode and signs Doppler flow were obtained with the transducer in cardiac apex to determine the presence of mitral valve insufficiency, aortic, pulmonary and tricuspid, systolic opening of the aortic valve, systolic blood pressure of the main pulmonary artery, left ventricular systolic diameter, septal diastolic thickness of the left ventricle, segmental contractility left ventricle, systolic displacement of the tricuspid ring, ejection fraction of the left ventricle and pulmonary arterial hypertension. The mean age was 42 + 13 years. The mean FT4 levels in toxic nodular goiter was 2.6 ng/dl + 1.3 and with diffuse toxic goiter, FT4 levels were 3.5 ng/dl + 1.4 FT4 distribution being the same between categories (p .035). 12 (100%) patients with toxic nodular goiter had mild mitral insufficiency, patients with diffuse toxic goiter of 56 (87.5%) was found with mild mitral insufficiency. In aortic regurgitation, 12 (100%) patients with toxic nodular goiter had mild impairment, patients with diffuse toxic goiter of 56 (87.5%) was found with mild impairment. In patients tricuspid valve regurgitation was reported 12 (100%) with toxic nodular goiter of mild tricuspid regurgitation, and with diffuse toxic goiter 56 (87.5%) was found with mild impairment. Pulmonary arterial hypertension was detected in the group of toxic nodular goiter 3 (25%) patients and mild in the group with diffuse toxic goiter diagnosis of 33 (51.6%) was mild. A higher prevalence regarding the diagnosis of diffuse toxic goiter and etiology of hyperthyroidism. FT4 and TT3 levels are

Poster 177 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM THE CURE RATE IN FIRST LINE TREATMENT OF GRAVES DISEASE IN SWEDEN 7-9 YEARS AFTER DIAGNOSIS G.K. Wallin6, K. Bystro¨m1, G. Sjo¨lin6, O. To¨rring1, S. Khamisi1, M. Holmberg1, M. Abraham-Nordling2, J. Calissendorff1, B. Hallengren3, M. Lantz3, D. de Laval4, H. Filipsson5 1 ¨ rebro, Sweden; 2Surgery, Dept of Endocrinology, Medicine, O Surgery Karolinska University Hospital, Stockholm, Sweden; 3 Endocrinology, Dept of Endocrinology, Ska˚ne University Hospital, Malmo¨, Malmo¨, Sweden; 4Medicine, Dept of Medicine, Karlskrona,, Karlskrona, Sweden; 5Endocrinolgy, Dept of Endocrinology, Sahlgrenska University Hospital, Go¨teborg, Institute of Medicine Sahlgrenska Academy, University of Gothenburg, Go¨teborg, Go¨teborg, Sweden; 6Surgery, Dept of ¨ rebro University, Surgery, Faculty of Medicine and Health, O ¨ rebro, Sweden, O ¨ rebro, Sweden O The incidence of hyperthyroidism was 27.1/100000 inhabitants (children included)/year in a prospective study 2003–2005 with a catch up area of 40% of the Swedish population of 9 million inhabitants. 2916 patients were included and this cohort has been studied 7–9 years after the diagnosis with the intent to evaluate the long-term outcome. Sweden is considered iodine sufficient. 2916 patients were included in the original cohort (see figure 1:1) After 7–9 years from diagnosis 2451 were contacted for follow-up by questionnaires, Fifty-nine percent (1460 patients) agreed to participate. Patients answered three questionnaires at home and returned them by mail. There were two quality of life questionnaires (SF-36 and Thyr-Pro) and one which gave information about recurrence of hyperthyroidism, final treatment regime, symptoms and treatment of TAO, smoking habits and comorbidity Included 2916 Deceased 351 Faulty 115 Dispatch 2451 Declined 362 No answer 629 Participants 1460 (59%). 1262/1460 patients have been evaluated where 81.2% had Graves disease and 18.8% had Toxic Multinodular Goitre (TMNG). The outcome of first line treatment of the Graves’ patients are reported as Antithyroid Treatment (ATD,586) Cured by first treatm 42.2% Smokers/48.1% Non smokers Radioiodine 299 Cured by first treatment 81.5% Smokers/78.6% Non smokers Surgery 67 Cured by first treatment 89.5% Smokers/93.1% Non smokers No Treatment 73 Ongoing ATD after 7–9 years 24 patients 2% Smokers/2.7% Non smokers Ongoing Thyroxin after 7–9 years 665 patients 67.9% Smokers/61.3% Non smokers. In this prospective study 82% of patients with hyperthyroidism had Graves’disease, 19% had TMNG. All together 579/1025 (56%)

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patients with Graves’disease were cured with one initial treatment period, ranging from 43% for ATD in smokers to 97% with surgery in non smokers. The 629 individuals that did not respond the questionnaires will be studied to exclude recruitment bias.

deficiency (ID) are identical to the symptom spectrum of HT. However, diagnosing iron deficiency may be extremely challenging, since iron stores may be severely depleted without any changes in the blood hemoglobin concentration or red cell indices. Patients with ferritin concentrations up to 70 mg/l may, in fact, be severely iron deficient. Twenty five females with a history of overt HT were referred after appropriate and ongoing treatment with L-T4 for persisting hypothyroid symptoms. After careful clinical examination B12-vitamin deficiency, celiac disease, hypercalcemia and vitamin D deficiency were excluded. Their L-T4 dose was adjusted when necessary to achieve a TSH concentration of 1–2 mU/l. 4/5 and 14/20 of the patients with serum ferritin < 15 and 15–60 mg/l, respectively, became symptom free after oral iron substitution therapy for 6–12 months; now their serum ferritin concentration was at least 100 mg/l. The functional iron stores may be depleted while the serum ferritin concentration is within the current reference ranges. Iron deficiency is apparently one of the main causes for persisting hypothyroid symptoms during thyroxin treatment. Not all iron deficient patients, however, seem to respond to the restoration of their functional iron stores. Iron deficiency simulates symtoms of hypothyreosis.

Poster 178 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM REGIONAL VARIATION OF LEVOTHYROXINE USES IN FINLAND E.T. Soppi Out Patient Clinic, Eira Hospital, Helsinki, Finland Little is known about the regional variation in the use of levothyroxine (L-T4) medication. Data from Sweden indicates that there may be a 1.5-fold variation among the regions (Nordlund 2008). In Finland, L-T4 is fully reimbursed in clinical hypothyreosis (HT) (TSH > 10mU/l or after thyroidectomy or radioiodine ablation). L-T4 in subclinical HT is only partially reimbursed. The use of L-T4 was examined over 2008–2013 to study interregional variation and changes in the use of L-T4 in Finland. Data on the use of L-T4 (fully and partially reimbursed) were derived from the registry of the Social Insurance Institution of Finland (gender, age and hospital district distributions, years 2008– 2013). The corresponding population statistics were derived from the Population Register Centre. In 2008, the prevalence of L-T4 use was 3.25% among females and 0.65% among males; in 2013 the figures were 4.31% and 0.96%. In 2008 the regional variation of the total prevalence among the hospital districts varied from 3.3% to 4.8% and in 2013 from 4.2% to 7.0%. This variation did not correlate with the size of the hospital district, its population or the prevalence six years previously. The highest prevalence of L-T4 use occurred in aged patients ( ‡ 75 years), among females 18% and males 8%. In 2013 the prevalence of fully reimbursed L-T4 use was 1.32 % among females (1.33 % in 2008) and 0.25% among males (0.24% in 2008). The prevalence of partially reimbursed L-T4 use in subclinical HT was 2.99% among females (1.93% in 2008) and 0.71% among males (0.42% in 2008). The incidence of L-T4 use in overt and subclinical HT were 5 and 241/100,000/yr, respectively, Discussion. The incidence and prevalence figures of overall L-T4 use are the same as in international surveys. The regional variations in Finland are of similar magnitude as in Sweden; this variation was stable over a six-year period. The results show also that the increase of L-T4 use over time is exclusively due to the treatment of subclinical HT. The results imply that a significant part of the increased use of thyroxine may be due to treatment of patients that do not have genuine hypothyreosis.

Poster 179 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM IRON DEFICIENCY IS THE MAIN CAUSE OF SYMPTOM PERSISTENCE IN PATIENTS TREATED FOR HYPOTHYROIDISM E.T. Soppi Out Patient Clinic, Eira Hospital, Helsinki, Finland Symptoms of hypothyroidism (HT) persist in 5–10% of hypothyroid patients treated with levothyroxine (L-T4). These patients are a clinical challenge and are often difficult to treat or unresponsive to combination treatment with L-T4 and L-T3. The prevalence in the population of iron deficiency is as common as HT. Symptoms of iron

Poster 180 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM THYROID FUNCTION IN PATIENTS WITH CYSTIC FIBROSIS: NO LONGER A CONCERN? S.Y. Lee1, S. Chesdachai2, M.J. Lee2, X. He1, V. Tangpricha2,3, L.E. Braverman1 1 Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, MA; 2Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA; 3Division of Endocrinology, Atlanta VA Medical Center, Decatur, GA Development of goiter and hypothyroidism has been reported in patients with cystic fibrosis (CF) since the 1970s, especially when treated with iodine-based expectorants. Since iodine-containing expectorants are no longer in routine use, the prevalence of thyroid dysfunction in CF patients is unknown. We assessed thyroid function status in a large cohort of CF patients in this cross-sectional study. Sera from ambulatory subjects were obtained from an IRBapproved biorepository of patients seen at the Emory CF Center between 01/01/2011–12/31/2014. Sera from hospitalized subjects were obtained from banked specimens from an IRB-approved inpatient clinical trial. Demographics, forced expiratory volume at 1 min (FEV1), and medication use were assessed from medical records. Thyroid function tests were measured from the stored sera. Multivariate regression models assessed associations between covariates and TSH, free thyroxine (FT4), and thyroid dysfunction risk. The baseline characteristics of 89 subjects in the study are shown in Table 1. One subject was on thyroid hormone replacement, 93% were on pancreatic enzyme replacement, and 68% received antibiotics £ 6 months. None had CT scans with intravenous contrast £ 6 months. One patient had positive TPO antibodies. Of the 87 subjects with measured TSH values, 7 (8%) had abnormal levels (range: 0.27.6lIU/mL; 1 overt and 4 subclinical hypothyroidism, and 2 subclinical hyperthyroidism). Of the 56 subjects with measured FT4 values, 19 (34%) had slightly low levels (range: 0.49–0.79ng/dL; 17 isolated mild hypothyroxinemia). A positive correlation between age and BMI (p < 0.001) and a negative correlation between age and FEV1 (p = 0.041) were seen. Age, sex, race, body mass index (BMI), FEV1, hospitalization status, use of pancreatic enzyme or thyroid

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A-75 also inhibited LPS stimulated IL-6 release. As LPS induced cytokine production in some model of fatty liver, we then investigated the interaction with leptin and LPS. However, leptin had no significant effect on LPS induced IL-6 production. Leptin had no effects on IGFI or 8-bromo-cAMP induced IL-6 production neither. These observations suggested that infections or tissue destruction, which activate innate immune system may also potentiate the TSH and IGF-1 system in the affected tissue of GO. On the other hand, the local production of leptin may not have major role in pathogenesis of GO. Inhibition of IGF-I system may be effective for GO induced by infections and tissue damage in addition to TSHR receptor activation.

Poster 182

hormone replacement, recent antibiotic use, and TPO antibody positivity were not predictive of TSH or thyroid dysfunction risk. Increasing age predicted FT4 (p = 0.023). Stratified analyses by hospitalization did not predict TSH or FT4. Although 34%(19) of the patients had mild hypothyroxinemia, overt thyroid dysfunction was rare in our cohort of 89 patients with CF. There were no significant predictors of thyroid dysfunction.

Poster 181 Disorders of Thyroid Function Monday & Tuesday Poster Translational 9:00 AM THE ROLE OF ENDOTOXIN AND LEPTIN IN PATHOGENESIS AND EXACERBATION OF GRAVES’ OPHTHALMOPATHY: INTERACTIONS WITH TSH RECEPTOR PATHWAYS IN FIBROBLASTS FROM GRAVES’ OPHTHALMOPATHY O. Isozaki1, R. Inoue2, Y. Okubo1, T. Inoue2, Y. Mizoguchi1, A. Ichihara1 1 Department of Medicine 2, Tokyo Women’s Medical University, Tokyo, Japan; 2Olympia Eye Hospital, Tokyo, Japan Graves’ ophthalmopathy (GO) is one of the major clinical issues that remain unresolved. Antibodies against thyrotropin receptor (TSHR) may play important roles in pathogenesis of GO. However, additional mechanism should be involved in the inflammation and extracellular matrix deposition of affected tissues. Local infections and tissue damages are sometimes associated with the exacerbation of GO and leptin production in the affected adipose tissue of GO was reported. Therefore, we investigated the interaction of endotoxin and leptin with TSH/IGF-I signaling system of fibroblasts from GO tissue. LPS, human leptin, 8-bromo-cAMP, human IGF-1 and receptor kinase inhibitor, PQ401were obtained from Sigma Aldrich. Orbital tissues were obtained as surgical waste during decompression surgery for Graves’ ophthalmopathy conducted in Olympia Eye Hospital. Primary culture of orbital fibroblast was carried out by a standard method. Cell proliferation was measured by MTS assay. IL6 secretion and mRNA was estimated by ELIA kit (Diaclone, France) and RT-PCR. LPS increased IL-6 mRNA levels as well as IL-6 release from GO fibroblasts. It also potentiated 8-bromo-cAMP and IGF-1 stimulated IL-6 mRNA and IL-6 release. LPS had no effect on cell proliferation estimated by MTS assay. PQ401, inhibitor of IGF-1 receptor kinase, inhibited IGF-I as well as 8-bromo-cAMP stimulated IL-6 release. It

Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM BIOTIN INDUCED THYROID FUNCTION TEST ARTIFACT C.N. Mariash, P. Skierczynski Medicine, Indiana University, Indianapolis, IN The use of dietary supplements has gained increasing popularity. The public is guided by advertisements and social media that suggest these supplements are both safe and helpful in promoting health. We have recently found several patients whose abnormal thyroid function tests were related to biotin use. The first patient was referred to Endocrinology for severe hyperthyroid labs, including an elevated thyroid stimulating immunoglobulin with suppressed TSH and elevated free T4 and total T3. She had no hyperthyroid symptoms or positive findings on exam. She was placed on methimazole after which she was found to a still have an elevated free T4 and total T3 but a TSH that was above normal. Testing at a different lab noted that the free T4 value was normal for the similar TSH on several lab draws. The second patient who was on a stable dose of levothyroxine was found to have an elevated free T4 and a normal TSH when evaluated by her primary care physician. She was referred to Endocrinology because of the confusing results. Additional laboratory testing showed that the free T4 remained elevated and was associated with an elevated total T3. However, the total T4, T4 Index, and TSH were normal. Upon further questioning, we found that both patients recently started taking biotin supplements to improve their health. Upon review of the local laboratory testing, we found that both the free T4 assay and the total T3 assay use a biotin-strepavidin florescent detection system while the TSH and total T4 assays do not. A similar assay artifact was presented at the Endocrine Society Meeting in March of this year. With the proliferation of various thyroid function assays now available, it is difficult to be aware of all possible artifacts. Based on these observations, we believe it is critical for the consulting endocrinologist to be aware of the assay details in their own laboratory in order to prevent the ordering of further unnecessary laboratory and imaging studies.

Poster 183 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM AN UNUSUAL CASE OF GRAVES’ DISEASE COEXISTING WITH STRUMA OVARII I. Javeed1, A. Sabet2, J. Kung1 1 Endocrinology, Tufts Medical Center, Boston, MA; 2 Signature Healthcare, Brockton, MA

A-76 Struma ovarii is a rare tumor consisting primarily of thyroid components occurring in a teratoma or dermoid in the ovary. Only one other case of struma ovarii presenting as a pseudo-Meigs’ syndrome coexisting with Graves’ disease has been described in the literature. 54 yo Caucasian woman who presented to her PCP with fatigue and weight loss of 40 lbs in the last 1.5 years. Her history was significant for tremors, irritability, and prominent, bulging eyes. Physical exam was significant for a non-palpable thyroid, bitemporal wasting, proptosis of 22 mm in the R eye, 18 mm in the L eye, R eyelid retraction, periorbital edema, and lid lag. TSH < 0.005, FT4 4.32 ng/dl (nl 0.70-1.48), TT3 530 ng/dl (nl 58-159). Thyroid stimulating immunoglobulin was elevated at 441% baseline (normal < 140). Based on her exam and laboratory results, she was diagnosed with Graves’ disease and started on methimazole 20mg daily. Three weeks later, she presented to the hospital with severe bloating and was found to have a 10cm pelvic mass along with ascites and a right pleural effusion. TFTs now showed a suppressed TSH with normal FT4 and TT3. Her methimazole dose was decreased, and she underwent ovarian surgery. Pathology of the ovarian mass showed a 13.5cm ovarian teratoma predominantly composed of mature thyroid tissue (struma ovarii) notable for hyperplastic changes suggestive of Graves’ disease without any evidence of malignancy. On post-op day 2, TFTs showed TSH < 0.005, FT4 0.81mg/dl and TT3 < 25 ng/dl, and methimazole was discontinued. On POD 5, hypothyroidism worsened with FT4 0.46 ng/dl and TT3 < 25ng/dl, and levothyroxine 25mcg daily was initiated. The thyroid was visible on imaging and within normal limits in size. A month after her surgery, the patient developed recurrent hyperthyroidism (T3-predominant); therefore, levothyroxine was stopped and methimazole restarted. This is the only case reported in the literature where a patient with Graves’ disease transiently became hypothyroid due to resection of a functional struma ovarii. The diagnosis of struma ovarii should be considered in patients who present with thyrotoxicosis and a pelvic mass. TFTs need to be monitored carefully pre- and post-operatively in these patients.

Poster 184 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM TSH AND FREE T4 SERUM VALUES IN AN ADULT POPULATION IN MEDELLı´N, COLOMBIA C.A. Builes-Barrera1,2, J.M. Marquez-Fernandez2, R. Gomez-Baena3, M. Cardenas-Gomez3 1 Endocrinology, Hospital Universitario San Vicente Fundacion, Medellin, Colombia; 2Endocrinology, Universidad de Antioquia, Medellin, Colombia; 3Dinamica IPS, Medellin, Colombia Reference values for thyroid tests should be standardized in local population. There is not local data in Colombia. Objective: To describe serum values of thyroid hormones in adults from Medellin, Colombia. Retrospective study based on information from an electronic database. Normality graphics were made. Linear regression analyses between free T4 (FT4) and TSH, and between FT4 and LogTSH were performed. Patients: 18–50 year old adults with TSH and FT4 values within the reference range supplied by Abbot. Exclusion criteria: pregnant women, hypothyroid and positive anti-TPO patients. Interventions: Simultaneous measurement of TSH and FT4 by chemiluminescence. Data from February to April 2015 were obtained from 2.438 individuals, 80.5% were women, mean age 35.74 – 8.4 years. TSH mean values were 2.19 – 1.10 mUI/L and 1.00 – 0.11 ng/dL in FT4.

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FT4 curve distributed as a normal one, while TSH one showed asymptotic to the left. 95% of FT4 values were between 0.74–1.26 ng/ dl and 0.36–4.55 mUI/L for TSH. There was no difference between TSH or FT4 values by gender or by age. Linear regression analysis did not show any relationship between TSH and FT4 values. 95% of TSH values range between 0.36–4.55 mUI/L, and 0.74– 1.26 ng/dl for FT4 in adult population. There were no differences by gender or age groups, or relationship between TSH and FT4 values. This is the first study from Colombian population that describes the values of thyroid tests.

Poster 185 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM ¿WHAT IS THE UTILITY OF T3 MEASUREMENT IN THE EVALUATION OF PATIENTS WITH PRIMARY HYPOTHYROIDISM? C.A. Builes-Barrera 1 Endocrinology, Universidad de Antioquia, Medellin, Colombia; 2 Dinamica IPS, Medellin, Colombia The objective of this study is to evaluate the role of T3 in the evaluation or diagnosis of patients with primary hypothyroidism. Two hundred and six patients with primary hypothyroidism were included in the study. 31.6% were male and 68.4% were female. The mean age was 46.2 years in all cohort, for men the mean age was 47.8 – 16.6 (range 16–87 years) and for women the mean age was 45.5 – 17.5 (range 17–83). The mean value of TSH was 75.3 – 89 mUI/L (between 10.5 y 490). In the group of patients with TSH level between 10 and 19.9 mUI/ L the T4 was low in 31.2%, with a median free T4 of 0.77 – 0.06 ng/ dl, and a mean TSH value of 17.36 mUI/L. In that group (n = 48) the T3 measurements was normal in all patients. Low T3 was found in 78 of 206 patients (37.8%), with a mean of TSH of 136 – 115 in the free T3 group (46 of 124) and mean TSH of 124 – 123 mUI/L in the total T3 group (32 de 82). In 5 patients (6.4%) we found low T3 with normal free T4 with a mean TSH of 28.1 – 11.9 mUI/L and mean free T4 of 1.07 – 0.02 ng/ dl. This study confirms the lack of utility of measurement of T3 for the diagnosis of primary hypothyroidism. Low T3 levels were found only in cases of severe hypothyroidism ( mean TSH: 136 mUI/L).

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Poster 186 Iodine Uptake & Metabolism Monday & Tuesday Poster Basic 9:00 AM PROPYLTHIOURACIL, PERCHLORATE, AND THYROID-STIMULATING HORMONE MODULATE HIGH CONCENTRATIONS OF IODIDE INSTIGATED MITOCHONDRIAL SUPEROXIDE PRODUCTION IN THE THYROIDS OF METALLOTHIONEIN I/II KNOCKOUT MICE Q. Duan1, T. Wang1, L. Lin2, L. Miao3, X. Yao1 1 Department of Physiology and Pathophysiology, School of Basic Medicine, Tianjin Medical University, Tianjin, China; 2Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China; 3Department of Cardiology, Tianjin Third Central Hospital, Tianjin, China Oxidative stress plays a crucial role in iodide excess instigated thyroid diseases. Metallothioneins are scavengers of reactive oxygen species (ROS) in oxidative stress. We aimed to figure out the effects of thyroid peroxidase (TPO) inhibitor propylthiouracil (PTU), a competitive inhibitor of iodide transport perchlorate (KClO4), and thyroid-stimulating hormone (TSH) on mitochondrial oxidative stress instigated by high concentrations of iodide exposure in the thyroids of metallothionein I/II knockout (MT-I/II KO) mice. Eight-week-old 129S7/SvEvBrd-Mt1tm1BriMt2tm1Bri/J (MT-I/ II knockout, MT-I/II KO) mice and background-matched wild-type (WT) mice were used. A mitochondrial superoxide indicator (MitoSOX Red), lactate dehydrogenase (LDH) release and MTT (methyl thiazolyl tetrazolium, MTT) assay were used as well. We demonstrated that the decreased relative viability, increased in LDH release and mitochondrial superoxide production instigated by KI (100 lM) can be relieved by 300 lM PTU, 30 lM KClO4 or 10 mU/ml TSH in both MT- I/II KO and WT mice (P < 0.05). A significant decrease in relative viability along with significant increase in LDH release and mitochondrial superoxide production were detected in MT- I/II KO mice when compared to the WT mice (P < 0.05). We conclude that PTU, KClO4 or TSH relieved the oxidative stress instigated by high concentrations of iodide exposure in the thyroids of both MT- I/II KO and WT mice. MT-I/II demonstrated its antioxidative effect against high concentrations of iodide instigated mitochondrial superoxide production in the thyroid. (This work is supported by the National Natural Science Foundation of China, No. 81273009).

Poster 187 Iodine Uptake & Metabolism Monday & Tuesday Poster Basic 9:00 AM THE RELATIONSHIP BETWEEN POPULATION’S IODINE STATUS AND WATER IODINE DISTRIBUTION IN CHINA H. Shen, P. Liu Centre for Endemic Disease Control, Chinese Centre for Disease Control and Prevention, Harbin Medical University, Harbin, China In the early 1980s, the national investigation of water iodine distribution was carried out in China. Thirty out of thirty-one provinces and 1,778 countries, out of 2,835, were classified as endemic iodine deficiency areas. Thereafter, water iodine was investigated as an optional indicator in national IDD surveillance of 1997, 2002 and 2011. In this investigation, water iodine was measured in 702 villages of 25 provinces. Urine iodine was measured of children 8–10 years old, pregnant women and lactating women.

Median water iodine (MWI) was 5.6lg/L. The villages of MWI < 10lg/L were 76.3%, the villages of MWI between 10-49.9lg/ L were 20.3%, the villages of MWI between 50-99.9lg/L were 2.8%, and the villages of MWI > 100lg/L were 0.6%. Median urine iodine (MUI) of children 8–10 years old, pregnant women and lactating women were 238.4lg/L, 187.4lg/L and 170.9lg/L in the villages of MWI < 10lg/L, respectively. MUI of children 8–10 years old, pregnant women and lactating women were 239.5lg/L, 194.1lg/L and 166.9lg/L in the villages of MWI between 10–49.9lg/L, respectively. MUI of children 8-10 years old, pregnant women and lactating women were 301.4lg/L, 238.2lg/L and 213.9lg/L in the villages of MWI between 50–99.9lg/L, respectively. MUI of children 8–10 years old was higher than that of pregnant women and lactating women. MUI of three populations in the villages of MWI between 50–99.9lg/L were higher than those in the villages of MWI < 10lg/L and MWI between 10–49.9lg/L. Universal salt iodisation should not be implemented mandatory in regions of MWI between 50–99.9 lg/L.

Poster 188 Iodine Uptake & Metabolism Monday & Tuesday Poster Basic 9:00 AM DENDROGENIN A AND IODINE 131, A COMBINE ANTI-CANCER TREATMENT IN UNDIFFERENTIATED THYROID CELLS M. bauriaud, S. Brillouet, F. Courbon, M. Poirot, S. Poirot Equipe 12, CRCT, Toulouse, France Anaplasic thyroid carcinoma (ATC) is a very aggressive cancer refractory to radioiodine (131-I) and chemotherapy. ATC derives from differentiated thyroid cancer cells, most commonly from papillary thyroid cells. They have lost the expression of well-characterized proteins involved in hormone biosynthesis: Sodium iodine Symporteur NIS) thyroid stimulating hormone receptor (TSH-R) and the thyroperoxidase (TPO). The lack of these proteins makes the thyrocytes resistant to iodine therapy. Re-induction of NIS expression is considered as a potentential therapeutic target. Recent studies have demonstrated that Dendrogenin A (DDA) induced gene expression and re-differentiation of various cancer cell lines. We cultured one well differentiated thyroid cell line: B-CPAP and an anaplasic thyroid cell line: 8505c. These two cell lines were cultured without TSH. Characteristic of these cells were visualized by transmission electron microscope. Endogenous and stimulated NIS, TPO and TSH-R protein expression was determined by immunocytochemistry. Analysis of iodine uptake in vitro: cell cultures were stimulated with DDA for 48 hours, irradiation with iodine-131 was performed and iodine incorporation was measured on each condition with a gamma counter (Wizzard). Treatment for 48 hours with DDA (8505c : 3.10-6 Mol/L ; BCPAP: 2.10-6Mol/L) markedly increased NIS, TPO and TSH-R expression in the two ATC cell lines. Transmission electron microscope showed a re-organization of the cells. DDA increased the iodine uptake on the anaplasic 8505c cell line compared with non treated cells. No significant increase of the uptake of iodine 131 was obtained on the differentiated thyroid cell line: BCPAP. These data suggest that DDA stimulates the expression of the NIS pathway. DDA promotes expression or re-expression of NIS, TPO

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and THS-R and a re_organization of the cells. These findings indicate that DDA in combination with iodine-131 may enhance its capture and be efficient to treat anaplasic cells.

Potassium iodate (KIO3) and potassium iodide (KI) are the major salt iodization agents used worldwide. Unlike iodide, iodate should be reduced to iodide before it can be effectively used by the thyroid. Some studies have demonstrated that KIO3 inhibits the growth of Escherichia coli and may increase oxidative damage to membrane lipids in vitro. In the 1960s and 1970s, some studies using in vitro assays revealed that tissues can reduce KIO3. However, none of these researches involved the effect of KIO3 on the oxidation resistance of the organism and most used outdated detection technologies. In this study, we developed a new method for analyzing iodate and iodide in tissue homogenates using high performance liquid chromatography coupled to inductively coupled plasma mass spectrometry (HPLC-ICP-MS). We further applied the method to demonstrate the KIO3 reduction process by tissues in vitro. The effects of KIO3 on the total antioxidative activity (TAA) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) were also investigated here. We have developed a new method using a HPLC-ICP-MS assay that allows for the quantification of iodate and iodide in tissues. Our results show that the liver homogenate had a stronger capacity than the thyroid or kidney homogenates for reducing KIO3in vitro, and KIO3 decreases the total antioxidant activity of the tissues. We also confirmed for the first time that NADPH contributes to the reduction of KIO3 in tissue. We found that iodate can be reduced to iodide by tissue homogenates and iodate irreversibly decreases the antioxidant capability of tissues. Our study provides positive evidence that KIO3 might result in oxidative stress and tissue damage of organisms.

Poster 189 Iodine Uptake & Metabolism Monday & Tuesday Poster Basic 9:00 AM POTASSIUM IODATE DECREASES THE ANTIOXIDANT CAPACITIES OF TISSUE HOMOGENATES IN VITRO X. Cao, Y. Gu, J. Xu National Reference Laboratory for IDD, National Institute for Nutrition and Health, China CDC, Beijing, China

Poster 190 Iodine Uptake & Metabolism Monday & Tuesday Poster 9:00 AM A CASE OF ACUTE THYROIDITIS FOLLOWING THERAPY WITH TOPICAL CADEXOMER IODINE (IODOSORB) OINTMENT I. Shaikh1, A. Varanasi1,2 1 Palms of Pasadena Hospital, St Petersburg, FL; 2Endocrinology, University of South Florida, Tampa, FL

FIG. 1. Typical chromatogram of speciation of iodide and iodate in mixed standard solution. An HPLC-ICP-MS chromatogram of a mixed standard solution containing iodate and iodide, where c(iodate) = c(iodide) = 25 lg/L.

Iodine is an essential requirement for thyroid hormone synthesis and in the adult the recommended daily iodine intake is 150 mg.The thyroid gland has intrinsic mechanisms that maintain normal thyroid function even in the presence of iodine excess. Large quantities of iodide are present in drugs, antiseptics, contrast media and food preservatives. Iodine induced hyperthyroidism is frequently observed in patients affected by euthyroid iodine deficient goiter when suddenly exposed to excess iodine. Patient is a 86 year old male who presented to the hospital with new onset Atrial Flutter. He has a history of Hairy cell leukemia being treated with rituximab, BPH, dyslipidemia, necrotising fascitis and venous ulcers for which he has been receiving local wound care with Cadexomer Iodine ointment. Workup revealed low TSH level of 0.03. elevated T4 and T3 at 18 and 229 respectively. Ultrasound of thyroid gland revealed multinodular goitre. Iodine 123 uptake scan showed decreased uptake level at 0.8%. Anti Thyroid peroxidase Antibodies were absent and Thyroid stimulating Antibodies were normal at 40% Serum and urine iodine levels of iodine were significantly elevated at 173.8 Ug/l & 712.1 Ug/l respectively. Patient was started on methimazole and cardizem.He converted back to normal sinus rhythm. Follow up TSH 2 months later was

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 elevated at 9. He is currently being tapered off Methimazole.He remains asymptomatic and in normal sinus rhythm. Significant elevation in patients serum and urine iodine levels could only be explained from the exposure to topical cadexomer iodine ointment that he had been receiving for local wound care for 10 days just prior to onset of symptoms. The possible mechanism by which patient had hyperthyroidism is jod basedow phenomenon, iodine induced hyperthyroidism in the setting of preexisting multinodular goiter. Topical treatment with cadexomer iodine can induce hyperthyroidism difficult to manage clinically as the treatment options are limited.This should be borne in mind when cadexomer iodine treatment is considered.

Poster 191 Iodine Uptake & Metabolism Monday & Tuesday Poster Clinical 9:00 AM FOLLOW-UP AND EVALUATION OF THE PREGNANCY OUTCOME IN WOMEN AT REPRODUCTIVE AGE WITH GRAVES’HYPERTHYROIDISM AFTER 131-IODINE TREATMENT N. Jiang, L. Zhang, J. Li, H. zhang, S. Liu, Q. Tian Nuclear medicine, Sun Yat-Sen memorial hospital of Sun Yat-Sen University, Guangzhou, China Study about 131I treatment in women of child-bearing age with hyperthyroidism is less. We aimed to analyze and evaluate the pregnancy outcomes to women at reproductive age with Graves’ hyperthyroidism after 131iodine treatment. From 2009 to 2014, 257 pregnant female patients of Graves hyperthyroidism in the outpatient of department of Nuclear Medicine and 167 normal healthy pregnant women at the same period in department of obstetrics in Sun Yat-Sen Memorial Hospital were included in our study. The hyperthyroidism patients were divided into 131I therapy group (n = 130) and antithyroid drug (ATD) group (n = 127) according to their therapy method before being pregnant.The time interval between 131I therapy or ATD therapy and being pregnant was at least 6 months.Patients were told to take serum thyroid function tests and antenatal care monthly. Followed up patients and normal women until the termination of pregnancy and recorded relevant parameters:serum thyroid function,dose of drug, health conditions of the fetus and pregnancy outcome included abortion, cesarean or natural birth and fetal sex, birth weight, preterm birth and so on.To compare the difference using statistical package. Women with hyperthyroidism were at increased risk for abortion (OR = 2.023) and cesarean delivery (OR = 1.552) than the normal women and showed no difference on the neonatal gender, preterm birth, body weight ratio, low birth weight and fetus growth restriction compared to the normal women (P > 0.05). In 131I group, ATD group and the normal group, 114,108,154 had normal delivery and 16,19,12 had abortion respectively. There were no significant difference on pregnancy outcome in both mothers’and neonates’ aspect among three groups ( P > 0.05). Besides, in 131I therapy group, pregnant outcomes of patients treated with PTU or Levothyroxine or nothing during pregnancy had no significant difference also (P > 0.05). 131I therapy is a safe and effective therapy method for women with Graves hyperthyroidism at reproductive age,they can have normal delivery and healthy baby as the population on condition that their thyroid function could be reasonably controlled and maintained by the proper therapy before and during pregnancy.

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Poster 192 Iodine Uptake & Metabolism Monday & Tuesday Poster Clinical 9:00 AM IODINE CONTENT OF US ENTERAL AND PARENTERAL NUTRITION SOLUTIONS D. Willard, L. Young, X. He, L. Braverman, E. Pearce Boston Medical Center, Boston, MA Iodine deficiency may cause goiter and hypothyroidism. Patients on long-term enteral (EN) or parenteral (PN) nutrition may be at risk for micronutrient deficiencies. An Italian study revealed that adults receiving long-term total PN (TPN) had low urinary iodine concentrations, suggesting inadequate iodine intake, and some had subclinical hypothyroidism. The recommended dietary allowance (RDA) for iodine is 150lg/day in nonpregnant adults. Recommendations vary for iodine content of adult EN and PN formulas. We measured EN and PN solution iodine content to determine whether US patients on longterm artificial nutrition are at risk for iodine deficiency. Iodine content of 10 EN solutions from Nestle and Abbott Nutrition and 4 PN solutions from Central Admixture Pharmacy Services (CAPS) (a B Braun company) and Clinimix (a Baxter product) was measured spectrophotometrically and compared with labeled content. Measured and labeled EN iodine content were similar, range 131– 176lg/L and 114-160lg/L respectively. Mean measured iodine content for EN solutions was 164 – 15lg/L (Table 1), or 39lg/237L serving. PN labels did not report any iodine content, but measurement revealed small amounts of iodine (13–40lg/L) in each solution. Patients on long-term total EN (TEN) would require on average 3.8 EN servings/day to meet iodine requirements. Typical fluid requirements are 30-40ml/kg/day for adults receiving either TEN or TPN, so adults on TEN likely consume enough servings to meet their daily iodine requirements. PN formulas were found to contain small, unlabeled, amounts of iodine. Patients on TPN would require on average 5.6L PN/day to meet the RDA of iodine. This volume of PN is far in excess of typical consumption. While patients on long-term TEN are likely to have adequate iodine intake, those on long-term TPN are vulnerable to iodine deficiency unless they are also ingesting iodine-rich foods or supplements. Studies are needed to investigate the iodine status of these patients, and to develop national standards for the iodine content of artificial nutrition solutions.

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MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015

Poster 193

1

Iodine Uptake & Metabolism Monday & Tuesday Poster Clinical 9:00 AM PREVALENCE OF IODINE DEFICIENCY DISORDER IN HIGH RISK PREGNANT WOMEN L.S. Souza1,2, R.D. Campos1,2, V.D. Alves1, S.C. Rebouc¸as1, R. Beck1, T.M. Xavier1, T.L. Oliveira1, C.M. Mendes3, C.A. Oliveira4, L.S. Gomes5, A.C. Feitosa6, H.E. Ramos1 1 Biorregulation, Federal University of Bahia, Salvador, Brazil; 2 Post-graduate Program in Interactive Processes of Organs and Systems, Federal University of Bahia, Salvador, Brazil; 3 Biofunction, Federal University of Bahia, Salvador, Brazil; 4 Health & Science Center, Federal University Reconcavo of Bahia, Santo Antonio de Jesus, Brazil; 5Institute of Chemistry, Federal University of Bahia, Salvador, Brazil; 6Bahiana School of Medicine, Salvador, Brazil Despite progress in poverty reduction, children in northeast of Brazil are vulnerable to malnutrition. In 2013, the levels of salt iodization were reduced to 15–45 mg/Kg and the scarcity of new representative data is worry, mainly because most of the previous studies was based on subnational analysis.Objective: Assess the iodine nutritional status of HRPW in a reference center in Bahia, Brazil. Cross-sectional study conducted in a randomly selected 83 HRPW (16–44 years old). Questionnaire was designed to obtain socioeconomic, demographic and health information. Urinary iodine concentration (UIC) by Sandell-Kolthoff reaction, and anthropometric evaluation were performed. The mean age was 29.4 – 6.8 years old and median was 30 years old. 73.5%, 24.1% and 2.4% of HRPW were in the third, second and first trimester, respectively. The mean UIC was 204 – 8lg/L and median was 190lg/L (25th–75th percentile: 148–263 lg/L, with a range of 2–405 lg/L). Low UIC ( < 150lg/L) was detected in 26.5% (22/83), with 25th–75th percentile: 92–139 lg/L. 18.07% between 100–150lg/L; 7.23% between 50–100lg/L and 1% with UIC < 50lg/L (severe IDD). 44.6% and 28.9% had UIC between 150–250lg/L and > 250lg/L, respectively. There were a raised proportion of IDD in patients ‡ 35 years old (42.1%), compared with 23.3% and 19% in patients with 25–34 and < 25 years old, respectively (p = 0,73). 39.8% of HRPW had hypertension, and 30.3% of them presented UIC < 150lg/L vs. 24% in non-hypertensive (OR = 1.26; 95% CI:0.62-2.58; p = 0.52). Use of iodized multivitamin was not able to significantly reduce the risk of IDD: 20% (4/16) of HRPW using supplements vs. 29% (18/44) of patients not using had IDD (OR = 1.45; 95% CI: 0.56– 3.79; p = 0.42). There was no association between obesity, educational level, annual income and IDD. It is concerning that 26.5% of HRPW screened at a single center were iodine-deficient. Particular attention is required to ensure that HRPW receive an adequate iodine supply.

Poster 194 Iodine Uptake & Metabolism Monday & Tuesday Poster Clinical 9:00 AM IODINE NUTRITIONAL STATUS IN SCHOOLCHILDREN FROM PUBLIC SCHOOLS IN BRAZIL: A CROSS-SECTIONAL STUDY EXPOSES ASSOCIATION WITH SOCIOECONOMIC FACTORS AND FOOD INSECURITY R.D. Campos1,2, S.C. Rebouc¸as1, R. Beck1, L.R. Maia1, Y.R. Ramos1, I.D. Barreto1, T.M. Xavier1, W.A. Santos2, T.L. Oliveira1, V.C. Souza5, F.B. Junior5, C.A. Oliveira3, L.S. Gomes4, H.E. Ramos1,2

Biorregulation, Federal University of Bahia, Salvador, Brazil; Post-graduate Program in Interactive Processes of Organs and Systems; Health & Science Institute, Federal University of Bahia, Salvador, Brazil; 3Health & Science Center, Federal University Reconcavo of Bahia, Santo Antonio de Jesus, Brazil; 4Institute of Chemistry, Federal University of Bahia, Salvador, Brazil; 5Toxicology Laboratory, University of Sao Paulo, Ribeirao Preto, Brazil

2

Despite progress in poverty reduction, children in northeast of Brazil are vulnerable to malnutrition. In 2013, the levels of salt iodization were reduced to 15-45 mg/Kg and the scarcity of new representative data is worry, mainly because most of the previous studies was based on subnational analysis. Objective: To clarify the association of iodine nutritional status and socioeconomic, demographic and household food insecurity (HFI) among schoolchildren from public schools living in state of Bahia, Brazil. Cross-sectional study conducted in 1419 (728 M/ 691 F) schoolchildren (6–14 years old), randomly selected, in five cities in Bahia. Questionnaire was designed to obtain Socioeconomic, demographic and HFI information. Urinary iodine concentration (UIC) by SandellKolthoff reaction, TSH in filter-paper blood and anthropometric evaluation were performed. The mean UIC (MUIC) was 206.4 – 80.5lg/L and median was 221.6lg/L, indicating sufficient iodine intake. Low UIC ( < 100lg/L) was detected in 12.3 (N = 174) (6.2% < 100lg/L; 3.0% between 2049lg/L and 3.1% with UIC < 20lg/L (severe IDD). Indeed, 9.4% (N = 134) had UIC > 300lg/L, indicating coexistence of excessive iodine intake (EII). The mean TSH was 1.0 – 0.6lUI/L. Obesity and industrial seasoning utilization protected against EII (OR = 0.64; 95% CI: 0.4–1.0; p = 0.07) and (OR = 0.65; 95% CI: 0.4–0.9; p < 0.05), respectively. Urban areas (73%) had MUIC of 213.1 – 80lg/L vs. rural MUIC of 176.8 – 76.1lg/L. Living in a house with more than six people and water consumption from shallow well increased the risk for EII (OR = 1.62; 95% CI: 0.9–2.6; p < 0.05) and (OR = 1.70; 95% CI: 0.9– 3.1; p = 0.09), respectively. Moderate or severe food insecurity by HFIAS raised the risk for IDD in 70% (OR = 1.70; 95% CI: 0.9–3.0; p < 0.05). A significant proportion of schoolchildren still has IDD or EII, increasing the importance of committed public policies to address this problem. It appears that many socioeconomic and nutritional aspects could be important influencing factors for the coexistence of IDD and EII in developing countries.

Poster 195 Iodine Uptake & Metabolism Monday & Tuesday Poster Clinical 9:00 AM IODINE CONTENT OF IODIZED SALT IN SPAIN S. Wengrowicz1,2, M. Saenz-Torre2, P. Santiago Fernandez2, M. Bandres Nivela2, E. Menendez Torre2, S. Donnay Candil2, F. Vich Sastre2, G. Moll Mascaro2, A. Lucas Martin2, L. Vila Ballester2, J. Arrizabalaga Abasolo2 1 Servicio de Endocrinologia y Nutricion, IDECA, Barcelona, Spain; 2 Thyroid Working Group TiroSEEN - Spanish Endocrine Society, Barcelona, Spain Optimization of iodine intake goal is prevention of potential irreversible damage of the developing CNS and thyroid disorders, caused either by iodine deficiency (ID) or iodine excess. The best worldwide strategy to provide additional dietary iodine is the iodination of table salt. Production of iodized salt (IS) in Spain is not compulsory and is regulated since 1983, considering as adequate an iodine content of 60 mg iodine/kg salt (60 ppm) – 15% (51–69 mg/ kg), but there are no control programs to ensure that optimal levels of fortification. Our aim was to know the actual current iodine content

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015

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of IS by different forms of fortification with potassium iodide (KI) or iodate (KIO3). We have performed an analysis by HPLC in 74 samples of different IS brands available at food market. Samples were obtained during summer-fall 2014 at Spanish autonomous communities of Andalucia, Aragon, Asturias, Baleares, Catalonia, Madrid and Pais Vasco. The mean (SD) and median (P25–P75) iodine content of IS samples were 63.5 (23.0) and 60 (51–70) ug iodine/g salt, respectively. The widest range of variation in iodine concentration was found as inadequate in 68.7% of samples with KI form, in contrast to 37.5% of inadequate iodine content in samples among KIO3 form (p < 0.001). Although recent surveys of Spanish school children and adult population, found median urinary iodine levels higher than 100lg/L, being considered an optimal iodine nutrition, iodine intake is probably being achieved through an increase, neither promoted nor controlled, in the consumption of iodine-rich milk and dairy products, and other population groups such as pregnant women are still very likely to have ID. Recent studies detected that close to 40% of children in pre-school age and adults have urinary iodine levels lower than 100lg/L, and the reported household use of IS in less than 50%. We conclude that fortification of IS with KIO3 is a better alternative to KI, which has a poor shelf life in hot and humid climates. Since the eradication of ID in Spain is far from being achieved, there is a need of national health policies that should address an adequate control of population iodine nutrition.

tylation, increased histone deacetylase activity, decreased histone acetyltransferase activity and hypermethylation of total DNA and Pax8/TTF1 genes. Therefore, our data indicated that even mild IE exposure during pregnancy/lactation can be as harmful as iodine deficiency to the progeny HPT axis, by inducing primary hypothyroidism through increased ROS production and epigenetic mechanisms. Iodine intake should be carefully monitored throughout pregnancy and lactation to avoid the occurrence of thyroid disorders in the offspring at adulthood. Financial Support: FAPESP.

Poster 196 Thyroid & Development Monday & Tuesday Poster Basic 9:00 AM MATERNAL EXPOSURE TO IODINE EXCESS THROUGHOUT PREGNANCY AND LACTATION INDUCES HYPOTHYROIDISM IN MALE RAT OFFSPRING THROUGH EPIGENETIC MECHANISMS C. Serrano-Nascimento, M. Nunes Department of Physiology and Biophysics, Institute of Biomedical Sciences, Sao Paulo, Brazil Both iodine deficiency and excess promote alterations on thyroid function, which can cause serious consequences for individuals, especially during fetal and neonatal periods. Several studies have shown that hormonal/nutritional disturbances during intrauterine and lactation periods may influence gene expression programming in adulthood through epigenetic mechanisms. This study aimed to investigate the consequences of rat dam’s iodine excess (IE) treatment throughout pregnancy and lactation (P + L) periods on the hypothalamus-pituitary-thyroid (HPT) axis of their male offspring in adult life. Female Wistar rats were treated or not with 0.6 mg NaI/L (5X the physiological dose) in drinking water during P + L periods and the gene expression of the hypothalamus, pituitary and thyroid of their adult male offspring (90 days) were evaluated by qPCR and Western blotting. Thyroid histological analysis and oxidative stress evaluation were also performed. Moreover, IE-induced programming of the offspring thyroid gene expression through epigenetic mechanisms was investigated. Maternal IE exposure increased TRH/TSH expression/secretion in the hypothalamus and pituitary, altered thyroid morphology and increased thyroid ROS production in the male offspring rats. Thyroid expression of NIS, TSHR, TPO, Tg, Pax8, TTF1, Megalin and MCT8 were decreased in the offspring of IE-exposed rats. Epigenetic mechanisms seem to be involved in the repression of thyroid gene expression, as demonstrated by increased DNA methyltransferases expression, histone 3 hypermethylation, histones 3 and 4 hypoace-

Poster 197 Thyroid & Development Monday & Tuesday Poster Clinical 9:00 AM INCREASE IN THYROID DYSFUNCTION AND AUTOIMMUNITY IN DANISH PREGNANT WOMEN UPON THE IODINE FORTIFICATION IS NOT ASSOCIATED WITH NEGATIVE OBSTETRIC OUTCOMES S. Bliddal1, M. Boas2, L. Hilsted3, L. Friis-Hansen4, A. Tabor5, U. Feldt-Rasmussen1 1 Dep. of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark; 2Dep. of Growth and Reproduction, Copenhagen University Hospital, Copenhagen, Denmark; 3Dep. of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark; 4Dep. of Clinical Biochemistry, Slagelse-Naestved Hospital, Naestved, Denmark; 5Center of Fetal Medicine, Dep. of Obstetrics, Copenhagen University Hospital, Copenhagen, Denmark Aberrations in maternal thyroid function and autoimmunity during pregnancy have been associated with negative obstetric outcome. A Danish iodine fortification program was implemented in the year 2000 with the aim to alleviate the mild-moderate iodine deficiency. Following the iodine implementation there has been an increase in thyroid autoimmunity in the background population. This study investigated thyroid status of pregnant Danish women following the iodine fortification program, and a possible association with preterm delivery. Cohort study of 1278 randomly selected pregnant Danish women attending the national Down’s syndrome screening program at Copenhagen University Hospital in 2008. Main outcome measures were thyroid status according to laboratory- and gestational-age-specific reference ranges, and association with risk of abnormal obstetric outcome. Antibody-positivity was defined as an antibody-level (thyroid peroxidase and/or thyroglobulin antibodies) above our clinical cut-off of 60 U/ml. Establishing own laboratory-specific gestational-age-dependent reference ranges, we found a prevalence of maternal thyroid dysfunction of 10%, but 15.8% by use of the cut-off suggested by the ATA and Endocrine Society. Antibody-positivity above the clinical cut-off was found in 16.1% of the women, but low levels ( > 20 U/ml) were present in more than half of the women. No associations were found between preterm delivery and thyroid dysfunction (adjusted OR 0.6, 95% CI: 0.1–2.3) or autoimmunity (adjusted OR 1.1, 95% CI: 0.4–2.7). After implementation of the Danish iodine fortification program, the prevalence of thyroid dysfunction and autoimmunity in Danish pregnant women is high-even higher by use of pre-established reference ranges from International consensus guidelines. However, no associations were found with abnormal obstetric outcome. Large randomized controlled trials are needed to clarify the benefit of treating slight aberrations in pregnant women’s thyroid function. The use of pre-established trimester-specific reference ranges from populations with a different iodine status will misclassify pregnant women’s thyroid status and pose a risk to patient safety.

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MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015

Poster 198

University Hospital, Aalborg, Denmark; 3Department of Medicine, Silkeborg Hospital, Silkeborg, Denmark; 4Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark; 5 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

Thyroid & Development Monday & Tuesday Poster Clinical 9:00 AM INCREASED RISK OF STILLBIRTH IN WOMEN FIRST TIME DIAGNOSED AND TREATED FOR HYPOTHYROIDISM AFTER A PREGNANCY: COMPARISON WITH OTHER AUTOIMMUNE DISEASES IN A DANISH POPULATION-BASED STUDY S.L. Andersen1,2, J. Olsen3, P. Laurberg1,4 1 Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 2Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark; 3Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark; 4 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark Stillbirth is in Denmark defined as the birth of a child with no signs of life in or after gestational week 22. We hypothesized that women first time diagnosed and treated for hypothyroidism in the two-year-period after a pregnancy had an increased risk of suffering from untreated thyroid dysfunction already during the pregnancy which could have attributed to the termination of pregnancy with stillbirth. We compared the risk of stillbirth in such women with women developing other autoimmune diseases in the two-year-period after a pregnancy: hyperthyroidism, diabetes mellitus (DM), rheumatoid arthritis (RA), inflammatory bowel disease (IBD). Population-based cohort study using Danish nationwide registers. All singleton pregnancies, 1997–2008, terminated with live birth (n = 714,499) or stillbirth (n = 2,653) were identified plus information on maternal hypo- and hyperthyroidism (hospital diagnosis/drug prescription), DM, RA and IBD up to two years after the pregnancy. The Cox proportional hazards model was used to estimate adjusted (e.g. age, smoking) hazard ratio (aHR) with 95% confidence interval (CI) for stillbirth, reference: no hypo- or hyperthyroidism/DM/RA/ IBD (n = 696,059). We identified 2,080 pregnancies where the mother was first time diagnosed and treated for hypothyroidism in the two-year period after the pregnancy under study and redeemed prescriptions of thyroid hormone for more than two years. In this group, 14 pregnancies (0.67%) had terminated with stillbirth which was significantly higher than in reference pregnancies (0.36%, p = 0.017); aHR 1.94 (95% CI 1.12–3.34). Looking at other autoimmune diseases first time diagnosed and treated after the pregnancy under study; the risk that the pregnancy had terminated with stillbirth was similarly increased in hyperthyroidism (aHR 2.28 (95% CI 1.39–3.73)) and markedly increased in diabetes (9.13 (6.15–13.57)), but not in the non-endocrine disorders RA and IBD (1.08 (0.41–2.89)). An increased risk of stillbirth was observed when maternal hypothyroidism was first time diagnosed and treated after the termination of the pregnancy. Notably, a high risk was also observed for other endocrine diseases, but not for the autoimmune diseases of nonendocrine origin.

Physiological changes in the maternal immune system during and after a pregnancy may influence the onset of autoimmune disease. An increased incidence of hyperthyroidism has been observed both in early pregnancy and postpartum, but it remains to be elucidated if the incidence of hypothyroidism varies in parallel in and around pregnancy. Population-based cohort study using Danish nationwide registers. All women who gave birth to singleton live-born children from 1999–2008 (n = 403,958) were identified as well as information on hospital diagnosis of hypothyroidism and redeemed prescriptions of thyroid hormone. Incident hypothyroidism (age 15–45 years) in the period from 1997–2010 was defined as a) no previous hospital diagnosis or treatment of thyroid disease, b) ‡ 2 redeemed prescriptions of thyroid hormone within a period of more than 2 years and c) no hospital diagnosis of congenital or iatrogenic hypothyroidism. The incidence rate (IR) of hypothyroidism was calculated in 3-month intervals before, during and after the woman’s first pregnancy in the study period and compared with previously published IR of hyperthyroidism. Altogether 5,220 women (1.3%) were identified with onset of hypothyroidism from 1997–2010 with an overall IR of 92/100,000/ year. A total of 1,572 women (0.4%) developed hypothyroidism in the period from 2 years before to 2 years after birth of the first child birth in the study period. The IR of hypothyroidism decreased during the pregnancy (incidence rate ratio (IRR) vs. the overall IR in the rest of the study period 1997–2010: first trimester: 0.89 (95% CI 0.66– 1.19)), second trimester: 0.71 (0.52–0.97)), third trimester: 0.29 (0.19–0.45)), and increased after birth with the highest level 3–6 months postpartum (3.62 (2.85–4.60)). Compared with hyperthyroidism, no incidence peak was observed in early pregnancy (see Figure). On the other hand, the postpartum peak was of the same magnitude, but confined to one year after birth. These are the first population-based data on the incidence of hypothyroidism in and around pregnancy. The incidence declined during pregnancy followed by a sharp increase postpartum. Notably, hypothyroidism as opposed to hyperthyroidism showed no early pregnancy peak.

Poster 199 Thyroid & Development Monday & Tuesday Poster Clinical 9:00 AM COMPARISON OF HYPOTHYROIDISM AND HYPERTHYROIDISM INCIDENCES DURING PREGNANCY AND POSTPARTUM: A DANISH POPULATION-BASED STUDY S.L. Andersen1,2, A. Carle´1,3, J. Olsen4, P. Laurberg1,5 1 Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 2Department of Clinical Biochemistry, Aalborg

Relative frequencies of incident maternal hypothyroidism and hyperthyroidism.

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015

Poster 200 Thyroid & Development Monday & Tuesday Poster Clinical 9:00 AM THYROID DISEASE BEFORE, DURING AND AFTER PREGNANCY IN RELATION TO REGIONAL DIFFERENCE IN IODINE INTAKE: A STUDY WITHIN THE DANISH NATIONAL BIRTH COHORT S.L. Andersen1,2, J. Olsen3, P. Laurberg1,4 1 Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 2Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark; 3Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark; 4 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark Thyroid disease is common in women of reproductive age, but the exact burden of disease before, during and after a pregnancy is not clear. We describe the frequency of thyroid disease in pregnant women enrolled in the Danish National Birth Cohort (DNBC) in relation to the Danish regional difference in iodine intake. Population-based study within the DNBC which included 101,032 pregnancies, 1997–2003. We studied women enrolled in DNBC who gave birth to a live-born child. Information on maternal thyroid disease (hyper-, hypothyroidism, goiter/nodules, other) before, during and up to 5 years after the woman’s first pregnancy in the cohort was obtained from self-report by interview (median gestational week 17) and from nationwide registers on hospital diagnosis/surgery (from 1977) and prescriptions of thyroid drugs (from 1995). Among 77,671 mothers included; 3,018 (3.9%) were identified with onset of thyroid disease before (2.0%): hyper- (n = 627), hypothyroidism (n = 371), goiter/nodules (n = 495), other (n = 30); during (0.1%): hyper- (n = 44), hypothyroidism (n = 30), goiter/nodules (n = 10); or in the 5-year period after the pregnancy (1.8%): hyper(n = 551), hypothyroidism (n = 538), goiter/nodules (n = 303), other (n = 19). During the pregnancy, 153 (0.2%) women received ATD, whereas 324 women received treatment for hyperthyroidism before the pregnancy alone and 90 women were treated before and after, but not in the pregnancy. Altogether 365 (0.5%) received L-T4 for hypothyroidism in the pregnancy: 83 had hypothyroidism after previous hyperthyroidism, 42 after previous surgery for goiter/nodules, and 240 had no previous hyperthyroidism or surgery. Overall, nonsurgical hypothyroidism was more common in East Denmark with mild iodine deficiency (ID): 1.44% vs. 1.11% in West with moderate ID (p < 0.001), whereas no regional difference was observed for hyperthyroidism (p = 0.2). Thyroid surgery was more frequent in West with moderate ID: 0.74% vs. 0.61% in East (p = 0.03). Around 4% of Danish pregnant women had either a history of thyroid disease, thyroid disease in the pregnancy or were first time diagnosed with thyroid disease in the years following a pregnancy. The spectrum of thyroid disease was influenced by iodine intake levels.

Poster 201 Thyroid & Development Monday & Tuesday Poster Basic 9:00 AM ALTERED CEREBELLAR DEVELOPMENT OF MICE DEFICIENT IN DUAL OXIDASE MATURATION FACTORS I. Amano1, Y. Takatsuru1, S. Toya1, A. Haijima1, T. Iwasaki1, H. Grasberger3, S. Refetoff2, N. Koibuchi1 1 Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Japan; 2Department of Medicine, The University of Chicago, Department of Medicine, IL; 3Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MS

A-83 Thyroid hormone (TH) plays a key role in the developing brain including the cerebellum. TH deficiency induces organizational changes of the cerebellum, causing cerebellar ataxia. However, the mechanisms underlying such an abnormal development are poorly understood. To clarify the mechanism, various animal models have been generated. Lacking dual oxidase (DUOX) and its maturation factor (DUOXA) are major risk factors for congenital hypothyroidism. Thus, we aim to examine the organizational changes of the cerebellum using knockout mice of Duoxa gene (Duoxa - / - ). We studied the morphological, behavioral, and electrophysiological changes in wild-type (Wt) and Duoxa - / - mice from postnatal day (P) 10 to P30. To detect the changes in the expression levels of presynaptic proteins, Western blot analysis was performed. As previously reported for hypothyroid animals, the proliferation and migration of granular cells were delayed after P15 in the Duoxa - / - mice. However, these changes disappeared by P25. Although the structure of the cerebellum was not significantly different between the Duoxa - / - and Wt mice at P25, motor coordination impairment was detected in the Duoxa - / - mice. We also found that the amplitude of paired-pulse facilitation at parallel fiber-Purkinje cell synapses decreased in the Duoxa - / - mice particularly at P15 without marked changes in the expression levels of presynaptic proteins that regulate neurotransmitter release. Based on our results, we hypothesize that the anatomical catchup growth of the cerebellum cannot normalize its function because the neuronal circuits were disturbed not only by hypothyroidism but also by the lack of function of DUOX/DUOXA components.

Poster 202 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM PREANALYTIC SOURCES OF ERROR IN NEWBORN THYROID SCREENING: SPECIMEN TRANSPORT DELAY AND AMBIENT TEMPERATURE AND HUMIDITY EXPOSURE REPRESENT SIGNIFICANT SOURCES OF ERROR IN THE MEASUREMENT OF DRIED BLOOD SPOT TSH W. Charoensiriwatana3, A. butler4, G. Snow4, P. Krasao3, R. Pankanjanato3, P. Thong-ngao3, R. Polson5,2, J. Ehrenkranz1,2 1 Medicine, Intermountain Healthcare, Murray, UT; 2i-calQ LLC, Salt Lake City, UT; 3Newborn Screening Operations Center, Thailand Ministry of Public Health, Bangkok, Thailand; 4 Intermountain Healthcare, Salt Lake City, UT; 5 Nanofab Laboratory, University of Utah, Salt Lake City, UT Measuring TSH eluted from a dried blood spot (DBS) is used to screen over 30 million newborns annually for congenital hypothyroidism (CHT). TSH measurement is customarily performed in regional laboratories to which DBS specimens are shipped. TSH ‡ 20 mIU/L is used to identify infants requiring additional testing. In the United States, specimen transport time exceeds 5 days in up to 70% of DBS samples. Preanalytic factors, including insufficient DBS volume, contamination, and deterioration are the most common causes of missed CHT diagnosis. Although heat, sunlight, humidity, and moisture are detrimental to DBS specimen stability and analyte recovery, there are no data on the effects of temperature and humidity on the stability of DBS TSH. The following studies were performed to determine whether ambient temperature and humidity affect the immunopotency of DBS TSH. Reference preparation TSH was added to blood to obtain specimens with a hematocrit of 54% and plasma TSH concentrations in the range 12.84–41.6 mIU/L. 100 microliter aliquots of each specimen were placed on Whatman 903 filter paper, dried at room temperature

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Effect of Ambient Temperature and Humidity on Dried Blood Spot TSH Immunopotency.

overnight, and stored in closed containers at: 4.1 – 0.7o C., relative humidity (RH) = 88.5 – 5.9% 24.4 – 0.6o C. RH 51.5 – 5.3% 30.1 – 0.1o C. RH 92.2 – 4.1% 37.2 – 0.4o C. RH 93.8 – 4.4 % TSH was measured at 24–48 hour intervals for 14 to 17 days from 6 chads punched from dried blood spot samples with TSH concentrations below, near to, and above the newborn TSH screening cutoff value of 20 mIU/L. Each chad was assayed for TSH using the Thailand Ministry of Public Health newborn TSH ELISA. A mixed effects model was used to predict measured TSH. Variables included in the model were mean TSH at day 1, temperature, day, and a temperature by day interaction. All variables had significant (p < . 001) effects on TSH concentration measured by ELISA. A progressive and dose-dependent decrease in TSH immunopotency due to DBS exposure to ambient temperature and humidity > 51% occurred at all TSH concentrations. Specimen transport delay and ambient temperature and humidity exposure represent significant sources of error in the measurement of DBS TSH that can result in the missed diagnosis of CHT.

Poster 203 Thyroid & Development Monday & Tuesday Poster Clinical 9:00 AM EFFECTS OF HEMATOCRIT ON THE MEASUREMENT OF DRIED BLOOD SPOT TSH W. Charoensiriwatana2, P. Krasao2, R. Pankanjanato2, P. Thong-ngao2, A. Butler3, G. Snow3, R. Polson4,5, J. Ehrenkranz5,1 1 Medicine, Intermountain Healthcare, Murray, UT; 2Newborn Screening Operations Center, Ministry of Public Health, Bangkok, Thailand; 3Statistical Data Center, Office of Research, Intermountain Healthcare, Salt Lake City, UT; 4Nanofab Laboratory, University of Utah, Salt Lake City, UT; 5i-calQ LLC, Salt Lake City, UT The diagnosis of primary congenital hypothyroidism is based on a serum TSH > 20 mIU/L in newborns older than 48 hours who are not underweight or ill. Newborn TSH is routinely measured by immunoassay of a dried blood spot (DBS) eluate. DBS performance testing samples use a hematocrit of 55%. Hematocrit is known to alter the quantitative recovery of serum analytes and affect the predictive value of diagnosing metabolic disease from a DBS, but the effect of hematocrit on the measurement of dried blood spot TSH is not

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known. We studied the effect of hematocrit in the range found in neonates on the quantitative recovery of TSH from a DBS. Aliquots of plasma or serum with TSH concentrations 6.3 – 0.4, and 26.6 – 8.0 mIU/L were added to packed red blood cells to obtain blood samples with hematocrits of 35, 40, 45, 50, 55, 60, and 65%. 100 microliters from each hematocrit were deposited on newborn screening filter paper, dried at room temperature overnight, and stored at 4o C. TSH was measured by ELISA in the eluate of 4 replicate DBS punches at each hematocrit. Data were analyzed using a linear mixed effects model. Hematocrit had a significant (p < .001) effect on quantitative TSH recovery from dried blood spots. Additionally, changes in hematocrit had a significant effect (p < .028) on the amount of TSH recovered from dried blood spots. The quantitative recovery of TSH from a DBS was inversely proportional to the DBS hematocrit. A 1% increase in hematocrit resulted in a 0.04 mIU/L decrease in eluate TSH when TSH was 6.3 – 0.4 mIU/L and a 0.16 mIU/L decrease in eluate TSH when TSH was 26.6 – 8.0 mIU/L. Hematocrit has a significant effect on the quantitative recovery of TSH from a DBS. Failure to take hematocrit into account when measuring TSH from a dried blood spot can result in false negative results when the DBS hematocrit exceeds 55% and false positive results when the DBS hematocrit is less than 55%.

Poster 204 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM FUNCTIONAL RESULTS OF UNINTENTIONAL PARATHYROIDECTOMY DURING THYROID SURGERY V. Makarin, A. Bubnov, Y. Fedotov, R. Chernikov, I. Sleptsov, A. Semenov, I. Chinchuk, K. Novokshonov, U. Karelina, A. Uspenskaya, E. Fedorov, Y. Malugov Endocrine surgery, Saint Petersburg State University, Saint-Petersburg, Russian Federation Unintented parathyroidectomy during thyroid surgery - is one of typical complications, especially when an operation is augmented by lymphodissection. In this work we present the results of calcium metabolism analysis in such patients. 3929 operations of patients with different thyroid diseases were performed during 2010–2012 years. 82 unintentionally resected parathyroid glands were revealed at histological examination (2.1% of all thyroid surgeries). We followed up serum calcium level each month in this group of patients. Out of 82 patients 24 (29.3%) had follicular adenomas at histological examination, 46 (56.1%) had papillary carcinomas, 2 (2.4%) had medullary carcinomas, 3 (3.7%) had follicular carcinomas, 7 (8.5%) had diffuse toxic goiter. Lobectomies were performed in 19 (23.2%) patients, thyroidectomies in 59 (71.9%) patients, central lymphodissections in 4 (6.1%) patients. One parathyroid gland was unintentionally resected in 77 (93.9%) of cases, two glands - in 5 (6.1%) cases. Postoperative hypocalcemia appeared in 33 (40.2%) patients and it lasts more than 6 months in 15 (18.2%) patients. These results suggest that parathyroid injury during thyroid surgery remains a serious problem, and hypocalcemia may develop even if one parathyroid gland is resected.

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Poster 205 Thyroid & Development Monday & Tuesday Poster Clinical 9:00 AM CONVENTIONAL PREOPERATIVE LARYNGOSCOPY IS NOT COST-EFFECTIVE IN THYROID AND PARATHYROID SURGERY: ANALYSIS OF 5172 CONSECUTIVE PATIENTS V. Makarin, Y. Fedotov, A. Bubnov, R. Chernikov, I. Chinchuk, A. Uspenskaya, U. Karelina, Y. Malugov, E. Fedorov, K. Novokshonov, V. Malkov, N. Timofeeva, V. Rusakov Endocrine surgery, Saint Petersburg State University, Saint-Petersburg, Russian Federation One of serious complications after thyroid and parathyroid surgery is larynx paresis. The latter leads to decrease of quality of life, and sometimes to gaining status of a disable patient. Gold standard for the diagnosis of postoperative larynx paresis is endoscopic laryngoscopy, but it is still a matter of argument, whether it is rational to perform it conventionally in preoperative period. The goal of this study was evaluation of reasonability of conventional laryngoscopy in patients with thyroid and parathyroid diseases in preoperative period. We present the results analysis of 5172 laryngoscopies in patients, who were operated on in the period of 2010–2013 at the department of endocrine surgery, North-Western Center of Endocrinology & Endocrine Surgery, St.Petersburg, Russia. Endoscopic laryngoscopy was performed in every patient before thyroid and parathyroid surgery. Among 5172 patients larynx paresis was revealed in 13 cases (0.25%) preoperatively. In this group 11 patients (0.2%) had thyroid surgery previously (from 1 to 5 operations). The indications for surgery were: papillary carcinoma - 8 (57%), diffuse toxic goiter - 3 (22%), secondary hyperparathyroidism - 2 (14%). Only two patients(0.038%) had larynx paresis not due to previous operative treatment. Thus larynx paresis is caused by previous neck operations in most cases, the rest are very rare. Total conventional preoperative endoscopic laryngoscopy is not not cost-effective because of low probability to find an accidental RLN palsy. The indication for preoperative laryngoscopy should be a history of previous neck surgery.

thyroid nodule size was 2.01 – 0.94 cm. All cases were completed successfully via a single retroauricular incision. There were no conversions to an open approach. Six out of 38 patients underwent additional neck lift surgery with a mean total operative time of 189 – 45 minutes. The mean operative time for the remaining 34 cases that underwent retroauricular robotic assisted hemithyroidectomy without neck lift surgery was 156 – 39 minutes. Five patients underwent this surgery without using the robot. Two of 38 patients developed postoperative hematoma in which one of them needs surgical evacuation. There were no cases of permanent vocal cord paralysis or permanent hypoparathyroidism. However, two patients developed transient hoarseness, which resolved 9 weeks and 10 weeks postoperatively. Mean blood loss was 19.0 – 30.93 ml. Twenty one patients were discharged on the same day of surgery. Single-incision retroauricular robotic hemithyroidectomy and parathyroidectomy can be safe and feasible approach. Concomitant neck lift surgery can be offered in a select group of patients. Interestingly, non-robotic retroauricular approach can be performed safely. Future studies are warranted to further evaluate the benefits and limitations of this novel approach.

Poster 207

Thyroid & Development Monday & Tuesday Poster 9:00 AM ROBOTIC THYROIDECTOMY AND PARATHYROIDECTOMY: AN INITIAL EXPERIENCE WITH RETROAURICULAR APPROACH M. Alshehri, H. Mohamed, E. Kandil Surgery, Tulane University, New Orleans, LA

Thyroid & Development Monday & Tuesday Poster Clinical 9:00 AM CONGENITAL HYPOTHYROIDISM (CH) WITH PROPERLY LOCATED GLAND AND ISOLATED HYPERTHYROTROPINEMIA (IH) IN CHILDREN AND ADOLESCENTS: CLINICAL, BIOCHEMICAL AND MOLECULAR ANALYSIS AT DIAGNOSIS AND AFTER RE-EVALUATION B. Bagattini, C. Di Cosmo, L. Montanelli, G. De Marco, P. Agretti, P. Vitti, M. Tonacchera 1 Department of Clinical and Experimental Medicine, Endocrinology Section, University of Pisa, Pisa, Italy

New approaches for robotic assisted thyroidectomy were recently described. Here we are reporting our initial experience using a retroauricular approach for thyroid and parathyroid surgery. This is a prospective study that was conducted under IRB approval and all surgeries were performed by a single surgeon at a North American academic institution. Some patients underwent an additional concomitant neck lift surgery in addition to the thyroid surgery. Some cases performed without use of the robot. Clinical characteristics, total operative time, blood loss, surgical outcomes and length of hospital stay were evaluated. Forty cases were performed during the study period on thirtyeight female patients, 30 thyroid lobectomies, 7 completion thyroidectomies and 3 parathyroid surgeries. Mean age was 44 – 13 years, and mean body mass index (BMI) was 26.9 – 5.31. Mean

In recent years increasing cases of CH with properly located and normal sized thyroid are identified. When slightly higher TSH values are found after perinatal age, in absence of anti-TG and anti-TPO Ab in patients with normal thyroid gland, IH is diagnosed. We evaluated 136 patients aged under 18 years, 64 with CH with normal thyroid gland and 72 with IH. At the first diagnosis all were treated with LT4 and during the clinical follow up and we evaluated the need for LT4 therapy, after discontinuation of it, and performed perchlorate test in most patients. In these patients genetic analysis of DUOX2 and TSHr genes was performed. After discontinuation of LT4 at the end of follow-up, among CH patients 21.6% confirmed a hypothyroidism, 49% had a hyperthyrotropinemia and 29.4% revealed a normal thyroid function. Of these

Poster 206

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patients, 4 showed a total organification defect performing a perchlorate discharge test, and 8 showed a partial organification defect. Among patients with IH, at the end of follow up, 1.4% showed a hypothyroidism, 43% confirmed a hyperthyrotropinemia and 55.6% showed a normal thyroid function. Of these patients, 6 showed a partial organification defect. 2.2% of the patients showed the appearance of TG-Ab during checks. Genetic analysis revealed: 4 polymorphisms, a mutation in compound heterozygosity, a point mutation and a deletion of the DUOX2 gene; 1 point mutation and 2 polymorphisms of TSHr gene. The patients with the same mutation showed a different phenotype. In conclusion, 29% of patients with CH and in 55% of patients with IH revealed a normalization of thyroid function. Mutations in DUOX2 gene were the most frequent, however, children carrying the same mutation had a different phenotype, suggesting that other factors are responsible of the clinical characteristics.

Poster 209

Poster 208 Thyroid & Development Monday & Tuesday Poster Clinical 9:00 AM MUTATION OF GENE TSH RECEPTOR (TSHR) AND THE CLINICAL CHARACTERISTICS OF CONGENITAL HYPOTHYROIDISM S. Lee1, K. Han2, J. Yu1 1 Pediatrics, Dankook University Hospital, Cheonan, Korea (the Republic of); 2Nanobiomedical science, Dankook University, Cheonan, Korea (the Republic of) Etiologies of congenital hypothyroidism (CH) in newborn period are various, and TSH receptor (TSHR) mutation is known as one of them. It is useful to know the genetic causes of CH and the clinical characteristics of subjects with TSHR mutation. We evaluated mutational analysis of the gene TSHR and clinical characteristics in the patients with congenital hypothyroidism (CH) or neonatal hyperthyrotropinemia. Mutation analysis was done in 96 children with congenital hyothyroidism or transient hyperthyrotropinemia who were managed at the Department of Pediatrics in Dankook University Hospital from January to December 2014. Clinical findings including gestational ages, birth weights, total T3, free T4, TSH, thyroglobulin as well as thyroid sonography were analyzed by the review of their medical records. A P value of less than 0.05 was considered statistically significant using SPSS software program (version 20.0) and Mann-Whitney U test, Chi-Square test were used in the study. A total of 96 subjects were included in the study. Eighty nine were diagnosed as having congenital hypothyroidism and seven were as having transient hyperthyrotropinemia. TSH receptor (TSHR) gene mutation was detected in twelve subjects (12.5%). R450H was the most common (n = 4) followed by R519C (n = 2), C390F (n = 2), R531W, G245S, I81N, S305R. C390F, I81N, and S305R was the novel mutation. One subject with S305R mutation showed ectopic thyroid. There were no statistically significant differences in age at TSH elevation, gender, birth weights, findings of thyroid sonography, and the levels of total T3, free T4, thyroglobulin between a group with TSHR mutation and a group without TSHR mutation. Initial TSH levels were significantly lower in the sujects with TSHR (P < 0.05). Thyroid hormone replacement was required in four (44.4%) among nine subjects with TSHR mutation who were followed over 3 years of age. This study showed that the mutation of the gene TSHR is the common cause of congenital hypothyroidism. More than half of patients with TSHR mutation could discontinue the replacement of thyroid hormone after three years of age.

Thyroid & Development Monday & Tuesday Poster Clinical 9:00 AM PREVALENCE OF SHORT STATURE IN JUVENILE HYPOTHYROIDISM AND THE IMPACT OF TREATMENT ON VARIOUS SKELETAL MANIFESTATION AND GROWTH VELOCITY IN A TERITARY CARE CENTER M. Gutch1,3, S. Kumar2, S.M. RAZI3, A.K. Gupta3 1 Endocrinology, King George’s Medical University, Meerut, India; 2 RADIODIAGNOSIS, KGMU, Lucknow, India; 3ENDOCRINOLOGY, LLRM MEDICAL COLLEGE, Meerut, India Juvenile hypothyroidism is very common problem in developing parts of world, and produces various skeletal manifestations. One of them is short stature and it is the most common reason for referral to endocrinologist. To study the prevalence of short stature in juvenile hypothyroidism, to study the various radiological manifestations of juvenile hypothyroidism and to study the impact of treatment on growth velocity and various skeletal manifestations. Out of total nine hundred hypothyroid patients, eighty seven patients found to be of juvenile hypothyroidism were enrolled in the study that were 6–18 years of age with newly diagnosed or on follow in the endocrine clinic over a period of 1½ years were evaluated clinically and by laboratory tests. Serial assays of TSH, T4, and skeletal X rays and anthropometry were done at regular interval and clinical and radiological outcome of patients were analyzed. The mean age of diagnosis of juvenile hypothyroidism was 11.2 years, and the females had twice the incidence than that of males, the mean TSH value were 118 – 24.3 lIU/ml. Prevalence of short stature was found to be 45% while delayed bone age was found to be 72% in juvenile hypothyroid populations. Height SDS increased from - 2.9 – 0.9 at the start of thyroxine therapy to - 1.8 – 0.8 after 12 months later (p < 0.001). Bone age SDS increased from 8.9 – 2.5 at the start of thyroxine therapy to 10.8 – 2.7 after 12 months later. Height velocity increased from 4.9 – 0.8 cm/year in the year before treatment to 8.7 – 1.3 during treatment (p < 0.001). The presentations of juvenile hypothyroidism may be varied; prompt recognition of the findings can lead to early and effective treatment, and improving the skeletal defects.

Poster 210 Thyroid & Development Monday & Tuesday Poster Clinical 9:00 AM NEW ENDOSCOPIC THYROIDECTOMY WITH THE TRANSORAL-VESTIBULE APPROACH: A COMPARISON WITH THE BILATERAL AREOLAR APPROACH Y. Fan General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China Recently, natural orifice transluminal endoscopic surgery (NOTES) has generated excitement among surgeons and patients as potentially scar-free surgery. We have been utilizing the transoral-vestibule

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approach (TOVA) for less invasive endoscopic thyroidectomy to avoid any scar on neck and chest areas. Here, we report our experience with the TOVA technique in treatment of benign thyroid tumors and evaluate its feasibility, safety, efficacy, and cosmetic results through comparison with the bilateral areolar approach (BAA). From August 2013 to December 2014, 30 patients with benign thyroid nodules were enrolled into the TOVA (n = 15) and the BAA (n = 15). The TOVA technique was performed using one 10-mm trocar at the vestibulum under the center of the inferior lip and a 5mm incision was made on both sides of the mucous membrane of the buccal cavity. The BAA procedure was performed using one 10-mm trocar and two 5-mm trocars through bilateral circumareolar incisions. All patients were followed to evaluate therapeutic effects and scar formation. Postoperative pain was assessed by means of a visual analog scale (VAS). 30 operations were performed successfully without any conversion to open operation. There were significant differences in the mean operative time (91.2 – 22.1 vs 72.3 – 18.2 min). However, there were no significant differences in the average operation blood loss (12.5 vs 15.3), the duration of hospitalization (4.6 vs 4.3), occurrence of postoperative complications, and postoperative pain (2.3 vs 2.1). No postoperative bleeding, no permanent damage to the recurrent laryngeal nerves, superior laryngeal nerve and parathyroid glands, and no hypoparathyroidism. All the patients were satisfied with the cosmetic result after mean follow-up of 6 months. 1 of the cases showed skin scrap ecchymosis in TOVA group. The TOVA technique was found to be safe and feasible, affords the advantages of minimal invasiveness and excellent cosmesis results and is technically more challenging procedure which may become alternative procedure for treatment of patients with benign thyroid tumors, especially those with strong desire for cervical cosmesis.

tula, 1 died of tracheal bleeding, 1 case of severe chylous leak, postoperative hoarseness 12 cases, 2 cases of permanent hypoparathyroidism. No hemiplegia cerebral ischemia and blood pneumothorax. The multi-disciplinary joint surgery may be better for the treatment of locally advanced thyroid cancer patients, reduce complications, prolong survival and improve quality of life.

Poster 211 Thyroid & Development Monday & Tuesday Poster Clinical 9:00 AM MULTI-DISCIPLINARY JOINT SURGERY FOR LOCALLY ADVANCED THYROID CANCER Y. Fan General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China To investigate the feasibility and safety of multi-disciplinary joint surgery for locally advanced thyroid cancers. The Multi-disciplinary joint surgery data of 60 patients with locally advanced thyroid cancer was retrospectively analyzed. The operation type, surgical procedures, operative time, the incidence of postoperative complications and survival period were analyzed. 60 cases of thyroid cancer, including 26 cases of papillary carcinoma, 34 cases of poorly differentiated carcinoma; 57 cases of reoperation or multiple surgeries. The operating time was 4-8.5h. Intraoperative blood-transfusion volume, was 0-1000 ml. Surgical sleeve tracheal resection in 5 cases, 8 cases of tracheal resection windows, replacement of carotid artery in 5 cases, 11 cases of jugular vein resection, esophageal resection in 9 cases, local skin flap transpositionturn in 5 cases, carotid artery replacement Joint jugular vein resection in 7 cases, turn the flap joint carotid artery and jugular vein resection replaced in 3 cases, the total tracheal resection and replacement of internal carotid artery and jugular vein resection, 4 cases of esophageal tracheal resection and partial resection in 3 cases, including 6 cases thoracotomy, clavicle removal of four cases, nine cases of intraoperative radiotherapy. Two departments joint surgery was in 38 cases, more than three departments 22 cases. The complications included 1 case flaps bleeding, 2 cases of esophageal fis-

Poster 212 Thyroid & Development Monday & Tuesday Poster Clinical 9:00 AM PROSPECTIVE VALIDATION STUDY OF CERNEA CLASSIFICATION IN PREDICTING EMG ALTERATIONS OF EXTERNAL BRANCH OF THE SUPERIOR LARYNGEAL NERVE IN THYROID SURGERY G. Dionigi1, H. Kim2, G.W. Randolph3, C. Wu4,2, F. Chiang4, M.L. Tanda5, E. Piantanida5, V. Pappalardo1, D. Inversini1 1 Department of Surgical Sciences and Human Morphology, University of Insubria (Como-Varese), Division of Surgery, Research Center for Endocrine Surgery, Varese, Italy; 2Department of Surgery, Korea University Anam Hospital, KUMC Thyroid Center, Seoul, Korea (the Republic of); 3Department of Laryngology and Otology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Division of Thyroid and Parathyroid Endocrine Surgery, Boston, MA; 4Department of Otolaryngology-Head and Neck Surgery, 4. Institute of Clinical Medicine Kaohsiung Medical University Hospital,, Kaohsiung, Taiwan; 5University of Insubria (Varese-Como), Department of Endocrinoly, Varese, Italy Cernea classification is applied to descry external branch of the superior laryngeal nerve (EBSLN). We evaluate by intraoperative neural monitoring (IONM) the hypothesis whether this classification is useful for predicting which EBSLN subtype has increase risk of injury. Analysis of 400 EBSLN. Identification of EBSLN was achieved with both cricothyroid muscle (CTM) twitch and glottis evoked electromyography (EMG) response. We defined S1 initial EBSLN stimulation at identification and S2 final nerve stimulation achieved in the most cranial aspect of nerve exposed above the area of surgical dissection after superior artery ligation. Mean S1 amplitude acquired was 259 + /67(180–421), 321 + / 79(192–391), 371 + /38 (200–551)lV respectively for type 1, 2A, 2B (p = 0,08). S1 and S2 amplitudes were similar in type 1 (p = 0.3). S1 and S2 determinations changed significantly in type 2A and 2B (p = 0.04 and 0.03). EBSLN that experienced > 25% decreased amplitude in S2 increased significantly from Type 1 (4,9%) to Type 2A (11,2%) and 2B (18%) (p = 0,01). None of type 1, 2,8% type 2A and 3% type 2B experienced loss of EBSLN conductivity. Latency determinations did not vary significantly for any parameter compared. Cernea classification predicts risk of EBSLN stress. We identified amplitude differences between S1 and S2 determinations in type 2A and 2B, confirming that surgical dissection in these subtypes is demanding.

Poster 213 Thyroid & Development Monday & Tuesday Poster Clinical 9:00 AM PREDICTORS OF FAILURE OF PLANNED TOTAL THYROIDECTOMY G. Dionigi1, H. Kim2, C. Wu3, C.C. Ferrari1, M. Lavazza1, A. Leotta1, F. Chiang3, M.L. Tanda4, E. Piantanida4, V. Pappalardo1, D. Inversini1

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was his usual weight), BMI: 24,4kg/m2. Achilles reflex exacerbated. No tremors of hands nor Graves’ orbitopathy signals. Blood tests result: TSH 0,008UI / mL (N: 0.34 to 5.6), FT4 6NG / dL (N: 0.7 to 1.8), Anti-TPO 386,7U / mL (N: < 9, 0), JOB 23,39U/ml (N: < 1.75) Conduct: Methimazole (30mg/day) and propranolol (120 mg/day). After three months, there was an improvement of symptoms, absence of fever, 6 kg of weight gain, laboratory improvement, except for the still suppressed TSH (0.02). Complementary exams should be requested on the basis of suspicions raised by the clinical history and a detailed physical examination. Such a rare condition, as a HT associated with FUO, may confound the differential diagnosis. In the reported case, with weight loss, hot and clammy skin and goiter, the diagnosis of hyperthyroidism became clear. The delayed diagnosis of HT was due to the rare clinic prented, and to few reports in the medical literature of Hyperthyroidism presenting as a FUO.

Department of Surgical Sciences and Human Morphology, University of Insubria (Como-Varese), 1st Division of Surgery, Research Center for Endocrine Surgery, Varese, Italy; 2Department of Surgery, University, Anam Hospital, Seoul, Korea, Division of Breast and Endocrine Surgery, Minimally Invasive Surgery and Robotic Surgery Center, Seoul, Korea (the Republic of); 3Kaohsiung Medical University Hospital, Kaohsiung Medical University, Department of Otolaryngology, Kaohsiung, Taiwan; 4University of Insubria (Varese-Como), Department of Endocrinoly, Varese, Italy To determine the rate and predictors of failure of planned total thyroidectomy (TT). Retrospective analysis, prospective collection of 988 patients with benign bilateral thyroid disease admitted for surgery between 1999– 2012. Main outcome measure was failure of total thyroidectomy (f-TT). Of the 988 patient who were offered a TT, the treatment failed in 71 patients (7,2%). Multivariate analysis identified as pre-operative independent predictors of f-TT: age > 75 years. Intra-operative predictors of f-TT: non identification of recurrent laryngeal nerve, no use of neuromonitoring. Post-operative predictors: gland volume > 85ml. The likelihood of f-TT was 10% if no predictor was present, 32% if 1 was present, and 56% if > 2 were present. The percentageydistribution curve of f-TT is correlated with time period. Overall morbidity of f-TT patients was almost 6-fold higher than those with successful TT (s-TT) (8.7% vs 4.7%; P < .05). During the study period, 18% of patients (13/71) need for completion thyroidectomy. 7% of patients undergone less than total thyroidectomy. We identify pre-, intra- and post-operative factors predict failure of TT. This data must be taken into account when generalizations are made about the overall high success rates of TT.

Poster 214 Disorders of Thyroid Function Monday & Tuesday Poster 9:00 AM HYPERTHYROIDISM PRESENTING AS A FEVER OF UNKNOWN ORIGIN (FUO). CASE REPORT A.K. ARBEX1,2, D.R. Rocha1,2, V.R. Bizarro1, D.D. Carvalho1, J.C. Santos1, A.C. de Jesus1, L.M. Arau´jo1, L.C. Portari1 1 ENDOCRINOLOGY DEPT., IPEMED BRAZIL, Rio de Janeiro, Brazil; 2Federal University of Rio de Janeiro, Rio de Janeiro, Brazil We report a case of an atypical presentation of hyperthyroidism (HT) initially presented as a Fever of Unknown Origin (FUO). The differential diagnosis of fever of unknown origin is complex and difficult. Several diseases may manifest as FUO, the most common ones being infections (40%), neoplastic diseases (20–30%) and inflammatory diseases (15–30%). Endocrine diseases are rare causes of FUO. MGM, 27 y. old, male, arrived at the Endocrinology ambulatory reporting the onset of clinical symptoms six months before. He presented intermittent fever, as high as 40,5C. Sore throat followed, so he consulted a general practitioner, who made the diagnosis of tonsillitis and prescribed antibiotics.One month thereafter, he started complaining about fatigue and weakness. Five months thereafter he showed a loss of 15Kg of weight, nervousness, and increased thyroid volume. Tobacco user, 20 cigarettes / day, for 10 years. He denied alcoholism. Physical exam: Good general condition, lucid, normal skin color and anicteric, warm, damp skin. Increased thyroid volume diffusely (twice the normal size), painless, mobile, no murmurs, nodules or thrills. HR: 90bpm. BP: 160x80mmHg, height: 1,81m, weight: 80Kg (95kg

Poster 215 Thyroid & Development Monday & Tuesday Poster 9:00 AM JUVENILE HYPOTHYROIDISM: AN EARLY DIAGNOSIS PREVENTS SEVERE ASSOCIATED DISORDERS A.K. ARBEX1,2, D.R. Rocha1,2, L.M. Arau´jo1, V.R. Bizarro1, J.C. Santos1, D.D. Carvalho1, A.C. de Jesus1, L.C. Portari1 1 ENDOCRINOLOGY DEPT., IPEMED BRAZIL, Rio de Janeiro, Brazil; 2Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Hashimoto’s thyroiditis is the most common cause of goiter and acquired hypothyroidism in children and adolescents, in sufficient iodine regions. Its prevalence in children is around 0.15%, with a ratio of three girls for each boy. ESS, male, 14 years old. His mother took him for the first time to health care in 2008, complaining about agitation, aggression, insomnia, ‘‘bedwetting’’, eating disorders and increased weight of her son. Physical exam: Height 132 cm, weight 41,7 Kg, BMI 23.93 kg/ m2. In March 2009, the patient was consulted by a psychiatrist, who defined the diagnosis of an ’Anxiety Disorder’. Fluoxetine 20 mg/day was started, and gradually increased to 60 mg / day in June 2009, when he was sent to a Centre of Psychosocial care. In October 2009, the mother reported worsening of the clinical picture, with new visit to psychiatry, where Imipramine 25 mg/day was prescribed. In 2011, he started psychological group therapy and in 2012, he consulted a nutritionist, due to weight gain. Physical exam: Weight 60,4 Kg Height 147 cm, BMI 27.95 kg/m2. Palpable thyroid, increased 2 · normal size. Height: 155 cm Weight: 66,3 Kg, BMI: 27.59 Kg/m2. Tests: TSH: > 150 lUI/ml (n = 0.3-4.3), negative EPF Anti TPO: 376.6UI/ml (N < 35), anti-thyroglobulin antibody: 119.0 IU/ml (N115 IU/mL), Free T4: 0.57 ng/dl (N: < 0.70). US thyroid: no change. Conduct: Levothyroxine 50mcg was prescribed/Imipramine’s dosis was stepwise lowered. After 6 weeks, the dose was increased to Levothyroxine 75mcg/day and further tests were required. In February 2015, the patient had lost 7 kg and there was an improvement of all symptoms. The patient felt ’peaceful’. After 40 days, Imipramine was taken out. Free T4: 1.64 ng/dl, TSH: 0.18 lUI. Juvenile hypothyroidism usually occurs between 6–12 years of age. It may cause developmental delays such as: short stature, weight gain, difficulty in school performance, hyperactivity or fatigue and delayed onset of puberty. It is therefore relevant to be diagnosed early in the pubertal development age. An early diagnosis of Hypothyroidism in childhood is tricky, because clinical signs may not be specific, it is a rare event and may severely impact on an adolescent’s life.

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Poster 216 Thyroid Hormone Metabolism & Regulation Monday & Tuesday Poster 9:00 AM CENTRAL HYPOTHYROIDISM AND PLEURAL EFFUSION RESULTING FROM SHEEHAN SYNDROME: CASE REPORT A.K. ARBEX1,2, D.R. Rocha1,2, V.R. Bizarro1, D.D. Carvalho1, J.C. Santos1, L.M. Arau´jo1, A.C. de Jesus1, L.C. Portari1 1 ENDOCRINOLOGY DEPT., IPEMED Medical School, BRAZIL, Rio de Janeiro, Brazil; 2Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Central hypothyroidism is a key issue on the diagnosis and treatment of Sheehan Syndrome (SS) and its associated clinical conditions, such as central adrenal insufficiency, amenorrhea and agalactia. A pleural effusion (PE) as a manifestation of central hypothyroidism is even rarer in an already rare clinical condition. AR, female, 39 years old, arrived complaining of ‘‘water in the lungs’’ (sic), evolving with mild dyspnea for 26 days at the date of clinical consultation. Pleural effusion presented without any apparent cause. When referred to a rheumatology clinic because of arthralgia, a normal TSH with a low FT4 were documented. Therefore she was referred to an Endocrinologist. History of 2 pregnancies in the last 9 years with cesarean section and important hemorrhage, no breastfeeding because of ‘‘lack of milk’’(sic). Amenorrhea, asthenia, depression, decreased libido, visible thining of pubic and axillary hair were the main clinical presentations. Parents had hypertension. Physical Exam: BP: 100X60mmHg, HR: 68bpm, Weight: 80,3kg, Height: 1,65m. Infiltrated face, dry skin, overweight (BMI: 29.52 kg/ m2). RESULTS: Chest X-ray: bilateral PE. E2 < 20pg/mL. FSH 1.8mUi/mL. LH: 2.1mUI/mL. TSH: O, 8 MIU/mL (0.34–5.60). FT4: 0.50 ng/dL (N = 0.54–1.24) Cortisol: 3,5Mcg/dl (6.7 to 22.6). ACTH: 8,0pg/ml (7.2 to 63.3) PRL: 2,0ng/ml (3.30 to 26.70) GH: 1.0 Calcium 8.9 mg/dL (8.6 to 10.0), 25OHVitD: 21.0 (N > 30), PTH: 31 (4 to 58cg/ml) Bone densitometry: decreased bone mass. Pituitary gland of reduced size in MRI. Levothyroxine was started at 100mcg/day. Prednisone was kept at 10 mg/day, along with 0.02 mg ethinylestradiol, drospirenone 3mg, calcium carbonate 1gr/day and cholecalciferol 1000 IU / day. After 60 days, symptoms were clearly improved, with resolution of the PE and FT4 reached the normal level of 1.18 ng/dL. Pleural effusion is an unusual presentation of Central hypothyroidism, and usually shows full resolution with levothyroxine replacement. The delay in the diagnosis of SS may severely worsen the clinical picture.The treatment is hormone supplementation: levothyroxine and steroids. Early and appropriate treatment is essential to reduce morbidity and mortality.

Anatomy, diagnosis and intraoperative detection of arteria lusoria and a non recurrent right laryngeal nerve.

symptoms known as dysphagia lusoria. This vascular anomaly may be predictive of a nonrecurrent right laryngeal nerve at the time of thyroidectomy(see figure). A 74-year-old woman who presented with a long history of difficulty swallowing and a large multinodular goiter was found to have aberrant right subclavian artery anatomy during investigation of dysphagia, reflux and chronic cough. On further imaging review, this was identified as arteria lusoria, which is the most common anomaly of the aortic arch (see figure). This occurs concurrently with abnormal regression of the right fourth pharyngeal arch artery during embryologic development, which under normal circumstances becomes the right subclavian artery. This abnormal regression results anatomically in a nonrecurrent right laryngeal nerve (see figure). Prior to proceeding with thryoidectomy for a symptomatic large multinodular goiter, the patient’s preoperatve imaging was reviewed in detail which revealed arteria lusoria in addtion to the patient’s large multinodular goiter both of which were thought to be at least partially responsible for the patient’s dysphagia and compressive symptoms. Understanding of this pre-operative vascular anomaly predicted and assisted in the intraoperative identification and preservation of a nonrecurrent right laryngeal nerve (see figure) confirmed by intraoperative nerve monitoring and postoperative laryngoscopy. Other anomalies identified on pre-operative imaging including situs inversus may also predict the very rare non recurrent left laryngeal nerve. Preoperative diagnosis and recognition of aortic arch anomalies including arteria lusoria are critical and helpful in predicting intraoperative aberrant laryngeal nerve anatomy and potentially avoiding intraoperative injury during thyroidectomy.

Poster 218 Poster 217 Thyroid & Development Monday & Tuesday Poster 9:00 AM AORTIC ARCH ANOMALIES, ARTERIA LUSORIA AND THE NONRECURRENT RIGHT LARYNGEAL NERVE: PREOPERATIVE UNDERSTANDING OF VASCULAR ANOMALIES PREDICTS NERVE VARIANTS INTRAOPERATIVELY S. Goldstein2, K. Makris3, A. Dackiw1 1 Surgery, UT Southwestern, Dallas, TX; 2Surgery, Johns Hopkins, Baltimore, MD; 3Surgery, Baylor College of Medicine, Houston, TX Arteria lusoria is characterized by an origin of the right subclavian artery off of the descending thoracic aorta rather than the aortic arch. Typically the aberrant artery passes behind the trachea and esophagus to supply the right arm. This can cause esophageal compressive

Thyroid Cancer Monday & Tuesday Poster Basic 9:00 AM NEXT GENERATION SEQUENCING BASED MUTATIONAL PROFILES OF DIFFERENTIATED THYROID CANCER WITH DISTANT METASTASIS S. Sohn1, J. Jang2, S. Kim2, J. Chung2 1 Division of Endocrinology, Department of Internal Medicine, Myongji Hospital, Goyang, Korea (the Republic of); 2Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Seoul, Korea (the Republic of) Distant metastasis are uncommon in differentiated thyroid carcinoma (DTC), but it is main cause of death in DTC patients. Identification of molecular profile of metastatic DTC could be important for therapeutic decision making. However, there are few comprehensive studies of mutations in both primary and metastatic DTC. Here we describe the mutational profile of DTC with distant metastases and

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also evaluated whether these mutations were concordant between primary tumor and metastatic tumor. Next generation sequencing(NGS) using the Ion Ampliseq Cancer Panel to target 50 cancer genes were performed to obtain comprehensive genetic information in 10 papillary thyroid carcinoma(PTC) patients and 10 follicular thyroid carcinoma(FTC) patients with distant metastases. 17 primary tumors and 25 metastatic or recurrent tumor samples were analyzed. NGS identified at least one genetic alteration in most DTC tumors, 8/9 primary PTC, 12/13 metastatic PTC, 8/8 primary FTC and 11/12 metastatic FTC. The most common mutations were BRAF mutation in both primary (7/8) and metastatic PTC (11/13) and RAS mutation in both primary (6/8) and metastatic FTC (9/12). These mutations were highly concordant between primary and metastatic tumor, with higher mutant allele frequency in metastatic tumor. Novel mutations including MLH1, PDGFRA, KIT, FBXW7, APC, GNAQ, ATM, PTPN1, SMAD4, SMARCB1, ALK, RB1, ERBB4 and CDH1 were also found and more commonly observed in metastatic DTC. However, most of these mutations were coexistent with BRAF or RAS mutation. BRAF or RAS mutations were highly prevalent in DTC and these mutations were concordant between primary and metastatic tumor. NGS also identified novel mutations which were more commonly observed in metastatic DTC. Further studies are needed whether these novel mutations drive tumor progression.

could be extremely interesting as potential predictors of prognosis in this type of neoplasms.

Poster 219 Thyroid Cancer Monday & Tuesday Poster Basic 9:00 AM DIGITAL GENE EXPRESSION PROFILING OF A CONSECUTIVE SERIES OF PAPILLARY THYROID CARCINOMAS F. Basolo, A. Proietti, R. Giannini, P. Miccoli Department of Surgical, Medical, and Molecular Pathology and Critical Care, University of Pisa, Pisa, Italy Classical variant papillary thyroid carcinoma (CVPTC) is a common endocrine neoplasms, whose prognosis is extremely variable. Testing for specific genes expression should potentially predict the clinical behavior of these neoplasms. A series of 21 consecutive CVPTCs was collected and clinicopathological features, as level of invasion, multifocality and lymphnode metastasis were retrieved. 34 genes expression level were determined from RNA extracted from FFPE slides by a NanoString custom assay. Non parametric tests were performed to determine the level of specific genes expression in different steps of CVPTCs progression. A statistically different genes expression was observed according to the clinicopathological features considered. We were able to put in evidence some of the genes involved in CVPTCs invasion, multifocal spread and lymph-node metastatization. In particular, we found that in presence of node metastases Fibronectin-1, Laminin B3 and Metallo-phospho-esterase 2 are significantly overexpressed (p < 0.05) while Serine protease 23 and E-Selectin mRNAs were significantly downregulated. While gamma-glutamylcyclotransferase and Protein S expression were significantly deregulated in extra-thyroidal invasive and multifocal CVPTCs respectively. This study indicates that different aspects of CVPTCs’ diffusion into and outside the thyroidal parenchyma are modulated by several genes. The expression analysis of those genes considered singularly or in groups could give important informations about the pathological behavior of thyroid cancer. Although, these are preliminary data that should be tested on a wider series of samples and with a larger number of genes tested, we could speculate that this panel of genes

Poster 220 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE CHANGING PATTERNS OF URINE IODINE EXCRETION WITH LOW IODINE DIET(LID) TO PREPARE FOR RADIOACTIVE IODINE ABLATION(RIA) IN THYROID CANCER PATIENTS: PROSPECTIVE COMPARATIVE STUDY OF THYROXINE WITHDRAWAL VS RECOMBINANT TSH USING GROUPS S. Kang, C. Lee, E. Ban, M. Kim, T. KIM, S. Lee, J. Choi, J. lee, J. jeong, K. Nam, W. Chung, C. Park Yonsei University Health System, Seoul, Korea (the Republic of) After total thyroidectomy for the differentiated thyroid cancer, the radioactive iodine ablation(RIA) is usually followed to reduce disease relapse and disease-related death in high risk group. However, RIA requires many weeks of preparation- thyroxine withdrawal and low iodine diet(LID) - which causes various discomfort to the patients. Especially in Korea and Japan, where the iodine intake is quite high, many patients have severe troubles to follow complex LID schedule since the actual menu of the diet doesn’t suit their tastes. In this study, we tried to confirm the optimal period of iodine restriction for RIA in iodine rich are through analyzing the changing pattern of urine iodine excretion (UIE) during LID, and evaluated whether there is any differences in the UIE level between the differently prepared two groups. A total 94 patients who has been performed total thyroidectomy and prepare RIA fir thyroid cancer enrolled in this study. All the patients have been prospectively allocated in the two study groups according to the patient preference (thyroxine withdrawal (TW) or using recombinant TSh(RT) for TSH stimulation) with informed consent. For the evaluation of changing pattern of the UIE, we have collected 6-7 separated morning spot urine specimen during the LID period(0,3rd, 5th, 7th, 10th, 14th days in TW and 0,3rd, 7th, 10th, 11th, 12th, 14th in RT group). We also analyzed the each pattern and differences of the UIE during LID between the two groups. There was no statistically difference in the clinicopathological characteristics between the two groups. The mean values of the morning UIE value(I/Cr ratio) serially reduced with time relapse and I/Cr ratio of 7th day and 14th day were 27.27 – 29.09 and 21.75 – 17.0, respectively in TW group. The adequate preparation rate of 7th day and 14th day for UIE(cutoff value 66.2 lg/gCr) were 95.2% and 97.6% respectively. In RT group, the I/Cr ratios of 7th day and 14th day were 55.61 – 32.42, 45.01 – 15.66 lg/gCr, respectively, and the adequate preparation rate were 75.6% and 91.1% in RT group. For RIA preparation, just one week of strict LID is sufficient, and one week schedule of LID can be even safely applied in the patient using RT.

Poster 221 Thyroid Cancer Monday & Tuesday Poster Basic 9:00 AM THE EFFECTS OF SIMVASTATIN ON PROLIFERATION AND APOPTOSIS IN HUMAN ANAPLASTIC THYROID CARCINOMA CELLS Y. Xu, H. Zhu, D. Zhu, X. Li, S. Xu, G. Chen, C. Liu Endocrine and Dibetes Center, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, China Anaplastic thyroid carcinoma (ATC) is a kind of rare but extremely aggressive human malignancy. Currently, it’s difficult to effectively control the disease progression by surgery, radiotherapy or

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chemotherapy. Multiple studies have implied that simvastatin might influence the growth of human anaplastic thyroid carcinoma cells. However, how simvastatin is involved in alteration of cancer growth is largely unknown. Here, we showed that simvastatin significantly inhibited the proliferation of HTh-74 cells (a human anaplastic thyroid carcinoma cell line) in a concentration- and time-dependent manner. Various concentrations of simvastatin (0 lmol/L, 1 lmol/L, 2 lmol/L) were given to treat HTh-74 in vitro. The MTT assay, crystal violet staining, Annexin V and PI double staining and Western blotting were used to determine cell proliferation rate, cell clone formation, apoptotic rate of HTh-74 cells and the expression of apoptosis related proteins Caspase-3, Bcl-2 and Bax, respectively. After crystal violet staining, we observed that simvastatin significantly inhibited HTh-74 cells colony formation. Furthermore, a representative experimental result showed that cell apoptosis rate increased dose- and time-dependently by using flow cytometry. This was supported by the findings that expression of cleav-Caspase-3, Bax increased and Bcl-2 decreased after simvastatin stimulation. Our findings suggested that simvastatin inhibit the growth and induce the apoptosis of human anaplastic thyroid carcinoma cells by down-regulating Bcl-2, up-regulating Bax, and activating Caspase-3 pathway.

Thyroid goiter, Grave’s disease, Hashimoto disease have been considered for a long time as benigns diseases. However, incidental thyroid carcinoma isn’t rare. The aim of the study was to review the incidence of thyroid carcinoma in benign pathology and to evaluate the benefit of ultrasound sonography and fine needle aspiration to predict the malignancy. All patients send to our instutition between January 2010 and april 2014 to underwent a thyroid surgery for a benign pathologic were included in this monocentric prospective study. We performed for those patients a physical exam, hormonal blood test and ultrasonography. One hundred sixty four patients benefited for a fine needle aspiration before surgery. Definitive histology classification was established. The incidence of carcinoma in the different thyroid pathology, the usefull of ultrasound and fine needle aspiration was determined by exact test and chi 2. Thirty two carcinomas and 281 benigns diseases were found after histological examination. The global incidence of carcinoma was 10,2 %. The incidence of thyroid carcinoma in goiter, in Graves disease and in solitary nodule was respectively 12 %, 15,15%, 9%. The ultrasound sonography wasn’t able to predict malignancy. The combinaison of fine needle aspiration and ultrasound allows us to predict malignancy in multinodular goiter (p = 0,0001). Our study shows that cancer in benign pathology isn’t rare. The analyse of both fine needle aspiration and sonography can help to predict the malignancy especially in multinodular goiter.

Poster 222 Thyroid Cancer Monday & Tuesday Poster Basic 9:00 AM INCIDENCE OF MALIGNANCY IN PATIENT SURGICALLY TREATED FOR GRAVES’ DISEASE A. BIGI CHU Pointe a` Pitre, Les abymes, Guadeloupe Increased incidence of cancer in patient surgically treated for Graves’ disease has been reported. The aim of the study was to evaluate the frequency of incidental thyroid cancer in patient surgically treated for Graves’ disease. Between 2010 and 2015, 39 patients underwent surgery for Graves’s disease. Thyroid ultrasonic was performed by one operator. None patient had pre operative malignant cytology. All patient had total thyroidectomy. The incidence of carcinoma in Graves’ disease was determined, and the influence of age, sex, presence of multinodular goiter in thyroid ultrasonic was evaluated. Post operative histopathological examinations revealed thyroid malignancy in 6 patients. The incidence of malignancy was 15,38%. There was 5 papillary carcinomas and 1 follicular carcinoma. Three patients had micro carcinomas and two were multifocal. None of the patient had histopathologic agressivness. There was no significant difference in age and sex between patients with cancer and patients without cancer. The incidence of malignancy in patient with multinodular goiter were significantly higher than in patient with homogenous goiter (p < 0,05). Graves’ disease have a risk of cancer. A correct pre operative assessment with a careful thyroid ultrasonography and a selection of nodule for fine needle aspiration cytology seem necessary. It could predict the risk of malignancy and decide the choice of surgery.

Poster 223 Thyroid Cancer Monday & Tuesday Poster Basic 9:00 AM MANAGING BENIGN THYROID PATHOLOGY BEFORE SURGERY REGARDING INCIDENCE OF MALIGNANCY A. BIGI CHU Pointe a` Pitre, Les abymes, Guadeloupe

Poster 224 Thyroid Cancer Monday & Tuesday Poster Basic 9:00 AM THE ROLE OF AUTOPHAGY IN THYROID CANCER CELLS RESPONSE TO THE TREATMENT WITH HIV PROTEASE INHIBITOR NELFINAVIR Y. Kushchayeva3, K. Jensen1, A. Bikas2, J. Costello1, A. Patel1, K. Burman2, V.V. Vasko1 1 Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD; 2Division of Endocrinology, MedStar Washington Hospital Center, Washington, DC; 3Department of Medicine, MedStar Washington Hospital Center, Washington, DC HIV protease inhibitor Nelfinavir (NFV) induces autophagy and apoptosis in various cancer cell lines. Microtubule-associated protein 1 light chain 3B (LC3B) is involved in formation of autophagosome and is considered as a marker of autophagic activity. Autophagy can either lead to cell death or promote cell survival. The role of autophagy in differentiated thyroid cancer cell response to NFV has not yet been examined. Human thyroid cancer cells (FTC133 and BCPAP) were used to create LC3B-deficient cells by infection with lentiviral particles containing human LC3B specific shRNA. The efficiency of LC3B inhibition was confirmed by real-time PCR and Western blot. The effects of LC3B inhibition on cell proliferation, migration and response to the treatment with NFV were examined. LC3B expression was inhibited in FTC133 and BCPAP cells without significant effect on expression of other autophagic molecules (Beclin 1, Atg3, Atg5 and Atg7). The inhibition of LC3B had no significant effect on cells viability, rate of growth and migration. Inhibition of LC3B was associated with increased expression of p62, suggesting inhibition of autophagic flux. In both non-transfected cell lines, NFV (10 mM) induced LC3BII and decreased p62 protein level, indicating activation of autophagy. NFV-inducible cytotoxicity was more prominent in LC3B-deficient cells. The viability of control and LC3B-deficient cells was decreased by 46% and 98% respectively after treatment with NFV. The pharmacological inhibitor of autophagy, Chloroquine (CQ) potentiated the effects of NFV, and

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combination of NFV with CQ resulted in massive cell death in both examined cell lines. NFV induces autophagy in thyroid cancer cells. Autophagy seems to be a protective mechanism, favoring thyroid cancer cell survival under treatment with NFV. The anti-cancer activity of NFV can be potentiated by inhibition of autophagy.

meds were stopped, and she was placed on 125 mcg thyroxine qd. Three weeks later thyroglobulin (Tg) was 356 ( < 10 ng/ml) and a completion thyroidectomy was performed. The left lobe was small and unremarkable. The patient feels much better since surgery. Our plan is to keep the TSH suppressed and monitor Tg. Whether or not to treat with an ablative dose of RAI is under discussion. This case demonstrates that rarely a hyperfunctioning nodule may be an occult follicular carcinoma. Progressive growth of a hot thyroid nodule suggests possible carcinoma. The prognosis for a patient such as ours, who is under 40 with early stage disease, is very good.

Poster 225 Thyroid Cancer Monday & Tuesday Poster 9:00 AM AUTONOMOUS HYPERFUNCTIONING FOLLICULAR CARCINOMA OF THE THYROID - A CASE REPORT A.D. Carey, R.B. Stein Endocrinology, Keck School of Medicine University of Southern California, Los Angeles, CA Autonomously hyperfunctioning follicular thyroid carcinoma is rare. Such patients are often thought to have a simple hyperfunctioning thyroid nodule, and the cancer is unrecognized. They frequently are treated with radioactive iodine, thereby curing both the hyperthyroidism and the cancer. Our patient underwent a right lobectomy for a presumed hot nodule and was found to have Stage 1 follicular carcinoma. A 33 year old woman presented with an enlarging neck mass. She first became aware of the mass in 2010. In 2012 lab tests showed a depressed TSH and otherwise normal thyroid function studies. Ultrasound showed right lobe enlargement (2.4 x 4.6 cm). She was clinically euthyroid and was thought to have a simple goiter. No specific treatment was advised. In 2015 she sought consultation with us because of progressive thyroid enlargement. Despite appearing clinically euthyroid, lab studies showed hyperthyroidism with T4 17.8 (4.5–12 mcg/dL), fT4 7.5 (1.4–3.8), TSH 0.01 (0.4–3.5 mIU/L), T3 417 (76–181 ng/dL), RAIU 69.6%/6hrs, 75.5%/24 hrs, TSI < 89 ( < 140). Thyroid scan showed uptake only in the right lobe. Ultrasound showed a 6.8 cm right lobe with normal sized left lobe. She was started on 20 mg of methimazole and 50 mg atenolol qd. The patient opted for a right lobectomy over RAI. At surgery the right lobe measured 6.0 · 4.5 · 4 cm and weighed 33g. Pathology reported minimal capsular and lymphovascular invasion consistent with follicular carcinoma. According to the pathologist the tumor was completely excised. Postoperatively, the preoperative

Poster 226 Thyroid Cancer Monday & Tuesday Poster 9:00 AM RESPONSE TO DABRAFENIB AND TRAMETINIB IN A PATIENT BRAF V600E-MUTATED (BRAFM) ANAPLASTIC THYROID CANCER (ATC) M. Cabanillas, R. Dadu, S.G. Waguespack Department of Endocrine Neoplasia and HD, The University of Texas M. D. Anderson Cancer Center, Houston, TX Few options for novel therapies are available to pts (pts) with ATC. Since *25% of ATC tumors harbor a BRAF mutation and BRAF inhibitors have shown efficacy in BRAFm PTC, interest in using these drugs for ATC has emerged. Herein we describe a pt with BRAFm ATC treated with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor). An 82 y/o woman presented 9 months (mos) prior with a growing neck mass. FNA results were interpreted as medullary thyroid cancer and she was taken to surgery. Surgical pathology revealed a 9 cm ATC. No lymph nodes were resected. The pt presented to MD Anderson (MDA) 1 week later for treatment options. Upon presentation she had gross tumor in the thyroid beds but no distant metastases. Her tumor was tested for 50 genetic mutations and found to harbor a BRAFV600E mutation. She was treated on clinical trial with external beam radiation therapy (RT; 66 Gy), paclitaxel and an anti-angiogenic TKI. She had a complicated course due to poor tolerance of chemo but completed RT and returned home. The following mo she was found to have lung metastases and progression in the neck. She received more RT to the neck at home followed by pazopanib. Her neck and lung masses continued to progress, therefore she sought our opinion. We referred her to a closer site offering a dabrafenib + trametinib clinical trial, however she did not qualify due to inability

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 to swallow pills. Thus, she returned to MDA for treatment. Because her airway showed some compromise, the suspension formulation of dabrafenib and trametinib (administed by PEG tube) were obtained on an emergency IND. She started treatment and returned home. After 2 weeks of treatment she began to feel less pressure in her neck, however the following week was admitted to a local hospital with aspiration pneumonia. CT chest was obtained and showed a remarkable tumor response (fig 1). She tolerated drug well. This is the first reported case of an ATC pt responding to dabrafenib + trametinib. A clinical trial with these drugs in rare tumors, including ATC, is currently enrolling (NCT02034110). Simultaneous BRAF-MEK inhibition may be efficacious in pts with BRAFm ATC. The use of liquid formulations of kinase inhibitors are needed in ATC trials.

Poster 227 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM EPIDEMIOLOGICAL AND HISTOLOGICAL VARIABLES PREDICTING RECURRENCE IN PAPILLARY THYROID CANCER D.V. Bann1, N. Goyal1, J. Lin1, F. Camacho2, D. Goldenberg1 1 Otolaryngology - Head & Neck Surgery, Penn State College of Medicine, Hershey, PA; 2Public Health Sciences, Penn State College of Medicine, Hershey, PA Over the last 30 years the incidence of papillary thyroid cancer (PTC) has increased in the United States. PTC is associated with an excellent prognosis, however disease recurrence may result in significant morbidity. Our objective is to identify specific epidemiological and histological variables that predict thyroid cancer recurrence. Data were collected from a retrospective chart review of 209 patients with PTC treated at Pennsylvania State University Hershey Medical Center between 2001 and 2009. Odds and hazard ratios were determined for specific demographic (sex, race, age, personal or family history of cancer, history of X-ray therapy), tumor (TNM stage, multifocal disease, capsular invasion, vascular invasion), and treatment (positive margins, extent of thyroidectomy, lymph node dissection, radioactive iodine ablation) variables with respect to thyroid cancer recurrence. We identified several variables associated with increased odds of recurrence including capsular invasion (odds ration [OR] 3.38; 95% confidence interval [CI] 1.03, 11.07), vascular invasion (OR 3.53; 95% CI: 1.12, 11.19), and positive pathologic margins (OR 4.37; 95% CI: 1.76, 10.83). The absence of lymph node involvement was associated with decreased odds of recurrence (OR 0.13; 95% CI: 0.03, 0.52). Variables associated with significant hazard rations [HR] included capsular invasion (HR 7.05; 95% CI: 1.27, 39.18) and absent nodal involvement (HR 0.17; 95% CI 0.07, 0.41). Interestingly, the use of radioactive iodine ablation did not affect the risk of recurrence. While the TNM staging system can be used to accurately predict survival in thyroid cancer, TNM stage does not accurately reflect the risk of recurrence. Our data indicate that additional variables should be considered when evaluating the risk of PTC recurrence.

Poster 228 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE PREVALENCE OF INCIDENTAL PAPILLARY THYROID CANCER IN PATIENTS UNDERGOING THYROID SURGERY FOR PRESUMED BENIGN DISEASE H. Anaedo1, M. MARCHESE1, G. Kim1, L. choi1, H. Lydecker2, D. Niyazov2, K. Thomas2, T. Jennings2, V. sharma1

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Endocrinology, Albany medical center, Albany, NY; Albany medical college, Albany, NY

The clinical significance of incidental thyroid carcinoma (IPTC) in patients with Graves’ disease (GD) is uncertain. In the United States, the use of antithyroidal medications and radioiodine is the traditional therapy for GD. The prevalence of thyroid carcinoma in GD has been reported to range from 0-10%. The aim of our study was to determine the prevalence of IPTC in GD compared to toxic (TMNG) and nontoxic multinodular goiter (NTMNG) as well as Hashimoto’s thyroiditis (HT). Our secondary aim was to evaluate for risk factors that may help guide our decision for definitive management for GD without missing PTC. A single center retrospective chart review was performed. After excluding patients with known PTC by pre-operative FNA, 176 patients underwent partial or total thyroidectomy for benign thyroid disease in 2014. They were divided into 4 groups: GD (26.7%), HT (10.8%), NTMNG (47.8%) and TMNG (14.7%). Data was analyzed for the presence of PTC in each group. Clinical information including age, sex, thyroid function test (TFT), antibodies and smoking history were collected. 176 patients were included in the study, female to male ratio of 4:1 with an average age of 47 – 1. The prevalence of IPTC noted on pathology was 21.6%. [17 (65.4%) microcarcinoma, incidence 8.5%; 9 (34.6%) macrocarcinoma, incidence 5.1%] Mean size for microcarcinoma 0.42 – 0.008 cm and macrocarcinoma 2.46 – 0.39 cm. NTMNG had the highest incidence of PTC 22.6%, followed by TMNG 15.4%, GD 6.4%, HT 0%. ( p < 0.05) GD was the only group that did not present with macrocarcinoma on final pathology. GD and TMNG were found to have a lower TSH level 0.14 – 0.09 UIU/mL and 0.16 – 0.83 UIU/mL respectively compared to NTMNG 1.44 – 0.23 UIU/mL ( p < 0.05), however no correlation was found between the size of PTC and TFTS (r = 0.24, p = 0.24). Prevalence of IPTC in patients undergoing surgery for benign disease is substantial. IPTC is less prevalent in GD compared to NTMNG and TMNG irrespective of age, TFT and smoking. Although the majority of IPTC are microcarcinomas, it is still higher than the general population. Further studies should be done to determine additional risk factors that may help guide our decision on which patients need surgical intervention.

Poster 229 Thyroid Cancer Monday & Tuesday Poster Basic 9:00 AM HIGHER CYTOPLASMIC 15-LIPOXYGENASE ACTIVITY IN RECURRENT THYROID CANCERS THAN IN THYROID ADENOMAS T.T. Hakala1, J. Sand3,5, P. Kellokumpu-Lehtinen4,5, I. Kholova´2 1 Department of Surgery, Tampere University Hospital, Tampere, Finland; 2Department of Pathology, Tampere University Hospital, Tampere, Finland; 3Division of Gastroenterology, Surgery and Oncology, Tampere University Hospital, Tampere, Finland; 4 Department of Oncology, Tampere University Hospital, Tampere, Finland; 5Medical School, University of Tampere, Tampere, Finland Transformations occurring in malignant tumors include upregulation of the activity of cell signaling pathways and changes in angiogenesis and lymphangiogenesis. Increased activity of lipoxygenase in tumor cells may associate with modified signaling in EGF and MAKP pathways and upregulation of angiogenesis or lymphangiogenesis. Elevated angiogenic activity may result in higher risk of lymph node metastasis and unfavorable prognosis. Twenty-seven recurrent differentiated thyroid cancers (DTCs), 24 non-recurrent DTCs and 24 thyroid adenomas were evaluated using

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15-lipoxygenase (15-LOX) and podoplanin immunohistochemical staining. Surgeons of Tampere University Hospital operated recurrences from cervical lymph nodes or soft tissue of cervical region. The study included a total of 108 histological samples of primary tumors and metastases. Cytoplasmic activity of 15-LOX was positive in 22/27 (81%) of recurrent DTCs and in 14/22 (64%, p = 0.159) of non-recurrent DTCs and in 13/24 (54%, p = 0.036) of thyroid adenomas. Nuclear activity of 15-LOX was positive in 1/27 (4%) recurrent DTCs and in 4/22 (18%, p = 0.096) of non-recurrent DTCs and 5/24 (21%, p = 0.058) of thyroid adenomas. In operatively managed recurrent tumors, 15LOX was positive in the cytoplasm in 17/29 (59%) and in the nucleus in 3/29 (10%) of the samples. In this study, we observed the higher cytoplasmic activity of 15LOX in recurrent thyroid cancers than in thyroid adenomas. The tendency towards the lower nuclear activity of 15-LOX was observed in recurrent thyroid cancers when compared to non-recurrent thyroid cancers. The higher cytoplasmic activity of 15-LOX may associate with increased angiogenesis in recurrent thyroid cancers.

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Poster 230 Thyroid Cancer Monday & Tuesday Poster Basic 9:00 AM IN VITRO EVALUATION OF TERT PROMOTER TRANSCRIPTIONAL ACTIVITY IN THE PRESENCE OF WILD-TYPE AND MUTANT BRAF J. Vinagre1,3, A. Pestana1, M. Reis1, P. Soares1,2 1 Cancer Biology, IPATIMUP, Porto, Portugal; 2 FMUP, Porto, Portugal; 3ICBAS, Porto, Portugal TERT promoter mutations were recently reported in follicular-derived thyroid carcinomas. The fact that these mutations generate a new binding consensus for ETS/TCFs transcription factors (CCGGAA) makes BRAF an attractive candidate. It has long been demonstrated that BRAF mutation has the capacity to activate this family of transcriptions factors. Furthermore, BRAF mutation has been correlated with the presence of TERT promoter mutations in most of the series studied and we have already demonstrated that tumors that bear both mutations present a higher level of telomerase expression. It was our objective to demonstrate in vitro that BRAF could lead to increased transcription in TERT promoter mutated luciferase reporters. HEK293 cells were transfected with luciferase reporters either for TERT promoter wild-type sequences and the most frequent alteration ( - 124:G > A). Concomitantly we performed co-transfections of the luciferase reporters with wild-type BRAF and mutant BRAF V600E vectors. In vitro, the presence of the TERT promoter mutations revealed an increase by 2 fold of telomerase transcription activity. Cotransfections of the luciferase reporters with BRAF vectors lead to a diminished transcriptional activity. Previously it had been demonstrated that in vitro the TERT promoter mutations led to an increase of 2 to 4 fold of the telomerase transcription. Our results are in accordance with the previous findings. On the other hand and contrarily to what was expected, the co-transfection of BRAF, either wild type or V600E, does not lead to changes in transcriptional activity. These findings point that further studies are needed to address the role of BRAF in TERT promoter mutated thyroid carcinomas. Either, the cell line used in the in vitro co-transfection system is not proper for this type of evaluation or other factors might be necessary to modulate BRAF signaling towards activation of the mutated promoter of telomerase.

Thyroid Cancer Monday & Tuesday Poster Basic 9:00 AM A STUDY OF THE QUALITY OF SURVIVAL IN RADIOIODINE-REFRACTORY THYROID CANCER S. Hudgens1, C. Pelletier2, A. Forsythe2, M. Taylor3 1 Clinical Outcomes Solutions, Tucson, AZ; 2Eisai Inc., Woodcliff Lake, NJ; 3Oregon Health and Science University, Portland, OR Thyroid cancer is the 5th most prevalent cancer and the most common endocrine cancer worldwide with a small population of patients who develop radioiodine-refractory differentiated thyroid cancer (RRDTC). Yet, the survival benefit and the impact of treatment on quality of survival (e.g., patient reported symptoms and impacts) in this hard-to-treat, rare indication is not well understood. While there is little published information on the medium and long-term impact of this disease on quality of life, published research suggest that the humanistic burden associated with RR-DTC includes patient reported symptoms of fatigue, as well as impact on emotional, physical, cognitive, and daily functioning. The purpose of this study is to generate insight on the crosssectional and longitudinal impact of RR-DTC and associated treatment on symptom burden and psychological, functioning, and physical aspects of quality of life. Data will be presented on a sample of 120 patients in this observational study population of patients currently undergoing systemic therapy as well as patients receiving no systemic therapy. Outcomes include an online survey constructed of quality of life endpoints including the Functional Assessment of Cancer Therapy-General (FACT-G), EQ-5D-5L, Symptoms experience, Impressions of Treatment Satisfaction, and Subject Preference.

Poster 232 Thyroid Cancer Monday & Tuesday Poster Basic 9:00 AM ANALYSIS OF THYROID CANCER AT GUILLERMO ALMENARA NATIONAL HOSPITAL - LIMA (PERU) DURING 5 YEARS (2009–2013) D.L. Aranda, C.R. Verano Head and Neck Surgery, ‘‘Guillermo Almenara Irigoyen’’ National Hospital, Lima, Peru The incidence of Thyroid Cancer in Peru has been increased over the years. Actually, according to epidemiological data from the Ministry of Health, Thyroid Cancer is in the 4th place of cancers that affect the peruvian population. The aim of this study is to show the progressive incidence of Thyroid cancer at Guillermo Almenara National Hospital (Lima-Peru) during 2009 to 2013. We present a descriptive, observational and retrospective study. The population includes patients with histopathological diagnosis of thyroid cancer in different varieties and clinical stages and treated (surgery and adjuvant treatment: Iodine 131 and/or radiotherapy, chemotherapy) in the Head and Neck Surgery Department at Guillermo Almenara Irigoyen National Hospital between 1999 to 2013 were excluded patients operated for recurrent disease; and patients who have undergone surgery at another institution and reach the Service Head and Neck Surgery with recurrences, locoregional metastases and/or systemic. Processing and data analysis was performed with SPSS v19. In the period 1999 to 2013 were treated 373 patients with thyroid cancer, 316 (84,7%) women and 57 (15,3%) men. The number of patients treated each year has been increasing: 47 (12,6%) in 2009, 62 (16,6%) in 2010, 72 (19,3%) in 2011, 80 (21,4%) in 2012 and 112 (30%) in 2013. The histological subtype of thyroid cancer in order of

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 frequency found was: Papillary 321 (86,1%), Folicular 31 (8,3%), Medular 11 (2,9%), Anaplastic 6 (1,6%), Lymphome 2 (0,5%) and Insular 2 (0,5%). The surgical treatment was: Thyroidectomy total, Thyroidectomy sub-total and Hemithyroidectomy. In our hospital, thyroid cancer has shown a progressive increase in incidence during the five years evaluated in this study. Higher percentage of female patients diagnosed with thyroid cancer was found. The main histological type found was papillary cancer.

Poster 233 Thyroid Cancer Monday & Tuesday Poster 9:00 AM MUTATIONAL HETEROGENEITY OF PAPILLARY THYROID CANCER WITH UNUSUAL DISTANT METASTASES I. Dotan1, E.J. Mitmaker2, R.J. Tabah2, D. Caglar3, A.K. Murugan4, M. Xing4, J. How1 1 Division of Endocrinology and Metabolism, McGill University Health Center, Montreal, QC, Canada; 2Department of General Surgery, McGill University Health Center, Montreal, QC, Canada; 3 Department of Pathology, McGill University Health Center, Montreal, QC, Canada; 4Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, MD Papillary thyroid cancer (PTC) harboring the activating BRAF V600E mutation has been suggested to pose an increased risk of aggressiveness. The TERT promoter mutation also has been linked to an increased risk. The co-existence of these 2 mutations is associated with synergistic risk of aggressiveness and increased recurrence. A 61-year-old man was diagnosed with PTC and lymph node (l.n.) metastases (mets). He had undergone total thyroidectomy with right cervical l.n. dissection. Negative 123I whole body scan was achieved following 150mCi of 131I and 60 Gy of external beam radiation therapy. However, elevated post-therapy thyroglobulin (Tg) level persisted. A second dose of 150mCi of 131I was administered. Four years later, 18 FDG PET/CT scan (PET) uncovered a focal hypermetabolic lesion (HML) in the liver, which on biopsy proved to be metastatic PTC. Another 200mCi of 131I following rosiglitazone pre-treatment failed to decrease Tg. Radiofrequency ablation (RFA) of the liver metastasis (met) achieved complete radiologic response. Small, bilateral pulmonary nodules were then discovered, and RFA was undertaken but failed. An updated PET revealed a HML in the right kidney. The inability to exclude renal cell carcinoma lead to partial nephrectomy, but the histology confirmed metastatic PTC. The activating BRAF and the TERT promoter mutations were positive in the primary tumor and neck l.n. mets but negative in both liver and kidney mets. Additional mutational studies for RAS, PIK3CA, AKT2, MET receptor and p53 were all negative. We report a case of PTC metastatic not only to cervical l.n.s and lung but also to unusual sites, namely the liver and kidney. The distant mets were non-iodine avid and uncovered by PET, suggesting de-differentiation and loss of Na-I symporter expression. This rare case demonstrates intra-tumoral genetic heterogeneity of BRAF and TERT promoter mutations as well as clonal evolution, creating variation in the phenotype of the tumor cells, as evidenced by mutational differences between the primary tumor/neck nodal mets and the distant mets in the liver and kidney. In PTC, the primary thyroid cancer and its distant mets may show disparities in their expression of mutational alterations.

Poster 234 Thyroid Cancer Monday & Tuesday Poster 9:00 AM LIMBIC ENCEPHALITIS AS A PARANEOPLASTIC MANIFESTATION OF MEDULLARY THYROID CANCER E. Scott1, V. Tsang1,2, R. Joffe1, D. Learoyd3

A-95 Royal North Shore Hospital, Sydney, NSW, Australia; 2Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia; 3University of Sydney, Sydney, NSW, Australia

1

Limbic encephalitis is reported with small cell lung cancer, testicular germ cell tumours and other malignancies1. We present a case of metastatic medullary thyroid carcinoma presenting with limbic encephalitis. A 64 year old man presented in 2008 with short term memory loss and personality change. MRI brain showed bilateral increased signal change in the amygdala consistent with limbic encephalopathy. EEG and lumbar puncture were non-diagnostic. Anti-neuronal antibodies were negative. Neuropsychological assessment showed an amnestic profile with preservation of executive function. CT identified submandibular lymphadenopathy. Core biopsy revealed metastatic thyroid carcinoma. Total thyroidectomy with central and lateral lymph node dissection identified multi-focal medullary carcinoma arising from an area of C-cell hyperplasia. Pre and post operative calcitonin was 7696 ng/L [ < 20] and 1944 ng/L respectively. MEN2 screening showed normal calcium, PTH, urinary catecholamines, metanephrines and negative germline RET mutation analysis. Plasma calcitonin and annual CT monitoring continued until behavioural deterioration prevented follow up. CT identified small hepatic metastases in 2011. Disease progression was indolent, with moderate calcitonin progression and he was asymptomatic. Limbic encephalitis was treated with immunoglobulins, intravenous methyl prednisolone and plasmapharesis without effect. Progressive behavioural decline occurred with disinhibition and aggressive outbursts. He was admitted to a psychogeriatric facility in 2012. He was not appropriate for Tyrosine Kinase inhibitor therapy due to behavioural difficulties. He remains a challenging management problem. There are no reported cases of limbic encephalitis with medullary thyroid carcinoma2. Limbic encephalitis presents with subacute amnestic and progressive affective disorders. Although autoantibodies are described in a proportion of patients these are absent, as in our case. There is variable response of encephalitis to tumour treatment. There are reports of response to immunosuppression3, although many progress. Paraneoplastic limbic encephalitis can be associated with medullary thyroid cancer, but existing therapies may be ineffective.

Poster 235 Thyroid Cancer Monday & Tuesday Poster 9:00 AM COMPLETE BIOCHEMICAL AND STRUCTURAL RESPONSE IN A PATIENT WITH POORLY DIFFERENTIATED THYROID CANCER (PDTC) ON CABOZANTINIB (CABO) S.P. Weitzman, M. Cabanillas Endocrine Neoplasia and Hormonal Disorders, MD Anderson Cancer Center, Houston, TX PDTC is an uncommon variant with aggressiveness intermediate between well-differentiated and anaplastic thyroid cancers. Multikinase inhibitors (MKI) benefit patients (pts) with thyroid cancer but fail over time. Radiographically, there have been reports of complete response (CR) in differentiated thyroid cancer but no indication of complete biochemical response. We describe a pt with metastatic PDTC who achieved both biochemical and radiographic CR on CABO. This is a 60 y/o woman who had a total thyroidectomy 6 yrs prior for goiter. Pathology was interpreted as benign but it recurred 16 months later. Excisional biopsy and re-review of her initial pathology showed follicular thyroid cancer. She received 2 empiric doses of I-131 due to persistently elevated thyroglobulin (Tg). Within a year of her second surgery, imaging showed a neck mass and 3 new lung

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lesions. She was seen at our institution and biopsy of the neck mass revealed PDTC. Our interpretation of the original pathology was PDTC with an insular pattern. She underwent neck dissection and molecular testing of that specimen which was negative for BRAF, KRAS, NRAS, PIK3CA mutations. She received external beam radiation to the neck (50 Gy) but within months a neck mass reappeared. It was confirmed PDTC on biopsy and there was progression of the lung lesions. She received pazopanib for 6 months (discontinued due to grade 3 transaminitis) and then sorafenib for 7 months (discontinued due to progression). Next she started CABO. Tg was 6041 ng/mL prior to CABO but after 16 months of treatment, imaging (ultrasound, cross-sectional, PET, bone scan) showed complete disappearance of target and nontarget lesions with undetectable Tg (antibody negative). She has had no evidence of disease for > 1 year since CR. Molecular characterization of her tumor showed mutations in PTEN, NF1 and PKHD1L1. Here we describe a pt with PDTC who had a biochemical and radiographic CR on CABO after developing resistance to prior MKI. We believe this represents the first report of such a response in a pt with metastatic thyroid cancer. CR is rare but possible in thyroid cancer pts on MKI. Additional molecular testing is in process to provide insight into the mechanism of her response.

Poster 236 Thyroid Cancer Monday & Tuesday Poster 9:00 AM PAIN MAY REPRESENT TREATMENT RESPONSE TO TARGETED THERAPY IN PATIENTS WITH THYROID CANCER S.P. Weitzman, S.G. Waguespack, A. Ying, M.I. Hu, M. Cabanillas Endocrine Neoplasia and Hormonal Disorders, MD Anderson Cancer Center, Houston, TX In patients (pts) with thyroid cancer, skeletal or soft tissue metastases (mets) can result in pain. As a result, new or worsening pain is often thought to be due to disease progression. Here we describe 3 pts with thyroid cancer who experienced pain after initiation of targeted therapy. The first pt is a 48 y/o female with papillary thyroid cancer (BRAF V600E) with mets to the skull base, lung and neck. Following surgery, radiation and external beam radiation, she experienced progression and vemurafenib was started. Within weeks, she experienced neck tightness and pain which worsened following each dose and resolved several hours later. CT was performed and showed interval decrease in the size of the met. The second pt is a 62 y/o man with follicular thyroid cancer (ARID1A mutated) with mets to the humerus, chest, lung, and right acetabulum. After multiple surgeries, external beam radiation, and cyroablation of the tumor in his humerus, he continued to experience progressive disease. As a result, lenvatinib was started. Within one week, he experienced worsening pain in his humerus radiating down his arm. He was treated symptomatically

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with good results. The pain resolved within one week and later imaging showed radiographic improvement. The third pt is a 78 y/o female with stage IVA anaplastic thyroid cancer. She had a R0 resection followed by chemoradiation but had a recurrence in the neck 1 month later. Since she did not tolerate cytotoxic chemotherapy well, she was started on lenvatinib. Within days, she noted a mild pain in the neck which progressed to become severe with radiation to the shoulder. She presented to the emergency center where CT showed a reduction in tumor size as well as intratumoral necrosis. These 3 pts with thyroid cancer developed new or worsening pain shortly after starting targeted therapy. The mechanism of pain is not clear but imaging and laboratory data indicate a response to therapy rather than progression causing pain. To our knowledge, pain representing response to targeted therapy in pts with thyroid cancer has not been described. Although the pain is likely related to cell death and inflammation, further study is needed to define the mechanism of pain in these circumstances.

Poster 237 Thyroid Cancer Monday & Tuesday Poster 9:00 AM AN UNSUSPECTED BREAST NEUROENDOCRINE TUMOR WITH THYROID METASTASIS J. Lavigne1, M. Massicotte1, R. Temmar2, N. van Rossum1 1 Endocrinology, CIUSS-CHUS, Sherbrooke, QC, Canada; 2 Pathology, CIUSS-CHUS, Sherbrooke, QC, Canada Thyroid neuroendocrine tumors (NETs) are rare lesions originating from C cells (medullary carcinoma). More rarely, NETs arising from other sites, like the lungs, can spread to the thyroid. We hereby describe a case of breast NET that metastasized inside a follicular adenoma of the thyroid. A 65 yo woman was evaluated for a 35 mm FDG-PET positive thyroid nodule. In 1983, she was diagnosed with breast cancer, an infiltrative ductal carcinoma, initially treated with partial mastectomy and external beam radiotherapy. She had local recurrence in 2001, treated by surgery and radiotherapy, followed by tamoxifen. In 2012, 6 years after having stopped the tamoxifen, multiple bone metastases were found. All the lesions were FDG-PET scan positive. No other hypermetabolic lesion was found, except for a mildly active (SUV 2,2) right 20-mm thyroid nodule. She was first put on letrozole and monthly pamidronate, then switched to tamoxifen and denosumab because of progression. In 2014, a FDG-PET showed an increase in the activity and size of the thyroid nodule. She was asymptomatic. The FNA revealed a follicular neoplasm and a hemithyroidectomy was performed. The final pathology showed a follicular adenoma with many areas of neuroendocrine cell proliferation. Immunohistochemistry was negative for thyroglobulin and calcitonin, but positive for synaptophysine, keratin-19, E-Cadherine, estrogen and progesterone receptor. On follow-up, FDG-PET

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positive right hilar lesions apppeared as well as new bone metastases. Hilar lesions were benign. A bone biopsy showed a NET, with the same immunohistochemical pattern than the thyroid lesion. After reviewing the initial pathological material of the breast cancer with new immunohistochemical studies, it was concluded that it was an infiltrative ductal carcinoma with extensive neuroendocrine differentiation, with bone and thyroid metastases. Hormonal therapy was stopped. She was treated with exemestane and then switched to fulvestrant because of progression. She refused everolimus because of side effect profile. This is a rare case of infiltrative ductal breast carcinoma with extensive neuroendocrine differentiation that metastasized to bones and thyroid after almost 30 years.

carcinoma. She was discharged 30 days after surgery, with calcium carbonate 2g/day, vitamin D 1200UI/day and levothyroxine 150 mcg/day. The parathyroid carcinoma prognosis is quite variable and depends primarily on two factors: early diagnosis and success of the initial surgical procedure. While the thyroid depends on age at diagnosis and metastasis. The recurrence is 30 to 65% 6 months to 3 years after surgery. The 5-year survival is approximately 49%. Mortality is about 29% and, in general, due to the dramatic effects of severe and uncontrolled hypercalcemia.

Poster 238 Thyroid Cancer Monday & Tuesday Poster 9:00 AM THE ASSOCIATION OF THYROID AND PARATHYROID CANCER CASE REPORT G.R. Silva1, D.R. Rocha1, M.B. Correa2, C.P. Rangel1, T.D. Hana1, B. Vanzillotta1, J. Valverde1, K. Silva1, A.K. ARBEX1 1 Ipemed, Rio de Janeiro, Brazil; 2Hospital Tijutrauma, Rio de Janeiro, Brazil Thyroid cancers are about 1% of malignancies and approximately 10% of these are follicular type. The peak incidence of this kind of cancer is in the fifth decade. Parathyroid cancer is rare and affects less than 1% of cases of primary hyperparathyroidism (PHP) and 0.005% of all malignancies. About 3% of patients operated by PHP feature thyroid cancer. MCRS, female, 82, a native of Rio de Janeiro, with a history of total thyroidectomy due to follicular carcinoma without thyroid hormone replacement. Ten days after thyroidectomy presented confusion, disorientation and decreased strength in UL. On examination, she was disoriented in time and space, interactive, cooperative and eupneic, with difficulty understanding verbal commands. Change in motor coordination and trembling in the extremities. LL:bilateral edema perimalleolar without signs of DVT. Blood pressure:168 · 115 mmHg, Heart rate: 82 bpm, Respiratory rate: 19 irpm, Saturation: 96%. Twelve hours after admission, the patient evolved with atrial fibrillation with high response and after a week with relegation level of consciousness of and hemodynamic instability, requiring tracheal intubation. After two days of hospitalization was initiated levothyroxine 50mcg/day. The treatment to surgery was hydration with saline, Alendronate 70mg/week, Pamidronate Sodium (once) and Cinacalcet 60mg/day. TC neck: subcutaneous organized collection capturing peripherally the intravenous contrast, in line media the distal third of the neck measuring 3.0 · 2.5 · 0.7cm (LXPXAP). After 40 days of hospitalization, she underwent exploratory neck surgery, and a tumor of parathyroid was removed. A pathological examination revealed

Poster 239 Thyroid Cancer Monday & Tuesday Poster 9:00 AM TUMOR-TO-TUMOR METASTASIS: RENAL CELL CARCINOMA METASTASIS TO FOLLICULAR CARCINOMA OF THE THYROID D. Krcelic1, J.T. Collins2 1 General Surgery, Western Michigan University, Kalamazoo, MI; 2 Borgess Medical Center, Kalamazoo, MI Metastasis to thyroid gland are rare with incidence at time of surgery approximately 0.5% with incidence as high as 24% in post autopsy studies in those with diffuse metastasis. Tumor to Tumor Metastasis to the thyroid are even rarer with less than 30 known cases reported in review of English Literature. The most common occurrence, with nine known cases, is Renal Cell Carcinoma Metastasis. 69-year-old Female presented with symptoms of choking and difficulty swallowing with palpable mass. Patient underwent ultrasound of the neck and found to have a right 3.8 cm left nodule and 2.8 cm module in the isthmus. Given her symptoms patient elected to undergo elective subtotal thyroidectomy. Prior to surgery patient was started on 0.88 mgm of Synthroid daily. Patient underwent uneventful subtotal thyroidectomy. Pathology revealed Follicular Neoplasm with Hurthle Cell features with an adjacent multi-nodular goiter. Further review of pathology demonstrated a Renal Cell Metastasis contained within the Follicular Neoplasm. Patient had a CT of the abdomen and found to have a left renal mass extending into the left adrenal gland consistent with neoplasm. Patient underwent radical nephrectomy and pathology revealed renal cell carcinoma. Tumor-to-Tumor Thyroid Metastasis are exceedingly rare. With less than 30 known cases in review of English Literature. More commonly is primary metastasis to normal thyroid gland with metastasis making up 0.5%-24% of thyroid neoplasms. Malignant melanoma and carcinomas of lung, breast, kidney, gastrointestinal tract, and head and neck are the most common to metastasize to the thyroid. In the review of the literature in tumor-to-tumor metastasis the most common receiving thyroid mass was follicular adenoma in approximately 60% of cases. Papillary Carcinoma was the most common malignant recipient of metastasis. In our case findings of

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clear cells consistent with Renal Cell Carcinoma led to discovery of primary lesion in an asymptomatic patient allowing for margin negative resection of primary tumor. We present a rare case tumor-to-tumor metastasis: Renal Cell Carcinoma to Follicular Thyroid Neoplasm.

Differentiated follicular thyroid carcinoma (DFTC) usually has a slow progression. Sorafenib, a selective tyrosine kinase inhibitor (TKI), has been recently approved for the treatment of advanced DTC. A 65-year-old man underwent in February 2005 to total thyroidectomy for a DFTC. The patient was treated with four courses of high-dose (150–200 mCi) 131-I for increased serum thyroglobulin (Tg) (10–40 ng/dl) and suspicious iodine uptake areas in the mediastinum. In 2010, bone scintigraphy identified a metastatic lesion (ML) in left humerus which was treated by partial resection. Histological exam confirmed a ML from DFTC (Tg + + ). After 9 months a new osteolytic lesion was documented, surgically removed and histologically confirmed. One year later total body computed tomography (TBCT) revealed synchronous left adrenal mass and an osteolytic cranial lesion, which were again surgically removed: histology confirmed in both cases metastases from DFTC with positive immunohistochemistry for thyroid transcription factor-1 (TTF1) and Tg. From 2010 to the end of 2013 serum Tg values ranged between 10–144 ng/ml up to 400 ng/ml. Subsequently, TBCT documented the progression of bone metastases and the new appearance of lung metastases (LMs). Sorafenib was therefore began in March 2014 and stopped in January 2015 for prostate surgery, while the disease was stable by RECIST criteria (serum Tg increased up to 800 ng/ml) and the patient was asymptomatic and in general good conditions. Two weeks later the patient reported intense pain in the sacral region and a TBCT identified an enormous right gluteus muscle lesion (RGML) and additional LMs. A biopsy of RGML revealed an undifferentiated neoplasia with positive for TTF1, cytokeratine (CK) 7, vimentin, pancytokeratin but negative for Tg. The patient died two weeks later for progression of metastatic disease. This case reports a sudden acceleration of progression of a metastatic DFTC. The biggest of the newly developed MLs lost the thyroid differentiation marker Tg, although high serum Tg levels were indicative of persisting differentiated metastases. It may be speculated that the final progression was due to the emersion of sorafenib-resistant undifferentiated tumor cell clones.

Poster 240 Thyroid Cancer Monday & Tuesday Poster 9:00 AM THE DANGER OF ANCHORING BIAS: CERVICAL LYMPHADENOPATHY PRESUMED TO BE FROM ORAL CANCER IS ACTUALLY METASTATIC PAPILLARY MICROCARCINOMA A. Paulus, I. Folaron Endocrinology, San Antonio Military Medical Center, Live Oak, TX Thyroid nodules are commonly found incidentally on imaging for other indications. Fluoro-d-glucose (FDG) positive nodules have been found to carry a higher risk of malignancy and warrant careful consideration. A 40 year old male with no prior medical problems initially presented to his primary physician with a three month history of a nonhealing lesion on his left buccal mucosa. The patient underwent a biopsy and imaging. He was diagnosed with Stage IVb Squamous Cell Carcinoma (SCC) of the oral cavity. Positron emission tomography (PET) scan revealed extensive local spread, bilateral cervical lymphadenopathy and a 6 mm right thyroid nodule with FDG avidity. The lymphadenopathy was attributed to his oral SCC and no further evaluation of the thyroid nodule was pursued. Due to extensive local spread, surgical resection was not possible and the patient was definitively treated with cisplatin and radiation therapy. However, he continued to have persistent lymphadenopathy eight weeks after completion of his treatment. A fine needle aspiration (FNA) biopsy of a cervical lymph node revealed papillary thyroid cancer (PTC). A total thyroidectomy with bilateral neck dissection was performed and final pathology showed a 0.8 cm PTC on the R and 0.1 cm PTC on the left with 12/40 lymph nodes positive for PTC metastasis. After surgery, the patient was treated with radioactive iodine and thyroid stimulating hormone (TSH) suppression. Current American Thyroid Association guidelines do not recommend FNA of thyroid nodules less than 1 cm unless the patient has a high risk history which includes FDG avidity on PET scan. FDGpositive nodules carry a 33% chance of malignancy and can be more aggressive. The patient’s cervical lymphadenopathy was attributed to his oral SCC, but papillary thyroid cancer involves lymph node metastases in 20-50% of patients. This misassumption prevented further evaluation of his thyroid nodule and led to a delay in treatment of his thyroid cancer. Patients with FDG positive thyroid nodules and cervical lymphadenopathy should be evaluated with an FNA regardless of another malignancy which could account for lymph node metastasis.

Poster 241 Thyroid Cancer Monday & Tuesday Poster 9:00 AM ACCELERATED DISEASE PROGRESSION AFTER DISCONTINUATION OF SORAFENIB IN A PATIENT WITH METASTATIC FOLLICULAR THYROID CARCINOMA F. Pani1, A. Maccioni2, F. Atzori1, S. Marini3, G. Bianchi4, A. Delisa5, S. Mariotti1 1 Policlinico Universitario Monserrato, Decimoputzu (Ca), Italy; 2 Hospital SS.Trinita`, Cagliari, Italy; 3Hospital SS.Trinita`, Cagliari, Italy; 4Hospital Rizzoli, Bologna, Italy; 5Hospital SS.Trinita`, Cagliari, Italy

Poster 242 Thyroid Cancer Monday & Tuesday Poster 9:00 AM DEDIFFERENTIATION OF RECURRENT DIFFERENTIATED THYROID CANCER - POSSIBLE AND DANGEROUS D. Henderson1, P. Dickson2, A. Gosmanov1 1 Endocrinology, University of Tennessee Health Science Center, Memphis, TN; 2Surgical Oncology, University of Tennessee Health Science Center, Memphis, TN Studies have shown that a small subset of previously treated well differentiated thyroid cancers may recur in the form of poorly differentiated non-iodine avid, non-thyroglobulin (Tg) producing tumors. A 54-year-old white female with a history of Hodgkin’s lymphoma treated with cobalt radiation as a teen and resected stage IA melanoma presented for a second opinion regarding thyroid cancer management. She underwent subtotal thyroidectomy in 2005 for benign multinodular goiter. In 2012, follow up neck ultrasound (US) revealed two thyroid nodules and a suspicious 1.6 · 0.8 · 0.7 cm subcutaneous nodule in the right neck. FNA of both thyroid and subcutaneous nodules was positive for papillary thyroid cancer (PTC). Completion thyroidectomy with limited right neck dissection revealed TTF-1 positive PTC in the subcutaneous nodule. Following withdrawal of levothyroxine, she was treated with 160mCi of 131I, and a post-ablative scan showed uptake only in the thyroid bed.

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During post-operative follow-up, a new mass in the lower right neck was identified; however, nonstimulated and stimulated Tg levels were below 1 ng/mL and routine observation and levothyroxine therapy were continued. In 2014, she felt a subcutaneous nodule in the right neck and sought a second opinion. In our clinic, Tg was 0.28ng/mL and post Thyrogen administration increased to 0.83ng/ mL. 123I whole body scan showed no abnormalities. FNA of the subcutaneous nodule showed poorly differentiated carcinoma negative for BRAF, Tg, and TTF-1. US of the neck demonstrated multiple pathologic appearing nodes in the right lateral neck. Subsequent, non-stimulated PET/CT also revealed disease confined to the right lateral neck. Pathology from the right modified lateral neck dissection exhibited multiple level II-V lymph nodes with poorly differentiated carcinoma positive for pankeratin, CK-7, and CK-8/18 and negative for Tg, TTF-1, Melan-A, S-100, SOX-10. As proven in our case, clinicians should have a low threshold for biopsy of new neck lesions even in the presence of non-elevated Tg levels during the long-term follow up of PTC. In addition to cervical US, PET/CT may be useful in clinical staging and surveillance for these patients.

Differentiating these histologically grey zone lesions can be difficult and even experts will disagree with each other. The essence is to manage the patient according to the overall clinical picture.

Poster 243 Thyroid Cancer Monday & Tuesday Poster 9:00 AM NECK LYMPH NODE METASTASIS AFTER COMPLETE THYROIDECTOMY WITH BENIGN HISTOLOGY A CASE REPORT AND LITERATURE REVIEW X. Lo1, T. Tam1, H. Leong1, C. Poon2 1 Department of Surgery, North District Hospital, Hong Kong, Hong Kong; 2Department of Pathology, North District Hospital, Hong Kong, Hong Kong Endocrine pathologies are known to have dissociation between histology and clinical behaviour in terms of malignancy. We present a case with such a diagnostic problem. Ms W is a 29 year old lady with history of complete thyroidectomy 1 year ago. Pathology was multinodular goitre and an incidental clinically benign lymph node found intraoperatively at the left paratracheal space was labelled ectopic thyroid tissue. She presented to our surgical unit with a left side level 3 neck mass. Ultrasonography showed multiple nodules at left thyroid bed and lateral compartment up to 4cm in size. FNA and core biopsy of these showed benign hyperplastic nodule. Though clinically it raised the suspicion of malignancy, histology review of the previous and current biopsy specimens by local pathology expert, still believed strongly these showed a benign process. At the same time patient was pregnant while the nodules were still increasing in size and thyroglobulin (TG) rapidly rising. Patient finally agreed to central compartment with level II-V functional neck dissection despite risks and uncertain pathology in her second trimester. Specimen still showed a histologically benign lesion, compatible with hyperplastic nodules. Case history and slides were then further reviewed by experts with divided opinion : Final diagnosis issued was a well differentiated follicular carcinoma. Patient then had thyroxine suppression for the rest of her pregnancy and her radioactive ablation session after childbirth. I131 scan showed bone metastasis which was controlled after 2 more sessions radioactive iodine. She is now 5 years after her second operation and unstimulated TG was 2.0 and a proud mother with a healthy child. Pathological differentials including macrofollicular variant of papillary thyroid carcinoma, well differentiated tumor of unknown malignant potential and parasitic thyroid nodules each have some similarities with this case. Presence of distant metastasis proved this was indeed a case of malignancy.

Poster 244 Thyroid Cancer Monday & Tuesday Poster 9:00 AM PRIMARY FOLLICULAR THYROID LYMPHOMA: A 16-YEAR FOLLOW-UP V. Sivabalasundaram, C. Kelly Endocrinology & Metabolism, University of Toronto, Toronto, ON, Canada Primary thyroid lymphoma is rare, comprising only 1-5% of thyroid neoplasms, and 1-3% of malignant lymphomas. Diagnosis and initial treatment of thyroid lymphoma usually involves external beam radiation therapy (EBRT). Recurrence of lymphoma is often extrathyroidal and can be quite removed from the initial diagnosis. Ms. X presented with an enlarging neck mass 16 years ago. A multinodular gotire with a right dominant nodule measuring 3.7 · 2.3 · 1.5 cm was found on ultrasound. Cytology showed small mature lymphocytes & a hemi-thyroidectomy was performed. The pathology revealed a low-grade B-cell follicular lymphoma on the background of Hashimoto’s thyroiditis. She underwent EBRT for local control of Stage 1A disease. Within 1 year recurrence was detected in her left thyroid lobe requiring a completion thyroidectomy. Repeat CT scans found new mesenteric lymphadenopathy consistent with Stage 4 disease. She remained disease-free in her thyroid bed and systemically well over the next 8 years. Soon after, multiple abdominal and retroperitoneal masses were detected, with the largest measuring 18 · 8 · 8cm. Biopsies of two masses were positive for grade 1 follicular lymphoma. When she developed obstructive nephropathy from retroperitoneal lymphadenoapthy, she was treated with six cycles of bendamustine and rituximab. She had significant reduction in her lymphadenopathy and is now tolerating rituximab maintenance therapy well at the age of 70 years. Primary thyroid lymphoma is predominantly of B-cell origin; 70% of cases are diffuse large B-cell lymphoma (DLBCL), and 6–27% are marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) which are associated with Hashimoto’s thyroiditis. Follicular lymphomas are less common. The choice of treatment depends on the stage of disease and histologic subtype. Aggressive DLBCL subtypes are treated with combination chemotherapy (CHOP) and rituximab, with potential EBRT. MALT & follicular lymphomas are initially treated with EBRT alone. Advanced stages are treated with rituximab which is tolerated well by older patients due to reduced toxicity. This case provides a valuable insight over a sixteen-year followup period of primary B-cell follicular thyroid lymphoma.

Poster 245 Thyroid Cancer Monday & Tuesday Poster 9:00 AM OSTEOSARCOMA IN THE THYROID H.K. Akturk1, R.C. Smallridge1, J. Casler3, S. Attia2, J.P. Lagmay4 1 Endocrinology, Mayo Clinic, Jacksonville, FL; 2Hematology & Oncology, Mayo Clinic, Jacksonville, FL; 3Otolaryngology, Mayo Clinic, Jacksonville, FL; 4Hematology & Oncology, University of Florida, Gainesville, FL Metastases to the thyroid are reported in autopsy series of cancer patients who died with wide spread metastases. The most common sites are kidney, lung, breast, esophagus and uterus. We report a case of osteosarcoma recurrence in the thyroid after 4 years of disease free survival without other metastases.

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A 32 year old female noticed a painless left neck mass about 4 weeks ago. The mass was palpable at exam and not mobile. She had no history of radiation exposure or family history of thyroid cancer. She denied any history of thyroid function problems. She denied swallowing or breathing problems. Her thyroid function tests were normal. CT of the neck showed a 6 · 3.4 · 4.4 cm calcified left thyroid lobe mass. PET CT showed increased uptake in the left thyroid gland. She had a history of high grade osteosarcoma with areas of leimyosarcoma of tibia which is treated with right above knee amputation and chemotherapy 4 years ago. She has routinely followed oncology clinic without any recurrence or metastases. Last visit was 6 months ago. She had a left thyroid lobectomy. Pathology revealed metastatic osteosarcoma in a 6.5 cm mass. The mass showed apparent bony tissue. The neoplastic cells were positive for p53, vimentin, and smooth muscle actin. They are negative for S-100, TTF-1 and CD34. Six months later PET CT showed a new lung nodule with concern for metastasis. She was also recently diagnosed with squamous cell carcinoma in situ of cervix at routine gynecologic exam and was waiting for surgery. Sarcomas are derived from mesenchymal cells like bone, fat, and muscle. Sarcomas of thyroid both primary and metastatic are rare. Immunohistochemistry is important to establish a diagnosis. Osteosarcomas express vimentin; leimyosarcomas express vimentin, desmin and smooth muscle actin. The treatment is surgical excision of the lesion with or without lymph node dissection. Chemo or radiotherapy is also considered in selected cases of local recurrence or concomitant metastases. Metastasis of osteosarcoma to the thyroid gland is a rare entity. It is important to keep intrathyroidal metastases in the differential diagnosis when evaluating a thyroid nodule, particularly in patients with a previous history of malignancy.

multiple comorbidities including stroke that delayed follow up. The patient had right thyroidectomy last year and pathology showed a well-differentiated 3.2 · 2.8 · 2.2 cm follicular carcinoma with capsular and extracapsular vascular invasion. The tumor capsule was widely invasive, and there was extensive lymphovascular invasion with more than 4 vessels involved. There was no extrathyroidal extension or perineural invasion and no lymph nodes were reported. Her mother also had thyroid cancer. On physical exam, right thyroid bed has a non-mobile mass. Thyroid US showed highly vascular 6.2 · 1 · 1.3 cm soft tissue mass at the level of the right mid internal jugular vein, consistent with non-occlusive tumor thrombus. PET CT revealed asymmetric mild hypermetabolic activity (SUV max 3.4) within the right internal jugular vein. She had right neck exploration with removal of the right internal jugular vein and tumor. Pathology showed metastatic follicular thyroid carcinoma. Thyroglobulin tumor marker was 589 ng/ml prior to surgery and 3.9 ng/ml 2 weeks after surgery with TSH of 0.2 mIu/L. Thrombosis of the internal jugular vein (IJV) is a generally associated with central venous catheterization, neck surgery, trauma, coagulation disorders, or head and neck tumors. It is rare that IJV thrombosis results from direct thyroid tumor invasion. Follicular and Hurthle cell carcinomas are the most common pathological types of thyroid carcinomas that invade the great cervical veins. Invasion of the internal jugular or great cervical veins by thyroid cancer is rare and usually indicates the aggressive nature of the disease. Radical resection of the involved venous segment is recommended.

Poster 246 Thyroid Cancer Monday & Tuesday Poster 9:00 AM METASTATIC THYROID CANCER THROMBUS OF INTERNAL JUGULAR VEIN H.K. Akturk1, R.C. Smallridge1, J. Casler2 1 Endocrinology, Mayo Clinic, Jacksonville, FL; 2 Otolaryngology, Mayo Clinic, Jacksonville, FL Internal jugular vein invasion is a rare complication of thyroid cancers. We report a case of internal jugular vein tumor thrombosis with metastatic follicular thyroid carcinoma. A 69 year old female presented with enlargement of a known neck mass. She had left thyroid lobectomy over 20 years ago for benign reasons. She noticed a right thyroid mass 9 years ago. She had

Poster 247 Thyroid Cancer Monday & Tuesday Poster 9:00 AM AN ENLARGED THYROID GLAND FULL OF SURPRISES A.J. Manzano1, A.A. Andrade1, T. Mesko2, M. Schwartz2 1 The Thyroid, Parathyroid and Pituitary Center for Miami, Miami Beach, FL; 2Oncology, Mount Sinai Medical Center, Miami Beach, FL Primary thyroid lymphoma is a very uncommon type of thyroid malignancy, representing less than 5% of all thyroid cancers. The initial presentation can mimic other primary thyroid disorders. Men are less commonly affected compared to women. We present a case of marginal zone lymphoma of the thyroid. 74 years old Hispanic male who initially presented with sudden increase size and painful thyroid gland. Initial labs showed an ESR 33 mm/h, TSH 1.04 mIU/L and T4 6.7 mcg/dl. History of DM2, Recent MI and HTN. Thyroid ultrasound showed enlarged, inhomogeneous thyroid architecture with two areas of calcification.

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015

CT scan neck with contrast showing enlarged thyroid gland encasing the larynx and trachea (arrow).

Initial diagnosis was sub acute thyroiditis managed with oral steroids, with plans for futuere FNA. 3 weeks later, he returns with improvement of swelling and pain over thyroid gland. Follow up ultrasound showed same pattern but smaller thyroid parenchyma, ESR 2 mm/h. One month later, he present with worsening breathing, enlarged, hard thyroid gland. CT scan of neck/chest showed ‘‘markedly enlarged thyroid encasing the larynx and trachea narrowing oropharyngeal airway’’. He was referred for evaluation for total thyroidectomy. Procedure was held as patient had a recent cardiac event and was label as ‘‘high risk’’ for surgey. Core biopsy of the thyroid was done and pathology revealed ‘‘B cell lymphoma, favor marginal zone lymphoma/MALT’’. Immunohistochemical stains showed ‘‘diffuse CD20 B cell + CD79a and CD43, negative CD5, CD10 abd CD3. Ki-67: + 40%’’. Patient was kept in the hospital as he had vocal cord paralysis and possible airway compromise. Decision was to start chemotherapy to prevent tracheotomy or intubation. Based on borderline LV function, Rituxan and Bendamustine were selected. Dramatic improvement in goiter size and airway obstructions 48 hrs after chemotherapy. Follow up PET SCAN showed ‘‘ Diffuse heterogeneous uptake over the thyroid with focal hypermetabolic activity over right upper pole SUV MAX 4.4’’. He recently finished 2 cycles of Rituxan/Bendamustine with clinical improvement. Although infrequent, primary lymphoma of the thyroid needs to be consider in the differential diagnosis of new onset large goiters. Our case shows an uncommon behavior for the less aggressive subtype of thyroid lymphoma.

Poster 248 Thyroid Cancer Monday & Tuesday Poster 9:00 AM PAPILLARY CARCINOMA IN THE THYROGLOSSAL DUCT CYST (TGC) WITH PRIMARY FOLLICULAR CARCINOMA IN A THYROID GLAND D. Save, J. Bressler Internal Medicine, John H Stroger Jr Hospital of Cook County, Chicago, IL Malignant transformation is a very rare(less than 1%) complication of TGC. We report a case of synchronous occurrence of papillary carcinomas in the TGC and Follicular carcinoma thyroid gland.

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Enlarged Thyroglossal Cyst in our patient.

48 year old African-American female with no significant medical history presented with a neck swelling present since birth, but growing rapidly for the past 6–7 months. Physical examination was pertinent for midline, cystic, tense, mobile, illuminant neck swelling of 6 · 5 centimeter (cm), moving with swallowing and protrusion of tongue. Laboratory findings were unremarkable including normal thyroid function tests. Chest radiograph revealed a rightward deviated trachea. Thyroid Ultrasound demonstrated a 6.0 · 4.4 · 5.4 cm complex cystic mass above isthmus with internal vascularity, microcalcifications, and a 5.4 · 3.3 · 4.3 cm hyper-echoic nodule within the lower pole of the left lobe with internal vascularity but no calcification. A Computed tomographic (CT) scan of the neck revealed a large irregular enhancing solid cystic mass, likely TGC, and a large solid mass in the left lobe of thyroid gland. Fine Needle Aspiration cytology (FNAC) of the cystic neck mass was non diagnostic. Patient underwent Sistrunk Surgery & total thyroidectomy. Pathology was positive for papillary carcinoma arising in a TGC with no vascular invasion and margins free of carcinoma. Biopsy of the thyroid mass showed a follicular thyroid carcinoma variant with focal Hurthle cell differentiation. Papillary Carcinoma is the most common type (80%) of TGC malignancy usually presenting as an asymptomatic mass but rarely as a rapidly enlarging mass causing dysphagia, voice change and draining cutaneous sinus. TGC carcinoma can be a primary malignancy or secondary to metastasis from primary thyroid gland carcinoma. Our case represents the primary TGC carcinoma for the following reasons: 1. Lack of lymph node involvement. 2. Absence of any patent tract from thyroid to TGC. 3. Fibrous encapsulated cyst on gross appearance. 4. Pathologically different malignancy in a thyroid gland with no local lymph node spread. Coexistance of pathologically two distinct malignancies in the same gland makes our case an interesting and rare clinical vignette.

Poster 249 Thyroid Cancer Monday & Tuesday Poster 9:00 AM CAVERNOUS SINUS METASTASIS FROM CRIBRIFORM PAPILLARY THYROID CARCINOMA A. Lowenstein1, A. Reyes1, L. Fernando1, A. Colobraro1, M. Monteros Alvi2, A. De los Rios2, V. Concilio1, A. Rogozinski1 1 Hospital JM Ramos Mejia, Buenos Aires, Argentina; 2 Hospital Dr A. On˜ativia, Salta, Argentina

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Distant metastases from papillary thyroid carcinoma (PC) is rare and usually occur synchronously. There are few reports of cavernous sinus (CS) metastasis. The cribriform variant from PC may be sporadic or associated to familial colonic polyposis. We present a clinical case, with a history of differentiated thyroid carcinoma (DTC), and a methacronous metastasis to cavernous sinus. A 61 year old male, who lives in an endemic area (Salta), complains of headache and bilateral ptosis. Four years before (2008), he had had a history of thyroidectomy and left lateral cervical dissection. Histology: Left lobe: 2 cm PC cribriform variant with extrathyroid invasion. Right lobe: 5 cm follicular thyroid carcinoma 2/ 4 nodes metastasis tall cell PC. Ablation: 150 mci 131I. WBS neck positive. E IVa (AJCC 7th ed). Two years later (2010) with THW:TSH 41 uUI/ml, Tg < 1 ng/ml, TgAb 1756 UI/ml, US negative WBS negative After one year without control (2011), he attends with neurological compromise. He is sent to our center for diagnosis and treatment. MNR : solid mass, on right selar and paraselar topography 24x26x17 mm, it englobes intracavernous carotid artery. Neck US negative. Under LT4 treatment: TSH 0,02 uUI/ml Tg 9,3 ng/ml Tg Ab 1473 UI/ml, PRL 13 ng/ml, cortisol 23 ug /dl, LH 5,6 mUI/ml FSH 7,3 mUI/ ml To 1,1 ng/ml, IGF1 158ng/ml. Colonoscopy could not be performed. Transnasal endoscopic biopsy: Cribriform PC metastasis. FDG-PET : cervical recurrence, lymph nodes, lung and brain secondarism. Hipermetabolic focus on CS. The patient was hospitalized and treated with recombinant human TSH (rhTSH Thyrogen) followed by 300 mCi 131I. WBS-131I uptake on skull base, thyroid bed and upper mediastinum. The dose was well tolerated without adverse effects. The patient died 2 years after radioactive iodine therapy. a) We report an unusual site of distant metastasis in cavernous sinus, in a patient with concurrent follicular thyroid carcinoma and cribriform, tall cell variants from PC. b) Radioactive iodine dose after rhTSH was administrated, without complications. c) FDG-PET was positive and had had an unexpected 131I uptake in CS. d) The patient would have been a good candidate for tyrosine kinase inhibitor therapy.

drawal, and basal and stimulated Tg. Scan were always negative. Tg were 0.6-1.8 lg/L on L-T4, but elevated (12 to 46) after T4 withdrawal. From 1998 until 2001 she had yearly ultrasounds which initially detected a lymph node with a cystic image of 2 · 1 · 1 cm attached to the left carotid artery which did not change in the following years. Basal Tg was always above 1.2 lg/ L, while the stimulated one remained at 8-18. In 2001 we treated her with 200 mCi of 131I, even if whole-body and PET scan were negative before and after treatment. Further follow up until 2015 has shown a progressive decrease of the lymph node which disappeared in 2011. Basal Tg fell to < 0.1-0.3 lg/L and the Thyrogen stimulated one to 4.3-5 (2014). She is now on 0.1 mg of L-T4. Previous studies showed that small ( < 1 cm) nodule could be followed by ultrasound without need of diagnostic or therapeutic intervention. Our case show that even larger nodes may be followed for many years before treatment and that response to treatment may be very slow. This case shows persistence of the disease by a lymph node metastasis which has evolved of a period of 30 years responding to the last treatment with 131I but not completing disappearing as shown by stimulated Tg.

Poster 250 Thyroid Cancer Monday & Tuesday Poster 9:00 AM A 30-YEAR RESIDUAL DISEASE OF AN AGGRESSIVE METASTATIC PAPILLARY THYROID CANCER D. Bellabarba Endocrine Division, FMSS & CHUS, Sherbrooke, QC, Canada In thyroid cancer patients after treatment there may be a persistent/ recurrent small volume disease, as detected by ultrasound or thyroglobulin (Tg). In such cases there are data suggesting that surgical approach may not provide better results than cautious observation with intervention when there is evidence of disease progression. We present a case in which evidence of persistent disease appeared 1 years after treatment with a lymph node metastasis and has persisted for 30 years. A 26 year-old female patient had in 1985 a biopsy of a large lymphadenopathy detected in the right side of the neck. The pathology showed a metastasis of a thyroid papillary carcinoma. She underwent a radical thyroidectomy with removal of more than 30 lymph nodes. Pathology confirmed the diagnosis in the gland and in most of the lymph nodes. 1 month later she received 100 mCi of 131 I and was put on L-T4 0.15 mg/day. From 1986 to 1997 she was followed yearly with whole-body scan after thyroxine with-

Poster 251 Thyroid Cancer Monday & Tuesday Poster 9:00 AM PAPILLARY THYROID CARCINOMA WHICH WAS MISDIAGNOSED AS A BENIGN AFTER ASSESSMENT USING BOTH FINE NEEDLE ASPIRATION AND CORE NEEDLE BIOPSY: A CASE REPORT J. Kim1, J. Choi1,2 1 Surgery, Jeju National University Hospital, Jeju-si, Korea (the Republic of); 2Jeju national university, School of Medicine, Jeju-si, Korea (the Republic of) Ultrasound-guided find needle aspiration (FNA) with cytological evaluation is considered as a gold standard for differential diagnosis of thyroid nodules, and has been reported to have diagnostic sensitivity of 80–98% and specificity of 70%-92%. Core needle biopsy (CNB) for thyroid nodule has been proposed as an additional diagnostic tool to compensate the limitations of inconclusive cytological diagnosis such as non-diagnostic and/or indeterminate results and allowed a higher diagnostic accuracy than FNA, although this was still in debate. Here we describe a case in which 24-year-old woman found out bilateral thyroid nodules from screening. Ultrasound finding presented two suspicious malignant nodules; one was in right lobe of thyroid and measured 0.6*0.6cm, and the other was in left lobe and measured 0.9*1.2cm. We performed FNA for both nodules, and right nodule was revealed as papillary thyroid carcinoma but left one as benign follicular nodule. Because the image finding of left nodule such as an ill-defined margin and hypoechogenicity with microcalcification suggested malignancy, CNB for left nodule was performed to confirm the diagnosis. The result of CNB was consistent with a benign follicular nodule, therefore the patient was planned to have a right thyroid lobectomy only. Because metastasis to lymph nodes of central compartment was identified during surgery through frozen section biopsy, she eventually underwent total thyroidectomy. However, final pathology demonstrated that not only right nodule but also left one was papillary carcinoma, even which had approximately 50% of undifferentiated carcinoma component with

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A-103 We propose whether routine ultrasound screening should be considered in the initial evaluation of Hashimoto’s thyroiditis and goiter, especially if found in young adolescent males. References 1. Chung BM, Park SH, Kim SJ, Seo JS, Kim YS, Shim HJ, Lee JB, Papillary thyroid carcinoma in children and adolescents, Ultrasound Q.2014 Sep;30(3):193–6. 2. Koo JS, Hong S, Park CS, Diffuse sclerosing variant is a major subtype of papillary thyroid carcinoma in the young. Thyroid.2009 Nov;19(11):1225–31. 3. Chen CC, Chen WC, Peng SL,Huang SM, Diffuse sclerosing variant of thyroid papillary carcinoma:diagnostic challenges occur with Hashimoto’s thyroiditis, J Formos Med Assoc. 2013 Jun;112(6):358–62.

Poster 253 Final pathologic fidning after thyroidectomy revealed papillary thyroid carcinoma containing undifferentiated component.

TTF-1-negative and p53-positive features. She will be going to have a radioactive iodine therapy due to node metastasis and extrathyroidal extension of tumor. Although FNA or CNB for thyroid lesion has been accepted as an accurate diagnostic method and even combination of these techniques showed a better result in some articles, small portion of cases can be misleaded. Physicians should make a careful decision with fully consideration of image finding and clinical risk factors when the imagehistology mismatching was suspected although histologic finding was reported as benign.

Poster 252 Thyroid Cancer Monday & Tuesday Poster 9:00 AM PAPILLARY THYROID CARCINOMA-DIFFUSE SCLEROSING VARIANT IN YOUNG TEENAGE MALES L. Estanislao, L. Underland, L. Lam Pediatric Endocrinology, Montefiore Medical Center, Paterson, NJ Thyroid carcinoma is the most common pediatric endocrine tumor representing 0.5-3% of all childhood malignancies (1). Diffuse sclerosing variant papillary thyroid carcinoma (DSV-PTC) is a major subtype of PTC in pediatrics (2). DSV-PTC has several distinguishing characteristics and is often associated with Hashimoto’s thyroiditis (3). The occurrence of co-existing Hashimoto’s Thyroiditis can obscure the diagnosis of DSV-PTC. We present two cases of DSV-PTC in young adolescent males recently diagnosed and treated at our institution with extensive disease at initial presentation. Both cases exhibited features classically associated with DSV-PTC such as multifocal involvement, extra-thyroidal extension, vascular invasion and significant nodal disease. One patient also had pulmonary metastases at presentation. Using our cases as references, we will describe the clinical characteristics of DSV-PTC and compare its pathologic features to other variants of PTC. The disease as it relates to the pediatric population will also be discussed.

Thyroid Cancer Monday & Tuesday Poster 9:00 AM ‘‘MIXED TALL CELL VARIANT PAPILLARY THYROID CANCER AND BRONCHIAL CARCINOID - UNIQUE CASE REPORT’’ J. klubo-gwiezdzinska1, M. Zemskova2, T. Brown1, A. Molinolo1, M. Raffeld1, A. Filie1, E. Kebebew1, M. Skarulis1 1 NIH, Arlington, VA; 2FDA, Beltsville, MD Synchronous presence of papillary thyroid cancer (PTC) and neuroendocrine tumors (NET) is extremely rare and is associated with diagnostic and therapeutic challenge. A 64 year old man underwent total thyroidectomy with modified neck dissection for stage T4b/N1b/M1 tall-cell variant PTC with pulmonary metastases. The patient received two dosimetry based radioiodine (RAI) treatments 12 months apart while hypothyroid (260 mCi and 306 mCi). First post therapy scan revealed uptake in thyroid bed, left lateral neck and at sternal notch, the second was negative. Three surgical resections and EBRT were performed for locally persistent/recurrent tall cell variant PTC. Follow up studies documented progression of non-RAI avid pulmonary metastases, with increasing over time metabolic activity of metastatic lesions documented by FDG-PET. Suppressed thyroglobulin (Tg) measuring 10.7 ng/ml did not correlate with radiographic disease burden. Thus the patient underwent core biopsy of the largest 2 cm lung lesion. Pathology revealed mixed tumor consisting of metastatic tall cell variant PTC (TTF1 and Tg positive) with a spindle cell NET component (positive for chromogranin, synaptophysin, TTF1 and focally positive for calcitonin). Immunohistochemical analysis revealed overactivation of pI3K/Akt/mTOR signaling pathway in 80% of malignant cells. Review of pathology slides from primary tumor and local recurrences did not reveal any evidence of primary medullary thyroid cancer and documented negative calcitonin, chromogranin and synaptophysin staining. Serum calcitonin level was < 2 pg/ml and chromogranin was 80 ng/ml (N < 94). This is a unique case report describing a collision tumor consisting of metastatic tall cell variant PTC and bronchial carcinoid. The undetectable serum calcitonin level and lack of calcitonin staining in primary and recurrent lesions argues against the diagnosis of metastatic medullary thyroid cancer. The immunohistochemistry results suggest potential utility of combined PI3K/Akt and mTOR inhibitors in management of disease progression in this patient.

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the metastasis. To make the story more complicated, he had a profound shock during both of his surgeries due to presence of IVC thrombus and the component of Addisonian crisis from bilateral adrenal metastasis. Pathological rarities can occur but the initail management is no different from the usual thyroid nodule.

Thyroid Cancer Monday & Tuesday Poster 9:00 AM REFRACTORY SHOCK DURING THYROIDECTOMY DUE TO A SURPRISE IN PATHOLOGY A CASE REPORT AND LITERATURE REVIEW X. Lo1, T. Tam1, S. Cheung2, H. Leong1 1 Department of Surgery, North District Hospital, Hong Kong, Hong Kong; 2Department of Pathology, North District Hospital, Hong Kong, Hong Kong Pathological surprises are uncommon. We present a case who had a clinical suspicious thyroid nodule complicated with intraoperative intractable shock with a very rare pathology and discuss the mangement with a review of literature. A 60 years old gentleman, with background of coronary stenting for ischemic heart disease, presented to the thyroid clinic with an enlarging left thyroid mass with a background of multinodular goitre. Ultrasonography showed a background of benign looking nodules over both sides with a dominant heterogenous still circumscribed lesion of 5cm. Fine needle aspiration of the lesion yielded clusters of follicular cells with Hurthle cell changes. Total thyroidectomy was arranged, however the patient developed refractory shock once under anaesthesia which the operation was aborted. All further investigations for potential causes of shock were negative. The lesion further increased in size and he agreed to go under the knife again with more invasive monitoring prepared 3 months later. He still had shock but seemed to be still manageable by anaesthetists and thus a hemithyroidectomy aiming just to remove the index lesion was performed. He then was found to have mild deranged liver function tests and answers were finally found. Ultrasonography of the abdomen then showed an aggressive mass over the right kidney with IVC thrombus, Further workup by computer topography showed bilateral lung and adrenal metastasis. He finally made an uneventful recovery from the thyroid surgery but sadly refused all other treatment for his renal cell carcinoma (RCC). True tumor-to-tumor metastasis are rare. With the thyroid as recipient there had been less than 30 cases reported. The rarity of this gentleman’s condition is that for a Hurthle cell carcinoma as recepient he would be the second reported case and a first worldwide if you considered that the RCC was not known before presentation of

Poster 255 Thyroid Cancer Monday & Tuesday Poster 9:00 AM POORLY DIFFERENTIATED THYROID CANCER PRESENTING WITH SKIN NODULES M. Mellati, M.Y. Roth Medicine-Endocrinology, University of Washington, Seattle, WA Skin is a rare site for thyroid cancer metastasis and is extremely rare as presenting site of disease. We present a case of rapidly progressive poorly differentiated thyroid carcinoma presenting with skin nodules. 47 year-old male presented with two pink nodules on his scalp. Biopsy revealed neuroendocrine cells. Neck ultrasound showed a 3.8 · 3.4 · 3.2 cm left sided hypervascular thyroid nodule with coarse calcifications and three enlarged left sided lymph nodes. Body imaging showed two additional cervical lymph nodes and numerous small bilateral pulmonary nodules. Aspiration of the thyroid nodule and bilateral cervical lymph nodes showed thyroid carcinoma with widespread oncocytic/Hurthle cell features and areas suggestive of medullary thyroid carcinoma. Serum calcitonin was undetectable. Total thyroidectomy and bilateral modified neck dissection revealed poorly differentiated thyroid cancer with insular growth pattern. He was staged T3N1bM1. Following the surgery he developed two new lip lesions that were resected. Pathology was consistent with the primary tumor. Following dosimetric calculations radioiodine ablation was dispensed using recombinant human TSH (rhTSH). His thyroglobulin peaked to 30705ng/ml with a TSH of 11.06microIU/ml post rhTSH injection. Pre and post-therapy scans showed minimal radiotracer uptake in the neck and lungs. Additional lip and scalp lesions developed rapidly in the first month post-I131 therapy. Sorafenib was initiated. Brain MRI prior to I131 therapy showed no metastatic disease. One month post-therapy he developed left abducens nerve palsy and a new clivus metastasis was identified on brain MRI. Stereotactic radiotherapy was initiated, but the patient’s clinical status rapidly deteriorated and he chose to stop additional interventions. Patient died 7 months after his initial diagnosis. This case highlights the heterogeneity of poorly differentiated thyroid cancer with unique characteristics. Skin lesions are rarely seen in metastatic thyroid carcinoma and in this case illustrated the rapid progression and poor responsiveness of the disease.

Poster 256 Thyroid Cancer Monday & Tuesday Poster 9:00 AM ECTOPIC PAPILLARY THYROID CARCINOMA: AN UNUSUAL PRESENTATION M. Plazarte, G. Plazarte Endocrinology and Metabolism Department, University of Florida-Jax Campus, Jacksonvile, FL

50X TTF1 staining showing the background Hurthle cell tumor and another tumor within that is TTF1 negative.

Defects during early stage embryogenesis can generate ectopic thyroid tissues along the gland’s embryological descending pathway which also can have malignant potential. 68-year-old male status post MOH’s procedure for removal of BCC was found to have an incidental enlarged left cervical lymph node. During reconstructive intervention for his ear defect he

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 underwent an open cervical node biopsy. The pathology of the lymph node was metastatic papillary thyroid cancer. Ultrasound of the thyroid revealed unremarkable thyroid gland except for subcentimeter hypoechoic lesion in the inferior right thyroid lobe thought to represent a small colloid cyst. Subsequently the patient underwent total thyroidectomy with bilateral neck dissection. Surgical pathology revealed no evidence of tumor identified in the thyroid gland. Most of the lymph nodes were negative for malignancy except for 3 out of 6 lymph nodes in left level 7 neck dissection which were positive for microscopic foci of metastatic papillary carcinoma. The metastatic tumor deposits stained positive for thyroglobulin and TTF-1 on immunohistochemical staining. Hospital course was unfortunately complicated with aspiration pneumonia and need for tracheostomy. Once more stable he underwent I-123 whole body scan which showed mildly increased radiotracer activity within the thyroid bed, likely residual thyroid tissue and no metastatic disease. Patient was treated with oral administration of 106 mCi of I-131. During post RAI scanning patient was found to have only the expected distribution in residual thyroid tissue. Both thyroglobulin and anithyroglobulin antibodies were undetectable while TSH was greater than 100 uIU/mL. Ectopic thyroid tissue has a reported prevalence of approximately 1 in 10,000. Most frequent sites of ectopic tissue include lingual, sublingual, thyroglossal, laryngotracheal and lateral cervical areas. However, ectopic thyroid tissue has also been found in the mediastinum, esophagus, adrenal, pancreas and gallbladder which are areas associated with thyroid anlage during development. The present case adds to the limited previous reports of papillary thyroid cancer in ectopic locations; in particular cases were no primary tumor has been found.

Poster 257 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM PATIENTS YOUNGER THAN 40 YEARS OLD WITH INTERMEDIATE RISK OF RECURRENCE THYROID CANCER HAVE LOW RATES OF STRUCTURAL INCOMPLETE RESPONSE F. Pitoia, F. Jerkovich, A. Schmidt, F. Bueno, G. Cross Hospital de Clinicas - University of Buenos Aires, Buenos Aires, Argentina Age at diagnosis is an important predictor of disease specific survival in patients with differentiated thyroid cancer (DTC). However, scarce bibliography is present considering the influence of age on the rates of structural incomplete response (SIR) according to the risk of recurrence (RR) classifications. This was the aim of our study. A retrospective analysis of 207 patients with DTC followed-up for at least 3 years after initial treatment were reviewed. The median follow-up in the whole cohort was 6.1 years. Patients were classified according to the modified 2009 risk stratification system in low (61.8%), intermediate (26.1%) and high RR (12.1%). They were also divided by using different age cut-offs (older and younger than 40, 50 or 60 years old). There was no significant difference in the rate of SIR between patients older and younger than 50 or 60 y.o. considering the final outcomes according to any of the RR classifications. However, when the same analysis was done by using the 40 year-old threshold as a cut-off in patients with intermediate RR, subjects younger than 40 y.o. had a SIR at the end of follow-up that was significantly lower than in patients older than 40 y.o (0% vs. 22%) (p = 0.01) (Table 1). In our patients the rates of SIR in patients with intermediate RR younger than 40 years old was very similar to that observed in subjects with low RR. These data could help to better classify this

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heterogeneous group of patients by adding this variable to the RR classification.

Poster 258 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM COMPARISON OF SERUM THYROGLOBULIN LEVELS AT THE MOMENT OF REMNANT ABLATION FOR PREDICTING EXCELLENT INITIAL RESPONSE TO TREATMENT IN PATIENTS WITH DIFFERENTIATED THYROID CANCER PREPARED AFTER THYROID HORMONE WITHDRAWAL OR RECOMBINANT HUMAN TSH F. Pitoia, E. Abelleira, A. Schmidt, G. Cross Hospital de Clinicas - University of Buenos Aires, Buenos Aires, Argentina Several studies have correlated thyroglobulin (Tg) levels measured at the time of remnant ablation (RA) and the probability of an excellent initial response to treatment in patients DTC. However, there are scarce data when the risk of recurrence is considered together with the Tg levels at the moment of ablation, whether it is performed after thyroid hormone withdrawal (THW) or rhTSH. We included 219 patients with undetectable serum antithyroglobulin antibodies (TgAb) measured by ultrasensitive assay, followed-up for at least during 36 months after RA. Patients were prepared after i) G1: rhTSH, administered not later than 40 days after surgery (n = 51, 23%). ii) or G2: THW for 3 weeks, starting from thyroidectomy (n = 168, 77%). The primary endpoint of the study was the best response to initial therapy (surgery + RAI ablation) usually assessed in the first 9–18 months follow up as defined in ATA 2015 guidelines. 78% of included patients were women with a mean age of 45 – 12 years. Both groups (G1 and G2) were comparable in terms of sex, age, risk of recurrence and RAI received doses. The mean follow-up after RA was 42 – 16.5 months in the rhTSH group and 73 – 34 months in the THW group (P = NS). Sensitivity, specificity, PPV and NPV was calculated and the cutt-off values were: Tg 8 ng/mL after rhTSH and 22 ng/mL after THW for predicting an excellent response (ROC curve analysis was used)(Table 1). The cut-off value of 8 ng/ mL after rhTSH was similar for patients with low-risk and intermediate- to high-risk patients. However, when the cut-off value of 22 ng/mL for THW was considered, we found a statistically

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MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 Our data validates the newly proposed response to therapy assessment in DTC treated with L or TT without RAI as an effective tool for ongoing risk stratification that could be used to modify initial risk estimates and better tailor follow-up and future therapeutic approaches.

Poster 260

significant difference between patients with low-risk vs. those with intermediate- to high-risk of recurrence (P = 0.003). The Tg cut-off values for predicting an excellent response after THW was 12 ng/mL in low risk patients vs. 16 ng/mL in intermediate-high risk patients (NPV: 54.2% and 97.6%, respectively, P = 0.00002). Tg levels are prognostic indicators for an excellent response to treatment with different cut-offs depending on the modality of preparation for RA and on the risk of recurrence.

Poster 259 Thyroid Cancer Monday & Tuesday Poster 9:00 AM RESPONSE TO THERAPY ASSESSMENT IN DIFFERENTIATED THYROID CANCER PATIENTS SUBMITTED TO TOTAL THYROIDECTOMY OR LOBECTOMY WITHOUT RADIOACTIVE IODINE THERAPY D.P. Momesso2, M. Vaisman2, R. Corbo1,2, R.M. Tuttle3, F. Vaisman1,2 1 Endocrinology, Instituto Nacional do Cancer, Rio de Janeiro, Brazil; 2Endocrinology, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 3Memorial Sloan Kettering Cancer Center, New York, NY While response to therapy assessment is a validated tool for ongoing risk stratification in differentiated thyroid cancer (DTC) patients submitted to total thyroidectomy (TT) and radioactive iodine therapy (RAI), it has not been well studied in patients treated with lobectomy (L) or TT without RAI. Because the response to therapy definitions are heavily dependent on serum thyroglobulin (Tg) levels, modifications of the original definitions were needed to appropriately classify patients treated without RAI. The aim of this study was to evaluate and validate these previously proposed response to therapy definitions in DTC patients submitted to L or TT without RAI. 507 adults with DTC submitted to L (n = 187) or TT (n = 320) without RAI were retrospectively evaluated. Median age was of 43.7 years, 88% were female, 85% had low and 15% intermediate ATA risk. During follow-up period (median 100.5 months) recurrent/persistent structural disease (SD) was diagnosed in 3.6% of patients. All patients (100%) classified as having excellent response to therapy (non-stimulated Tg for TT < 0.2 ng/ml and for L < 30 ng/ml; n = 326) had NESD at final follow-up. SD was observed in 1.3% of patients with indeterminate response (non-stimulated Tg for TT 0.2- 5 ng/ml, stable or declining Tg antibodies and/or nonspecific findings on imaging studies; n = 2/152); 31.6% of patients with biochemical incomplete response (non-stimulated Tg for TT > 5 ng/ml and for L > 30 ng/ml and/or increasing Tg antibodies; n = 6/ 19) and all patients (100%) with structural incomplete response (n = 10/10) (p < 0$0001). Initial ATA risk estimates were significantly modified based on response to therapy assessments, since excellent response to therapy significantly decreased the risk of SD to 0% and incomplete response (biochemical or structural) increased the risk of SD.

Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM RISK OF RECURRENCE FROM PAPILLARY THYROID MICROCARCINOMA BY METHOD OF DISCOVERY S. Londero1, A. Krogdahl2, L. Bastholt3, J. Overgaard4, C. Hahn5, H. Pedersen6, J. Bentzen7, S. Schytte8, P. Christiansen9, C. Godballe1 1 ORL Head and Neck Surgery, Odense University Hospital, Odense M, Denmark; 2Pathology, Odense University Hospital, Odense, Denmark; 3Oncology, Odense University Hospital, Odense, Denmark; 4Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark; 5ORL Head and Neck Surgery, Rigshospitalet, Copenhagen, Denmark; 6ORL Head and Neck Surgery, Aalborg University Hospital, Aalborg, Denmark; 7 Oncology, Herlev Hospital, Herlev, Denmark; 8ORL Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark; 9 Surgery, Aarhus University Hospital, Aarhus, Denmark Worldwide the incidence of papillary microcarcinoma is increasing. In a previous publication it was shown that incidental papillary thyroid microcarcinoma has a very favorable prognosis. The prognosis of non-incidental carcinoma is however seldom described in the literature. We aim to explore the risk of recurrence by the method of discovery. Eligible patients were identified in the DATHYRCA-database, a validated national prospective database of thyroid carcinoma in Denmark. In all 406 patients were diagnosed with papillary microcarcinoma. Subsequently patients were divided into three groups according to the method of discovery; Incidental at surgery (250 patients), Non-incidental with symptoms from index tumor prior to surgery (70 patients), and Non-incidental with symptoms from a metastasis prior to surgery (86 patients). During a median follow-up of 7.98 years five recurrences were found in the Incidental at surgery group, one in the Non-incidental with symptoms from index tumor prior to surgery group, and nine in the Non-incidental with symptoms from a metastasis prior to surgery group. The Kaplan-Meier method was used to calculate recurrence free survival and 5 year recurrence free survival was 98.1%, 98.6% and 88.9% in the three respective groups. By log-rank testing no significant difference in outcome was found between the first two groups (p = 0.71). However, significant difference was seen when comparing the Incidental at surgery group and the Non-incidental with symptoms from a metastasis prior to surgery group (p = 0.02) and when comparing the two non-incidental groups (p = 0.0006). While patients with incidental papillary thyroid carcinoma can expect a very favorable prognosis, risk stratification according to method of discovery does not seem sensible. Most non-incidental carcinomas carry the same risk of recurrence as the incidental cases and only cases discovered by metastatic disease have significantly worse recurrence free survival.

Poster 261 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM DOSIMETRY BASED RADIOACTIVE IODINE THERAPY WITH EITHER THYROID HORMONE WITHDRAWAL OR RECOMBINANT HUMAN TSH IN INTERMEDIATE AND HIGH RISK DIFFERENTIATED THYROID CARCINOMA J.L. Guerra1, M. Namias2, M. Urrutia1, S. Iorkansky3, G. Arron˜ada2, P. Saco4, D. Cragnolino2, M. Negueruela1

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 1

Endocrinolgy, Hospital Universitario Austral, Pilar, Argentina; Nuclear Medicine, Hospital Universitario Austral, Pilar, Argentina; 3 Pediatric Endocrinology, Hospital Garrahan, Buenos Aires, Argentina; 4Head and Neck Surgery, Hospital Universitario Austral, Pilar, Argentina 2

Internal dosimetry (D) determines the maximum tolerated activity (MTA) that can be given safely to avoid unacceptable toxicity. The aim of our study was to examine radioiodine (RAI) toxicity based on a D approach and to evaluate clinical outcomes using high 131I activities in intermediate and high risk of recurrence (IRR,HRR) differentiated thyroid carcinoma (DTC) patients (p) with both thyroid hormone withdrawal (THW) and recombinant human thyrotropin (rhTSH). We analyzed hematologic toxicity in 29 D p [decreased platelets (PTL)/white blood cells (WBC) vs. bone marrow dose] and we also retrospectively compared in empiric (E) and D guided doses (activities) groups the best initial response to therapy and final clinical status in a whole group of 46 p IRR and HRR DTC, with THW and rhTSH aided (Table 1). Therapeutic activities were in the range of [4.8-15.8 GBq], with (9.5 – 3) GBq mean – std. Dose to bone marrow were (78.3 – 31) [25.0-162] cGy (mean – std,range) and was a significant predictor of percentage decrease of PLT and WBC counts at nadir after RAI vs. baseline (p = 1.6E-04 and p = 2.7E-06 respectively). Highest Common Terminology Criteria for Adverse Events (CTCAE) toxicity grades were 1 (20%) and 2 (14%) for PLT and WBC respectively. No significant differences were found in red marrow dose coefficients between THW and rhTSH groups (p = 0.24). It was a significant best response to therapy in 65.2% with rhTSH vs 31.6% with THW (p < 0.03) and free disease status in 65.2% with rhTSH vs 36.8% with THW (p < 0.04), regardless using D or E RAI doses. We obtained 50% of excellent response in D and E RAI groups. In D group IRR, 83% with rhTSH and 20% with THW reached excellent response. This pilot study showed D is safe and allowed to predict bone marrow toxicity, with both rhTSH or THW. The higher toxicity was grade 2, only in 14%. It was a significant best response with rhTSH regardless D or E doses. We need analyze deeply, in a prospective randomized study all clinical outcomes in a greater p cohort.

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Poster 262 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM RECOMBINANT HUMAN THYROID STIMULATING HORMONE (RH-TSH) IN THE FOLLOW UP OF PATIENTS WITH DIFFERENTIATED THYROID CANCER(DTC): INSTITUTIONAL EXPERIENCE A. Orlandi, A. Puscar, G. Frascaroli Endocrinology Unit, Hospital Alvarez, buenos Aires, Argentina The use of rhTSH has been reported to allow the assessment of stimulated thyroglobulin (Stim-Tg) associated with performance or not of whole body scans (WBS) in the follow up of patients with DTC; avoiding symptoms of hypothyroidism with equivalent information to that obtained with endogenous TSH stimulation. However, its widespread use in public institutions has been limited.The aim of our study was to review the use of rhTSH at our hospital. We analyzed retrospectively 64 patients (p) between 13 to 74 years,followed by 1 to 20 years, who received rhTSH for diagnostic and/or to facilitate 131I therapy of DTC.Histological distribution was:41 classic papillary;13 follicular variant; 3 sclerosant; 4 follicular carcinoma;2 tall cell.TNM at diagnosis:T1: 40 p,T2:12,T3:10 and T4:2.15/ 64 N1 and 1/64 M1.Regarding the recurrence risk,3 p were classified as very low risk(VLR);38 low risk(LR);21 intermediate risk(IR) and 2 high risk(HR).rhTSH was used for diagnostic purposes in 67 occasions and in 14 to facilitate 131I therapy. Stim Tg was defined as positive:greater than 1 ng/ml.To analyze these results, p were grouped in:Group A (GA):VRL + LR and Group B (GB):IR + HR. 14 p received rhTSH to facilitate 131I therapy,8 ablative(AD) and 6 therapeutical dose(TD). In AD,5 p received 30mCi, the other 3p received 100,150 and 200mCi respectively. In TD,5 p received 100 and the other 200mCi. 6/8 p who received AD, showed consistency between + Tg/ + WBS(4 GA and 2 GB).The other 2p from GA exhibited - Tg/ + WBS. 5/6 p who received TD, showed consistency between + Tg/ + WBS(4 from GA and 1 from GB) the remaining patient (GB) showed - Tg/ + WBS Two GA p showed satisfactory ablation. In one p of GB,structural and biochemical persistence was evident. The use of rhTSH in DCT patients, proved to be safe and effective for diagnostic and /or treatment. This was equally evident in patients with LR,IR and HR risk of recurrence.A decrease of comorbidities associated with the state of hypothyroidism, with preservation of working capacity and quality of life was observed.This experience was conducted in a public institution, in patients with low economic means. The incorporation of this resource within public health policies, would allowed it use in more cases.

Poster 263 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM STIMULATED THYROGLOBULIN AT RECOMBINANT HUMAN TSH-AIDED ABLATION IS AN INDEPENDENT PROGNOSTIC MARKER IN THE SETTING OF PROPHYLACTIC CENTRAL NECK NODE DISSECTION J. Moon1, S. Moon2, Y. Song2, Y. Hwangbo2, S. Cho2, Y. Park2, K. Yi3, D. Park2, H. Jang1 1 Seoul National University Bundang Hospital, Seongnam-si, Korea (the Republic of); 2Seoul National University Hospital, Seoul, Korea (the Republic of); 3Seoul National University Boramae Hospital, Seoul, Korea (the Republic of)

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In the absence of routine central neck node dissection (CND), thyroglobulin (Tg) levels measured at the time of remnant ablation performed under recombinant human TSH (rhTSH) stimulation were reported to predict disease-free status of differentiated thyroid cancer (DTC). However, it is still unclear whether rhTSH-stimulated Tg levels at remnant ablation play a role as an independent predictive evaluator in the setting of prophylactic CND which results in more precise staging of DTC and relatively lower number of local recurrence. This study included 253 consecutive DTC patients who underwent total thyroidectomy with prophylactic CND or modified radical neck dissection, followed by ablation under rhTSH. Patients with an evidence of initial distant metastasis or positive Tg antibodies were excluded. The predictive value of rhTSH-stimulated Tg at ablation for disease persistence at 1 year after ablation was assessed. Among the included patients, 228 patients (90.1%) were considered disease-free at 1 year after remnant ablation. Patients with persistent disease at 1 year after were older and showed higher TNM stage and higher level of rhTSH-stimulated Tg at ablation. The cutoff value of rhTSH-stimulated Tg level for predicting disease-free status was 1.79 ng/mL, with a negative predictive value of 99.5%. Stimulated Tg at ablation after rhTSH was independent prognostic marker of disease persistence 1 year later. In the setting of routine prophylactic CND, rhTSH-stimulated Tg at ablation independently predicted disease-free status. A low rhTSH-stimulated Tg level at ablation may predict good prognosis in DTC patients who underwent total thyroidectomy with CND.

achieved cure. After 8.3 – 3.8 years follow up, only 8 of cN0 patients had persistent disease, 4 of them biochemically only. Higher AJCC stage and ETE were the only factors that predicted disease persistence at last follow up in this group. Our study indicates that PTC patients with cN0 and no distant metastases have an excellent prognosis and pCND may not be required.

Poster 264 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM IMPLICATIONS OF LYMPH NODE STATUS ON DISEASE OUTCOME IN PATIENTS WITH PAPILLARY THYROID CARCINOMA: A FOCUS ON CLINICALLY N0 DISEASE D. Hirsch1,2, A. Gorshtein1,2, E. Robenshtok1,2, I. Shimon1,2, C. Benbassat1,2 1 Endocrinology, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel The correct approach to treat papillary thyroid carcinoma (PTC) remains controversial. While macrometastatic lymph nodes involvement is an independent predictor for adverse course, clinicopathological variables associated with disease persistence/recurrence in patients with clinically node-negative (cN0) PTC are not well defined neither are the indications for prophylactic central neck dissection (pCND). Our aim was to investigate the risk factors associated with short- and long term persistence in PTC patients with cN0 at presentation and to compare them to PTC patients with cervical lymph node involvement (N1). This retrospective analysis included 229 consecutive PTC patients with cN0 disease and 169 consecutive patients with N1 disease treated and followed at a same tertiary university-affiliated medical center were pCND is not routinely performed. Compared to N1 disease, patients with cN0 had significantly smaller tumors, lower rates of multifocality and less extrathyroidal extension (ETE). Persistency rates at 1 year and last follow up in cN0 and N1 patients were 8.1% vs 47% and 3.6% vs 33.5%, respectively (p = 0.001). Within the cN0 group, patients with persistent disease at 1 year (n = 18) had significantly larger tumors and higher stimulated Tg level. Total thyroidectomy and RAI treatment was the first treatment for all cN0 patients with persistency of whom only 8 had structural residual disease, 6 of them lymph nodes metastases (LNM). Additional RAI was given to 16 patients and additional surgery (neck dissection) was performed in 3 patients, 2 of them

Poster 265 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM GENDER AND RESPONSE TO THERAPY IN THYROID CANCER PATIENTS: A MATCHED CASE-CONTROL STUDY A. Akirov1,2, D. Hirsch1,2, C. Benbassat1,2, I. Shimon1,2, E. Robenshtok1,2 1 Endocrinology, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Thyroid cancer carries worse prognosis in males, mostly due to more advanced age and disease stage at presentation compared with females. However, it is debatable whether treatment should differ based on gender in cases where baseline characteristics are similar. Previously published multi-variable analyses had limited ability to differentiate between the impact of disease severity at presentation versus response to therapy. Therefore, current treatment recommendations are based on disease status and age, irrespective of gender. Our aim was to investigate whether response to therapy differs in males and females who have similar baseline characteristics. A Matched case-control study of patients from the Rabin Medical Center Thyroid Cancer Registry (1,187 patients, 21% males) treated with total thyroidectomy and radioiodine ablation. Matching was performed based on gender for age, histology, and TNM staging. Three-hundred thirty four patients (169 males, 169 females) met inclusion criteria and were well matched for age (mean 51.6 vs. 51.2, NS), histology (92% papillary thyroid carcinoma in both groups), and stage (46% stage I, 11% stage II, 24% stage III, 19% stage IV). The median follow-up was 6 years (range 1–19 years). Disease-free survival (DFS) at the end of follow-up was lower in men (116/169, 69%) compared with women (133/169, 79%, p = 0.03). This difference was not evident when evaluated one year after initial therapy (62% vs. 70%, p = 0.07). Male patients required more repeated radioiodine treatments (33% vs. 19%, p < 0.01), resulting in higher cumulative doses compared with females (199 – 146mCi vs. 167 – 127mCi, p = 0.04). On subgroup analysis, the DFS difference at the end of follow-up was related to stage II and higher disease, and was not significant in patients with stage I disease. Gender difference was not related to age or histology. Adverse outcome in males is related not only to the known gender difference in disease severity at presentation, but also to worse response to therapy. More aggressive treatment should be considered in males with stage II-IV disease.

Poster 266 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM LONG TERM MANAGEMENT OF HYPOPARATHYROIDISM RESULTING AFTER THYROID SURGERY; WHERE ARE THE GUIDELINES? M.D. Brooks1, N. Bin Hareez1,2, C. Tran1,2, T. O’Leary1, H. Lochnan1,2 1 Medicine, University of Ottawa, Ottawa, ON, Canada; 2Medicine, The Ottawa Hospital, Ottawa, ON, Canada

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015

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Hypoparathyroidism is a condition marked by inadequate production of parathyroid hormone as well as hypocalcemia and hyperphosphatemia. Hypoparathyroidism is associated with a multitude of health consequences and associated symptoms. The incidence of hypoparathyroidism is estimated to occur 0.5–6.6% of total thyroidectomies and even higher based on some reports. Management principles are well described for the post-operative and even first year of hypoparathyroidism however there is a marked deficit of guidelines for long-term management. In light of new treatment options and relatively high prevalence of hypoparathyroidism clinicians require formal evidence graded guidelines to aid in decision making. A search strategy focusing on the long term management of postsurgical hypoparathyroidism was used. A search of the PubMed database for articles focusing on long term management of hypoparathyroidism and included reviews and a search of references. Only articles available in English were included. In addition a browser search for guidelines was also done to look for guidelines that included recommendations with graded evidence. A secondary question was to determine rates of long term complications such as nephrolithiasis or renal failure. In searching for specific advice related to long term follow up of hypoparathyroidism 40 articles were included for full review. No formal evidence based or graded guidelines were identified. Only several papers made formal recommendations for the long term follow up of patients on treatment for hypoparathyroidism in regard to frequency of monitoring and specific tests. There appears to be no consensus on the frequency of testing calcium or whether or not 24h urine calcium is necessary and a paucity of information on long term outcomes. There remains a significant gap in knowledge in regard to long term consequences and best practices for treatment and monitoring of postsurgical hypoparathyroidism. Further research in regard to outcomes as well as development of formalized guidelines is needed. Meanwhile we propose an algorithm for long term monitoring based on published recommendations and in consideration of new therapies.

pump. Due to cost and eventual lack of response to continuous SC teriparatide, twice weekly IV calcium was started. Thereafter, she has been receiving 2 g/day of IV calcium gluconate continuously via a CADD pump delivered through a permanent central line and was able to maintain iCa about 1.0 mmol/L. She developed a line infection and pulmonary embolism requiring antibiotics and anticoagulation; she is unable to work due to the complexity of her treatment. No explanation has been found to account for her resistance to high doses of calcitriol, including no identified mutation in her Calcium-sensing receptor gene (CaSR). Treatment with teriparatide and where possible 1-84 PTH may be needed in challenging cases of hypoparathyroidism but are costly and not available to all patients. Cadaveric parathyroid transplant is not commonly done. Avoidance of hypoparathyroidism, including by reducing the extent of surgery for low risk thyroid cancers should be considered. We describe an unusual course of refractory hypocalcemia, dramatic hypercalciuria unresponsive to very high doses of calcitriol and usual treatment approaches. The less aggressive approach low risk PTC’s should be considered as a strategy to avoid serious complications.

Poster 267 Thyroid Cancer Monday & Tuesday Poster 9:00 AM REFRACTORY HYPOPARATHYROIDISM AS A CONSEQUENCE OF COMPLETION THYROIDECTOMY: A CASE REPORT N. Bin Hareez, C. Tran, T. O’Leary, D. Liu, H. Lochnan Endocrinology and Metabolism, University of Ottawa, Ottawa, ON, Canada We describe a case of refractory hypoparathyroidism as a consequence of a completion thyroidectomy done for treatment of a low risk papillary thyroid cancer (PTC). A 36 year old female diagnosed with PTC (0.8 cm and 0.3 cm) after hemi-thyroidectomy underwent completion thyroidectomy. Postoperatively she developed hypocalemia; her course was complicated by requirement for large and frequent doses of calcitriol and IV calcium. Extremely high levels of urine calcium raised concerns for development of renal failure. She required teriparatide injections 30 mcg t.i.d. in combination with oral calcium 12 g/day, calcitriol 2 mcg t.i.d., magnesium oxide 12 g/day, amiloride/ hydrochlorothiazide 5/50 daily, in order to maintain an ionized calcium (iCa) of about1.0 mmol/L. After several months, the response to teriparatide injections diminished and there was subsequently better response to continuous SC teriparatide infusion via an insulin

Poster 268 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM DURATION OF TSH SUPPRESSION FOR THYROID CANCER: IS THERE CONSENSUS? M. Papaleontiou1, B.L. Gay1, S.T. Hawley2, M. Haymart1 1 Internal Medicine; Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Novi, MI; 2General Medicine, University of Michigan, Ann Arbor, MI Standard treatment for differentiated thyroid cancer (DTC) includes thyroidectomy with or without radioactive iodine ablation, often followed by thyrotropin (TSH) suppression therapy. The appropriate duration of TSH suppression therapy and factors influencing physician decision-making remain unclear. Members of the American College of Physicians, American Academy of Family Practice and Endocrine Society were randomly surveyed to determine current practice patterns regarding duration of TSH suppression therapy in thyroid cancer patients. The modified Dillman survey method was used and clinical vignettes were employed. A total of 269 physicians completed the survey (42% endocrinologists, 26% family practitioners, 25.7% internists and 6.3% other). We found that 40% of physicians would continue TSH suppression therapy beyond 5 years for a 40 year-old without comorbidities and low-risk DTC, 38% for a 65 year-old without comorbidities and low-risk DTC, 44% for a 65 year-old with comorbidities and high-risk DTC and 33.6% for an 85 year-old without comorbidities and high-risk DTC. In multivariable logistic regression analyses, more years in practice (p 0.013) and specialty (endocrinology p 0.002, internal medicine p 0.044) were significantly associated with duration of TSH suppression therapy > 5 years in a 65 year-old without comorbidities and low-risk DTC. Only specialty (endocrinology p 0.005) was significant in a 65 year-old with comorbidities and high-risk DTC. Factors influencing decision-making regarding TSH suppression therapy included cardiac arrhythmias (87.4%), patient symptoms (74.8%), heart disease (71.5%), osteoporosis (66.8%) and age (49.1%). Despite current guidelines to maintain TSH in the low normal range in patients with low-risk DTC, up to 40% of physicians

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maintain TSH suppression for > 5 years even in older patients who are at increased risk for cardiac arrhythmias and osteoporosis. Interestingly, endocrinologists are most likely to suppress TSH for > 5 years both in low-risk patients and in patients with comorbidities. More physician education and future research to determine patientlevel factors involved in decision-making are needed.

arms, respectively, with 82 (41.0%) and 50 (24. 6%) of patients having levothyroxine dose adjustment, respectively. There were no differences in mPFS for patients within (or across; not shown) treatment arms based on successful TSH management, or for patients whose serum TSH values exceeded 0.5 mU/L (Table). Approximately twice as many patients in the sorafenib arm compared to the placebo arm of the DECISION trial had elevated serum TSH requiring levothyroxin dose adjustment. In an exploratory post-hoc analysis, PFS outcomes did not appear to be negatively impacted by failure to maintain TSH target levels. These results highlight nonetheless the need for active monitoring of TSH and levothyroxine dose adjustment for optimal management of RAIrDTC patients receiving sorafenib therapy.

Poster 269 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM MANAGEMENT OF THYROID STIMULATING HORMONE (TSH) AND POSSIBLE IMPACT ON OUTCOMES FOR PATIENTS WITH RADIOACTIVE IODINE-REFRACTORY DIFFERENTIATED THYROID CANCER (RAI-RDTC) RECEIVING SORAFENIB OR PLACEBO ON THE PHASE III DECISION TRIAL. J.W. Smit1, M. Schlumberger2, C. Kappeler3, G. Meinhardt4, M.S. Brose5 1 Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; 2Gustave Roussy, Villejuif, France; 3Bayer Pharma AG, Berlin, Germany; 4Bayer HealthCare Pharmaceuticals, Whippany, NJ; 5Department of Otorhinolaryngology: Head and Neck Surgery, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA TSH suppression with levothyroxine is standard of care for management of patients with thyroid cancer post-thyroidectomy. One third of RAI-rDTC patients randomized to receive sorafenib in the phase III DECISION trial had increased serum TSH values (Brose et al., Lancet 384:319, 2014). Here we examined the management of TSH for patients from the DECISION trial and conducted an exploratory post-hoc analysis to determine whether progression-free survival (PFS) was impacted based on successful TSH management. A total of 417 patients were randomized to receive placebo (n = 210) or sorafenib (n = 207). Serum TSH and thyroxin levels were assessed every 28-day cycle and levothyroxine dosing adjusted for TSH values > 0.5 mU/L so as to maintain a desired level < 0.1 mU/L. Median PFS (mPFS) was assessed by independent radiologic assessment using modified RECIST 1.0 every 8 weeks. Elevated TSH values > 0.5 mU/L at any cycle were reported in 69 (33.3%) and 28 (13.4%) of patients in the sorafenib and placebo arms, respectively. Most new occurrences of elevated TSH in the sorafenib arm were reported in cycle 2 (11.4% of evaluable patients), at which time mean TSH values were 0.37 – 1.20 mU/L compared to 0.18 – 1.07 mU/L in the placebo arm. Successful control of TSH (defined as > 75% of TSH values < 0.1 mU/L) was reported in 96 (48.0%) and 155 (76.4%) of patients in the sorafenib and placebo

Poster 270 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE IMPACT OF DELAYED SURGICAL RESECTION OF PAPILLARY THYROID CANCER ON TUMOR GROWTH AND PATIENT OUTCOMES T.E. Angell1, M.G. Lechner2, X. Liu3, M. Medici4, N. Kwong1, E. Marqusee1, M.I. Kim1, E.K. Alexander1 1 Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Boston, MA; 2Medicine, Brigham and Women’s Hospital, Boston, MA; 3Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 4Endocrinology, Erasmus University Medical Center, Rotterdam, Netherlands Observational studies of unresected, sub-centimeter papillary thyroid cancer (PTC) indicate most follow an indolent course and may be safely observed without treatment. However, there are few data assessing the safety and efficacy of this approach for PTC > 1cm, for which the natural history of untreated disease remains unknown. Such data may modify the approach to patients with clinically relevant PTC. We retrospectively analyzed all patients with histologically proven PTC diagnosed at BWH between 1995–2011 identifying patients whose cancer was not surgically resected for ‡ 6 months (usually due to treatment of a separate illness or lack of patient follow up). Tumor growth of ‡ 3mm (considered a consistently reproducible difference in nodule measurement), recurrences, and disease-specific mortality were assessed. From the 827 patients diagnosed with PTC during this time, 92 patients (100 malignant nodules) experienced a delay in initial surgical treatment. The median delay was 2.0 yrs, ranging from 6 months to13.8 years (yrs). Cancers were low-risk, staged as T1/T2 and Nx/N0, in 78 of 92 cases (85%). During observation, US confirmed growth ‡ 3mm in 39 of 100 malignancies (39%). This was notably less frequent for 1–2cm PTC (11/45, 24%) compared to PTC > 2cm (28/55, 51%) (p = .007), though no new pathologic lymphadenopathy was identified. Following ultimate surgical resection and radioiodine ablation, PTC recurred in 5 of 92 (5.4%) patients. In each of these cases, initial tumor size was > 2cm. Importantly, no disease-specific mortality was confirmed over median follow up of 7.0 yrs (max = 18 yrs). Untreated low-risk (T1/T2, Nx/N0) PTC exhibits an indolent course, without new lymph node disease and having low recurrence risk, after a median 2-year delay in operative treatment. Nonetheless, cancer growth and recurrence is more likely when PTC is larger than 2cm. While these data cannot confirm the safety of an observational, non-operative approach for all PTC, they provide strong pilot data supporting further investigation of conservative management of lowrisk PTC measuring 2cm or smaller.

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015

Poster 271 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM IN LOW RISK DIFFERENTIATED THYROID CANCER PATIENTS TREATED WITH TOTAL THYROIDECTOMY AND RADIOACTIVE IODINE, SUPPRESSED AND STIMULATED THYROGLOBULIN HAVE SIMILAR NEGATIVE PREDICTIVE VALUE TO DETECT RECURRENT/PERSISTENT DISEASE J.M. Dominguez, F. Nilo, T. Contreras, R. Carmona, V. Iturrieta Department of Endocrinology, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile The follow-up of patients with low risk differentiated thyroid cancer (LRDTC) treated with total thyroidectomy (TT) and radioactive iodine (RAI) requires serial neck ultrasound (US) and serum thyroglobulin (Tg). The need to stimulate Tg is controversial. The aim of this study was to compare the negative predictive value (NPV) of suppressed and stimulated Tg to detect persistence/recurrence in LRDTC patients treated with TT and RAI. This retrospective study included adult LRDTC patients, followed for a median of 3.7 years (range 2.0–5.7) after TT and RAI, who received TSH suppressive therapy and had negative Tg antibodies. Clinical data obtained during follow-up were used to detect structural (locoregional or distant metastases) and biochemical (suppressed Tg ‡ 1 ng/mL or stimulated Tg ‡ 2 ng/mL, in the absence of structural disease) persistence or recurrence of DTC. Among those patients in whom persistence/recurrence was not diagnosed with neck US, we calculated the NPV of suppressed and stimulated Tg to detect structural disease. We included 148 patients, 129 (87.2%) women, age 45.3 – 13.4 years old. Persistence or recurrence was found in 8 (5.4%) patients: 5 structural (neck lymph nodes, found on US) and 3 biochemical (1 had suppressed Tg ‡ 1ng/dl and 2 had stimulated Tg ‡ 2ng/dl), so stimulated Tg was useful to detect disease in 2 patients. Among patients in whom persistence/recurrence was not detected on neck US or basal Tg ‡ 1ng/dl (n = 142), Tg was stimulated in 75 (52.8%) and was not in 67(47.2%). There were no differences regarding gender, age, length of follow-up or AJCC stages between both groups. Two out of 75 (2.7%) and none of 67 (0%) patients with stimulated and basal Tg had recurrence/persistence, respectively (p = 0.17). Both stimulated and suppressed Tg had NPV of 100% to detect persistence/recurrence (Table). The 2 patients who had persistence/recurrence had biochemical disease and are currently alive. From the whole group, 1 patient who had no disease died because of multiple myeloma and the rest are alive. In LRDTC patients treated with TT and RAI, suppressed and stimulated Tg have high and similar NPV to diagnose persistence/ recurrence, so there is no need to stimulate Tg during follow-up.

Poster 272 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM EVALUATION OF THE AFIRMA GENE EXPRESSION CLASSIFIER ON REPEAT FNA OF INDETERMINATE THYROID NODULES G.P. Harrison1, J. Sosa2, X. Jiang1

A-111 Pathology, Duke University Medical Center, Durham, NC; 2Endocrine Surgery, Duke University Medical Center, Durham, NC

1

The Afirma gene expression classifier (GEC) is a test that was developed to aid in management of indeterminate thyroid nodules (ITN) by fine needle aspiration (FNA). At our institution, Afirma testing is not performed on the first indeterminate result; rather, we utilize the GEC among patients with two consecutive indeterminate diagnoses in the same thyroid nodule. We reviewed results of thyroid nodules evaluated by Afirma GEC at our institution from August 2013 to March 2015. Results of cytopathology and the GEC were collected, as well as diagnoses from surgical resection when performed. 115 thyroid nodules were evaluated by the Afirma GEC. The FNA diagnostic categories for these nodules were: 100 (87%) Bethesda III, 10 (9%) Bethesda IV, 3 (2%) Bethesda I, 1 (1%) Bethesda V, and 1 (1%) non-diagnostic. Afirma GEC results for 45% of the nodules were ‘‘benign,’’ 50% were ‘‘suspicious,’’ and 6 specimens yielded no result due to low mRNA content. 6% of the benign nodules were treated surgically, all of which were benign on final surgical pathology. 77% of the suspicious nodules were treated surgically; final surgical pathology diagnoses for 61% were benign and 39% malignant, yielding a positive predictive value (PPV) of 39%. The majority of the malignancies (71%) were follicular variant of papillary thyroid carcinoma, 18% were Hurthle cell carcinomas, and 6% were classic variant of papillary thyroid carcinoma. Benign diagnoses included follicular adenoma (35%), nodular hyperplasia (38%), and chronic lymphocytic thyroiditis (23%). This is the largest single institutional study of Afirma GEC utilization to date, and unique in that Afirma was performed only for repeat-indeterminate nodules. In our experience in this context, half of the ITN were classified as ‘‘suspicious’’ by Afirma, with a 39% rate of malignancy in these nodules at surgical resection, in comparison with a historical rate of malignancy at our institution of 8% for Bethesda III nodules and 23% for Bethesda IV. Our use of the GEC is consistent with prior reports that it has a low PPV in ITNs. In our experience, it was uncommon for GEC ‘‘benign’’ nodules to go to resection, and all of these nodules were benign on final pathology.

Poster 273 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM REGIONAL VARIATION IN RADIOIODINE ADMINISTRATION FOR THYROID REMNANT ABLATION IN WELL DIFFERENTIATED THYROID CANCER ACROSS CANADIAN CENTERS OVER 2000–2010 I. Rachinsky3, M. Rajaraman4,5, W.D. Leslie7, A. Zahedi12, C. Jefford9, A. Pathak1,2, A. Boucher8, J. Young13, B. Lesperance11, M. Badreddine3,6, S. Nixey6, H. Fong5, S. Van Uum10 1 Surgery, University of Manitoba, Winnipeg, MB, Canada; 2 College of Medicine, University of Manitoba, Winnipeg, MB, Canada; 3Nuclear Medicine, Western University, London, ON, Canada; 4Dalhousie University, Halifax, NS, Canada; 5QEII Health Sciences Centre, Halifax, NS, Canada; 6London Health Sciences Centre, London, ON, Canada; 7University of Manitoba, Winnipeg, MB, Canada; 8Professor, department of medicine, Universite´ de Montre´al, Montreal, QC, Canada; 9Memorial University, St. John’s, NF, Canada; 10Medicine, Western University, London, ON, Canada; 11 Medicine, McGill Centre for Translational Research in Cancer, Montreal, QC, Canada; 12Women’s College Hospital, Toronto, ON, Canada; 13Surgery, McMaster University, Hamilton, ON, Canada Initial treatment with radioactive iodine (RAI) has been reported to vary significantly between studies. We explored variation in RAI

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treatment patterns between five thyroid cancer treatment centers in Canada. The Canadian Thyroid Cancer Consortium (CAN-TC) is a collaborative registry to describe patterns of care for thyroid cancer; currently nine centers participate. Here we present interim data from 5 centers (London, ON; Toronto, ON; Halifax, NS; Winnipeg, MB; and St. John’s, NL) on RAI ablation in patients diagnosed with welldifferentiated (papillary and follicular) thyroid cancer between 2000 and 2010. We compared RAI ablation protocols including indications (based on TNM staging), and doses administered. We excluded patients with known distant metastasis at time of RAI ablation. We included 2526 patients, varying from 100 to 1192 per center. There were no significant differences in TNM stage over time, with the following overall (range between centers) distribution: T1 45% (39–48), T2 28% (24–34), T3 24% (18–30) and T4 3% (0–7). RAI use increased in earlier years and then declined (Figure). During 2005–2010, the fraction of patients receiving RAI decreased from 74% to 31% for T1, and from 92 to 59% for T2, and from 92 to 70% for T3 (P < 0.001 for all comparisons, Chi Square). The T4 group showed fluctuation ranging from 80 to 100%. In addition, the fraction of patients receiving RAI varied significantly between centers: 20– 85% for T1, 44–100% for T2, 58–100% for T3, and 59–100% for T4. There also were significant differences in the doses of RAI between centers, with the majority of patients receiving 3.7 GBq in 3 centers versus 1.1 GBq in two centers. Our study confirms significant variation in use of RAI for ablation in patients with well-differentiated thyroid cancer both between Canadian centers and over time. The impact of this variation on longterm outcome and costs will be analyzed in future studies.

Poster 274 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM ROLE OF THYROID REMNANT ABLATION WITH LOW ACTIVITY OF 131I IN PATIENTS WITH LOW AND INTERMEDIATE RISK PAPILLARY THYROID CARCINOMA (PTC) L. Agate1, F. Bianchi2, F. Brozzi2, P. Santini2, E. Molinaro1, V. Bottici1, D. Viola1, P. Vitti1, R. Elisei1 1 Clinical and Experimental Department, Endocrinology Unit, Pisa, Italy; 2Clinical and Experimental Department, Nuclear Medicine Section-Endocrinology Unit, Pisa, Italy The real need to perform RRA is nowdays under debate in patients with low and intermediate risk PTC. Aim of our study is to evaluate the diagnostic and therapeutic role of this procedure. We retrospectively analyzed 548 consecutive patients (pts) with PTC treated with total thyroidectomy, referred to our Institute in 2006 to perform RRA. All patients were treated in hypothyroidism

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 with a standard activity of 30 mCi of 131I followed by a Whole Body Scan (pWBS). Serum thyroglobulin (Tg), thyroid hormones measurements and neck ultrasound were performed in all pts. We classified patients in two groups: low risk (LR; n = 348) and intermediate risk (IR; n = 200). In addition to the thyroid remnant, the pWBS showed further areas of 131I uptake in 16/548 pts (2.9%): 7 LR (2.2%) and 9 IR (4.3%) (p = 0.09). In 11/16 pts (4 LH, 7 IR) pWBS revealed latero-cervical lymph node metastases, 9 out of 11 were also detected by ultrasound followed by fine needle aspiration citology. The pWBS showed mediastinal uptake in 1/16 (1 IR), lung metastases in 3/16 (2 LR, 1 IR) and bone metastases in 1/16 (1 LR). Only 7/548 (1.3%) (5 LR and 2 IR) metastases were detected by pWBS only. The mean value of serum Tg was 86.329 – 112.398 ng/ml in LR and 242.411 – 260.779 ng/ml in IR (p = 0.1). At the end of follow-up (median 7.8 years), 8/16 pts were free of disease (5 LR, 3 IR) while the other 8 had persistent disease: 5 ‘‘biochemical’’ disease (1 lung and 4 lymph nodes) and 3 ‘‘structural’’ disease (1 bone, 1 mediastinum and 1 lymph node). Remission was achieved in 3 cases after one single 131I activity, in 1 case after surgical treatment and in the last 4 cases after several 131I courses. The pWBS after RRA played an important diagnostic role in only 7/548 (1.3%) PTC pts with no difference between LR and IR groups. Serum Tg was unable to predict pWBS positive cases. Three out of 3 cases with lung and 8/11 lymph nodes metastases revealed by pWBS have been cured by 131-I. We do not know what could happen to these subjects, especially those with lung metastases, if 131I and pWBS were not performed.

Poster 275 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM DIFFERENTIATED THYROID CANCER AMONG FORMER ‘‘CHERNOBYL CHILDREN’’: IS IT STILL ACTUAL AFTER 30 YEARS? S.M. Cherenko, V. Hoperia, O. Larin Endocrine Surgery, Ukrainian Research Center for Endocrine Surgery, Kyiv, Ukraine Influence on differentiated thyroid cancer (DTC) genesis by Chernobyl-1986 irradiation has been well established previously, particularly for children and adolescents lived in Ukraine at the moment of catastrophe. Featured peculiarities of ‘‘Chernobyl children’’ DTC were: short latency, multifocality, papillary type (particularly solidfollicular form), wide lymph nodes spreading, RET/PTC rearrangement. The peak of incidence of DTC among irradiated people born 1969–1986 was awaited within the first 10–15 years after catastrophe. Whether the risk of DTC development is still high for Ukrainian people who was in young age 30 years ago? We calculated separately annual share and clinical peculiarities of DTC of patients born 1969-1986 (0-17 years old in 1986) and 1982– 1986 (0–5 years old) among all thyroid malignancies, operated on in the national endocrine hospital during last 15 years. Surprisingly, the share of DTC patients which were in young age at the moment of Chernobyl disaster did not shrink after 30 years. Patients born 1969–1986 comprised 24.9 % of whole operated thyroid cancer within period 2000–2014 years, youngest (born 1982– 1986) children comprised 6.2 %. Year-to-year percentage of both age groups DTC demonstrates a trend to increasing with some fluctuations. Significant rising of respective groups proportions becomes evident at comparison of three consecutive 5-years periods (2000– 2004, 2005–2009 and 2010–2014): contribution of patients born 1969–1986 was 16.2%, 21.4% and 29.8%; patients born 1982–1986 - 3.3%, 5.1% and 7.9% correspondingly. DTC among ‘‘Chernobyl children’’ demonstrates significant rate of multifocality (21.2%).

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The role of screening in rising proportion of DTC patients born 1969–1986 years seems negligible considering absence of special medical programs and significant rate of advanced forms (29% of nodal involvement and 30% of extrathyroid tumor invasion). Comparative study using other clinical cohorts of non-irradiated patients might be interesting to elucidate consequences of Chernobyl catastrophe. Latency of radiation induced DTC lasts much longer than 30 years. Irradiated in 1986 children still have high risk of thyroid malignancy and need continued observation.

Medical College Hospital were reviewed. Clinical and pathological features were collected for univariate and multivariate analysis and all patients were allocated into Group A (Age < 40, 346 patients), Group B (Age between 40 and 60, 806 patients) and Group C (Age > 60, 74 patients). Of all patients, 438 cases (35.7%) have lymph node metastasis and 50 patients (4.1%) have more than 5 lymph nodes metastasis. In univariate analysis, older patients significantly had less lymph node metastasis (30.15% in Group B and 22.97% in Group C) comparing to younger patients (51.45% in Group A). Male, multiplicity, with chronic thyroiditis and tumor diameter > 0.5cm were also correlated to lymph node metastasis significantly except capsule invasion. In multivariate analysis, comparing to Group A, older patients had less lymph node metastasis (OR 0.398, 95%CI 0.304–0.520, P < 0.01 in Group B, OR 0.281, 95%CI 0.155–0.510 in Group C, P < 0.01). Male patient (OR 1.856, 95%CI 1.396–2.466, P < 0.01), diameter > 0.5cm (OR 1.785, 95%CI 1.314–2.425, P < 0.01) and multiplicity (OR 1.965, 95%CI 1.510–2.556, P < 0.01) were main risk factors for lymph node metastasis. Additionally, for patients with lymph node metastasis, patients in Group B may have lower risk of more than 5 lymph nodes metastasis comparing to group A (OR 0.489, 95%CI 0.290–0.825, P < 0.01), male (OR 2.202, 95%CI 1.276-3.800, P < 0.01) and chronic thyroiditis (OR 1.727, 95% 1.011-2.950) are the main risk factors of more than 5 lymph nodes metastasis. Older PTMC patients may have less lymph node metastasis and patients over 60 years old may be the candidates for observation.

Poster 276 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM AGE IS SIGNIFICANTLY RELATED TO LYMPH NODE METASTASIS IN PAPILLARY THYROID MICROCARCINOMA: OLDER PATIENTS WITH LESS LYMPH NODE METASTASIS X. Li1, J. Yang1, Q. Sun1, F. Liang2, H. Shi3, Y. Liu1, Z. Liu1, G. Chen1, S. Chen1, Z. Shang4, W. Gao1, L. Zhang1 1 General Surgery, Peking Union Medical College Hospital, Beijing, China; 2First Affiliate Hospital Of Hebei North University, Zhangjiakou, China; 3Jizhou City Hospital, Jizhou, China; 4General Surgery, Second Clinical Hospital of Shanxi Medical University, Taiyuan, China Lymph node metastasis is a critical consideration in treatment selection of papillary thyroid carcinoma. The aim of this study is to investigate the risk factors, including age, of lymph node metastasis in papillary thyroid microcarcinoma (PTMC). The medical records of 1226 PTMC patients (947 Female, 279 Male) who underwent thyroidectomy (ipsilateral of bilateral) with ipsilateral central neck dissection at least between November 2013 and October 2014 at the General Surgery Department, Peking Union

Poster 277 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE IMPACT OF OBESITY ON LONG-TERM SURGICAL OUTCOMES FOR PAPILLARY THYROID CARCINOMA E. Ban, M. Kim, J. Choi, T. KIM, S. Lee, C. Lee, J. lee, S. Kang, J. jeong, K. Nam, W. Chung, C. Park Department of Surgery, Yonsei University College of Medicine, Seoul, Korea (the Republic of) Epidemiological studies suggest that obesity increases the risk of thyroid cancer. However, the association between body mass index (BMI) and the aggressiveness of papillary thyroid carcinoma (PTC) still remains unclear. We conducted this study to determine whether high BMI is associated with more aggressive disease in patients with PTC. A total 7284 consecutive papillary thyroid carcinoma patients who underwent surgery were categorized into three groups according to the body mass index (BMI): nonobese ( £ 24.9 kg/m2), overweight (25-29.9 kg/m2), obese ( ‡ 30 kg/m2). The clinicopathological characteristics and the recurrence rates were compared between groups. A median follow-up time was 71 month. There was a trend toward larger tumors with increasing BMI (8.8mm versus 9.4mm and 11.1mm, P < .001).The obese group had higher extrathyroidal invasion rates (52.4% versus 57.0% and 66.7%, P < .001), higher bilaterality (19.7% versus 25.1% and 30.7%, P < .001), T4a (1.7% versus 2.5% and 4.4%, P < .001), and stage IVa disease (4.5% versus 7.3% and 10%, P < .001) than the nonobese and overweight groups. No positive associations were identified between BMI and nodal status. During follow-up, 120 patients (1.65%) experienced recurrent disease. There were no significant differences in recurrence of PTC among BMI groups. Although higher BMI has been strongly associated with more aggressive features of PTC except nodal metastasis, obesity was found not to be associated with a greater likelihood of recurrence.

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pre- and postoperative thyroid stimulating hormone (TSH), thyroiditis, and recurrence rate. The overall median follow-up period was 75 months. In levothyroxine withdrawal group, the mean levothyroxine maintenance and withdrawal period was 40 and 36 months respectively. Levothyroxine was administered to keep serum TSH levels 2mIU/L in these patients. Levothyroxine withdrawal was found not to be associated with a greater likelihood of cancer recurrence (0.4% vs 0.6%). Levothyroxine withdrawal group had a lower incidence of a highnormal preoperative TSH level compared with levothyroxine maintenance group (TSH ‡ 2.5mIU/L, 21.7% vs. 45.9%; P < 0.001). There were 38 (16.5%) patients who developed subclinical hypothyroidism after levothyroxine withdrawal. These hypothyroid patients had a higher pre-operative TSH levels compared with euthyroid patients (1.83 vs 1.45mIU/mL; P = .007). These patients with subclinical hypothyroidism had no significant differences of aggressive features of DTC compared with euthyroid patients. All hypothyroid patients recovered to normal levels within 24 months without levothyroxine replacement. Levothyroxine withdrawal after hemithyroidectomy could be considered to improve the quality of life of patients with low or intermediate risk DTC.

Autoimmunity Monday & Tuesday Poster Clinical 9:00 AM SURGICAL OUTCOMES FOR SECONDARY HYPERPARATHYROIDISM: SINGLE INSTITUTION EXPERIENCE E. Ban, M. Kim, J. Choi, T. KIM, S. Lee, C. Lee, J. lee, S. Kang, J. jeong, K. Nam, W. Chung, C. Park Department of Surgery, Yonsei University College of Medicine, Seoul, Korea (the Republic of) Secondary hyperparathyroidism (SHPT) is a common complication of long-term dialysis patients, and surgical parathyroidectomy (PTX) remains necessary in patients resistant to medical therapy. The aim of this study was to review our experience of surgical management of SHPT. We conducted a retrospective study of patients with chronic renal failure who received PTX over 10 years from January 2004 to september 2014. Surgical indication was established according to clinical or biological assessment. We included 61 patients with average age of 47.5 years, 27.9% male and 72.1% female in dialysis for 11.42 – 5.18 years before PTX. The most common indication of PTX (65.6% of cases) was the persistence of serum PTH of more than 800pg/ml associated with hypercalcemia and/or hyperphosphatemia refractory to medical treatment. The operations performed were: subtotal parathyroidectomy (SPTX) in 24 cases; total parathyroidectomy with autotransplantation (TPTX + AT) in 33 cases and total parathyroidectomy (TPTX) alone in 4 cases. Histological examination of parathyroid gland specimens disclosed diffuse hyperplasia in 48 patients (82.8%) and nodular hyperplasia in 8 patients (13.8%). The post-operative calcium level was in the normal range in 29 cases, low comparatively to the baseline in 20 cases and high in 12 cases. A parathyroid hormone (PTH) level of more than 300 pg/ml was checked in 4 patients (6.56%) on the 3 months postoperative day. After a mean follow-up of 40 months, three patients (4.92%) had persistent disease. In conclusion, PTX is very effective for the treatment of hyperparathyroidism in patients with advanced SHPT refractory to medical treatment.

Poster 279 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM DOES LEVOTHYROXINE THERAPY ROUTINELY NEED OVER LIFELONG AFTER HEMITHYROIDECTOMY FOR PATIENTS WITH DIFFERENTIATED THYROID CARCINOMA? A SINGLE CENTER EXPERIENCE E. Ban, M. Kim, J. Choi, T. KIM, S. Lee, C. Lee, J. lee, S. Kang, J. jeong, K. Nam, W. Chung, C. Park Department of Surgery, Yonsei University College of Medicine, Seoul, Korea (the Republic of) There were no criteria regarding the degree and the duration of levothyroxine therapy to prevent thyroid cancer recurrence after hemithyroidectomy in patients with differentiated thyroid carcinoma (DTC). And the incidence of hypothyroidism after levothyroxine withdrawal remains unclear. We aim to clarify follow-up outcomes after levothyroxine withdrawal in patients underwent hemithyroidectomy for DTC. We retrospectively reviewed 574 patients underwent hemithyroidectomy for DTC from October 2005 to December 2010. Patients were divided into two subgroups according to with levothyroxine withdrawal or not (230 vs 344). Patients were analyzed for clinicopathological characteristics including thyroid antibody levels,

Poster 280 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM DEMOGRAPHIC AND CLINICAL RISK FACTORS FOR THYROID CANCER IN KOREA: KOREAN NATIONAL HEALTH INSURANCE DATABASE STUDY J. An1, T. Kim2, N. Kim1, H. Kim1, D. Choi1, Y. Park2, S. Kim1 1 Internal Medicine, Korea University College of Medicine, Seoul, Korea (the Republic of); 2Statistics, Korea University, Seoul, Korea (the Republic of) Korea has the highest incidence of thyroid cancer in the world, and thyroid cancer has become the most common cancer in Korea. We evaluated the associations between demographic and clinical factors and thyroid cancer risk. Prospective cohort data of 1,025,340 subjects were collected from the National Health Insurance Service in Korea during 2002–2010. The cohort data represented about 2.2% of the source population in 2002 (n = 46,605,433) and was sampled systematically to represent an individual’s total annual medical expenses within each of 1,476 strata defined by age, sex, eligibility status (employed or self-employed), and income level combinations. Cox regression analysis was done using sex, age, socioeconomic status (SES), smoking, alcohol consumption, body mass index (BMI), and underlying thyroid disease as independent variables. A total of 3,567 new thyroid cancers were detected during the 8year of follow-up. The risk for thyroid cancer was higher in females (HR, 3.83; 95% CI, 3.41–4.31), with higher SES (HR, 1.45; 95% CI, 1.34–1.56) than those at a mid-SES level. Compared with subjects with BMIs of 23.0–25.0 kg/m2, the risk was higher in females with BMIs of 26.5–28.0 kg/m2 (HR, 1.20; 95% CI, 1.05– 1.38) and males with BMIs of 28.0–30.0 kg/m2 (HR, 1.47; 95% CI, 1.07–1.96) and 30.0–32.5 kg/m2 (HR, 1.94; 95% CI, 1.29–2.92). The risk was significantly lower in subjects whose BMI was below 21.5 kg/m2. Interestingly, current smokers had a lower risk than non-smokers (HR, 0.60; 95% CI, 0.51–0.71); additionally, frequent drinkers ( ‡ 3 times/week) and those who drank less than twice/ week had a lower risk than non-drinkers (HR, 0.79; 95% CI, 0.73– 0.87 and HR, 0.63; 95% CI, 0.53–0.75). Thyroid cancer risk was higher in subjects with hypothyroidism (HR, 4.42; 95% CI, 3.62–

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5.39) and thyrotoxicosis/hyperthyroidism (HR, 3.85; 95% CI, 3.52–4.21) status than in those without. These patterns were consistent in male and female subjects, but were more significant in male subjects. The higher incidence of thyroid cancer in the high-SES group could reflect incidental detection due to more frequent health checkups; however, we also identified modifiable risk factors which have public health implications.

during a median 10.6 years of follow-up; incidence rate 2.7/1000 person-years. Competing risks analyses showed that DTC patients had a 2.25 fold increased risk of AF (95% CI 1.40-3.63) in the crude model and a 2.47 fold increased risk after full adjustment (95% CI 1.55–3.95). Within the DTC cohort, higher age and presence of hypertension were related to an increased AF risk. TSH level was not associated with AF, whereas a higher cumulative radioiodine dose slightly increased AF risk; SHR 1.04 (95% CI 1.01–1.08) per 50 mCi increase, after adjustment. Patients with DTC have an increased AF risk, independent from established AF risk factors. Cumulative radioiodine dose, but not TSH level, slightly contributes to the risk of AF. ECG screening for AF may be warranted during follow-up of DTC patients.

Poster 281 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM INCREASED RISK OF ATRIAL FIBRILLATION AFTER TREATMENT FOR DIFFERENTIATED THYROID CARCINOMA E.N. Klein Hesselink1, J.D. Lefrandt2, E.P. Schuurmans2, J.G. Burgerhof3, B. Groen1, R.T. Gansevoort5, A.N. van der Horst-Schrivers1, R.P. Dullaart1, I.C. van Gelder4, A.H. Brouwers6, M. Rienstra4, T. Links1 1 Endocrinology, University Medical Center Groningen, Groningen, Netherlands; 2Vascular medicine, University Medical Center Groningen, Groningen, Netherlands; 3Epidemiology, University Medical Center Groningen, Groningen, Netherlands; 4Cardiology, University Medical Center Groningen, Groningen, Netherlands; 5 Nephrology, University Medical Center Groningen, Groningen, Netherlands; 6Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, Netherlands Patients with differentiated thyroid carcinoma (DTC) have a favorable prognosis after treatment with thyroidectomy, radioiodine and TSH suppression. However, this treatment may cause long-term cardiovascular toxicity. Aim of the present study was to evaluate whether there is an increased risk of atrial fibrillation (AF) in DTC patients, and whether AF occurrence is related to DTC treatments. Incident AF was compared between 518 DTC patients and 1563 matched controls from a population based study, free of AF at baseline. A cumulative incidence curve was plotted, and Fine&Gray competing risks regression analyses with adjustment for all-cause mortality were performed. Within the DTC cohort, associations between time-varying DTC treatment variables and incident AF were analyzed. For both cohorts, mean age was 48.6 years, and 75% of patients were female. Thirty-five DTC patients (6.8%) developed AF during a follow-up of median 8.7 years, representing an incidence rate of 6.2/ 1000 person-years, see Figure 1. Of controls, 42 (2.7%) had AF

Poster 282 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM EXPRESSION OF INSULIN-LIKE GROWTH FACTOR 1 AND 2 (IGF-1 AND IGF-2), AND IGF-1 RECEPTOR (IGF-1R) IN PAPILLARY THYROID CARCINOMA E.O. DIAS1, C.T. Kanamura2, M. Basso2, C. Kliemann2, S. Marui1, R.Y. Camargo1 1 Endocrinology, University of Sa˜o Paulo Medical School, Sa˜o Paulo, Brazil; 2Pathology Departament, Adolfo Lutz Institute, Hospital das Clinicas FMUSP, Sa˜o Paulo, Brazil Insulin-like growth factor 1 and 2 are believed to play a key role in the progression of tumors, resistance to apoptosis and therapies. The insulin resistance has been associated with increased risk in developing thyroid nodules and thyroid cancer. However, few studies have evaluated the role of IGFs and their receptors on papillary thyroid carcinomas (PTC), and the relationship between IGF axis and PTC behavior. The aim of this study was to investigate the expression of IGF-1, IGF-2, and IGF-1R in PTC, including papillary microcarcinoma (PTMC), and correlate the expression data with clinical, histologic variants, TNM staging, and risk of recurrence. We selected 110 paraffin-embedded tumoral tissues from patients with PTC who underwent thyroidectomy at Hospital das Clı´nicas of Sa˜o Paulo. These patients were divided into two groups: 62 PTMC and 48 PTC > 1.0 cm. The presence and intensity of expression of IGF-1, IGF-2, and IGF-1R were evaluated through immunohistochemical staining in tumoral tissues, and non-tumoral tissues (control group). Positive cases were classified according to the numbers of staining cells in: + less than 10% of staining cells; + + in 10-50% of the staining cells, and + + + in more than 50% of staining cells. The degree of expression was classified as mild, moderate and strong. The presence and degree of IGF1, IGF2, and IGF1R staining were correlated with clinical features, histologic type, TNM staging, and risk stratification. IGF-1 and IGF-1R were expressed in 100% and 99% of PTC, and were significantly overexpressed in both PTMC and PTC > 1.0 cm, in comparison with non-tumoral tissues (control group) (p < 0.001). IGF-2 was expressed in 46.7% of PTC and had mild expression in only one non-tumoral tissue (p < 0.001). IGF1 was significantly overexpressed in PTMC on stage III and IVa and was less expressed in stage I and II. There was no significant difference on IGF1 and IGF1R expression between PTMC and PTC > 1.0 cm. IGF-2 presented greater expression in multicentric PTMC (p = 0.017), specially in stage III and IVa. In our study, both IGF-1 and IGF2 were significantly overexpressed in PTMC group in advanced stages. IGF-2 was also significantly overexpressed in PTMC multicentric tumors.

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A total of 47 intermediate risk DTC patients (32 female and 15 male, mean age at diagnosis 39.34 – 11.01 year) with unsuccessful initial RAI were included. Of these, 23 patients did not receive further treatment. Seventeen of 23 patients achieved disease-free and 6 patients had persistent disease at follow-up. Among 24 patients who were given further treatment, 10 achieved diseasefree and 14 had persistent disease. On logistic regression analysis, pre-ablation stimulated Tg < 10ng/ml and stimulated Tg at 6–18 month after RAI < 8ng/ml were the only prognostic factors that increased disease-free rate by 9.69 and 45.33 respectively (pvalue < 0.05). More than half (57.4%) of intermediate risk DTC patients achieve disease-free status over time despite unsuccessful initial RAI. Preablation stimulated Tg and stimulated Tg at 6–18 months after RAI were significant predictors for disease-free status in these patients.

Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM STIMULATED THYROGLOBULIN IS A GOOD PREDICTOR OF DISEASE-FREE STATUS IN INTERMEDIATE RISK DIFFERENTIATED THYROID CANCER PATIENTS WITH UNSUCCESSFUL RADIOIODINE ABLATION P. Lee1, Y. Huang1, L. Juan2, Y. Hsu2 1 Nuclear Medicine, Koo Foundation Sun-Yat Sen Cancer Center, Taipei, Taiwan; 2Internal Medicine, Koo Foundation Sun-Yat Sen Cancer Center, Taipei, Taiwan Despite unsuccessful initial radioiodine ablation (RAI), some patients may still achieve disease-free status over time. The aim of this study is to determine factors that predict disease-free status in intermediate risk differentiated thyroid cancer (DTC) patients with unsuccessful initial RAI. A retrospective study was performed on intermediate risk (tumor size > 4cm, tumor with aggressive histology, vascular invasion or microscopic extrathyroid invasion, cervical lymph node metastasis) DTC patients with unsuccessful RAI. Unsuccessful RAI was defined as positive diagnostic RAI scan or stimulated thyroglobulin level > 1ng/ml in the absence of antithyroglobulin level at 6–18 month after RAI. These patients received further treatment or follow-up only as appropriate. Final disease status was determined after a mean follow-up of 52.7 – 20.9 months. Patients were considered disease-free if (1) there is no imaging evidence of tumor by neck ultrasound (2) suppressed Tg level < 0.2ng/ml. Potential prognostic factors were correlated with disease-free status.

Poster 284 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM CLINICOPATHOLOGICAL CHARACTERISTICS OF 38 CASES OF PRIMARY THYROID LYMPHOMA: A MULTICENTER STUDY Y. Chai1, J. Hong3, D. Koo2, J. Yi3, H. Yu3, J. Lee3, R. Song3, H. Kwon3, S. Kim3, J. Choi4, K. Lee3 1 Surgery, Seoul National University Boramae Medical Center, Seoul, Korea (the Republic of); 2Surgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea (the Republic of); 3 Surgery, Seoul National University Hospital and College of Medicine, Seoul, Korea (the Republic of); 4Seoul National University Bundang Hospital and College of Medicine, Seongnam, Korea (the Republic of) Primary thyroid lymphoma (PTL) is a rare disease and it has been investigated in a limited number of studies. The present multicenter study evaluated the clinical features and treatment outcomes of PTL. The medical records of patients diagnosed with PTL between 2000 and 2013 in three centers were retrospectively reviewed. The study included 11 men and 27 women with a median age of 63.3 years (range, 42–83 years). The median follow-up was 56.0 months (range, 3–156 months). B symptoms and compressive symptoms were present in 2 (5.3%) and 9 (23.7%) patients, respectively. Hashimoto’s thyroiditis was present in 33 (86.8%) patients. Diagnostic modality were surgery (52.6%), needle or surgical biopsy (44.7%), and fine needle aspiration cytology

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 (2.6%). Of the 38 patients included, 16 had mucosa-associated lymphoid tissue (MALT) lymphoma, 16 had diffuse large B-cell lymphoma (DLBCL), and six had mixed MALT and DLBCL. Thirty-five (92.1%) patients had early stage (stage I/II) disease. Of the 16 MALT lymphoma patients, 14 were treated by surgery, and RT or chemotherapy was combined in five patients. Two patients received RT or chemotherapy alone. Of the six mixed MALT and DLBCL patients, three underwent surgery with chemotherapy and three underwent chemotherapy alone, RT alone, or surgery with RT. All of the 16 DLBCL patients received chemotherapy. Surgery and RT was combined in four and one patients, respectively. Chemotherapeutic agents were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab was combined in 12 patients. There was one disease-specific mortality during follow-up. The patient was treated with surgery and adjuvant chemotherapy for stage II DLBCL, and died of the disease after developing distant metastasis. The 5-year survival was 100% for MALT lymphoma (7/7) and mixed MALT and DLBCL patients (5/ 5) and 87.5% for DLBCL patients (7/8). Early stage PTL has an excellent prognosis when managed by single or combined treatment modalities. Clinicians should consider PTL in patients with underlying Hashimoto’s thyroiditis presenting with an enlarging thyroid mass.

Poster 285 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM FACTORS ASSOCIATED WITH THE SENSITIVITY OF FINE NEEDLE ASPIRATION CYTOLOGY FOR THE DIAGNOSIS OF FOLLICULAR VARIANT PAPILLARY THYROID CARCINOMA Y. Chai1, H. Suh2, J. Yi3, H. Yu3, J. Lee4, R. Song3, H. Kwon3, S. Kim3, J. Choi4, K. Lee3 1 Surgery, Seoul National University Boramae Medical Center, Seoul, Korea (the Republic of); 2Surgery, Mount Sinai Beth Israel

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3

The diagnostic accuracy of fine needle aspiration (FNA) for follicular variant papillary thyroid carcinoma (FVPTC) is lower than that for classical PTC. The aim of this study was to evaluate the factors associated with diagnostic accuracy of FNA for FVPTC. The medical records of patients who underwent thyroidectomy due to FVPTC between 2007 and 2014 were reviewed. The patients were divided into two groups according to the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC): ‘‘Group A’’ (category II, III, or IV) versus ‘‘Group B’’ (category V or VI). Total number of the enrolled patients was 225. The number of the patients with TBSRTC category II, III, IV, V, and VI was 7 (3.1%), 61 (27.1%), 49 (21.8%), 60 (26.7%), and 48 (21.3%), respectively. Finally, 117 were classified into Group A and 108 were classified into Group B. Group B was associated with older age (p = 0.005), malignant ultrasonographic features (p < 0.001), smaller tumor size (p = 0.001), extrathyroidal extension (p = 0.001), higher stage (p = 0.045), and higher BRAFV600E mutation rate (p < 0.001) compared to Group A. The proportion of Group B in each size group differed and it was 58.7% for £ 1.0 cm, 44.0% for 1.1-2.0 cm, 39.3% for 2.1-3.0 cm, and 16.7% for > 3.0 cm, respectively (p = 0.006). Proportion of Group B in the tumors £ 3.0 cm was 50.7% while it was 16.7% in the tumors > 3.0 cm (p = 0.006). In multivariable analysis, malignant ultrasonographic features and tumor size £ 3.0 cm were independent predictive factors for Group B with odds ratios of 2.922 and 4.811, respectively. To diagnosis FVPTC as suspicious malignancy or malignant is challenging and a sensitivity is low. In this study, we could demonstrate that malignant USG features and size £ 3.0 cm are independent predictive factors for FNA diagnosis of suspected malignancy or malignant. By contrast, FVPTCs > 3.0 cm without malignant features on USG may pose a diagnostic dilemma as FNA appears to have limited diagnostic value. For the diagnosis of the thyroid nodule > 3.0 cm, clinicians should have FVPTC in mind and it is necessary to discuss diagnostic lobectomy with a patient.

Poster 286 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM ENCAPSULATION IS POSITIVELY ASSOCIATED WITH OUTCOME IN FOLLICULAR VARIANT OF PAPILLARY CARCINOMA THYROID A. Pankajakshan1, C. Prasad2, P.V. Pavithran1, V. Nair1, M.V. Joy3, H. Kumar3 1 Endocrinology, Amrita Institute of Medical Sciences, Cochin, India; 2Pathology, Amrita Institute of Medical Scinces, Kochi, India; 3 Amrita Institute of Medical Sciences, Kochi, India

The proportion of Group B for tumors £ 1.0, 1.1-2.0, 2.1-3.0, and > 3.0 cm

Follicular variant of papillary carcinoma is a common but unique variant of papillary carcinoma of thyroid. Whether FVPTC behaves like follicular adenoma/carcinoma or papillary carcinoma is still under debate. Encapsulation has been shown in few studies as a predictor of outcome. We set out to study if encapsulation helps to predict the outcome in FVPTC in a south Asian population. 42 patients with follicular variant papillary carcinoma thyroid (2005–2013) with complete records and under routine follow-up

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were chosen for this retrospective analysis. Histopathology slides of all these patients were examined by a single pathologist and reclassified based on Royal College of Pathologists Feb 2014 data set for thyroid cancer reporting. For the purpose of analysis they were grouped into either encapsulated category or non-encapsulated category. Capsulated variants were further divided into those with/ without capsular invasion. Outcome at the end of 1 year was classified as disease free, excellent, acceptable and incomplete structural/ biochemical or both. The first three categories were taken together as complete /acceptable response category and three incomplete response categories were taken together as a single incomplete response category. Clinical and histological factors potentially associated with these categories were analyzed. 29 patients (69%) had encapsulated variant of FVPTC .3 patients ( 7.1%) with non encapsulated tumors had metastasis at presentation. This was associated with worse response (incomplete response) when compared with the non metastatic group (P - 0.04). 23 patients (54.7%) of the group with encapsulation had complete/acceptable response compared to 4 patients (9.5%) in the non encapsulated group (P - 0.005). Patients with incomplete response were older (Median age in years, 49 vs 42, P - 0.036 ) when compared to patients with complete/acceptable response. Presence of capsular invasion did not make a difference in the outcome in patients with capsulated variants (P–0.365). Capsulated histology in follicular variant of papillary thyroid carcinoma is associated with better outcome. Poor outcome is also associated with advanced age group and presence of metastasis.

Poster 287 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM CHRONIC LYMPHOCYTIC THYROIDITIS INDICATES LESS AGGRESSIVENESS CONVENTIONAL PAPILLARY THYROID CARCINOMA REGARDLESS OF BRAF V600E MUTATION STATUS S. Kim1, J. Woo1, J. Lee2, I. Park1, J. Choe1, J. Kim1, J. Kim1 1 Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of); 2Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea (the Republic of) It has been reported that papillary thyroid carcinoma (PTC) with chronic lymphocytic thyroiditis (CLT) is less associated with extrathyroidal extension (ETE), advanced tumor stage, and lymph node (LN) metastasis. Other studies have suggested that concurrent CLT could antagonize PTC progression even in BRAF-positive patients. The purpose of this study is to determine the clinical significance of CLT according to BRAF mutation status in conventional PTC patients. A total of 3307 pathologically proven conventional PTC patients with age older than 18 years and tumor size smaller than 4cm were retrospectively reviwed between January 2008 and December 2014. CLT was an independent predictor for low prevalence of ETE both in BRAF-negative (OR = 0.643, p = 0.015) and BRAF-positive (OR = 0.812, p = 0.024) conventional PTC patients. And also, CLT was an independent predictor for low prevalence of CLNM both in BRAF-negative (OR = 0.673, p = 0.043) and BRAF-positive (OR = 0.822, p = 0.036) conventional PTC patients.

CLT was shown to be an independent predictor for less aggressiveness in conventional PTC patients regardless of BRAF mutation status.

Poster 288 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM RECURRENCE OF PAPILLARY THYROID CARCINOMA IN PATIENTS WITH POSITIVE SURGICAL MARGINS J. Lee2, H. Yu1, J. Yi1, R. Song1, J. Jung2, H. Kwon1, S. Kim1, Y. Chai3, J. Choi2, K. Lee1 1 Endocrine Surgery, Seoul National University Hospital, Seoul, Korea (the Republic of); 2Endocrine Surgery, Seoul National University Bundang Hospital, Seongnam, Korea (the Republic of); 3 Endocrine Surgery, Seoul National University Hospital Boramae Medical Center, Seoul, Korea (the Republic of) Papillary thyroid carcinoma (PTC) patients with microscopic residual disease are classified as high-risk group of recurrence and

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aggressive treatment modalities are recommended. In this study, we analyzed the recurrence rate and risk factors of recurrence for these patients. Medical records of the PTC patients who underwent thyroidectomy from 2007 to 2013 at Seoul National University Hospital and Boramae Medical Center were retrospectively reviewed. Patients with positive microscopic resection margin and subsequently treated by total thyroidectomy with radioactive iodine treatment (RAIT) were enrolled. Patients with gross residual disease or preoperatively confirmed metastasis were excluded. Recurrence was confirmed when pathologic or imaging studies proved recurrence (anatomical recurrence). Isolated elevation of suppressed thyroglobulin (Tg) level above 2ng/ml was also defined as recurrence (biochemical recurrence). Of the total 3188 PTC patients, 269 (8.4%) satisfied the inclusion criteria. Anatomical recurrence was found in 16 (5.9%) patients and biochemical recurrence was observed in 20 (7.4%) patients when treated by total thyroidectomy with RAIT. Median follow-up period was 45.6 months (12.0-96.6). For anatomical recurrence, size larger than 1cm (p = 0.002), LN metastasis (p = 0.017) were risk factors in univariable analyses. Age and sex adjusted multivariable analysis revealed tumor size larger than 1cm as the independent risk factor for anatomical recurrence (OR 11.621, 95% CI: 1.497-90.187). For biochemical recurrence, male sex (p = 0.005), multiplicity (p = 0.001), size > 1cm (p = 0.010), lymphatic invasion (p = 0.002), vascular invasion (p < 0.001), and LN metastasis (p < 0.001) were statistically significant in univariable analyses. Multivariable analysis confirmed male sex (OR 4.566, 95% CI: 1.342-15.385), multiplicity (OR 5.498, 95% CI: 1.371-22.047), vascular invasion (OR 27.359, 95% CI: 3.699, 202.361), and LN metastasis (OR 11.771, 95% CI: 1.279, 108.298) as independent risk factors for biochemical recurrence. Patients with risk factor for recurrence should undergo closer surveillance after treatment.

weight change and BMI. Only in subgroup of female over 45 years old patients, total thyroidectomy group had higher risk of postoperative obesity than lobectomy group. (OR = 3.28, p = 0.046). Despite the perception of many patients that thyroid tissue loss after thyroidectomy is correlated with obesity, patients who had undergone total thyroidectomy did not, in fact, gain more weight than those who had undergone lobectomy. Only in subgroup of female over 45 years old patients, obesity risk was higher in total thyroidectomy group than lobectomy group.

Poster 289 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THYROID CANCER SURVIVOR AND OBESITY M. Park1, K. Park1,2, J. Yang1,2, Y. Yoo1,2, M. Cho1,2, S. Nam1, J. Sim1 1 Konkuk University Medical Center, Seoul, Korea (the Republic of); 2 Department of Surgery, Konkuk University School of Medicine, Seoul, Korea (the Republic of) Thyroidectomized patients frequently complain weight gain, identifying their thyroidectomy as the event precipitating subsequent weight gain. However, the relationship of obesity after thyroidectomy and remnant thyroid amount is not clear. The purpose of this study was to investigate how thyroidectomized patient experienced obesity postoperatively in both total and lobectomy group. We performed a retrospective chart review of subjects receiving medical care at an academic medical center From Jun. 2009 to Dec. 2013. We compared 227 patients who underwent total thyroidectomy (n = 124) or lobectomy (n = 103). We analyzed the clinical characteristics and obesity related factors of preoperative and postoperative status at each group. At baseline, patients who underwent total thyroidectomy were older than those who underwent lobectomy (mean 48.2 vs 43.4, p < 0.001). There were no significant differences in baseline weight, height and laboratory result (TSH, Glucose, Triglyceride, HDL, 25OH-Vit D). There were no significant differences in between the changes in weight and BMI from the start to completion of the study. (p = 0.284, p = 0.418) In subgroup of suppressed TSH level (TSH < 0.1lIU/mL), there were also no significant differences in both

Poster 290 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM ARE ENCAPSULATED AND INFILTRATIVE FOLLICULAR VARIANT OF PAPILLARY THYROID CARCINOMA DIFFERENT ENTITIES? A. Jesus1,2, A.U. Bastos1, H. Cuellar2, O. Curioni2, M. de Carvalho2, J.M. Cerutti1 1 Universidade Federal de Sao Paulo, Sao Paulo, Brazil; 2 Hospital Helio´polis, Sao Paulo, Brazil Papillary thyroid carcinoma (PTC) is the most common neoplasm of the thyroid gland, being the classical (CVPTC) and the follicular (FVPTC) the most common variants. For FVPTC the diagnosis of malignancy relies on the presence of the nuclear features of PTC (grooves, clearing, overlapping), which often can be borderline. Additionally, sammoma bodies and nuclear pseudo-inclusions, hallmarks of CVPTC, are very rare in these tumors, difficulting the diagnosis. Recent studies have shown that FVPTC, according to its encapsulated and infiltrative forms, has clinical and molecular differences. Encapsulated form of FVPTC rarely metastasizes to lymph node while infiltrative form shown marked intratumoral fibrosis, extrathyroid extension, positive margins, and lymph node metastasis. Encapsulated FVPTC is therefore related to the follicular adenoma/ carcinoma group of tumors, whereas infiltrative FVPTC behaves similar to CVPTC. To correlate the presence or absence of tumor capsule with clinico-pathological features of PTCs, 124 cases whose information of encapsulation was available were retrospectively analyzed. The sample set comprises CVPTC (n = 64), FVPTC (n = 50), and other variants (n = 10). Clinical and pathological features such as age at onset, gender, tumor size, presence of lymph node metastases, extrathyroidal extension, multifocality and vascular invasion were evaluated. The association between the presence or absence of tumor capsule and the clinico-pathological features was determined by Fisher’s exact test. Overall, infiltrative PTCs (n = 88) were associated with presence of extrathyroidal extension (P = 0.01) and lymph node metastases at diagnosis (P = 0.007). No patient with encapsulated PTCs (n = 36) had extrathyroidal extension, and only 5% (n = 2) of them were metastatic at diagnosis. In FVPTC, we also observed that infiltrative FVPTCs were more metastatic than encapsulated FVPTCs (23% vs 5%), however the difference was marginally significant (P = 0.134). Infiltrative PTCs seems to have a more aggressive behavior than encapsulated PTCs. Encapsulated FVPTCs showed a less aggressive phenotype. Consequently, we might consider revising the classification of encapsulated and infiltrative FVPTC as different entities.

Poster 291 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM IS THE AGE CUTOFF OF 45 YEARS THE RIGHT CHOICE FOR FOLLICULAR THYROID CARCINOMA? X. Yu, S. Jang, G. Leverson, D. Schneider, H. Chen, R.S. Sippel University of Wisconsin, Madison, WI

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Age 45 is used to establish staging in differentiated thyroid cancer including papillary (PTC) and follicular carcinoma (FTC). Due to the much higher incidence of PTC, most of the contemporary literature is on the justifiability of the age cutoff in patients with PTC. Thus, the goal of this study was to determine the impact of age in predicting prognosis specifically in patients with FTC. All FTC cases larger than 1cm in the SEER Database from 1988 to 2007 were identified. The overall- (OS) and disease-specific survival (DSS) were determined by Kaplan-Meier amongst 8 different age categories. Cox proportional hazards models were used to identify factors associated with an increased risk of death. A total of 3,949 FTC cases with surgery were identified, including 1,790 (45%) patients < 45 years. Both OS and DSS were significantly different between the various age groups. Patients under the age of 45 with FTC did remarkably well. The 15-year estimates for DSS were 100%, 99.2% and 98.4% for patients in the groups of 3–24yr, 25– 34yr and 35–44 yr, respectively. The first obvious drop in DSS was observed in the group of 45–54yr with a 15-year survival of 90.5%. DSS continued to decline with each increasing age category. The 15-year estimates were 86.8% for 55–64yr, 79.1% for 65–74yr, 68.5% for 75–84yr, and 62.0% for 85yr and above. In the multivariate analysis age increment of 10 years was an independent risk factor for unfavorable OS and DSS (HR = 2.2, 95% CI: 2.0–2.4 and HR = 1.8, 95% CI: 1.6–2.1, respectively, p both < 0.0001). Other independent risk factors for DSS included tumor size larger than 3cm (HR = 2.0, 95% CI: 1.2–3.4), extrathyroidal extension (HR = 3.2, 95% CI: 2.1–4.9), positive lymph nodes (HR = 5.2, 95% CI: 3.0–9.2) and distant metastases (HR = 7.6, 95% CI: 4.0–14.5; p all < 0.001). Age < 45 years can accurately identify low-risk FTC patients. However, in FTC patients older than 45 years OS and DSS both decrease significantly. This decline in OS and DSS is stepwise with each added decade of age leading to a worse prognosis. Age remains an important prognostic variable in FTC, but its impact on prognosis becomes more pronounced the older the patient is at diagnosis.

primary endpoint was the safety of sorafenib and treatment efficacy variables including progression free survival (PFS) and overall survival (OS) were evaluated as the secondary endpoints. Patients received sorafenib 400mg orally twice daily on a continuous schedule. Patients continued on treatment until disease progression, unacceptable toxicity or withdrawal of consent. A total of 18 patients, including 10 with ATC and 8 with MTC were enrolled from April to September in 2014. The most common any grade drug related adverse events included Palmar-plantar erythrodysesthesia syndrome (72.2%), alopecia (55.6%), hypertension (55.6%) and diarrhea (44.4%). No unexpected adverse event was observed. For the ATC patients, median PFS was 85 days (95% CI: 21-170) and median OS was 151 days (95% CI: 21-172), the objective response rate (ORR) and disease control rate (DCR) in ATC were 0% and 40%, respectively. In MTC, both median PFS and OS have not been reached at the time of this analysis, with the ORR of 25% and DCR of 75%. The toxicities reported in this study were consistent with the known safety profile of sorafenib and overall manageable by appropriate dose modification. Sorafenib has a certain clinical benefit and a potential as a new treatment option for patients with ATC and MTC in addition to RAI-R DTC.

Poster 292 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM PHASE II CLINICAL TRIAL OF SORAFENIB IN JAPANESE PATIENTS WITH ANAPLASTIC THYROID CARCINOMA (ATC) AND LOCALLY ADVANCED OR METASTATIC MEDULLARY THYROID CARCINOMA (MTC) N. Onoda1, Y. Ito2, K. Ito3, I. Sugitani4, S. Takahashi5, I. Yamaguchi6, Y. Kawakami7, K. Tsukada8 1 Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan; 2Department of Surgery, Kuma Hospital, Kobe, Japan; 3Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan; 4Department of Endocrine Surgery, Nippon Medical School, Tokyo, Japan; 5Department of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 6Product Development, Clinical Statistics, Bayer Yakuhin Ltd, Osaka, Japan; 7Medical Affairs, Oncology & Hematology, Bayer Yakuhin Ltd, Tokyo, Japan; 8Clinical Development, Specialty Medicine, Bayer Yakuhin Ltd, Tokyo, Japan Anaplastic thyroid carcinoma (ATC) and medullary thyroid carcinoma (MTC) are rare histological subtypes in thyroid carcinoma and they show poorer prognoses compared with differentiated thyroid carcinoma (DTC), due partly to limited treatment options. Sorafenib is an oral multi kinase inhibitor approved for the treatment of patients with radioiodine-refractory DTC. This study aimed to evaluate the safety and efficacy of sorafenib for Japanese patients with ATC and MTC. Japanese patients with histologically or cytologically confirmed ATC and locally advanced or metastatic MTC were eligible. The

Poster 293 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM IS POST-THERAPY SCAN NEEDED FOR ALL THYROID CANCER PATIENTS AFTER RADIOACTIVE IODINE TREATMENT? S. Niwattisaiwong, M. Skugor, C. Nasr, S. Jana Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, Cleveland Heights, OH Post-therapy whole body scan (RxWBS) is routinely obtained after radioactive iodine treatment (RAI) to detect possible metastatic foci (MF). Pre-therapy whole body scan (DxWBS) – SPECT/CT is used for cancer staging prior to RAI in many institutions. In our experience, RxWBS rarely reveals MF that were unknown from clinical information and DxWBS – SPECT/CT. The prevalence of MF newly detected by RxWBS, predictors of having new MF on RxWBS, and impact of RxWBS on clinical management are unknown. This was a retrospective chart review of 856 patients with nonmedullary thyroid cancer who underwent RAI after total thyroidectomy. All patients received DxWBS – SPECT/CT prior to RAI. Patients were excluded if they did not receive initial RAI at our institution, had anaplastic cancer, ‡ 5% uptake in thyroid bed, positive thyroglobulin antibodies, or TSH < 25 mU/dL if prepared for RAI by levothyroxine withdrawal. Baseline characteristics, pathology, TNM staging, MACIS score, ATA risk, preablative stimulated thyroglobulin (sTg) were compared between patients with and without new MF on RxWBS. A total of 331 patients were recruited in our study. Only 21 patients (6.3%) had MF newly detected by RxWBS. Out of 127 patients with low risk per ATA classification, 6 patients (4.7%) had new MF on RxWBS which were all locoregional metastasis and did not change clinical management. RxWBS upstaged disease in 12 patients (3.6%) and resulted in additional management in 1 patient. Those with new MF had significantly higher MACIS score, higher N and M stages, and tended to have distant metastasis on DxWBS – SPECT/ CT. sTg and increment of Tg after stimulation were not different between the 2 groups. Six patients (1.8%) had false positive uptakes on RxWBS, confirmed by pathology, serial Tg, and imaging. When DxWBS – SPECT/CT was used, RxWBS added little information on cancer metastasis in newly diagnosed low risk thyroid cancer patients with low MACIS score and no metastasis at

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presentation. RxWBS in such patients may not be cost-efficient. Although previous studies suggested a role for sTg in predicting disease-free status, sTg was not a reliable predictor of new metastatic findings on RxWBS in our study.

Poster 294 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM PREOPERATIVE SERUM THYROGLOBULIN COULD INCREASE THE PREDICTION FOR ADVANCED STAGE OF CARCINOMA IN THYROID FOLLICULAR NEOPLASM D. Shin1, K. Kim2, S. Hwang1, W. Lee1, Y. Jo1, E. Lee1 1 Internal Medicine, Endocrinology, Yonsei University College of Medicine, Seoul, Korea (the Republic of); 2Severance Executive Healthcare Clinic, Yonsei University Health System, Seoul, Korea (the Republic of) Cytologic examination based on fine needle aspiration biopsy cannot distinguish between follicular adenoma and carcinoma, often necessitating thyroid surgery for accurate diagnosis. The aim of this retrospective study was to find predictive factors for malignancy in patients with follicular neoplasm. Medical records of 133 patients (106 females, 27 males; mean age 47.9 – 15.8 years, range 10-85 years) with cytology results of Bethesda category IV, follicular neoplasm who were surgically treated between 2010 and 2014 were reviewed. Predictive factors for malignancy were identified by the multivariate logistic regression. Among 133 cases of follicular neoplasm, differentiated thyroid carcinoma was pathologically confirmed in 51 cases (38.3%). The other histopathological diagnosis were follicular or Hu¨rthle cell adenoma, adenomatous hyperplasia, and Hashimoto thyroiditis in 44 (33.1%), 35 (26.3%) and three (2.2 %) patients, respectively. Malignant cases showed the larger tumor size and higher preoperative serum thyroglobulin (Tg) level. According to histopathology of follicular neoplasm and cancer stage, tumor size and serum Tg level were different. With serum Tg cut off level higher than 455.9 ng/mL, specificity and positive predictive value of serum Tg for advanced stage (III or IV) of carcinoma were higher than those of tumor size (96% and 91% vs. 70% and 64%, respectively). Although the independent predictor of malignancy was tumor size of 3.0 cm (OR 9.75, P < 0.001), significant predictor of advanced stage of carcinoma was serum Tg level (OR 25.51, P = 0.014). The independent predictor of malignancy in follicular neoplasm was tumor size larger than 3.0 cm. Higher level of preoperative serum Tg level was more accurate predictor for advanced thyroid cancer stage compared to tumor size. Considering them together can be useful to predict the malignancy with advanced stage in patients with follicular neoplasm.

Poster 295 Withdrawn

Poster 296 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM PREOPERATIVE TSH LEVEL CORRELATES AGGRESSIVENESS OF PAPILLARY THYROID CARCINOMA A. Chinnama Reddy1, G. Chand1, V. Agarwal2, R. Rao2, S. Mayilvaganan1, A. Mishra1, G. Agarwal1, A. Agarwal1, A. Verma1, S. Mishra1 1 Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India; 2Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

Histological variants of Papillary Thyroid Carcinoma (PTC) have been described with variable prognosis. Thyroid Stimulating Hormone (TSH) is one of the main factors which stimulate proliferation of follicular cell-derived carcinoma cells, and has been suggested to have relationship between preoperative level of TSH and aggressiveness of PTC. The aim of this study was to analyze the relationship between serum TSH and other clinical factors with aggressiveness of the variants of PTC. We prospectively analyzed the retrospectively collected data of 204 PTC patients treated at Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, between 2009 and 2012. Two pathologists who were blinded of the clinical and previous histopathology report individually reviewed the slides. Statistical analysis was done using SPSS Version 17.0 and non-parametric tests were used. The variants were classified into different groups based on their aggressiveness. 129 patients had Classic PTC, 17 had aggressive variants (Tall cell, Columnar, Solid and Classic PTC with poorly differentiated areas), 39 had PTC of variable prognosis (Follicular, Clear cell, Oncocytic, Classic PTC with tall cell areas, and Classic PTC with solid areas) and 19 had PTC of good prognosis (Microcarcinoma and Encapsulated Macrofollicular). TSH was found to be significantly higher in aggressive variants compared to other variants (p = 0.03) (patients with known clinical hyperthyroidism or hypothyroidism on medication were excluded). Compared to nonaggressive PTC, patients with aggressive PTC more commonly presented as Multinodular Goiter (p = 0.002), had significantly larger tumor size (p < 0.001) and more lymph node metastasis (p < 0.001). Histopathologically, aggressive PTC showed significantly more capsular invasion (p = 0.005) and more extra-thyroidal extension (p = 0.08). On multivariate logistic regression analysis, only TSH level (p = 0.03) and tumor size at the time of surgery (p < 0.001) were independent predictors of aggressiveness of PTC. High TSH level and larger size of the tumor shall predict aggressiveness in the clinical setting of Papillary Thyroid Carcinoma.

Poster 297 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM IDENTIFYING RADIOACTIVE IODINE REFRACTORY DIFFERENTIATED THYROID CANCER USING 68 GA-PRGD2 PET-CT K. Yang, Y. Lin, Z. Zhu, T. Zhao Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China

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The 131I whole body scan negative metastases were dectected by 68 Ga-PRGD2 PET/CT

Integrin avb3 is a molecular target involved in the angiogenic process. In our previous study, we demonstrated that 99mTc-3PRGD2 with SPECT is a potential imaging modality for the localization and growth evaluation of radioactive iodine-refractory (RAIR) lesions in differentiated thyroid cancer (DTC). The purpose of this study was to evaluate the role of 68Ga-PRGD2, a new Integrin avb3 PET-CT imaging agent, in RAIR DTC patients, and compare the same with 18 F-FDG PET-CT. Ten DTC patients with negative 131I whole-body scan (WBS) and rising thyroglobulin (Tg) levels were enrolled. Clinical data were collected including history, 131I-WBS, CT and serological results. For patient with measurable lung metastases, at least 2 target lesions were selected on the contemporary CT images using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 to assess structural changes within the 4–6 months before the study. All patients underwent 68Ga-PRGD2 PET-CT and 18F-FDG PET-CT within an interval of one week. PET-CT analysis was done on a per-patient basis and lesion wise by 2 experienced nuclear medicine physicians. The relationship between results of 68Ga-PRGD2, 18F-FDG, structural changes were investigated. 68 Ga-PRGD2 PET-CT demonstrated metastases in 7/10 patients and 18F-FDG PET-CT in 9/10 patients, with no significant difference on McNemar analysis (p = 0.500). All of 48 target lesions, 37/48 (77.1%) were detected by 18F-FDG and 21/48 (43.8%) were seen on 68 Ga-PRGD2 PET-CT (p < 0.001). A total of 25 measurable lung metastases with contemporary CT, a negative 68Ga-PRGD2 result was significant related to the structural stable status (P < 0.05). Meanwhile, there was a significant correlation between the SUVmax and diameter of target lesions on 68Ga-PRGD2 PET-CT (r = 0.810, P < 0.05). 68 Ga-PRGD2 is not inferior to 18F-FDG PET-CT on patient based analysis for detection of RAIR DTC. It might be a predictive marker for disease progression of RAIR metastases.

Poster 298 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM CHANGE OF PREABLATIVE THYROGLOBULIN BY SERIAL MEASUREMENTS–BETTER AVOID THE IMPACT OF THYROID REMNANT T. Zhao1,2, Y. Lin1, J. Liang3, T. Li2, K. Yang1 1 Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China; 2Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao, China; 3Department of Oncology, Peking University International Hospital, Beijing, China Stimulated thyroglobulin (sTg) is a well-established tumor marker in the follow-up of differentiated thyroid carcinoma (DTC) after thyroidectomy and subsequent radioactive iodine (RAI) ablation.

The increasing and decreasing trends of preablative stimulated thyroglobulin (ps-Tg) over the change of TSH (B) and the distribution of change parameter (C) in patients with 4 different conditions (A) including distant metastasis (DM) as well as non-DM with overt, moderate and none remnant thyroid (ORT, MRT and NRT).

However, preablative sTg (ps-Tg) is nonspecific to some extent because of the impact of surgical residual tissue. We aimed to avoid the impact of thyroid remnant by serial preablative sTg measurements, and to explore the potential predictive value of the change of ps-Tg. A total of 370 consecutive DTC patients with serial measurements of ps-Tg, thyrotropin (TSH) and anti-Tg antibody (TgAb) before RAI administration were divided into distant metastasis (DM, n = 76) and non-DM (n = 294) with none, moderate and overt remnant thyroid (NRT, MRT and ORT) based on the region of interest (ROI) ratio of thyroid to whole body. The initial and last measurements of ps-Tg were marked as Tg1 and Tg2, respectively. The change between Tg1 and Tg2 were traced among each group and represented quantitatively as DTg. So do TSH and TgAb. DTg’ represents the change of ps-Tg/TSH. The single parameters (Tg1, Tg2, Tg1/TSH1, Tg2/ TSH2) and change parameters (DTg, DTg’, DTg/DTSH) were compared among different groups. Patients with ORT presented significantly higher single ps-Tg than those with MRT and NRT (all P < 0.01), with the highest Tg1 of 194.4ng/mL, which was even higher than most patients with DM (median: 104.3ng/mL), but with gradual increasing or decreasing psTg trends over the change of TSH. Narrow ranges of the change parameters were observed around zero among ORT, MRT and NRT, with no statistical difference (all P > 0.05), especially when compared with the markedly wide dispersion in DM (all P < 0.01). Compared with single ps-Tg, change of ps-Tg can better avoid the interference of thyroid remnant before RAI therapy.

Poster 299 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM OUTCOME OF RADIOIODINE THERAPY IN PAPILLARY THYROID CARCINOMA CONCURRENT WITH HASHIMOTO’S THYROIDITIS J. Li1,2, Y. Lin1, T. Yang3, T. Zhao1,2, J. Liang4

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1

Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China; 2Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao, China; 3Department of Medical Records, PUMC Hospital, Beijing, China; 4Department of Oncology, Peking University International Hospital, Beijing, China

To evaluate the impact of low dose and high dose radioiodine (131I) therapy on the clinical outcome in papillary thyroid carcinoma (PTC) patients coexisting with Hashimoto’s thyroiditis (HT). A total of 140 non-distant metastatic PTC patients were enrolled. Patients concurrent with HT(n = 84) were further divided into lowdose group (30mCi, n = 56) and high-dose group (150mCi, n = 28) according to 131I ablation dose. Patients without HT (n = 56) were enrolled as control group, and received 30 mCi 131I therapy. The thyroid remnant ablation outcome were evaluated according to 131I diagnostic whole body scan (DX-WBS), neck ultrasonography (US) and serum stimulated thyroglobulin (s-Tg), thyroglobulin antibody (TgAb) level 6–8 months after 131I ablation therapy. There were no significant difference among the three groups in terms of both clinicopathological features and postoperative remnant thyroid. When negative DX-WBS and US were deemed as successful ablation criterion, complete ablation were found significantly more in patients without HT than those with HT (94.9% vs. 82.1%, P = 0.039), but no significant difference were found between lowdose group and high-dose group with HT(85.7% vs. 82.1%, P = 0.836). When combining negative s-Tg (s-Tg < 1ng/ml with TgAb < 46IU/ml) with above two criterion to assess remnant ablation outcome, patients without HT also had a higher successful rate to achieve complete ablation compared with those coexisting HT, though no statistical significance (85.7% vs. 75.6%, P = 0.067), and no difference either between low-dose and high-dose group with HT(80.0% vs. 75.6%, P = 0.587). Non-distant metastatic PTC patients coexisting with HT has undesirable 131I ablation outcome compared with those without HT, and 131I dose increasing is unhelpful to enhance efficiency of remnant ablation for these patients with HT.

Poster 300 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM CLINICAL AND PATHOLOGICAL STAGING CONCORDANCE IN WELL-DIFFERENTIATED THYROID CANCER: A REPORT FROM THE NATIONAL CANCER DATA BASE W. Lutfi1, P. Suman1, C. Wang2, E. Liederbach1, R.A. Prinz2, D.J. Winchester2, T. Moo-Young2 1 Surgery, NorthShore University HealthSystem, Evanston, IL; 2 NorthShore University HealthSystem, Evanston, IL The accuracy of clinical stage (cStage) compared to pathological stage (pStage) in thyroid cancer is unclear. We hypothesized that certain patient and tumor factors are often associated with inaccuracies in clinical staging. The National Cancer Data Base was queried to identify 27,473 patients ‡ 45 years old with cStage I through IV well-differentiated thyroid cancer who underwent surgery from 2008–2012. Patients with metastatic disease were excluded. Upstage was defined as change to any higher stage; downstage was similarly defined. There were 16,302 (59.3%) cStage I patients; 4,829 (17.6%) cStage II; 4,329 (15.8%) cStage III; and 2,013 (7.3%) cStage IV. The overall upstage rate was 15.1%, the downstage rate was 4.6%, and the no change rate was 80.2%. For cStage I, II, and III, there was a 16.4%, 25.5%, and 6.0% upstage rate, respectively. Of the upstaged patients, the change in cStage was a result of a T-category upstage in 40.8% of patients, N-category upstage in 36.3%, and both T and

N-category upstage in 22.9% of patients. On multivariate analysis adjusting for patient, hospital, and tumor factors (table), patients were more likely to be upstaged if they were male, aged 45–54 years old, of Hispanic or Asian ethnicity, had papillary histology, had tumors sized 2.1-4 cm on final pathology, had total thyroidectomy, had positive margins, or had multifocal disease. On subgroup analysis, the overall upstage rate for male patients was 19.4%; 17.1% for patients aged 45–54 years old; 19.4% and 21.6% for Hispanic and Asian race/ethnicity respectively; 16.8% for papillary (vs. 7.4% for follicular); 25.3% for tumors sized 2.1-4cm, 16.5% for total thyroidectomy; 30.5% for positive margins; and 18.9% for multifocal disease (all p < 0.05). Patients who were upstaged received adjuvant radiation therapy more frequently compared to those that were not upstaged (74.0% vs. 44.4%, p < 0.001). Approximately 20% of the time cStage is discordant to pStage. Specific patients are at an increased risk of upstage and should be advised pre-operatively of the accuracy of their clinical stage and its prognostic and treatment implications.

Poster 301 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM AFIRMA BRAF TESTING ACROSS CYTOLOGY SUBTYPES AMONG 9,188 THYROID FNA BIOPSIES DEMONSTRATES HIGH PREVALENCE OF BRAF V600E MUTATIONS IN BETHESDA V AND VI NODULES R.J. Monroe, J.W. Hanna, N. Sindy, M. Pagan, P.S. Walsh, J. Huang, K. Travers, B. Campbell, G.C. Kennedy, R.T. Kloos Veracyte, South San Francisco, CA In May 2014, Afirma BRAF, a validated and highly accurate mRNA classifier for BRAF V600E mutation status, was introduced for Bethesda III/IV cytologically indeterminate nodules with Afirma Gene Expression Classifier (GEC) Suspicious results, and for Bethesda V/VI Suspicious for Malignant and Malignant thyroid FNAs for which the GEC is not performed. FNAs referred for Afirma Thyroid FNA Analysis receive cytopathology evaluation by Thyroid Cytopathology Partners (TCP) in Austin, TX, a high volume cytopathology practice specializing exclusively in thyroid FNA diagnosis. In this large FNA data set, we evaluated the frequency of BRAF V600E mutations across cytology subtypes. Thyroid FNA cytology was evaluated among 69,114 FNA samples submitted for Afirma Thyroid FNA Analysis between May 1, 2014 and April 30, 2015. Afirma BRAF was performed only when requested. We compared the rate of Afirma BRAF positive diagnoses in this large FNA data set to that reported in the test validation by Diggans J, et al. Pac Symp Biocomput 2015. Afirma BRAF was requested on 9,188 (13%) FNA biopsy samples if the cytology diagnosis was Bethesda III/IV and GEC Suspicious, or cytology diagnoses Bethesda V/VI. Afirma BRAF was performed on 1,352 GEC Suspicious Bethesda III/IV FNAs. Sixty-six (5%) of these samples were Afirma BRAF positive and 1,283 (95%) were negative. Among Bethesda V/VI cytology samples, 327 Afirma BRAF tests were

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performed. Nineteen (5.8%) samples did not yield a result due to insufficient mRNA, 181 (55%) were positive, and 127 (39%) were negative. Afirma BRAF had a positive call rate in routine clinical practice consistent with the test validation results reported by Diggans of 1% in Bethesda III/IV (p = .065) and 55% in Bethesda V/VI (p = 0.42). It is established that BRAF V600E testing alone cannot rule-out cancer, but this mutation has a high specificity for carcinoma and may assist physicians in determining the extent of surgery among patients with malignant thyroid nodules. While BRAF V600E mutation is relatively uncommon among cytologically indeterminate nodules, when applied selectively to those indeterminate nodules with GEC Suspicious results the frequency nearly doubles to 5%.

1

Poster 302 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM FIRST META-ANALYSIS ANALYZING COMPARATIVE THYROIDECTOMY CLINICAL OUTCOMES ACCORDING TO ENERGY DEVICES IN INTERNATIONAL AND ASIAN STUDIES Y. Ma1, L. Metz1, Y. Koh2, E. Choi2 1 Johnson & Johnson Medical, Asia Pacific, Singaopre, Singapore; 2 Otrhinolaryngology, Yonsei University College of Medicine, Seoul, Korea (the Republic of) Thyroidectomy is one of the most frequent procedures in endocrine surgery globally. Because thyroid gland has an extensive vascular network adjacent to recurrent laryngeal nerves (RLN) and parathyroid glands, effective hemostasis and accurate dissection are essential for successful outcome. To understand the global and Asian clinical outcomes of thyroidectomy using different energy technologies, a meta-analysis was conducted reviewing publications in English and Asian languages. Literature search was conducted in international and Asian database for publications between Jan 2008 and Sep 2014. Inclusion criteria are: 1) randomized clinical trial (RCT) of thyroidectomy; 2) comparative clinical outcomes using Harmonic ultrasonic device (UHS) versus electrocautery (CE). Thirty-nine RCTs including 20 Asian studies were identified. Patients were treated for nodular goiter, thyroiditis, Grave’s disease, and/or thyroid cancers. In 39 RCTs, average OR time was reduced 27.19 minutes in the UHS vs CE group (P < 0.00001). An average reduction of 21.6mL intraoperative blood loss in the UHS vs CE group based on 25 RCTs (P < 0.00001). Twenty-six RCTs reported an average of 35% or 40.6mL reduction of postoperative drainage in the UHS vs CE group (P < 0.00001). Six RCTs reported that 24-hour postoperative pain score was 1.66 points lower in the UHS group (P < 0.00001). In 27 RCTs, the relative risk (RR) of transient hypocalcemia reduced 23% in the UHS group (P = 0.002). In 28 RCTs, the RR of transient RLN paralysis reduced 71% in the UHS vs CE group (P = 0.06). The event rates were low for permanent hypothyroidism and permanent RLN paralysis and not different between the two groups. Sub -group analysis on Asian studies showed similar results. Better outcome and clinical efficiency are consistent in UHS group in global and Asian studies. This suggests the advantage of ultrasonic technology in thyroidectomy performed by experienced surgeons, irrespective of patients’ race and surgeons’ techniques.

Poster 303 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM TIMING OF RADIOIODINE THERAPY DOES NOT INFLUENCE THE RESPONSE TO INITIAL TREATMENT IN DIFFERENTIATED THYROIDCANCER PATIENTS R.S. Scheffel1,2, J.M. Dora1,2, A.L. Maia1,2

Endocrine Division, Hospital de Clı´nicas de Porto Alegre, Porto Alegre, Brazil; 2Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil Radioactive iodine (RAI) is usually part of the management of differentiated thyroid cancer (DTC). Nevertheless, the impact of the time interval between total thyroidectomy (TT) and RAI on the response to initial therapy remains a matter of discussion. From a cohort of 880 DTC patients, 541 individuals whom received RAI and had disease status after the initial therapy available were allocated in group A (RAI administered in less than 6 months after TT) or group B (more than 6 months). Disease free was defined as no clinical, biochemical or imaging evidence of DTC at follow-up. Multiple logistic regression was performed using response to initial therapy as dependent variable and age, cervical metastasis, 2009 ATA risk and time interval between TT and RAI as independent variables. Of the 541 patients evaluated, 432 (79.9%) were women and 458 (84.7%) had papillary thyroid carcinoma. The TNM stage were as follow: 317 (58.6%) patients were in stage I, 62 (11.5%) in stage II, 66 (12.2%) in stage III and 81 (15.0%) in stage IV. The median time interval between TT and RAI was 6 months (IQR 6) and 291 patients were included in group A and 247 in group B. Group A received RAI at 3 months (interquartile range - IQR 2) and group B at 12 (IQR 43.2) months. There were no differences on gender, histological type, tumor size, distant metastasis and TNM status (all P > 0.10). However, patients in group B were older (47.2 vs. 42.9 years P = 0.01), had more cervical metastasis (73.7 vs. 59.1%, P = 0.002) and were more commonly classified as low ATA risk (53.4 vs. 43, P < 0.001). In the first year after initial therapy, 59.4% and 66.0% of patients in groups A and B, respectively, were disease free (P = 0.14). Importantly, the percentage of patients classified as disease free was similar even when analyzing the subgroup of high risk ATA patients (n = 71, 9.8 vs. 10.0%, P = 1.0). These figures do not change after a median of follow-up of 5 (IQR 6) years. In the multiple logistic regression the time interval between TT and RAI was not associated with persistent disease status (OR 1.20 95%CI 0.21-6.67). Timing of RAI therapy does not seem to interfere on the response to initial therapy in DTC.

Poster 304 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THYROID BIOPSY TECHNIQUE TO ENHANCE DIAGNOSTIC YIELD FOR CIRCUMSCRIBED SOLID THYROID NODULES WITHOUT MALIGNANT SONOGRAPHIC FEATURES S. Hahn1, J. Shin1, H. Lim2, S. Jung3 1 Radiology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea (the Republic of); 2Radiology, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea (the Republic of); 3 Radiology, Seoul St.Mary‘s Hospital, Seoul, Korea (the Republic of); The aim of this study was to evaluate whether the ultrasonographyguided core needle biopsy (US-CNB) technique containing the nodule, capsular portion and surrounding parenchyma was more effective than a conventional method in enhancing diagnostic yield for circumscribed solid thyroid nodules without malignant sonographic features. This retrospective comparative study evaluated 26 thyroid nodules in 26 consecutive patients between 2006 and 2010, which were biopsied using a conventional method, and 61 nodules from 60

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 patients, which were biopsied using a new US-CNB technique in 2013. The patients enrolled in this study presented with circumscribed solid thyroid nodules without malignant sonographic features, diagnosed as nondiagnostic or atypia/follicular lesions of undetermined significance at previous cytology. The US-CNB results of the two groups were compared. The rate of inconclusive US-CNB results was 34.6% (9/26) in the conventional method group and 11.4% (7/61) in the new technique group (P = .018). There was no significant difference in the mean size of the nodules between the two groups (P = .134). The malignancy rate was 33% (3/9) for the conventional group and 52% (27/52) for the new technique group (P = .473). The most common pathology was follicular variant of papillary thyroid carcinoma as malignant and follicular adenoma as benign. For circumscribed solid nodules without malignant sonographic features with indeterminate cytology, the US-CNB technique containing the nodule, capsular portion and surrounding parenchyma is more effective in enhancing diagnostic yield compared with a conventional method that biopsies the intranodular portion.

Poster 305 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM INCIDENTALLY DISCOVERED TUMORS CAN ONLY PARTLY EXPLAIN THE RISING INCIDENCE IN THYROID CANCER IN SWEDEN - A POPULATION-BASED STUDY P. Bu¨mming1, J. Dahlberg2, K. Gunnarsdottir3, E. Holmberg3, S. Jansson2 1 Surgery, Skaraborg Hospital, Sko¨vde, Sweden; 2Surgery, Sahlgrenska University Hospital, Go¨teborg, Sweden; 3Regional Cancer Centre Western Sweden Healthcare Region, Go¨teborg, Sweden Except for Scandinavia, there have been numerous reports on a worldwide increase in thyroid cancer incidence. Increased diagnostic activity has been suggested as the main contributing factor. The aims of this study were to analyze thyroid cancer incidence in Sweden over the last decade and mode of tumor detection in a long-time iodinesufficient, well-defined geographic population of 1,5 million inhabitants in Western Sweden. From the National Cancer Registry (NCR), all patients diagnosed with thyroid cancer in Sweden 2001 - 2012 were included. A detailed analysis of all patients (n = 969) with thyroid cancer in the region of Western Sweden was performed during this time period. All patient files (n = 461) from two centers in Western Sweden were scrutinized. Three time periods were selected (2001–2002, 2006 and 2011–2012). Variables studied were age, sex, tumor size, -stage, -type, and mode of tumor detection. The annual age-standardized thyroid cancer incidence in Sweden increased with 6.2% and 4.5% for males and females respectively. In Western Sweden, corresponding figures were 9.9% and 11.9%. Sex distribution, age, tumor types and tumor size did not change over time in the cohort. Twenty percent of the tumors were < 1 cm at diagnosis. The proportion of incidentally detected tumors was 9, 43 and 37 percent in the three time periods studied. The incidence of thyroid cancer is increasing for both sexes also in Sweden; in the Western Region the increase in female incidence is more pronounced. The increasing proportion of incidentally detected tumors during the study period may partly explain the rising incidence. In spite of this, no increase was observed for tumors < 1cm. Our results indicate contribution of other causative factors, than just better detection, to explain the increasing incidence.

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Poster 306 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM FROM NODE-PICKING TO IPSILATERAL CENTRAL NODE DISECTION IN CN0 PAPILLARY THYROID CARCINOMA H.H. Ching, Y.R. Anderson, M.S. Jones, A.E. Barber, R.C. Wang Surgery, University of Nevada School of Medicine, Las Vegas, NV In the treatment of nodal disease for cN0 papillary thyroid carcinoma (PTC), node-picking (NP) has largely been replaced by prophylactic central nodal dissection (CND). Ipsilateral CND (iCND) may reduce the complications of bilateral CND (bCND) while preserving its oncologic benefits. This study aims to compare outcomes of these three approaches (NP, bCND, iCND) in the management of PTC. Patients who underwent total thyroidectomy (TT) for cN0 PTC diagnosed on US-guided FNA were retrospectively reviewed. Exclusion criteria included preoperative evidence of nodal metastases by physical exam, ultrasound, or CT scan. From 2003 to 2006, patients underwent TT + NP. From 2006 to 2009, patients underwent TT + bCND. From 2010 to 2015, patients underwent TT + iCND in which ipsilateral paratracheal and bilateral pretracheal and superior mediastinal dissections were performed. A total of 69 patients were identified, with 23, 27, and 19 undergoing NP, bCND, and iCND, respectively. bCND yielded positive nodes significantly more often than NP (67% vs 30%, p = 0.02) but not iCND (47%, p = 0.23). In tumors < 1cm, there were positive nodes in 17% vs. 57% vs. 33% of patients for NP, bCND, and iCND respectively. In tumors ‡ 1cm, positive nodes were found in 45% vs 70% vs 54% of patients for NP, bCND, and iCND. bCND and iCND patients were similar in their likelihood of yielding positive nodes, regardless of tumor size. In those with positive nodes, bCND yielded significantly more positive nodes than NP (4.6 vs 1.7, p = 0.02) but not iCND (4.6 vs 4.0, p = 0.7). No recurrent nerve injuries were found. No patients after NP required calcium supplementation after 6 months, compared with 7% of bCND and 5% of iCND. Serum thyroglobulin levels after radioactive iodine treatment were undetectable in 80% of NP, 91% of CND, and 84% of iCND cases. Occult nodal disease is found and resected more frequently by bilateral CND than NP in < 1cm and ‡ 1cm cN0 PTC. Ipsilateral CND was not significantly different from bilateral CND in terms of frequency or quanitity of positive nodes resected. CND may have a greater incidence of hypoparathyroidism than NP, and unstimulated thyroglobulin levels were similar between the three groups after radioactive iodine ablation.

Poster 307 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM MALIGNANT AND BENIGN RADIOIODINE UPTAKE IN THE ABDOMEN AND PELVIS EXPLORED WITH SPECT/CT IN PATIENTS WITH DIFFERENTIATED THYROID CANCER: A PICTORIAL REVIEW R. Ciappuccini1, C. Raboutet1,2, N. Aide1, E. Quak1, E. Meyer1,3, S. Bardet1 1 Nuclear Medicine Department and Thyroid Unit, Centre Baclesse, Caen, France; 2Radiology Department, Centre Baclesse, Caen, France; 3Oncology Department, Centre Baclesse, Caen, France Single-photon emission computed tomography with CT scan (SPECT/CT) acquisition is of added value to explore radioiodine (RAI) uptake at neck and thorax level in patients with differentiated thyroid cancer (DTC) on post-ablation whole-body scintigraphy (WBS). A SPECT/CT acquisition focusing on the abdomen or pelvis

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is also justified in the presence of equivocal RAI uptake. We present a pictorial review of malignant and benign RAI uptake at abdomen or pelvis level on WBS with SPECT/CT in a cohort of DTC patients. In 420 consecutive DTC patients who underwent RAI ablation between January 2006 and December 2012, we retrospectively reviewed those patients in whom abdomen or pelvis SPECT/CT was performed because of equivocal focus on WBS. Abdomen or pelvis SPECT/CT was performed in 34 patients (8%). RAI uptake was related to distant metastases in 9 patients (2%) including 7 in the bone (pelvic bone, n = 5; vertebrae, n = 2) and 2 in the muscle. In contrast, SPECT/CT images enabled to rule out metastases in the remaining 25 patients. RAI foci were localized in the bowel (n = 13), in liver cysts (n = 4), in a kidney cyst (n = 1), in cervix nabothian cysts (n = 4), in a cystadenoma of the ovary (n = 1), in the gallbladder (n = 1) and in hydrocele of tunica vaginalis testis (n = 1). A pictorial review of some of the cases is presented. Equivocal RAI uptake at abdomen or pelvis level is rare on postablation WBS. Complementary SPECT/CT is warranted to discriminate between malignant and benign lesions.

presentation was more aggressive in children regarding extrathyroidal extension/vascular invasion (56.7%vs.47.8%,p = 0.0001), lymph node metastasis (67.3%vs39.1%, p = 0.0001) and the presence of distant metastasis (26.9%vs 7.9% p = 0.0001), respectively. No significant differences were seen in tumor size. There were 13 cancer- related deaths (2.8%) in adults and there were no cases in the children’s group. The persistence of the tumor was more frequent in children (32.7% vs. 22.1%, p = 0.0001) but progressive disease was more frequent in adults (11.9% vs 3.8%, p = 0.001). This study showed that despite the more aggressive presentation when compared to adults with similar tumors, children had a better outcome in the long term. Only 3.8 % of children evolved to progressive disease and there were no death in this group. Further studies are needed to clarify the behavior and biology of the tumor in children in order to understand these differences and individualize therapy.

Poster 308 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE CLINICAL PRESENTATION OF DIFFERENTIATED THYROID CARCINOMA IN CHILDREN IS MORE AGGRESSIVE AT PRESENTATION THAN IN ADULTS DESPITE BETTER CLINICAL OUTCOMES: A BRAZILIAN COHORT B.P. Pires1, R. Corbo1,2, M. Vaisman1, F. Vaisman1,2 1 Endocrinoloy, UFRJ, Rio de Janeiro, Brazil; 2 INCA, Rio de janeiro, Brazil Differentiated thyroid carcinoma is the most common endocrine tumor but represent only 2% of all cancers in children. Clinical presentation seems to be more aggressive than in adults despite the very good long term prognosis. However there are still few studies with this population. The aim of this study was to evaluate a large Brazilian cohort of pediatric patients compared to adults. Data from 575 patients treated and followed at the National Cancer Institute Brazil diagnosed with differentiated thyroid cancer (471 adults and 104 children) was retrospectively reviewed. Prognostic factors such as size, extrathyroidal extension/vascular invasion and presence of lymph node metastasis and/ or distant metastasis were analyzed. A comparison of tumor behavior has been done for both groups. The mean age was 13.3 years for children and 45 years for adults, in both groups the majority were females. The median follow-up was 8 (1-32) years for children and 10 (1–35) years for adults. Clinical

Poster 309 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM EXAMINER: A RANDOMIZED, DOUBLE-BLIND STUDY TO EVALUATE THE EFFICACY AND SAFETY OF CABOZANTINIB AT TWO DOSE LEVELS IN PATIENTS WITH PROGRESSIVE, METASTATIC MEDULLARY THYROID CANCER (MTC) ´ lvarez-Escola2, J. Capdevila3, Y. Yaron1, C. A C. De La Fouchardie`re4, B. Eriksson5, D. Gross6, E. Kapiteijn7, B. Keam8, A. Klochikhin9, T. Links10, M. Schlumberger11, J. Tennvall12, D. Clary1, A. Borgman1, F. Parnis13 1 Exelixis, Inc., South San Francisco, CA; 2Hospital Universitario La Paz, Madrid, Spain; 3Hospital Universitario Vall d’Hebron, Barcelona, Spain; 4Centre Le´on Be´rard Centre Re´gional de Lutte Contre Le Cancer Rhoˆne Alpes, Lyon, France; 5Akademiska Sjukhuset I Uppsala, Uppsala, Sweden; 6Hadassah Medical Center, Jerusalem, Israel; 7Leids Universitair Medisch Centrum, Leiden, Netherlands; 8Seoul National University Hospital, Seoul, Korea (the Republic of); 9Regional Clinical Oncology Hospital, Yaroslavl, Russian Federation; 10Universitair Medisch Centrum Groningen, Groningen, Netherlands; 11Institut Gustave Roussy, Villejuif, France; 12Ska˚nes Universitetssjukhus Lund, Lund, Sweden; 13 Adelaide Cancer Centre, Kurralta Park, SA, Australia Cabozantinib (cabo) is a tyrosine kinase inhibitor approved in the US and EU for the treatment of patients (pts) with progressive, metastatic MTC. In the phase 3 registrational study (EXAM) in which pts were randomized to cabo or placebo, the starting dose was 140 mg cabo qd. The primary analysis for EXAM demonstrated a statistically significant improvement in PFS (p < 0.0001) with median PFS of 11.2 months for the cabo arm versus 4.0 months for placebo (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.19 to 0.40) (Elisei et al, JCO 2013). Dose reductions to manage adverse events occurred in 82% of cabo-treated patients, and 46% of pts were reduced to a dose of 60 mg qd. Efficacy as measured by PFS was maintained in subjects who had a last recorded dose of 60 mg. In addition, RET and RAS mutational status appeared to influence the degree of PFS and OS benefit achieved in cabo-treated pts. In this global, randomized, double-blind study (EXAMINER, NCT01896479), 188 subjects with progressive, metastatic MTC will be randomized (1:1) to cabo at 140 mg qd or cabo at 60 mg qd. Eligible pts must have measurable disease that has progressed within the previous 14 mo. A tumor tissue sample collected within 6 mo of randomization or evidence of the presence of a RET mutation is required. Tumor samples will be analyzed for RET and RAS mutations and pts will be stratified based on RET M918T status. Pts will be treated until progressive disease per RECIST 1.1 or intolerable

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toxicities. Adverse event seriousness, severity per CTCAE v. 4.0, and relationship to study treatment will be assessed by the investigator. The primary endpoint is PFS per independent review, to determine whether PFS in pts treated with cabo at 60 mg qd is noninferior to pts treated with 140 mg. The non-inferiority margin was chosen to preserve 50% of the benefit of cabo at 140 mg demonstrated versus placebo in the EXAM study. The secondary endpoint is objective response rate, and additional endpoints include safety, pharmacokinetics and correlation of tumor mutational status with clinical response. The study is open and accrual is ongoing. This study will compare the efficacy and safety of cabozantinib at two different dose levels.

The diffuse sclerosing variant (DSV) is considered aggressive subtypes of papillary thyroid cancer (PTC). The aim of this study was to analyze the clinicopathologic features and outcomes of patients with DSV. Between January 2009 and October 2012, 166 patients with DSV of PTC were analyzed. Clinical and histological features (sex, age, tumor size,multifocality, bilaterality, extrathyroid extension, and local and distant metastases) were evaluated in all patients, as well as any persistent disease and the patients’ disease status at last observation. The rate of central and lateral neck metastasis was 91.0% and 65.1%. The group of lateral neck metastases was significantly related to these clinicopathologic features in multivariate analysis; the portion of age < 45 (p = 0.022), size > 1cm (p < 0.002), extrathyroidal extension (p = 0.043) and central node metastasis (p = 0.020). The mean stimulated thyroglobulin of patients underwent lateral neck dissection was similar with patients who did not undergo (14.1 mg/ dL vs. 10.5mg/dL, p = 0.675). The DSV of PTC was associated with more aggressive disease at the time of surgery. However, the age ‡ 45 patients had primary tumor size £ 1cm, without extrathyroidal extention of primary tumor and no central node metastasis may not be undergone prophylactic lateral neck dissection.

Poster 310 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM TRANSAXILLARY ROBOTIC MODIFIED RADICAL NECK DISSECTION: A 5-YEAR ASSESSMENT OF OPERATIVE OUTCOMES AND ONCOLOGICQQUALITY M. Kim, S. Lee, J. Choi, T. KIM, E. Ban, C. lee, S. Kang, J. lee, J. jeong, K. Nam, W. Chung Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Seoul, Korea (the Republic of)

Poster 312 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM PROGNOSIS OF PAPILLARY THYROID CANCER WITH EXTRATHYROIDAL EXTENSION ACCORDING TO THE LOCATION OF PRIMARY TUMOR S. Kim, H. Kim, H. Chang, B. Kim, H. Chang, C. Park Surgery, Gangnam Severance Hospital, Seoul, Korea (the Republic of)

Robotic modified radical neck dissection (MRND) using a gasless transaxillary approach has been reported to be a safe and meticulous technique in patients with papillary thyroid carcinoma (PTC) and lateral neck node metastasis (N1b). Few studies, however, have assessed the long-term oncologic outcomes of robotic MRND in these patients. This study compared the operative outcomes and 5year oncologic results of robotic MRND with conventional open procedures. Between September 2007 and February 2010, 193 patients with N1b PTC underwent total thyroidectomy (TT) and MRND by a single surgeon. Of these, 42 (21.8%) underwent robotic procedures and 151 (78.2%) underwent conventional open procedures. All patients received 3.7-5.5 GBq radioactive iodine (RAI) ablation, posttherapy whole-body scans (TxWBS), and diagnostic WBS (DxWBS) during follow-up. Postoperative outcomes and 5-year oncologic quality were compared in these two groups. Mean follow-up period was 66.0 months (range 60–90 months). The number of retrieved cervical lymph nodes (LNs) (p = .121) and postoperative ablation success rate (p = .709) were similar in the two groups. Serum thyroglobulin concentrations after TSH stimulation (p = .055) and recurrence rates in the robotic and open groups (1/39 [2.6%] vs. 6/141 [4.3%]; p = .326) were similar during the 5-year follow-up period; of the 7 patients with recurrence, 5 had regional lymph node metastasis and 2 had bilateral lung metastases. Operative outcomes and 5-year oncologic quality were similar after robotic and conventional open MRND. Prospective randomized clinical trials with long-term follow-up data are needed to validate these results.

Extrathyroid extension (ETE) has been recognized as a prognostic factor in papillary thyroid carcinoma (PTC). Even though there were posterior extensions to larynx, trachea, esophagus, or recurrent laryngeal nerve, complete resection with no microscopic residual tumor (R0 resection) could be performed. In this study, we investigated the prognostic significance of location of primary tumor in PTC with ETE. Between January 2007 and December 2009 at Gangnam Severance Hospital (Seoul, Korea), we identified 1,078 patients who had PTC with ETE and 1,199 patients with no or microscopic ETE. In 1,078 patients, we compared patients with anterior and posterior ETE. The mean follow-up period was 6.4 years. Although patients with ETE showed a significantly worse disease free survival (DFS) rate than those with no or microscopic extension (P < 0.001), there was no difference in the DFS rate between patients with anterior extension and those with posterior extension in case of R0 resection. Extrathyroidal extension of primary tumor appears to be an important prognostic factor for PTC, however the location of primary tumor could have little or no prognostic significance in case of R0 resection.

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Poster 313

Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM A DIFFUSE SCLEROSING VARIANT OF PAPILLARY THYROID CARCINOMA, CLINICAL AND PATHOLOGIC FEATURES AND OUTCOMES OF 166 CASES S. Kim, H. Kim, H. Chang, B. Kim, H. Chang, C. Park Surgery, Gangnam Severance Hospital, Seoul, Korea (the Republic of)

Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM PROGNOSIS AFTER BRAIN METASTASIS FROM DIFFERENTIATED THYROID CARCINOMA F. Saito, T. Uruno, Y. Ogimi, C. Masaki, J. Akaishi, C. Tomoda, K. Matsuzu, A. Suzuki, K. Ohkuwa, H. Shibuya, W. Kitagawa, M. Nagahama, K. Sugino, K. Ito Department of Surgery, Ito Hospital, Tokyo, Japan

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CSS and DMFS

In patients with differentiated thyroid carcinoma (DTC), lung and bone metastases sometimes occur. However, brain metastasis (BM) is extremely rare. Because most previous reports about BM from DTC included a relatively small number of cases, the clinical characteristics and outcomes of BM are still unclear. This study aimed to evaluate the prognostic factor for long survival after BM from DTC. Between 1965 and 2013, 25 patients were diagnosed with BM from DTC. Only one patient of them is still alive. To identify the prognostic factors for longer survival after BM, the medical records of these 25 patients were retrospectively reviewed. The median age at BM diagnosis was 66 years. Typical symptoms associated with BM had appeared in 21 patients (84%). The Karnofsky Performance Status (KPS) was good ( ‡ 70) in 10 patients and poor ( £ 60) in 15 patients. Seven patients had a single intracranial lesion of BM, 6 patients had 2 or 3 lesions, and 9 patients had 4 or more. Eleven patients did not receive any treatment for BM, and 14 patients underwent surgical resection, radiation therapy, or both. One-year and 5-year disease-specific survival rates after diagnosis of BM were 28% and 10.6%, respectively. Good KPS ( ‡ 70), small number of intracranial lesions ( £ 3), and treatment for BM were prognostic factors for long survival on univariate analysis (p < 0.05). On multivariate analysis, only treatment for BM was significant. The patient with BM is thought to have poor prognosis. Although, the prognosis of BM was poor, surgery or radiation therapy may provide better survival.

Poster 314 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM CLINICAL MANIFESTATION AND OUTCOMES OF PATIENTS WITH WIDELY INVASIVE FOLLICULAR THYROID CARCINOMA PRESENTING WITH TUMOR THROMBUS F. Saito1, T. Uruno1, Y. Ogimi1, T. Maeda1, C. Masaki1, J. Akaishi1, K. Matsuzu1, A. Suzuki1, K. Ohkuwa1, H. Shibuya1, W. Kitagawa1, M. Nagahama1, K. Sugino1, K. Kameyama2, K. Ito1 1 Department of Surgery, Ito Hospital, Tokyo, Japan; 2Division of Diagnostic Pathology, Keio University Hospital, Tokyo, Japan Microscopic vascular invasion is frequently observed in patients with widely invasive follicular thyroid carcinoma (WIFTC). However, macroscopic blood vessel invasion (i.e., tumor thrombus) is rare. Clinical manifestations and outcomes of patients with tumor thrombus are still unclear. This study assessed the clinical outcomes of WIFTC patients with tumor thrombus.

Between January 2000 and September 2014, 126 patients with WIFTC underwent surgery at Ito Hospital. These patients were classified into two groups: WIFTC with tumor thrombus (group T) and WIFTC without tumor thrombus (group C). Fifteen patients of group T and 111 patients of group C were studied. We compared the clinical features and outcomes between the two groups and evaluated the impact of the tumor thrombus on outcomes in patients with WIFTC. The diagnosis of the tumor thrombus was made preoperatively in seven patients (46.7%), intraoperatively in eight patients (53.3%) and postoperatively in one patient (6.7%). The median serum thyroglobulin (Tg) levels were significantly higher in group T (4054 vs. 552 ng/ml, p = 0.0024). All 15 patients in group T had extrathyroidal invasion to the adjacent tissue, while only three of 111 (2.7%) patients in group C had extrathyroidal invasion to the adjacent tissue (p < 0.0001). The incidence of clinical lymph node metastases was significantly higher in group T (86.7% vs 20.7%, p < 0.0001), and the incidence of distant metastasis at the time of initial diagnosis was also significantly higher in group T (60% vs 9.9%, p < 0.001). The causespecific survival (CSS) as well as distant metastases-free survival (DMFS) rates were significantly shorter in group T (p < 0.05). Patients with WIFTC presenting with tumor thrombus had aggressive clinical manifestations and worse outcomes than those of WIFTC patients without tumor thrombus.

Poster 315 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM DIGITAL IMAGE ANALYSIS OF BENIGN AND MALIGNANT THYROID NODULES D.D. Nowak Endocrinology T&S, Linden, NJ There are several sonographic features that can indicate the presence of thyroid cancer. Examples include echogenicity, presence of microcalcifications or if the nodule is taller than wide. Presence of multiple factors indicates a high index of suspicion, however we ask if there is a possibility that echogenicity alone is enough to predict malignancy. Digital image analysis of an ultrasound image makes it possible to determine the average color of a given thyroid nodule. Each pixel on the ultrasound image has a value from 0 to 255 which represents its color, with 0 being absolute black and 255 being absolute white. It is then possible to compare average colors, and distribution of color, of benign and malignant thyroid nodules and the surrounding thyroid tissue. Thirty-four cases of patients with documented thyroid nodule biopsies were selected for this retrospective study. Seventeen of these

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A-129 The aims of this retrospective single center study were to determine whether the intensity of FDG uptake was correlated to tumor progression or tumor growth rate (TGR) expressed as the percentage of increase in tumor size during a one year-period (TGR) and to TgDT. Fifty five patients (47 radioiodine refractory) affected by DTC with at least one distant metastasis measuring ‡ 1cm in diameter, evaluated by FDG-positron emission tomography/computed tomography (PET/CT), at least one CT or another FDG-PET/CT performed more than 3 months after the reference FDG-PET/CT in the absence of systemic or local treatment between the two imaging procedures were included. The two-year survival was 87% for patients with SUV max < 5 and 66% for patients with SUV max > 5. The median TgDT was 232 days (range 26–1611). One hundred fifty six metastatic lesions located in the lung (63), neck lymph nodes (28), chest lymph nodes (42), bone (11), liver (2) and other sites (10) were studied. The median size was 16 mm, median SUV max: 8.7, median metabolic volume: 3.7 cm3. The median one-year TGR by lesion was 16% (range 0- > 100%). SUV max and metabolic volume of each lesion were not correlated to their one-year TGR (p = 0.28 and p = 0.77 respectively) irrespective of their location or their size. The intensity of FDG uptake is not correlated to morphological tumor progression assessed by one-year TGR and cannot be used as a surrogate marker of morphological progression.

patients had malignant nodules, confirmed by FNA biopsy and subsequent pathological exam post thyroid surgery. The remaining cases had documented benign thyroid nodules. The ultrasound images were all taken on a single ultrasound machine with identical settings. All nodules were cropped with an image editing software. These images were then analyzed with Mathematica software to determine the average color of the nodules. Each nodule had an average color, a histogram of the pixel color distribution and a measured value for entropy. A filter was also applied to the pixel data to fill in gaps within the pixel distribution. The same analysis was performed on surrounding thyroid tissue. The average color of all selected malignant thyroid nodules was 45.9 – 12.8. The average color of all selected benign thyroid nodules was 43.4 – 12.8. The pixel distribution for the majority of cases was single peaked and resembled a normal distribution. Filtered images did not significantly change these findings. There was no significant difference in echogenicity between the selected cases of malignant and benign nodules. This indicates that echogenicity of the nodule alone should not be used as a single ultrasound measure that could indicate whether the nodule is malignant or benign.

Poster 316 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE INTENSITY OF 18FDG UPATKE IS NOT A SURROGATE MARKER OF MORPHOLOGICAL TUMOR PROGRESSION IN PATIENTS WITH METASTATIC THYROID CANCER M. Terroir, B. Franc¸ois, I. Borget, M. Schlumberger, S. Leboulleux Gustave Roussy, Villejuif, France In patients with metastatic differentiated thyroid carcinoma (DTC), thyroglobulin doubling time (TgDT) and fluorodeoxyglucose (FDG) uptake as well as age, tumor size and iodine uptake are prognostic factors for survival. High FDG uptake is a poor prognostic factor. Consequently, lesions with high FDG uptake are often considered aggressive and may be monitored and treated with local modalities.

Poster 317 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM HURTHLE CELL CARCINOMA: ANGIOINVASION AND TUMOR’S SIZE ARE ASSOCIATED WITH WORSE CLINICAL OUTCOME J. Simo˜es-Pereira, D. Macedo, M. Silva-Vieira, M. Bugalho Endocrinology, Instituto Portugueˆs de Oncologia de Lisboa, Francisco Gentil, Lisboa, Portugal Hurthle Cell Carcinoma (HCC) prognosis is controversial especially when compared with other differentiated thyroid cancers. Its worst outcome has been associated with a lower avidity for iodine. We aimed to compare patients with and without persistent clinical disease (CD) in terms of demographic, clinic and histological characteristics and analyze the response to Radioactive-iodine therapy (RAI) in the CD group. Patients were identified through the database of our center’s Pathology Department encompassing the period 2000–2014. Clinical files were retrospectively reviewed aiming to compare the subgroups with and without CD at last follow-up [locoregional disease (LRD), distant metastases (M1) and CCH-related death (CCH-D)]. Logistic regression was performed considering CD as the outcome and histological and demographic characteristics as independent variables. Statistical analysis was performed in SPSSv21. One hundred and ten patients (82% women) were included with a median follow-up period of 4 (interquartile range = 5) years; mean age at diagnosis was 57 – 15 years. Total thyroidectomy (TT) was performed in 92%, TT + lymph-node dissection in 3% and hemithyroidectomy in 5%. At presentation, 30% were in stage I, 34% in II, 25% in III and 10% in IV. RAI was offered to 92% of the patients. At last follow-up, 65% were disease-free, 8% were lost to follow-up, 2% had only measurable serum thyroglobulin and 25% had CD - 2% LRD, 11% M1 and 12% CCH-D. The table below summarizes the differences between those with and without CD. Among patients with CD, 65% had one or more RAI treatments further to the ablative one. Of these patients, 88% had negative post-therapeutic Whole Body Scan (WBS), despite the evidence of structural/metastatic disease in other conventional exams. On univariate analysis, male sex, capsule’s wide invasion, angioinvasion and tumor’s size > 40

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mm were associated with CD. On the adjusted model of logistic regression, only tumor’s size (p = .02) and angioinvasion (p = .01) remained significant. In sum, angioinvasion and tumor’s size portend a worse clinical outcome. Dissociation between the WBS and conventional imaging exams favors the hypothesis of a lower avidity for iodine.

Poster 318 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM FOLLOW-UP TIME NEEDED FOR TGAB + DIFFERENTIATED THYROID CANCER (DTC) PATIENTS TO CONVERT TO TGAB-NEGATIVITY FOLLOWING SUCCESSFUL SURGERY RELATES TO INITIAL TGAB CONCENTRATION AND NOT RADIOIODINE (RAI) REMNANT ABLATION C. Spencer1, S. Fatemi2, C. Nguyen1, J. LoPresti1, I. Petrovic1 1 Medicine, University Southern California, Pasadena, CA; 2 Endocrinology‘, Kaiser Permanente, Panorama City, CA Thyroglobulin autoantibodies (TgAb), present in *25% of DTC patients, interfere with Tg immunometric assay (IMA) measurements compromising serum Tg follow-up monitoring. Post-thyroidectomy(Tx) TgAb trends reflect changes in Tg-secreting tissue (normal remnant/tumor)*. Patients rendered disease-free by surgery typically display a declining TgAb trend, often becoming TgAbnegative**. How baseline TgAb and/or RAI remnant ablation influence TgAb-positive to TgAb-negative conversion time is unclear. This study evaluated relationships between baseline [0–3 month post-Tx] TgAb and post-operative TgAb trends [falling ( ‡ 50%), stable, or rising ( ‡ 50%)], and whether RAI influences the postoperative time needed to render TgAb undetectable in response to successful surgery. Chart review selected 1333/1554 DTC patients with ‡ 2 years post-operative follow-up monitoring with non-elevated TSH, who displayed TgAb-positivity on one or more occasions (Kronus > 0.4 kIU/L). Patients were grouped according to baseline TgAb concentration: very low (VL = 0.5-0.9, n = 225), low (L = 1.0-9.9, n = 708), medium (M = 10-99, n = 287) or high (H = ‡ 100, n = 113) kIU/L and history of RAI administration. TgAb fell in 76%, remained stable in 13% and rose in 11%. Most patients had low baseline TgAb: 17, 53, 22 and 9% for VL, L, M and H groups, respectively. Conversion from TgAb-positivity to TgAbnegativity was more likely the lower the baseline TgAb concentration: 63, 34, 21 versus 3% for VL, L, M versus H groups, respectively. Postoperative follow-up time needed for TgAb to become undetectable (in addition to serum Tg < 1 ng/mL) was directly related to the baseline TgAb concentration: medians: 0.6, 1.4, 4.2 versus 10.1 years for VL, L, M versus H groups, respectively, and did not appear to be influenced by RAI treatment. Follow-up time needed for serum TgAb to become undetectable (in addition to serum Tg < 1.0 ng/mL) following successful surgery for DTC, relates to the baseline TgAb concentration and does not appear to be influenced by RAI remnant ablation. *Chiovato Ann

Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM IDENTIFICATION OF THE AGK-BRAF FUSION ONCOGENE IN SPORADIC THYROID PEDIATRIC CANCER M.C. Cordioli1, L. Morais2, L. Sisdelli2, G. Carvalheira2, M.D. Alves3, R. Delcelo3, O. Monte4, C.A. Longui4, A.N. Cury4, J.M. Cerutti2 1 Endocrinology, Universidade Federal de Sa˜o Paulo- UNIFESP, Sa˜o Paulo, Brazil; 2Genetic Bases of Thyroid Tumor Laboratory, Universidade Federal de Sa˜o Paulo- UNIFESP, Sa˜o Paulo, Brazil; 3 Department of Pathology, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil; 4Endocrinology, Irmandade da Santa Casa de Miserico´rdia de Sa˜o Paulo, Sa˜o Paulo, Brazil Thyroid cancer is the fastest increasing cancer worldwide in all age groups. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer in both adults and children, accounting for 75-90 % of diagnoses. There has been suggested that distinct genetic alterations may explain the differences in the clinical presentation and outcomes of thyroid cancer in children and adolescents compared to adults. The aim of this study is to investigate the occurrence of the fusion oncogene AGK-BRAF, recently described in radiation-exposed pediatric PTC, in a cohort of predominantly sporadic pediatric PTC. The series consists of 33 pediatric PTC and 16-matched lymph node metastases (LNM). All of the patients were £ 18 years of age at the time of diagnosis. Twenty-nine cases had no history of radiation exposure (sporadic PTCs) and 4 cases had a history of previous radiation exposure. Primary tumors and matched LNM were screened for the presence of the AGK-BRAF fusion transcript by RTPCR. The cDNA generated from PCCL3 cells expressing the fusion transcripts was used as a positive control. To confirm the identity of the amplified products, randomly selected samples positive for the presence of the fusion transcripts were sequenced. Break-apart twocolor FISH was used to confirm the gene fusion event. Of the 33 primary PTC analyzed, the AGK-BRAF fusion gene was identified in 3 out of 29 (10%) of sporadic cases and 1 out of 4 (25%) cases exposed to radiation. LNM was available for one of four AGKBRAF positive PTC and tested positive for the fusion gene. Three cases harboring AGK-BRAF were classical PTC and 1 was follicularvariant of PTC. This study confirmed the presence of AGK-BRAF in radiation exposed pediatric PTC and also described the presence of this fusion oncogene in sporadic pediatric PTC. Understanding the molecular events underlying pediatric thyroid cancer may help determine the tumor’s biological behavior and ultimately allow molecular prognostication.

Poster 320 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM TREATMENT AND SURVIVAL OF PATIENTS WITH INSULAR THYROID CARCINOMA: 508 CASES FROM THE NATIONAL CANCER DATA BASE T.A. Pezzi1, V. Sandulache2, C. Pezzi3, A. Turkeltaub1, L. Feng4, M. Cabanillas5, M.D. Williams6, S. Lai7 1 Baylor College of Medicine, Houston, TX; 2Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX; 3Department of Surgery, Abington Health, Abington, PA; 4Biostatistics, Bioinformatics and Systems Biology, MD Anderson Cancer Center, Houston, TX;

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Endocrine Neoplasia & Hormonal Disorders, MD Anderson Cancer Center, Houston, TX; 6Department of Pathology, Head and Neck Section, MD Anderson Cancer Center, Houston, TX; 7 Otolaryngology, MD Anderson Cancer Center, Houston, TX Insular thyroid carcinoma (ITC) is a rare but aggressive thyroid malignancy. There remains uncertainty regarding the disease characteristics, optimal treatment and overall survival. Patients with ITC reported to the National Cancer Database from 1998–2012 were evaluated for patient, tumor and treatment characteristics. For comparison, patients with papillary (PTC), follicular (FTC) and anaplastic thyroid carcinoma (ATC) were also identified and evaluated. Of 355,028 cases of thyroid malignancy, 508 (0.14%) patients with ITC made up the study group. The mean age was 61.4 years. Positive regional lymph nodes were found in 20.7% and 16.1% had clinical evidence of distant metastasis at presentation. The 1 and 5 year survival was 89% and 57% respectively. Compared to PTC and FTC, patients with ITC cancer were older, more often male, had larger tumors, were more likely to present with distant metastasis, less likely to have a R0 resection, more likely to receive external beam radiation and chemotherapy, and had significantly lower survival. Multivariate cox regression analysis with hazard ratios (HR) identified age > 65 years (HR: 1.70), presence of at least one comorbidity (HR: 1.56), positive lymph nodes (HR: 1.82), the presence of metastasis (HR: 3.26), positive margins (HR: 2.43), and radioactive iodine therapy (HR: 0.57) as significant and independent predictors of survival in ITC. ITC is a rare thyroid cancer that has a significantly worse prognosis compared to well-differentiated thyroid malignancies. Treatment recommendations should incorporate the use of radioactive iodine following complete surgical resection and clearance of involved nodal basins.

Poster 321 Thyroid Cancer Monday & Tuesday Poster 9:00 AM DUAL RET AND HRAS MUTATIONS IN MEDULLARY THYROID CARCINOMA J. XU1,2, G. Cote1, E. Grubbs3, S.I. Sherman1 1 Endocrine Neoplasia AND Hormonal Disorders, MD Anderson Cancer Center, Houston, TX; 2 Endocrinology, Baylor College of Medicine, Houston, TX; 3 Surgical Oncology, MD Anderson Cancer Center, Houston, TX Introduction: Both RET and RAS gene-activating mutations play an important role in the tumorigenesis of sporadic medullary thyroid carcinoma (MTC), but they are generally mutually exclusive events. Here we report a patient with activating somatic mutations found in both genes in an aggressive metastasis. Case Presentation: 73-year-old man was diagnosed with stage IVA T3N1bM0 sporadic MTC at age 65. He underwent total thyroidectomy and right neck dissection requiring sacrifice of the internal jugular vein. Pathology revealed an 8.3 cm primary tumor and 22 positive lymph nodes. Six years later, he was found to have hepatic lesion of 1.1 cm and right paratracheal and upper mediastinal lymph nodes. A right paratracheal node progressed rapidly and was resected. Fifty-gene somatic analysis of the metastatic node identified mutations RET Cys630Arg in exon 11 and HRAS Gln61Arg in exon 3. Discussion: Although clinicopathologic features appear not to differ between sporadic tumors bearing either RET or RAS mutations, the aggressiveness of metastatic MTC in our case could be due to synergistic or additive effects of activating both RET and RAS. One MTC case with dual mutations has been previously re-

A-131 ported, carrying RET Cys618Arg and HRAS Gly13Val, though no clinical description of the case was provided. Limiting somatic RAS testing to tumors lacking known RET mutations would not identify such a dual mutation. The combination of a RET and VEGFR inhibitor with tipifarnib (an inhibitor of RAS farnesylation, which is essential for HRAS oncogenic activity) may be appropriate systemic therapy for such a patient at the time of distant progression, as suggested in a recent phase I trial that combined sorafenib with tipifarnib. Conclusion: Concomitant mutations of RET and RAS might contribute to the aggressive presentation of metastatic MTC. Dual inhibition of RET and RAS pathways could be optimal targeted therapy for patients harboring both mutations.

Poster 322 Thyroid Cancer Monday & Tuesday Poster 9:00 AM CLINICAL IMPLICATIONS OF TUMOR VOLUME RATIO FOR LYMPH NODE METASTASIS IN PAPILLARY THYROID CANCER I. Park, S. Shin, J. Woo, J. Choe, J. Kim, J. Kim Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of) Lymph node metastasis in patients with papillary thyroid cancer (PTC) has been known to increase local recurrence and the lymph node ratio can influence disease-specific mortality. The purpose of this study is to clarify the role of thyroid weight and volume in lymph node metastasis of PTC. We retrospectively reviewed the medical records of patients who underwent total thyroidectomy with bilateral central compartment neck dissection (CCND) performed by a single surgeon between March 2013 and May 2015. We measured the weight and volume of each thyroid after it was removed en bloc. After confirming the pathologic result, we checked the tumor size (width, length, height) and tumor volume ratio (TVR = calculated tumor volume/measured thyroid volume). A total of 402 patients underwent total thyroidectomy with CCND and eighty patients had lateral neck lymph node metastasis. Among them, 271 can confirm tumor volume and the mean TVR was 0.059 – 0.086. Thyroid weight and volume were larger in patients with lateral neck lymph node metastasis and a positive correlation was presented with the number of metastatic central lymph nodes. TVR was significantly higher in patients with cervical lymph node metastasis (p = 0.001), especially lateral neck lymph node metastasis (p = 0.044). In univariate analysis, the thyroid weight, volume and TVR were not associated with central lymph node metastasis but TVR ‡ 0.08 was a predictor of lateral neck lymph node metastasis (OR; 4.146, 95% CI 2.068-8.312, p < 0.001). Multivariate analysis showed that TVR was an independent risk factor for lateral neck lymph node metastasis after adjusting for variables, including weight of thyroid (OR; 3.099, 95% CI 1.386-6.932, p = 0.006). In our study, TVR was considered an independent risk factor with lateral neck lymph node metastasis in patients with PTC. Therefore, we suggest that patients with TVR ‡ 0.08 should be monitored closely for lateral neck lymph node metastasis.

Poster 323 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM PRESERVATION OF VASCULATURE AROUND THE PARATHYROID GLAND CAN LOWER THE RATE OF HYPOCALCEMIA RELATED TO THYROIDECTOMY I. Park, J. Woo, J. Choe, J. Kim, J. Kim

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Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)

Skip metastasis were found in 12 (10%) patients, nine female and three male, with a mean age of 44.8 – 10.5 years. The mean tumor size was 15.5 – 9.4 mm. Among these 12 patients, 3 patients (25%) were had family history of PTC and 11 patients (91.7%) were had extrathyroidal extension of primary tumor. There was no difference in tumor size, multifocality, bilaterality, and stage, however, the skip metastasis was occurred commonly with primary tumors of the upper pole (58.3 vs. 20.8 %; p = 0.039) and more frequently found at a single level (58.3 vs. 12.5 %; p = 0.018) compared with the non-skip metastasis group. No patient occurred recurrence of thyroid cancer in both groups (46.2 – 25.8 vs. 44.2 – 26.8 months). Skip metastasis occurs in a minority of patients with PTC. However the surgeon should perform precise preoperative evaluation to look lateral lymph node metastasis if the tumor located in upper pole.

Preserving parathyroid function after total thyroidectomy is a major concern of thyroid surgeons because hypocalcemia remains one of the most common complications and its prevention is not easily controlled. The purpose of this study was to introduce our procedure to preserve the vasculature around the parathyroid glands and report subsequent outcomes. We adopted a technique of separating the longer segment of a vessel more distally located from the thyroid gland to preserve the parathyroid. We reviewed retrospectively medical records of 1,411 patients who underwent total thyroidectomy with or without lateral neck dissection between January 2006 and June 2014. We divided the patients into three groups according to the time period: group A, 2006-2008 (before applying the vasculature preserving technique), group B, 2009–2011 (since starting the procedure), and group C, 2012-2014. We analyzed the incidence of hypoparathyroidism among the three groups and the risk factors influencing its development. The rates of transient and permanent hypoparathyroidism in group A were 25.4% and 4.3%, respectively. However, the incidence of hypoparathyroidism decreased significantly over time after applying the vasculature preserving procedure. Transient hypoparathyroidism developed in 4.8% of group C patients, and only four (0.7%) of 565 patients needed a calcium supplement, despite that a greater number of patients who underwent total thyroidectomy combined with lateral neck dissection were included. Although female sex and lateral neck dissection tended to increase the rate of transient hypoparathyroidism, a multivariate analysis showed that the vasculature preserving procedure was the only significant risk factor related with postoperative hypoparathyroidism. It is essential to preserve parathyroid vasculature and the parathyroid gland itself to maintain its postoperative function. Blood flow to the parathyroid gland is primarily in a distal-to-proximal direction from the vessel on the thyroid. Therefore, separating the longer segment of a vessel located more distally from the thyroid gland reduced the incidence of hypocalcemia.

Poster 324 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM SKIP METASTASIS IN PAPILLARY THYROID CARCINOMA: A SINGLE-CENTER STUDY WITH PROPENSITY SCORE MATCHING ANALYSIS S. Tae, G. Bae, Y. Kim Surgery, Ulsan university hospital, Ulsan, Korea (the Republic of) Regional lymph node metastases (LNM) develop in 40–90% patients with papillary thyroid carcinoma (PTC). Generally, metastases first involve the nodes in the central compartment and then lateral compartment of the neck. However, skip metastasis to the lateral compartment, leaping the central compartment, has also been reported in PTC. This study was performed to compare the patterns and characteristics of skip metastasis versus non-skip metastasis in PTC using a propensity score matching analysis. From March 2007 to July 2014, a total 119 patients underwent total thyroidectomy with bilateral central lymph node dissection and ipsilateral selective lymph node dissection (level II-V) for PTC. All patients were performed therapeutic lateral neck lymph node dissection by single surgeon. The clinicopathologic characteristics were reviewed and statistically analyzed. Propensity score matching was applied at a ratio of 1:2 comparing the skip metastasis (n = 12) and non-skip metastasis (n = 24) groups.

Poster 325 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM MULTIFOCALITY PREDICTS POOR OUTCOME OF PATIENTS WITH INSULAR THYROID CANCER: A RETROSPECTIVE CLINICOPATHOLOGICAL STUDY L. Liu1,2, D. Li1, L. Dong1, Y. Yu1, M. Gao1 1 Dept. of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; 2Dept. of Otorhinolaryngology (ENT), Tianjin 3rd Central Hospital, Tianjin, China Insular thyroid carcinoma (ITC) is a rare type of thyroid malignancy whose aggressiveness and propensity to local recurrence differ it from other thyroid malignancies. However, data pertaining to its clinical characteristics is still lacking. In this study, we retrospectively analyzed 10 ITC patients treated and followed in Tianjin Medical University Cancer Institute and Hospital during Apr 2007 to Aug 2010, and compared the clinical and pathological characteristics and long-term follow-up with 2221 patients with papillary thyroid carcinoma. These ten ITC cases comprised 7 women and 3 men, with an average age of 46 years at the time of diagnosis (range, 16–69 years). Of all the 10 ITC patients, 6 patients are multifocal ITC (mITC) and showed cervical lymph node metastasis to the lateral compartment, while the other 4 solitary ITC (sITC) had regional metastasis confined to level VI or even no cervical metastasis at all. The ITC group had more frequent retrosternal metastasis (40% vs 7.0%, P = 0.0006), recurrent laryngeal nerve invasion (40% vs 4.3%, P < 0.0001), esophageal invasion (50% vs. 1.8%, P < 0.0001), a higher proportion of distant metastasis (50% vs. 3.1%, P < 0.0001), and vascular invasion (50% vs. 1.0%, P < 0.0001). While the presence of lymph node metastasis and multiple nodularity showed no significant difference. Interestingly, although patients with ITC are lacking in number to perform survival analysis, we still noticed that all the four single focal ITC patients (4/4, 100%) have survived much longer (at least 45 months) than those who have multinodularity (5/6, 83.3%), indicating that the presence of multifocality in ITC might be risk factor for long time survival of ITC patients. Patients with insular thyroid carcinoma have a poorer outcome compared with patients with papillary thyroid carcinoma. The presence of multifocality might be a risk factor for long time survival of ITC patients.

Poster 326 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE FACTORS FOR PREDICTING THE PATTERN OF LYMPHATIC METASTASIS IN PAPILLARY THYROID CANCER : PROSPECTIVE STUDY K. Cho, M. Kim The Catholic University of Korea, Uijeongbu-si, Korea (the Republic of)

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To evaluate the predictive factors and the distribution of lymphatic metastasis and explore the surgical management modality for papillary thyroid carcinoma. We prospectively evaluated the clinical and pathological data of 265 patients (56 male and 209 female), who undergoing bilateral paratracheal lymph node (LN) dissection, or selective neck dissection (II-V) of involved side with radiological positive cervical node. Analysis of central LN involvement and clinical/molecular predictive factors of nodal metastasis were performed. For the central compartment, 81/265(30.6%) of cases showed metastatic disease at the ipsilateral paratracheal nodal site, and 11(4.2%) at the contralateral paratracheal site. Only ipsilateral paratracheal node metastasis was significantly correlated with contralateral paratracheal node metastasis (p = 0.02). For the lateral compartment, 65 patients who were clinical N1b received selective neck dissection, and 30 patients bilaterally. 25 patients (38.4 %) showed multilevel disease, and 20 (7.5%) showed skip lateral metastasis. Sex (male) and extracapsular invasion were significantly correlated with N stage (p = 0.02 and 0.03, respectively). When ipsilateral central LN metastasis is present, the possibility of contralateral central LN involvement is high. Therefore, complete bilateral central LN dissection would be a proper option. Lateral cervical metastasis frequently occurs in patients of male sex with extracapsular invasion, and with ipsilateral central LN metastasis. More precise pre-operative evaluation should be needed in those patients for lateral LN metastasis.

follow up of 46 months, 53 (8%) patients developed recurrent disease (1 local and 52 nodal). On multivariate analysis, nodal metastases (N1, OR 6.0), contralateral multifocality (OR 3.5) and treatment with RAI (OR 3.7) were independent risk factors for recurrent disease. Microscopic positive margin was not a risk factor for recurrence. Microscopic positive margin found only on final pathological analysis does not increase the risk of recurrence in T1-T2 WDTC. Clinicians should interpret such pathology findings accordingly when considering further surveillance and treatment decisions such as the use of radioactive iodine ablation.

Poster 327 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM MICROSCOPIC POSITIVE TUMOR MARGIN DOES NOT INCREASE THE RISK OF RECURRENCE IN PATIENTS WITH WELL DIFFERENTIATED THYROID CANCER W.P. Kluijfhout1,2, J.D. Pasternak1,3, N. Seiser1, J. Kwon1, J. Lim1, W.T. Shen1, J.E. Gosnell1, E. Khanafshar4, Q. Duh1, I. Suh1 1 Endocrine Surgery, University California San Francisco Medical Center, San Francisco, CA; 2Endocrine and Oncological Surgery, University Medical Center Utrecht, Utrecht, Netherlands; 3General Surgery, Toronto University Medical Center, Toronto, ON, Canada; 4 Department of Pathology, University California San Francisco Medical Center, San Francisco, CA Incomplete surgical resection with gross positive tumor margin increases the risk of recurrence in patients with well differentiated thyroid cancer (WDTC). It is not clear however, whether microscopic positive margin found only on final pathology has similar implications on patient outcomes. We conducted a single-institution retrospective review of all patients undergoing total thyroidectomy for T1-T2 WDTC ( January 2000 to January 2010) in a high-volume tertiary university medical center. Factors that may influence the risk of locoregional or distant recurrence were evaluated by univariate and multivariate analysis, including age, sex, tumor size, tumor subtype, angio-invasion, capsular invasion, positive margins, ipsilateral and contralateral cancer multifocality, and nodal metastases at initial surgery. Of 1000 consecutive patients undergoing surgical resection for WDTC, 684 T1-T2 cancers were included that underwent total thyroidectomy. Mean age was 46 years, and 81% were women. Mean tumor size was 1.4 cm. Of this total cohort, 78 (11%) patients had positive resection margin, all of which were microscopic (R1) as opposed to gross (R2). There were no differences in patient characteristics between patients with or without microscopic positive margins. RAI was given in 47/78 (60%) patients with positive margins versus 312/606 (51%) patients without positive margins. After a mean

Poster 328 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM PAIN AND PSYCHOLOGICAL OUTCOMES FOLLOWING TOPICAL LIDOCAINE CREAM USE IN THYROID FNA BIOPSY R.P. Davis, J. Lewi, M. True, I. Folaron, S. Graybill, J. Colburn, D. Carlsen, A. Paulus Department of Medicine, San Antonio Military Health System, San Antonio, TX Thyroid nodule fine needle aspiration (FNA) is the gold standard for thyroid cancer assessment. Clinical practice varies in the utilization of topical anesthesia during this procedure. Prior small studies were completed to address if anesthesia produces significant reductions of patient pain. Kim et al., 2009, studied fifty South Korean patients. They reported a paradoxical effect of increased pain following lidocaine skin infiltration vs placebo during ultrasound guided FNA. Gursoy et al., 2007, conversely reported significantly less pain during FNA following EMLA cream application. These trials focused solely on pain. Pain and clinical psychological outcomes have not been studied. This process improvement project quantified the patient’s procedural pain and psychological outcomes of general clinical importance. A short post-procedural questionnaire was developed to capture basic demographics and pain level (0-10). Four five-point Likert scaled (5 - strongly agree, 1- strongly disagree) questions were asked to include pain tolerance, met expectations, future FNA acceptance, and overall satisfaction. The questionnaire was administered to a total of 39 patients during a lidocaine (LMX 4% cream) non-availability baseline period and 72 patients following lidocaine procurement. Patients could accept or decline anesthesia. Comparisons were made between three groups: baseline, users (n = 44), and non-users (n = 28). One-tailed independent means t-testing was conducted between groups for significant differences in pain level and Likert scores. No significant difference between groups was noted for pain, pain tolerance, future FNA acceptance, or overall satisfaction. A slightly significant, p = 0.044, decrease in met expectations score was noted for the baseline group compared to the lidocaine non-users. Surprisingly, the lidocaine users showed a strongly significant, p = 0.005, decrease in met expectations score compared to the non-users. There was a non-significant trend toward lower scores for all other questions comparing users to non-users as well. Topical lidocaine cream provides no significant pain improvement during thyroid FNA biopsy and may lead to negative psychological outcomes due to overpromise underdelivery.

Poster 329 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM A SYSTEMATIC REVIEW OF LONG TERM TREATMENT RELATED MORBIDITY IN PATIENTS WITH DIFFERENTIATED THYROID CANCER O. Edafe1, S. Balasubramanian2,3, W. Parker2,1

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1

Medicine, Sheffield Teaching Hospitals, Sheffield, United Kingdom; 2Department of Surgical Oncology, University of Sheffield, Sheffield, United Kingdom; 3General Surgery, Sheffield Teaching Hospitals, Sheffield, United Kingdom Differentiated thyroid cancer (DTC) occurs in relatively young patients and is associated with a good prognosis and long survival. Management involves thyroidectomy, radioiodine therapy and long term thyroid hormone suppression therapy (THST). The long term effects of treatment and the interaction between subclinical hyperthyroidism and potential permanent hypoparathyroidism are poorly understood. We sought to examine the available evidence. A PubMed search using the search terms ‘‘Thyroid Neoplasms’’ AND (‘‘Thyroxine’’ OR ‘‘Hypocalcemia’’ OR ‘‘Thyrotropin’’) was carried out. Original English language articles from the last 30 years studying the morbidity from TSH suppression and hypoparathyroidism following standard treatment for DTC were retrieved and reviewed by two authors. Of 2866 studies, 64 papers including 4354 patients were analysed. Studies reported on a range of skeletal (33 studies, 1567 patients), cardiovascular (17, 957), psychological (8, 580) and other outcomes (10, 1348). [BS(S1] In those with DTC on THST 8/25 relevant studies showed a reduction in bone density and bone turnover markers were elevated in 13/22. Skeletal effects were more marked in post-menopausal women than other groups. There was no evidence of increased fracture risk and little data on hypoparathyroidism. 4/5 studies showed increased left ventricular mass index on echocardiography and one study showed a higher prevalence of atrial fibrillation. There was little difference in basic physiological parameters and limited literature on symptoms/significant events. Some studies showed higher SF-36 and HADS scores in DTC patients and there was some evidence of reduced insulin sensitivity and increase in coagulability. There is limited literature regarding long-term DTC treatment related morbidity, particularly regarding effects of long-term hypocalcaemia. Most studies have focused on surrogate markers and not on clinical outcomes. A large prospective study on defined clinical outcomes would help to characterise the morbidity more definitively.

Poster 330 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM FACTORS ASSOCIATED WITH EXTERNAL BEAM RADIATION FOR DIFFERENTIATED THYROID CANCER USING THE SURVEILLANCE, EPIDEMIOLOGY, AND END RESULTS DATABASE D. Schaerer, R. Orosco, K. Brumund, C. Choe, D. Chang, L. Mell, M. Bouvet Head and Neck Surgery, University California, San Diego, San Diego, CA External beam radiation (EBR) is an infrequently used treatment modality for differentiated thyroid cancer (DTC) that is generally reserved for patients with advanced tumors, poor surgical candidates, and cases where the cancer has lost radioactive iodine (RAI) avidity. We sought to evaluate factors associated with EBR usage. The Surveillance, Epidemiology, and End Results (SEER) database was queried to identify patients with DTC as their only malignancy for the period 2000–2009. Multivariate analysis was performed to evaluate for predictors of patients receiving EBR. Covariates included: age, ethnicity, sex, and tumor/nodal/metastasis (TNM) stage. Of the 496,110 patients identified with DTC, 4.5% of males, and 2.2% of females received EBR (N = 13,893 and 48,217, respectively). On bivariate analysis, African Americans were more likely to

receive EBR (3.6%) compared to Caucasians (2.7%) and other races (2.4%) (P = 0.001). EBR utilization increased with higher T and N stages. Compared to 28.2% of M1 patients, only 2% of M0 patients received EBR (P < 0.005). Multivariate analysis demonstrated increasing likelihood of EBR with advanced age—patients in their 80’s being 2.59 times more likely to receive EBR than those in their 30’s (P < 0.005). TNM staging demonstrated similar trends (T4 OR 4.6, P < 0.005; N1b OR 2.0, P < 0.005; M1 OR 5.3, P < 0.005). The only statistically significant racial trends on multivariate were lower likelihood of EBR usage for Asian (OR 0.4, P = 0.001), Hispanic (OR 0.7, P < 0.005) and other races (OR 0.6, P < 0.005) compared to Caucasians. African American race did not achieve statistical significance OR 1.1, P = 0.3. The usage of EBR is more likely in older patients with advanced TNM staging, particularly with M1 disease. There were racial disparities that cannot be accounted for by the variables available in this dataset. Future work detailing associated comorbidities, RAI avidity, and other clinical factors are needed to help identify patients bestsuited for EBR.

Poster 331 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE MACROFOLLICULAR VARIANT OF PAPILLARY THYROID CANCER: A RETROSPECTIVE ANALYSIS OF 30 CASES FROM A SINGLE CENTRE C. Giani1, D. Macedo2, R. Santos2, P. Marques2, V. Leite2 1 Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy; 2 Endocrinology, Instituto Portugueˆs de Oncologia de Lisboa, Francisco Gentil, Lisbon, Portugal Macrofollicular variant of papillary thyroid cancer (MF-PTC) is regarded as one of the rarest histological variant of PTC. It is a welldifferentiated carcinoma with macrofollicles ( > 50% of a crosssectional area) lined by follicular cells with nuclear features of PTC, that can be confused with goiter/follicular adenoma. MF-PTC is clinically characterized by non aggressive behavior. The prognosis is excellent although some reported cases showed an aggressive course, with lung and bone metastases. The aim of this study was to analyze the epidemiological, clinical and pathological features of a single cohort of MF-PTC.

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Retrospective analysis of the medical records of 30 patients (pts) with MF-PTC followed at the Cancer Institute of Lisbon between 1992–2015. MF-PTC incidence in the Cancer Institute of Lisbon was 0.6%. The median age was 42 (range 28–69) years; 73% were women. Twenty-nine pts underwent total thyroidectomy (TT) and among these, 4 pts central compartment dissection (2 of them laterocervical lymphadenectomy); 1 pt underwent lobectomy. The mean tumor diameter was 40 – 14mm (range 20–70). At diagnosis 57%, 20%, 13%, 7% and 3% were at stages I, II, III, IVa and IVc, respectively. According to ATA risk-class 80%, 17% and 3% were low, indermediate and high risk, respectively. Three pts (10%) had perithyroid soft-tissue invasion, none had vascular invasion, 1 pt had positive surgical margins and 3 pts had lymph node metastases. After surgical treatment 26 pts (93%) performed radioiodine (RAI) remnant ablation with a mean activity of 3.9 ( – 1) GBq. The whole body scan post-RAI remnant ablation showed cervical uptake in all pts, 1 pt exhibited lung and bone uptake. After a mean of 7 years of followup 85% had no evidence of disease, 11% had biochemical evidence of disease and 4% structural evidence of disease. Only the tumor diameter correlates with the outcome (p < 0.05). To our knowledge this is the first study with a long term follow-up in a single cohort of 30 MF-PTC. We confirm that MF-PTC has an excellent prognosis. Even the pt that presented lung and bone metastases demonstrated a very good response to RAI. Further molecular investigation will help us understand the reason.

Receiver operating characteristic of pre I-131 ablation Tg/TSH ratio as predictor of distant metastatic disease.

Poster 332 Thyroid Cancer Monday & Tuesday Poster 9:00 AM PREABLATION THYROGLOBULIN TO THYROIDSTIMULATING HORMONE RATIO MAY BE USED TO PREDICT DISTANT METASTASES IN CHILDREN WITH DIFFERENTIATED THYROID CANCER M.J. Livhits1, J.D. Pasternak2, M. Xiong2, N. Li3, J.E. Gosnell2, M.W. Yeh1, C.K. Harvey4 1 Section of Endocrine Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA; 2Endocrine Surgery, University of California, San Francisco, San Francisco, CA; 3 Department of Biomathematics, UCLA David Geffen School of Medicine, Los Angeles, CA; 4Division of Pediatric Endocrinology, Department of Pediatrics, UCLA David Geffen School of Medicine, Los Angeles, CA Differentiated thyroid cancer (DTC) is rare in the pediatric population but has a higher incidence of regional lymph node and distance metastases. Despite this metastatic potential the prognosis is excellent, although local recurrence is common. Most patients undergo total thyroidectomy followed by radioactive iodone (I-131) ablation. Thyroglobulin (Tg) is a sensitive tumor marker to detect disease recurrence after thyroidectomy, but its role in predicting distal metastatic disease prior to I-131 ablation is unclear. We studied the predictive value of pre-ablation Tg normalized to TSH levels in pediatric thyroid cancer. Retrospective analysis of pediatric patients (up to 21 years old) with DTC in three university hospitals over a 20-year time span. Patients were included who underwent total thyroidectomy followed by I-131 ablation. The Tg to TSH ratio was calculated following surgery but prior to I-131 ablation. Metastatic disease was determined from the whole body scan following I-131 ablation. There were 46 patients in the study with a mean age of 15.3 years (range 7 to 21 years). The majority had papillary thyroid cancer (76.1%), and mean tumor size was 2.8cm. Eight patients were found to have distant metastases on the post I-131 ablation scan. Patients with metastatic disease had a trend towards higher T stage of the

primary tumor, and all had involvement of regional lymph nodes (compared to 51.4% without distant metastases). The pre-ablation Tg/TSH ratio was highly predictive of distance metastases, with a mean value of 1.4 in non-metastatic patients and 12.5 in metastatic patients (P = 0.01). The area under receiver operating characteristic curve for Tg/TSH ratio was 0.93, yielding a sensitivity of 85.7% and specificity of 91.9%. Tg/TSH ratio following total thyroidectomy and prior to I-131 ablation may be useful to predict distant metastatic disease in children. This can be a potential adjunct to determine the treatment dose of I-131 in pediatric DTC.

Poster 333 Thyroid Cancer Monday & Tuesday Poster 9:00 AM IMPACT ON THE THYROID HORMONE WITHDRAWAL METHOD ON PATIENTS’ QUALITY OF LIFE AT THE TIME OF RADIOIODINE ADMINISTRATION M. Schlumberger1,2, B. Catargi3, D. Deandreis1, S. Zerdoud4, D. Rusu5, S. Bardet6, L. Leenhnardt7, D. Bastie8, C. Schvartz9, P. Vera10, O. Morel11, D. Benisvy12, C. Bournaud13, F. Bonichon14, A. Kelly15, M. Toubert16, S. Leboulleux1, E. Benhamou1, I. Borget1,2 1 Institut Gustave Roussy, Villejuif, France; 2university paris-sud, Chatenay-malabry, France; 3CHU Bordeaux, Bordeaux, France; 4 CLCC TOulouse, Toulouse, France; 5CLCC Nantes, Nantes, France; 6CLCC Caen, Caen, France; 7Pitie´ Salpetriere, Paris, France; 8 CHU Toulouse, Toulouse, France; 9Institut Jean Godinot, Reims, France; 10CLCC Becquerel, Rouen, France; 11CLCC Angers, Angers, France; 12CLCC Nice, Nice, France; 13CHU Lyon, Lyon, France; 14CLCC Bordeaux, Bordeaux, France; 15Centre Jean Perrin, Clermont-Ferrand, France; 16Saint-Louis, Paris, France Hypothyroidism induced by prolonged thyroid hormone withdrawal (THW) before radioiodine administration deteriorates the healthrelated quality of life (HRQoL) of thyroid cancer patients. Substitution of L-T4 by L-T3 for 3 weeks followed by a withdrawal for

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2 weeks has been used to reduce the deterioration of the HRQoL, but its benefits are not well documented. The objective of this study was to assess the impact of the withdrawal method on the HRQoL at the time of radioiodine administration. We used data from the ESTIMABL trial, a multicenter phase III trial where thyroid cancer patients were randomized after total thyroidectomy to one of 4 strategies of radioiodine ablation, each strategy combining one TSH stimulation method (THW or rhTSH) and one 131I activity (1.1 or 3.7 GBq). The withdrawal protocol was decided by the treating physician. Quality of life was assessed using the self-administered Short-Form 36 at randomization (when all patients were euthyroid on L-T4 therapy) and at the time of 131I administration 1) in 185 hypothyroid patients after withdrawal of LT3 for a mean of 14 days (range: 11 to 21 days); 2) in 114 hypothyroid patients after withdrawal of L-T4 for a mean of 28 days (range: 21 to 35 days); or 3) in 348 euthyroid patients on L-T4 after injections of rhTSH. As shown in figure 1, THW caused a clinically significant deterioration of HRQoL at radioiodine administration, whereas HRQoL remained stable with rhTSH. Patients who underwent a withdrawal of LT4 treatment for a mean of 4 weeks had a greater deterioration of HRQoL compared to patients who underwent a withdrawal of LT3 for a mean of 2 weeks. These results were also observed when the duration of withdrawal (less or longer than the mean withdrawal duration in each group) was taken into account. Substitution of L-T4 by L-T3 during 3 weeks and withdrawal of LT3 for 2 weeks reduces but does not prevent the deterioration of the HRQoL that remains significantly impaired compared to rhTSH stimulation.

Poster 334 Thyroid Cancer Monday & Tuesday Poster 9:00 AM PREDICTIVE VALUE OF PREOPERATIVE THYROGLOBULIN IN PEDIATRIC PATIENTS WITH THYROID MALIGNANCY E.E. Cottrill1,2, T.L. Ng1, K. Ken2,1, A. Bauer3,4, N.S. Adzick5,6, G. Krishnamurthy7, A. Buzi2,1, Z. Baloch8, B. Pierson3, M. Amberge3, S. mostoufi-Moab9,4 1 Otorhinolaryngology, University of Pennsylvania, Philadelphia, PA; 2Otorhinolaryngology, Childrens Hospital of Philadelphia, Philadelphia, PA; 3Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA; 4Pediatrics, University of Pennsylvania, Philadelphia, PA; 5Surgery, Children’s Hospital of Philadalphia, Philadelphia, PA; 6Surgery, University of Pennsylvania, Philadelphia, PA; 7Children’s Hospital of Philadelphia, Philadlphia, PA; 8Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA; 9Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA Several adult studies have found associations between preoperative thyroglobulin (Tg) and the presence and extent of differentiated

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 thyroid cancer (DTC). In pediatrics, inherent tumoral Tg secretion, lesion size, and extent of disease differ but a correlation has not been examined. This study was performed to determine if pre-operative Tg is predictive of surgical pathology and burden of disease in pediatric DTC. Retrospective chart review was carried out on 333 patients referred for fine needle aspiration biopsy and surgery at the Children’s Hospital of Philadelphia Thyroid Center between 2009 and 2015. Eighty-eight patients met inclusion criteria; preoperative serum Tg levels, FNA results, final surgical histopathology, and AJCC TNM classification. No significant difference was found in the mean pre-operative Tg or TSH when compared to final pathology for benign or malignant lesions (p = 0.28 and p = 0.10, respectively). In addition, no correlation was found between preoperative Tg and preoperative TSH (p = 0.98) or thyroglobulin antibodies (p = 0.21). ANOVA analysis showed a significant difference between the mean preoperative Tg levels for all tumor (T) (F = 2.46, p = 0.05) and lymph node (N) classification levels (F = 3.70, p = 0.03) and a significant association was found for T (F = 5.89, p = 0.02, r2 = 0.089) and N classification levels (F = 5.21, p = 0.03, r2 = 0.081). However, the low coefficient of determination implied that only a small amount of variation in the T and N classification could be explained by the preoperative Tg. Due to only one patient having positive metastasis, analysis could not be performed for M stage. Pre-operative Tg does not appear to be a clinically useful marker to predict final pathology in pediatric patients with thyroid nodules. In patients ultimately diagnosed with DTC, pre-operative Tg correlates with T and N, however, further analysis suggests that additional factors may have greater influence on T and N than the pre-operative Tg alone. Additional analaysis is being performed to determine if a larger sample and/or modeling variables will help strengthen the utility of pre-operative Tg as a marker of malignancy or diseaseburden in pediatric DTC.

Poster 335 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM RECENT INCIDENCE TRENDS OF CONVENTIONAL AND FOLLICULAR VARIANTS OF PAPILLARY THYROID CANCER IN THE UNITED STATES Y. MAO The Affiliated Hospital of Ningbo University School of Medicine, Ningbo, China The rapid incidence rise of papillary thyroid cancer (PTC) is well known in recent years, but its trend, especially in the most common variants—conventional PTC (CPTC) and follicular- variant PTC (FVPTC), remains poorly defined. To investigate the incidence trends of CPTC and FVPTC in the American population in recent years, we performed a retrospective population-based study using the most recent and comprehensive thyroid cancer database of Surveillance, Epidemiology and End Results 13 registries of USA, 1992–2010. Of the 63,755 pathologically confirmed thyroid cancers in SEER 13, 60.9% were CPTC and 25.5% were FVPTC, and their incidence rates were both significantly increased from 1992–2010 (P all< 0.001), with the former being 2.4-time the latter (P < 0.001) and the overall average annual percent change (AAPC) being 6.3% and 5.4% in CPTC and FVPTC, respectively. Joinpoint analyses revealed that the overall AAPC of CPTC before 1998 was 2.6% (P < 0.05), which jumped to 7.7% (P < 0.05) after 1998, while the AAPC of FVPTC before 2001 was 6.8% (P < 0.05), which dropped to 4.0% (P < 0.05) after 2001. On subgroup analyses, AAPC of CPTC in black females

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Poster 337 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THYROID CANCER OUTCOME AND ASSOCIATION WITH IMMUNE CHECKPOINT PROTEINS, PROGRAMMED CELL DEATH 1 (PD-1) AND PD-1 LIGAND (PD-L1), LYMPHOCYTIC INFILTRATES SUBSETS AND MUTANT B-RAF PROTEIN EXPRESSION E.J. Han, G.L. Sica, C. Zhang, Z. Chen, D. Lawson, N.F. Saba, D.M. Shin, F.R. Khuri, C. Cohen, T.K. Owonikoko Emory University, Atlanta, GA

was 0.2% before 1999, which jumped to 11.65% after 1999; AAPC of FVPTC in non-Hispanic white females was 12.3% before 1996, which dropped to 5.5% after 1996. AAPC in cases with tumor metastases or tumors > 4.0 cm also displayed a sharp jump and decrease in CPTC and FVPTC, respectively, in the recent decade. Some details are shown in figure 1. Although the overall incidence rates rose significantly both in CPTC and FVPTC from 1992 to 2010, the incidence rise trend, as reflected by AAPC, was sharply higher in CPTC than FVPTC in the recent decade, with a sharp rise even in CPTC with advanced disease. Thus, CPTC currently remains a dominant PTC variant and enhanced diagnostic detection cannot fully explain its rapidly rising incidence.

Poster 336 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE AGGRESSIVENESS ACCORDING TO TUMOR SIZE IN PAPILLARY THYROID CARCINOMA LESS THAN 2 CM IN SIZE IN KOREAN PATIENTS H. Park Division of Breast and Thyroid Surgery Department of Surgery, Kangnam Cha University Hospital, Seoul, Korea (the Republic of) Papillary thyroid carcinomas (PTC) less than 2 cm in size are believed to be a less aggressive subset of PTC which behave more like benign lesions and are often more conservatively treated. However, it is unclear whether carcinoma no larger than 2.0 cm in diameter can be expected to have a similar favorable clinical behavior as tumors no larger than 1.0 cm. Therefore, to address this question and to characterize the biology and optimal treatment for PTC less than 2 cm, we performed a retrospective chart review. 716 patients underwent surgery for PTC less than 2 cm. Data from these patients were retrospectively analyzed. The mean age of these patients was 42.9 years and 91.3% were female. 66.8% of the patients underwent a total or near-total thyroidectomy. Of the 716 patients, 228 (31.8%) had lymph node metastases. The patients present with signs of aggressiveness including multifocality (25.5%), bilaterality (20.7%), capsular invasion (4.1%). Lymph node metastases were associated with tumor size (p = 0.008) only, but not capsular invasion, bilaterality, multifocality, age and sex. With follow-up of up to 166 months, 5 patients had a local recurrence (recurrence rate = 0.7%). No patients have died during this period. In PTC less than 2 cm in size, progressively increasing frequency of signs of tumor aggressiveness including bilaterality, capsular invasion and lymph node metastasis with increasing tumor size.

Thyroid cancer is the fastest growing endocrine cancer worldwide. Immune checkpoint therapy has emerged as a realistic therapeutic option in various cancers. We studied the expression of immune checkpoint proteins and association with prognostic biomarkers in thyroid cancer. We assessed protein expression by immunohistochemistry using antibodies targeting PD-1, PD-L1, mutant B-Raf, CD3 ( + ) and CD8 ( + ) lymphocytes in tissue microarray constructed from archival samples of resected thyroid cancer. Expression was quantified using standard algorithm of intensity (0, 1, 2 and 3), percent cell staining and H-score. Differences and correlation between protein expression and patient demographics (age, gender, race) tumor characteristics (stage, histology) and overall survival (OS), biochemical recurrence (BR) and anatomic recurrence (AR) were assessed by ANOVA and Log-rank test. We included samples from 223 patients; female 146 (72%), Asian (2.2%) Black (24%), Caucasian (68.9%) and Hispanic (2.7%); papillary cancer (61.3%), follicular carcinoma (12.2%) and anaplastic (5.4%). There were 100 cases (59.5%) in stage I, 19 (11.3%) stage II, 16.7% stage II and 12.5% in stage IV. The 5-year OS, BR-free survival and AR-free survival were: 96.5%, 95.5% and 94.6% respectively. There were significant differences in OS based on age [HR:0.17 (0.04-0.79) p = 0.010), stage [HR: 0.03 (0.01-0.12), p < .001] and iodine therapy [HR: 5.12 (1.48-17.72), p = 0.004]. Absence of node involvement was associated with reduced risk of AR [HR: 0.31 (0.09-1.00) p = 0.038] but not with BR [HR: 0.63 (0.15-2.65); p = 0.529]. PD-L1 expression was > 2 fold higher in tumors of deceased patients and of patients with distant metastasis. There was a higher expression of CD3 ( + ) lymphocytic infiltrate in patients with nodal disease and of mutant B-Raf protein expression in patients with recurrence and deceased patients. There was no significant difference in PD-1 expression or CD (8 + ) lymphocytic infiltrate across all categories of patients or tumor characteristics. PD-L1 and mutant B-Raf protein expression are associated with worse outcome in thyroid cancer patients.

Poster 338 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM SKIP METASTASIS TO LATERAL NECK LYMPH NODES IN PAPILLARY THYROID CANCER Y. Ryu Surgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Korea (the Republic of) Papillary thyroid cancer (PTC) is commonly related with cervical lymph node metastases, which are usually in a consecutive pattern from central to lateral. However, a small number of patients have skip metastases, which present in a pattern of leaping metastasis without central lymph node metastasis. We conducted this study to evaluate the clinicopathological features of skip metastases in PTC.

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We retrospectively reviewed 346 patients who underwent total thyroidectomy, central lymph node dissection, and modified radical neck dissection. The clinicopathological results were analyzed according to the presence or absence of skip metastases. Skip metastases were found in 74 patients (21.4%). Patients with skip metastases tended to have tumors that were no more than 1cm in diameter (p = 0.008) and primary tumors of the upper pole (p = 0.031). The lateral lymph node metastases ratio was lower (0.28 – 0.16 vs. 0.20 – 0.17, p = 0.001) and the frequency of single lateral neck level involvement was higher (26.5% vs. 47.3%, p = 0.001) in the patients with skip metastases. Tumors of the upper pole and tumors £ 1cm in size were correlated with skip metastasis in the multivariate analysis. Skip metastases can occur frequently in PTC patients. Primary tumors of the upper pole or tumors that are no more than 1cm in diameter can be closely correlated with skip metastases in PTC. Therefore, lateral neck lymph nodes should be carefully evaluated to decide the extent of surgery.

Poster 340

Poster 339 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM CLINICAL, HISTOLOGIC, RADIOLOGIC CHARACTERISTICS OF PATIENTS WITH LUNG METASTASES IN DIFFERENTIATED THYROID CARCINOMA PRESENTING WITH NEGATIVE IODINE UPTAKE S. Kim, J. Seo, H. Rhu, N. Kim, S. Kim, D. Choi Endocrinology & Metabolism, Korea University Medical Center, Seoul, Korea (the Republic of) When lung nodules are found in DTC patients, it is important to distinguish metastases of DTC from other malignancies such as primary lung cancers or benign nodules to select the most optimal treatment. This study aimed to determine whether there are distinct characteristics of DTC patients with lung metastases compared to non-metastatic nodules. We performed a retrospective review of 58 patients with differentiated thyroid carcinoma (DTC) who had undergone the histopathologic comfirmation of lung nodules through surgery or percutaneous needle biopsy (PCNB) in Korea University Medical Center, between 2004 and 2014 were enrolled our study. We divided the patients into the group with lung metastases of DTC, as DTC metastases group (n = 12) and patients other than DTC metastases, as non DTC metastases group (n = 46, 26 cases of non small cell lung cancer, 2 cases of metastatic colorectal cancer,1 case of metastatic leiomyosarcoma, and 17 cases of benign nodules.) Hospital records of these patients were systematically reviewed. The factors that significantly differentiated DTC metastasis from non-DTC metastasis were the tumor size ‡ 2cm, N stage (N1b), recurrence of cervical lymph node, off Tg ‡ 2 ng/ml measured before the first RAI therapy, and off Tg ‡ 1 ng/ml at the time of detection of lung nodule. The factors that showed more than 90% of specificity were tumor size ‡ 3 cm, off Tg level measured before the first RAI ‡ 10 ng/ml, on Tg at the time of detection of lung nodule ‡ 1, ‡ 2 and ‡ 5 ng/ml. No radiologic features were noted in DTC metastasis group compared with non DTC metastases group, but when compared with primary lung cancer group the margin tend to be smoother in DTC metastasis nodules. Tumor size, N stage, recurrence of cervical lymph node, off Tg level measured before the first RAI, and the on Tg measured at the time of detection of lung nodule can be used as a predictive tools to differentiate DTC lung metastases from other lung nodules in DTC patients.

Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM TOTAL TUMOR DIAMETER OF MULTIFOCALITY AND A SCORING SYSTEM TO PREDICT CENTRAL NECK LYMPH NODE METASTASIS IN PTMCS Z. Liu, Y. Guo Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, WuHan, China Our aim was investigate the subgroup of total tumor diameter > 1cm of multifocality in papillary thyroid microcarcinoma (PTMC) inclined to central lymph node metastasis (CLNM). And more, found a scoring system to evaluate risk of CLNM in PTMCs. 1068 Patients who underwent total thyroidectomy with central neck dissection and had a pathologic diagnosis of PTMC were identified. Total tumor diameter (TTD) was calculated as the sum of the maximal diameter of each lesion. Univariate and multivariate analyses between clinicopathologic parameters and risk of central node metastasis (CLNM) were performed. Multinomial logistic regression analysis was performed for getting the most important variables that influence the CLNM. At last, a score system was founded to evaluate risk of CLNM in PTMCs. Univariate and multivariate analysis suggested that age, sex, subtype, multifocality, hashimoto and maximal tumor size (P value = 0.00,0.02,0.19,0.00,.011 and 0.00, respectively) were independent factors of CLNM. We further explored the risks of lymph node metastasis according to the category of total tumor diameter and demonstrated that as compared with patients who had total tumor diameter less than or equal 0.5cm, patients in the 0.51cm group had an increased risks (OR = 3.096, p < 0.001) for lymph node metastasis, 1-1.5cm group and ‡ 1.5 group also found to have more risks (OR = 5.220, p < 0.001) and (OR = 8.542, p < 0.001), respectively. Multinomial logistic regression analysis illustrated that age, multifocality and maximal tumor size (Unstandardized Coefficients of age, multifocality and maximal tumor size were 0.164, 0.122 and 0.184, respectively) were the most important variables influence the risk of CLNM. The score system of CLNM was: score of risk of CLNM = Age( £ 45 years = 2, > 45 years = 0) + Multifocality (Present = 1, absent = 0) + Maximal tumor size ( > 0.5cm = 2, £ 0.5cm = 0). We demonstrated that TTD of multifocality in papillary thyroid microcarcinoma could be used to predict central neck lymph node metastasis as a new clinical factor. And more, we founded an easy scoring system to assess the risk of CLNM in PTMC, and in this system, when scores more than 3, PCLND were recommended.

Poster 341 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE CLINICAL OUTCOME OF DIFFERENTIATED THYROID CANCER PATIENTS WITH LOCO-REGIONAL OR DISTANT METASTASIS DETECTED IN OLD AGE J. Han1, T. Kim2, J. Jung3, W. kim2, Y. Shong2, W. Kim2 1 Endocrinology and Metabolism, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea (the Republic of); 2Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of); 3Internal Medicine, Gyeongsang National University Hospital, Jin-Ju, Korea (the Republic of) Differentiated thyroid carcinoma (DTC) has an excellent prognosis and even patients with distant metastasis live many years. The recurrence rate is increased by age and old patients with recurrence

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shows poor prognosis. Deciding treatment strategies for recurrent disease in elderly is difficult, because old age patients are at greater risk of other health conditions and risk of treatment for recurrent disease. We were to evaluate clinical outcomes and treatment strategies of DTC patients with recurrence detected in old age. This is a retrospective observational cohort study from 1994 to 2012 in Asan Medical Center. Among the DTC patients with no clinical evidence of disease after initial treatment, 87 patients had recurrent disease at the age ‡ 65 years during the follow-up. 70 (80%) had isolated loco-regional recurrence and 17 (20%) had distant metastasis. The median age of patients at the time of recurrence was 71 years old and the median follow-up duration after recurrence was 4.1 years. During the follow-up after initial detection of recurrence, newly developed distant metastases found in 10 out of 70 patients with loco-regional recurrence. In the group of isolated loco-regional recurrence, 63 patients received additional treatment and 7 patients received supportive care only. Of the 70 patients, 19 patients were dead: 11 for thyroid cancer aggravation and 8 for unknown cause or other co-morbidity. In the group of distant metastasis, 10 patients received treatment and 7 patients had conservative management. Of the 17 patients, 7 patients were dead (6 for aggravation of distant metastasis, 1 for myocardial infarction). Cancer specific mortality was quite high in DTC patients with recurrence detected in old age. The mortality due to airway problem was more frequent in patients without additional treatment for recurrent disease than patients with treatment. The systemic evaluation and further careful follow-up strategies are needed, and the proper management for loco-regional recurrence could be helpful to improve disease related mortality in elderly patients.

tients (21.4%) with FSE positive. The final histopathological results showed CLN metastasis in 8 patients with negative FSE (including four patients with micrometastases( £ 2 mm)). The results also showed negative lymph node in 2 patients (8.7%) with positive FSE, and it was diagnosed with hashimoto’s thyroiditis. Sensitivity, specificity and overall accuracy of FSE in definition of N status were 84.0, 95.5, and 91.0%, respectively. Microextrathyroidal extension (P = 0.804) were not statistically significant. Age (P = 0.023), male sex (P = 0.03), tumor size (P = 0.004) and multifocality (P = 0.036) were statistically significant difference between the positive FSE group and the negative FSE group, respectively. Intraoperative FSE of CLNs in patients with PTMC is an accurate method in detecting node metastasis and determining the extent of thyroidectomy. The age, male sex, tumor size and multifocality should be considered when we performed intraoperative FSE of CLNs.

Poster 342 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM INTRAOPERATIVE FROZEN SECTION OF CENTRAL LYMPH NODE IN PAPILLARY THYROID MICROCARCINOMA(PTMC); PROSPECTIVE OBSERVATIONAL STUDY H. Kim, Y. Hong, S. Lee, B. Chae, J. Bae Surgery, The Catholic University of Korea, Seoul, Korea (the Republic of) Determining the extent of thyroidectomy in patients with papillary thyroid microcarcinoma (PTMC) is still controversial. Hemi-thyroidectomy (HT) is the less aggressive method of surgical management of PTMC. The identification of Central lymph node (CLN) metastasis in the treatment of PTMC is not easy before surgery because of the limitations in radiologic examinations including ultrasonography (US) and computed tomography (CT). The aim of this study was to evaluate the accuracy and usefulness of intraoperative frozen section examination (FSE) to determine the extent of thyroidectomy. From February 2013 to August 2014, 73 patients who had unilateral PTMC and no evidence of CLN metastasis on preoperative ultrasonography were prospectively enrolled. Patients underwent a HT with ipsilateral CLN. Removed ipsilateral CLNs were sent for FSE. If FSE was positive for metastasis, a total thyroidectomy was considered. Intraoperative FSE were performed in 73 cases, FSE diagnosed 23 patients (32%) as positive metastasis of CLN and the remaining 50 patients (68%) as negative. 14 patients underwent a total thyroidectomy with bilateral central neck dissection in FSE positive patients. Bilateral nodal involvement was observed in three pa-

Poster 343 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM GENDER DIFFERENCES IN INITIAL PRESENTATION AND MANAGEMENT OF DIFFERENTIATED THYROID CANCER IN A CANADIAN TERTIARY REFERRAL CENTER L. Bondaz1,2, R. Briones-Urbina1,2, C. Kelly1,2, A. Zahedi1,2 1 University of Toronto, Toronto, ON, Canada; 2Endocrinology Division, Women’s College Hospital, Toronto, ON, Canada Men use healthcare less often than women, especially for adhering to the primary healthcare screening recommendations. In many cancers, prevalence and disease presentation differ between genders. In thyroid cancer series, women are three times more likely to get the disease, but men present with more advanced disease and undergo more aggressive initial treatment. There is no Canadian data exploring gender differences in thyroid cancer. We hypothesized that, in a Canadian cohort of well-differentiated thyroid cancer (WDTC) patients, men present with more advanced disease and receive more intensive initial treatment. After approval by our institutional review board, we performed a retrospective cohort study of all patients diagnosed with WDTC between 2000 and 2013 who were seen in the Thyroid Program at Women’s College Hospital (Toronto, Canada). Patients ‡ 18 years at diagnosis were included. Data regarding initial pathology and management was collected and analyzed. Charts of 364 WDTC patients (303 women (83.24%) and 61 men (16.76%)) were reviewed. The female-to-male ratio was 5:1. The mean age at diagnosis was 45.6 years (\ 46.09 vs _ 47.46, p = 0.51). There were no statistically significant gender differences in the TNM staging or management in the overall cohort. However, lymphovascular invasion (LVI) was more frequent in men (17% vs 6%, p = 0.043). There was a trend towards more RAI use in men in the T1 subgroup (61% vs 42%, p = 0.09). Men ‡ 45 years old had a larger tumor size (2.89 vs 2.25 cm, p = 0.030), higher T stage (p = 0.036) and showed a trend towards more radioactive iodine (RAI) treatment use (85% vs 68%, p = 0.088). In our WDTC cohort (2000–2013), there were more women (83.24%) than in most series, likely related to the hospital’s women’s health mandate. There were no gender differences noted in the overall cohort, except for more LVI in men. In older males ( ‡ 45 years old), there was a larger tumor size and a trend towards more RAI therapy use. As a next step, we hope to look at gender differences in recurrence rates to determine if we should consider changes to our management algorithm.

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MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 Using DNA isolated from frozen tissue, the prevalence of EIF1AX mutations was studied in 148 thyroid tumors and 80 hyperplastic nodules by either Sanger or next-generation sequencing. In addition, 27 thyroid FNA samples positive for EIF1AX mutations were reviewed with surgical follow-up available on 5 of them. Glass slides from thyroid nodules positive for EIF1AX mutations were examined. Our analysis revealed EIF1AX mutations in 1/64 (1.5%) PTC, 2/27 (7.4%) follicular adenomas, 1/80 (1.3%) hyperplastic nodules, and in none of 53 follicular carcinomas studied. Among 5 FNA samples with surgical follow-up, 1 nodule was PTC and others were benign follicular adenomas or hyperplastic nodules. Overall, out of 31 mutations identified, the most common was A113_splice (42%), followed by G9R/D/V (26%), R13L/P/D (13%), G15D (6%), K10N (3%) and G6_splice (3%). Both PTCs positive for EIF1AX mutations had a A113_splice mutation found at high allelic frequency and were encapsulated follicular variant tumors, one with tumor capsule invasion. In 6 cases, including one PTC, a co-existing mutation involving NRAS (x4), HRAS, or GNAS gene was found. The results of the study demonstrate for the first time that EIF1AX mutations occur not only in PTC, but also in benign thyroid nodules. The most common mutation affects the intron 5/exon 6 splice site, followed by a cluster of mutations in exon 2. PTC harboring EIF1AX mutations are follicular variants and may demonstrate tumor capsule invasion. When found in thyroid FNA samples, EIF1AX mutations confer *20% risk of cancer, although the risk may be higher in nodules with high allelic frequency of mutant EIF1AX.

Poster 345 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM IMPACT OF THE MULTI-GENE THYROSEQ NEXT GENERATION SEQUENCING ASSAY ON CANCER DIAGNOSIS IN THYROID NODULES WITH ATYPIA OF UNDETERMINED SIGNIFICANCE/FOLLICULAR LESION OF UNDETERMINED SIGNIFICANCE CYTOLOGY Y. Nikiforov1, S. Carty2, S. Chiosea1, C. Coyne3, U. Duvvuri4, R. Ferris4, W. Gooding5, S. LeBeau3, P. Ohori1, R. Seethala1, M. Tublin6, L. Yip2, M. Nikiforova1 1 Department of Pathology, University of Pittsburgh, Pittsburgh, PA; 2 Division of Endocrine Surgery, University of Pittsburgh, Pittsburgh, PA; 3Division of Endocrinology, University of Pittsburgh, Pittsburgh, PA; 4Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA; 5Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, PA; 6 Department of Radiology, University of Pittsburgh, Pittsburgh, PA

Poster 344 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM PREVALENCE AND SPECTRUM OF EIF1AX MUTATIONS IN THYROID NODULES F. Panebianco, A. Karunamurthy, M. Nikiforova, Y. Nikiforov University of Pittsburgh, Pittsburgh, PA EIF1AX gene is located in the X-chromosome and codes for eukaryotic translation initiation factor 1A. Mutations in this gene have been reported in uveal melanomas, and recent TCGA study reported the presence of EIF1AX mutations in 1.5% of papillary thyroid carcinomas (PTC). However, the prevalence of these mutations in other types of thyroid cancers, such as follicular carcinomas, and in benign thyroid nodules is unknown.

Fine needle aspiration (FNA) cytology is a common approach to evaluate thyroid nodules, which offers definitive diagnosis of a benign or malignant nodule in *75% of cases. The remainder of the nodules yields one of the indeterminate cytologic diagnoses, resulting in suboptimal management of these patients. Atypia of undetermined significance/follicular lesion of undermined significance (AUS/FLUS) is a common indeterminate diagnosis with the cancer risk ranging from 6–48%. In this study, we tested whether a multi-gene next-generation sequencing (NGS) assay can offer significant improvement in diagnosis in these nodules. From May 2014 until March 2015, 465 consecutive FNA samples with the cytologic diagnosis of AUS/FLUS underwent prospective molecular testing using the ThyroSeq v2.1 panel. The panel included 14 genes analyzed for point mutations and 42 types of gene fusions occurring in thyroid cancer. In addition, 7 genes were assessed for expression in order to evaluate the cell composition of FNA samples. Ninety-eight (21%) of these nodules had definitive surgical (n = 95) or non-surgical (n = 3) follow-up and were used to determine the assay performance.

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Among 465 AUS/FLUS nodules, 3 were found to be composed of parathyroid cells and 462 of thyroid follicular cells, and of the latter 31(6.7%) were positive for mutations. The most frequently mutated genes were NRAS and HRAS, and overall point mutations in 7 different genes and 5 types of gene fusions were identified in these nodules. Among 98 nodules with known outcome, histologic analysis revealed 22 (22.5%) cancers. ThyroSeq v2.1 was able to detect 20 out of 22 cancers, showing a sensitivity of 90.9% (95% CI 78.8%– 100%), specificity of 92.1% (86.0%–98.2%), PPV of 76.9% (60.7%– 93.1%), and NPV of 97.2% (78.8%–100%), with the overall accuracy of 91.8% (86.4%–97.3%). The results of the study demonstrate that this multi-gene NGS panel of molecular markers provides both high sensitivity and high specificity of cancer detection in thyroid nodules with AUS/FLUS cytology, which should allow more optimal management for these patients.

able levels of Tg. The competitive assay employs a polyclonal antibody produced in rabbits immunized with human Tg, Tg labeled with biotin and for the solid phase separation, a monoclonal anti-rabbit IgG antibody adsorbed to microtiter plates was employed. Functional sentitivity is 5,0 ng/mL. The minimum Tg value found in the patients with lymph node metastases (n = 3) was 15.9 ng/ml, range 15.9–58 ng/mL; and in patients with lung metastases (n = 5): 8.2 ng/mL to above 200 ng/mL. Even in patients with positive anti thyroglobulin antibodies the competitive method was able to measured thyroglobulin levels. In those patients the lower level of thyroglobulin was 15.9 ng/mL in a patient with lymph node metastases. In DCT patients with methastatic disease and positive and negative ATgAb immunometric Tg assays can be misleading. In those cases, a competitive assay using polyclonal antibodies could be useful.

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Poster 347

Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM DETECTABLE THYROGLOBULIN LEVELS MEASURED BY A NEW POLYCLONAL COMPETITIVE ASSAY IN DIFFERENTIATED THYROID CANCER (DTC) PATIENTS WITH METASTATIC DISEASE AND UNDETECTABLE THYROGLOBULIN LEVELS BY ROUTINE IMMUNOMETRIC ASSAY R.M. Biscolla1,2, T. Kasamatsu1, C.C. Nakabashi1, C.P. Camacho1, D. Andreoni1, R. Padovani3, R.M. Maciel1,2, J.G. Vieira1,2 1 Endocrinology, Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil; 2 Fleury Medicina e Sau´de, Sa˜o Paulo, Brazil; 3Santa Casa de Sa˜o Paulo, Sa˜o Paulo, Brazil

Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM USING FOCI NUMBER TO PREDICT CENTRAL LYMPH NODE METASTASES OF PAPILLARY THYROID MICROCARCINOMAS WITH MULTIFOCALITY Y. Guo, Z. Liu Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Serum thyroglobulin (Tg) is the most sensitive DTC marker. However two potential problems exist with Tg measurements: the possible presence of endogenous anti-Tg antibodies (ATgAb), in almost 25% of (DTC) patients, and the heterogeneity of circulating Tg. In those cases undetectable or low levels of Tg can be observed in patients with structural metastases. The goal of this study was to develop and validate a new competitive Tg assay, in order to be used in patients with structural disease and low Tg levels by routine immunometric assays. We evaluated 9 DTC patients, 4/9 with classic papillary thyroid carcinoma and 5 with follicular variant of papillary thyroid carcinoma. All patients had been treated with total thyroidectomy and also received radioiodine treatment (150 to 800 mCi); 6 were women and the mean age at diagnosis was 29 years (22 to 54 years old). Five patients, besides having structural disease (lymph nodes and/or lung metastases) presented positive ATgAb (indirect electrochemiluminescent immunoassay, Roche) and undetectable Tg levels (Beckman Access - functional sensitivity of 0,1 ng/mL). The remaining 4 patients had negative ATgAb but also presented lymph node or lung metastases with undetect-

The aim of our study is to analyze the clinicopathological characteristics and treatment options for papillary thyroid microcarcinomas with multifocality and to investigated whether the number of foci in papillary thyroid microcarcinomas with multifocality can predict central lymph node metastases. Records of 329 consecutive PTMC patients with multifocality, and who were treated surgically between 2003 and 2014 were reviewed. Patients with multifocality were identified by histopathology. The number of foci, size of the largest tumour, presence of extrathyroidal invasion, infiltration, and other clinicopathological parameters were collected and analyzed for all the cases. Univariate analysis, age, sex, maximum tumour size, and extrathyroidal invasion were found to be significant prognostic factors (p = 0.001, 0.020, < 0.001, 0.043; respectively).Multivariate analysis found that age, sex, and maximum tumour size were independent prognostic factors for CLNM in PTMCs. Among them, Male patients (odds ratio 1.887; 95% confidence interval [CI] 1.053-3.380) and with maximum tumour size > 0.5 cm (odds ratio 2.819; 95% CI 1.721-4.616) were risk factors for increased incidence of CLNM. Patients ‡ 45 years (odds ratio 0. 497; 95% CI 0.309-0.800) were less likely to present with CLNM. However, extrathyroid invasion was not an independent predictor of CLNM according to our results. PTMCs with 2,3, ‡ 4 foci had a significantly greater risk of CLNM (odds ratio 1.675, 2.360, 2.703; 95% CI 1.195-2.347, 1.425-3.906, 1.411-5.178; respectively) compared to PTMCs with unifocality. Foci numbers were linked to an increased incidence of central lymph node metastases in papillary thyroid microcarcinomas with multifocality, and we could choose to perform more radical treatment in patients with multifocality.

Poster 348 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM NEPHROTOXIC EFFECT OF A TYROSINE KINASE INHIBITOR (TKI) WITH ANTI-VEGF RECEPTOR ACTIVITY L. Paschke, E. Karsay, T. Lincke, K.S. Mu¨hlberg, T. Linder, R. Paschke Universita¨t Leipzig, Leipzig, Germany

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TKIs including anti-VEGF receptor activity have shown promising results in phase 3 trials of patients with thyroid carcinomas. Proteinuria is a common side effect of TKIs. We report a 67 year old patient with metastatic thyroid papillary carcinoma who was treated with total thyroidectomy in 9/2006, followed by three radioiodine therapies (total dose 19 GBq). Because of progressive disease and radioiodine resistance he was treated with lenvatinib a novel anti-VEGF, -PDGFRalpha, -RET, -FGF multikinase inhibitor starting on 4/10/2012. In addition the patient suffered from long term arterial hypertension and coronary heart disease with myocardial infarction in 2005. His fasting blood sugar, creatinine, and urea were normal. After receiving 140 ml of Imeron 350 for a coronarography with stenting on 10/16/2012 because of unstable angina during lenvatinib stop 10/09/2012 - 10/25/2012 and 46 ml of ultravist 370 on 9/14/2012 and 11/30/2012 his creatinine rose to 146 lM until 12/20/2012. Renal ultrasonography determined kidney sizes of 9.8 and 9.7 cm most likely due to chronic (formerly inadequately controlled) arterial hypertension. His proteinuria increased to 682 mg/l on 01/09/2013 and creatinine further rose to 218 lM on 01/17/2013. Therefore Lenvatinib was discontinued on 01/15/2013. Serum creatinine declined to 142 lM on 02/28/2013. After further applications of 85 and 110 ml imeron on 03/13/2013 and on 05/24/13, respectively, his last creatinine was 150 lM on 09/26/2013). Renal damage by iodine containing contrast media occurs within 48 hours. The steady further rise 6 weeks after the last application of iodine containing contrast media during treatment with Lenvatinib is a strong indication of renal damage induced by a TKI (lenvatinib) with anti-VEGF receptor activity. However, it needs to be clarified if the concomitant application of imeron and ultravist together with lenvatinib led to an additive or cumulative nephrotoxic effect.

increase of cytoplasmic intermediate filaments (IF). All malignant lesions and 10 out 15 FA displayed this feature. On the other hand, 35 CN and 20 out of 25 HN exhibited small amount of intermediate filaments as well as fractured cell borders and ‘‘naked nuclei’’. 3. Lipofuscin granules were present in all CN, 20 out of 25 HN and only 1 T-FA. The complexity of the CBB and the BM reduplication increases the cell adhesiveness and the extracellular matrix, and reduces the number of cells in touch preparations. It is strongly suggestive that the cell numerical density on FNA smears is inversely related with CBB complexity and, accordingly, directly related with the probability of follicular neoplasm. Large amounts of IF prevent the cytoplasmic rupture during the smear preparations. Cells with preserved, sharp cell borders are more probably related with a neoplasm than cells with broken, fragmented cytoplasms. Lipofuscin granules are related with the functional activity (reabsorbtion cycles) of the thyreocytes.

Poster 349 Thyroid Cancer Monday & Tuesday Poster 9:00 AM ULTRASTRUCTURAL STUDIES ARE USEFUL FOR A MORE ACCURATE INTERPRETATION OF DIAGNOSTIC CYTOLOGY IN THYROID PATHOLOGY M. Trovato1, L. Calbo1, G. Sturniolo2, G. Cenacchi3, G. Arena1, O. Gambadoro1, L. Pispisa1, R. Randi4, V. Cavallari1 1 Human Pathology, University of Messina, Messina, Italy; 2, Dept of Clinical and Experimental Medicine, University of Messina, Messina, Italy; 3Dept. of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 4Dept of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy Pre-operatory evaluation of thyroid nodular lesions is difficult and controversial. A trend towards ‘‘cautelative overestimation’’ is observed, according with an increase of cases falling in the ‘‘indeterminate’’ categories of TBSRTC. The aim of the study was to integrate ultrastructural, histological and cytological observations with a large amount of thyroid nodular lesions to support rational bases for FNAB interpretation. A group of 100 thyroid nodular lesions of which 22 papillary carcinomas (PTC), 3 follicular carcinomas (FTC), 10 follicular adenomas (FA), 5 trabecular adenomas (T-FA), 25 hyperplastic nodules (HN) and 35 colloid nodules (CN) were individually sampled for touch preparations, electron microscopy and histology. 1. A great amount of cells on touch preparations correlated with linear cell basal borders (CBB) in electron microscopy. This feature was present in 25 malignant lesions, 15 FA and 25 HM. On the other hand, 35 CN showed a reduced cell numerical density associated with consistently infolded CBBs. 2. The cell preservation on touch preparations, i.e. sharp cytoplasmic borders, was correlated with an

Poster 350 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM CANADIAN COLLABORATIVE NETWORK FOR CANCER OF THE THYROID - CANNECT: A CANADIAN MULTICENTER PARTNERSHIP OF THYROID CANCER CLINICIANS AND RESEARCHERS M. Rajaraman1,2, W.D. Leslie15, A. Zahedi3, C. Jefford4, A. Boucher5, J. Young6, E. Leung7,8, A. McGibbon9,10, M. Badreddine11, S. Nixey12, H. Fong2,13, S. Van Uum14 1 Radiation Oncology, Dalhousie University, Halifax, NS, Canada; 2 Radiation Oncology, QEII Health Sciences Centre, Halifax, NS, Canada; 3Endocrinology, Women’s College Hospital, Scarborough, ON, Canada; 4Radiology and Nuclear Medicine, Memorial University, St. John’s, NF, Canada; 5Medicine, Universite´ de Montre´al, Montreal, QC, Canada; 6Surgery, McMaster University, Hamilton, ON, Canada; 7Medicine, The Ottawa Hospital, Ottawa, ON, Canada; 8 Medicine, University of Ottawa, Ottawa, ON, Canada; 9Medicine, Dalhousie University, Halifax, NS, Canada; 10Medicine, Memorial University, St. John’s, NF, Canada; 11Diagnostic Imaging, London Health Sciences Centre, London, ON, Canada; 12Nuclear Medicine, London Health Sciences Centre, London, ON, Canada; 13Radiation Oncology, Nova Scotia Health Authority, Halifax, NS, Canada; 14 Medicine, Western University, London, ON, Canada; 15Medicine and Radiology, University of Manitoba, Winnipeg, MB, Canada The incidence and prevalence of thyroid cancer (TC) is rising rapidly in Canada and worldwide. Despite ongoing increases in the burden of TC care and published international guidelines, the care of TC patients remains highly variable across Canada with a fragmented approach to data gathering. A multicenter partnership of TC clinicianresearchers has been assembled to collaboratively contribute to TC research, address the growing care delivery challenges and improve patient outcomes. The Canadian Thyroid Cancer Consortium (CTCC), established over 10 years ago, consists of clinician-researchers focused on multicenter TC database studies. Expanding on the CTCC, a face-toface meeting was conducted in Toronto on September 22, 2012. Supported by an industry grant, the group committed to a multicenter study entitled CAN-TC with the primary goals of describing the presentation, treatment and outcome of TC in Canada over time and by geography as well as their relation to socioeconomic parameters. The consolidation of this group into a collaborative team of Canadian TC clinicians and researchers formed the CANadian collaborative NEtwork for Cancer of the Thyroid, CANNECT. To date, the CAN-TC study has merged de-identified case data from 5 centers in 4 provinces with a current total of 2526 cases

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diagnosed during the years 2000 and 2010. Upon study completion later in 2015, it will contain an estimated 4300 cases from 9 centers in 6 provinces. Based on these results, CANNECT will apply for grants to support a second wave of studies focused on long term outcomes and surgical management. CANNECT is establishing a governance structure to describe its mission, composition, management of sponsors and finances, authorship and publications, privacy and confidentiality issues and management of quality and security. Through conduction of a multicenter data-merging study on TC (CAN-TC), a collaborative team of Canadian TC clinician-researchers has formed CANNECT. Further objectives of CANNECT are to establish prospective TC common data elements and improve the quality and consistency of TC care across Canada through endorsement, adaptation, and implementation of evidence-based guidelines.

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mined significance (FLUS) and suspected follicular neoplasm group (B3 and 4), 61.7% for the suspicious for malignancy group (B5), and 98.4% for the diagnostic for malignancy group (B6). However 17.8% of PTC and 18.2% or FTC had B2 cytology results and 62% of FTC had B3 or 4 cytology but only 6.9% of this group had FTC. Indeed PTC was twice as likely in this group. A B5-6 result had a sensitivity of 89%, specificity 88%, PPV 57% and NPV 97% for malignancy.The false positive rate was only 2%. Follicular lesions are more challenging. If B5-6 results are excluded B3-4 results have a sensitivity of 57%, a specificity of 74%, PPV of 23 and NPV of 92%, underlying the very poor diagnostic utility of these categories. Thyroid FNA has high sensitivity and specificity, but false negative and false positive results cause concern. Our findings suggest that the correlation of FNA with the final histology in our data compares broadly with previous published data. Our malignancy rate is higher for the B2 group (7%) compared to published literature of 03% but this is likely due to a bias towards those who proceed to surgery in our population. This suggests that when making treatment recommendations and counselling patients, local data should be used to help predict outcome and recommend surgery.

Poster 352 Poster 351 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM FINE NEEDLE ASPIRATION OF THE THYROID: CORRELATION WITH FINAL HISTOPATHOLOGY IN A SERIES OF 4702 PATIENTS FROM TWO INSTITUTIONS C.P. Gilfillan1, S. Goh1, M. Vereker2, J. Serpell2 1 Eastern Health Clinical School, Monash University, Box Hill, VIC, Australia; 2Surgery, Alfred Health, Melbourne, VIC, Australia The risk of malignancy associated with thyroid nodules is *5–15%. The Bethesda classification1 stratifies the risk based on fine needle aspiration cytology (FNAC) and is used to guide management. This study compares FNAC results with final histopathology, and evaluating the sensitivity, specificity and predictive values of FNAC for the diagnosis of thyroid malignancy. At one institution, records of 449 patients who underwent FNAC for thyroid nodules whom 187 were operated and have final pathological diagnosis were retrospectively reviewed from 2008 to 2014. At another institution a prospective database of thyroidectomy patients was maintained since 2007, and from 4035 subjects, FNACs were available for 3182. We calculated the malignancy risk for each category by following up histopathology in 3355 cases. Malignancy rates were 15.5% for the non-diagnostic group (B1); 6.8% for benign group (B2), 22.5% for follicular lesion of undeter-

Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM HOW I DO IT : LARYNX PRESERVATION IN THE SURGICAL TREATMENT OF LOCALLY ADVANCED THYROID CANCER M. Kim, S. Kim Otolaryngology - Head & Neck Surgery, Seoul St. Mary,s Hospital, The Catholic University of Korea, Seoul, Korea (the Republic of) Locally advanced thyroid cancer usually invades into the larynx and requiring total laryngectomy for oncologic safety, although tumor infiltration is limited to the half of the larynx. We have performed VHLP(vertical hemilaryngopharyngectomy) in locally advanced laryngopharyngeal cancer to preserve the laryngeal function by the reconstruction of radial forearm free flap with tendon. We have applied VHLP in locally advanced thyroid cancer with laryngeal invasion in three cases which are needs to take a total laryngectomy, and we evaluate oncological and functional results. All of three patients had advanced thyroid cancer with laryngeal invasion. The first case was spindle cell carcinoma of thyroid with paraglottic space invasion, the 2nd case was papillary carcinoma with paraglottic space invasion, and the 3rd case was anaplastic carcinoma with pyriform sinus invasion. In the case of anaplastic carcinoma, the cancer was recurred locally and distant metastasis, the patient died 2 months after surgery and other two cases were NED state. All three patients could preserve laryngeal function postoperative state.

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Vertical hemilaryngopharyngectomy is one of the good surgical procedure to preserve the laryngeal function in the surgical treatment of locally advanced head and neck cancer especially invading into the larynx. In selected cases of thyroid cancer, this method could be a useful option for preserving the function of the larynx.

From Feb. 2004 to December 2007total 1130 patients were treated, of them 940 patients were given dose between 75-150 mCi, included in this study. They sucked lemon candies 24 hours after dose in a every 2 hours, in non sleeping hours. Oral cleaning and sufficient hydration was also insured to all. Patients with SG disorders, history of 131- I therapy and irradiation to the neck were excluded. We able to follow up 640 patients for 2 years after the dose. This patients asked about their dry mouth and complication of salivary damage. Patients with the complain of dry mouth were done salivary scintiscan by standard citrus augmented SG scan protocol to asses functional status. Scan interpreted as normal, mild, moderate and severely reduced fuction. Among the 640 patients we followed up 2 years after therapy25(3.9%) patients have clinical xerostomia and scintiscan of SG was done to them. Of this 25 patients 9(1.4%) showed severe reduced uptake and 6(.9%) moderate, 5(.78%) mild reduction and 6 (.93%) was normal. In this study very few patient that is only (1.4 + .93) = 2.33% patient has got moderate to severe form of functional abnormality. A good number of patient(6) .93% has got xerostomia due to non SG cause. World wide study shows 4.4 to 20% has got Chronic xerostomia. Use of lemon candy, good oral health and hydration may reduce xerostomia in this study. Chronic xerostomia and its consequence could be successfully reduce by using lenon candy sucking 24 hours after radioiodine therapy, good oral hygiene and optimum hydration.

Poster 353 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM CAN WE PREDICT LATERAL NECK LYMPH NODE METASTASIS IN PAPILLARY THYROID CARCINOMA? M. Kim, S. Kim Otolaryngology - Head & Neck Surgery, Seoul St. Mary,s Hospital, The Catholic University of Korea, Seoul, Korea (the Republic of) Patient age, tumor subtype, extrathyroidal extension, and neck lymph node metastasis are known risk factors associatedwith increased recurrence of PTC(papillary thyroid carcinoma) and especially lateral neck lymph node metastasis is closely related to tumor recurrence and poor prognosis in patients with PTC. We designed this study to evaluate the risk factors for lateral neck node metastasis in PTC preoperatively. A retrospective review of the medical record of the patients who were diagnosed with PTC and had total thyroidectomy with lateral neck dissection from 2000 to 2013. 75 patients enrolled to this study and we also reviewed and compared medical record of 75 patients who had total thyroidectomy without lateral neck dissection in that period. We investigate age, sex, pre-operative location of tumor, post-operative pathology including size, multifocality, capsular invasion, extrathyroidal extension, central neck lymph node metastasis, lymph node density of central neck node. In univariate analysis, we found stastical differences of sex of patients(male), tumor location(upper), size, extrathyroidal extension, central lymph node metastasis, central lymph node density(more than 50%) between two groups. Logistic regression analysis showed tumor location(p-value = 0.04, Odds ratio 4.10), central neck lymph node metastasis(p-value = 0.05, Odds ratio 3.39), central neck node density(p-value = 0.03, Odds ratio 4.89) had strong relation with lateral neck node metastasis. Although with pre-operative precise evaluation, we sometimes overlooked lateral neck lymph node metastasis in PTC. We could conclude that central neck node metastasis and node density, location of tumor could be the predictive factor of lateral neck node metastasis.

Poster 354 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM CHRONIC XEROSTOMIA COULD BE MINIMIZED BY SUCKING LEMON CANDY, HYDRATION OF PATIENTS AND GOOD ORAL HYGIENE AFTER RADIOIODINE THERAPY IN DTC PATIENTS F. Alam, N. Naha NM, Prof (PLR) National Institute Nuclear Med & Allied Sceince, Shabag, Dhaka, Bangladesh One of the main adverse effects of radioactive iodine 131-I treatment in patients with thyroid cancer is damage to the salivary gland (SG). Dose related damage to the SG results from the 131-I irradiation. Acute SG swelling and pain are very common but long term complication like xerostomia can negatively affect the patient’s quality of life. Prevention of these damage is a challenging. Lemon candy sucking after therapy to stimulate the SG so that it clears radioactive iodine. This study is done to further evaluate its use.

Poster 355 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM EXTENT OF SURGERY IN MEDULLARY THYROID CANCER G. Bae, S. Tae, Y. Kim Department of Surgery, Ulsan University Hospital, Ulsan, Korea (the Republic of) Medullary thyroid cancer (MTC) is a malignant tumor originating from the parafollicular cells or C cells of the thyroid. It has various

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clinical course. Total thyroidectomy and central neck dissection is recommended for MTC patients. Serum calcitonin level is the most specific and sensitive marker of MTC for the postoperative follow up. Postoperative hypercalcitoninemia may show the possibility of occult MTC and a little chance of recurrence of MTC. But the extent of prophylactic lateral neck lymph node dissection is controversial. This study was aimed to show the relationship between postoperative calcitonin level and the extent of surgery. Between June 2008 and November 2013, a total of 9 patients underwent curative operation for MTC at the Ulsan University Hospital. Records of these patients were reviewed. All patients had checked preoperative and postoperative calcitonin levels, except 1 patient. Postoperative serum calcitonin was checked at 1 week, 3 months and a year after surgery. We compare the value of pre, postoperative serum calcitonin levels according to different types of surgery. They were 4 males and 5 females. The mean age at diagnosis was 47.3 – 11.1 years. 7 of these patients had clinical N0 state, and 4 had a total thyroidectomy with prophylactic lateral neck dissection. The mean follow-up time was 39.5 – 24.9 months. Calcitonin normalization was obtained in patients with prophylactic lateral neck dissection but calcitonin levels of patients with lobectomy remained elevated. The patients who had a prophylactic lateral neck dissection showed a more chance of normalization of serum calcitonin level. Our data shows that the extent of operation is associated with postoperative calcitonin level. The prophylactic neck dissection in MTC may reduce the chance of recurrence of tumor or increase a long term survival.

while 12 patients did not. Biochemical recurrence, however, was observed in 7 patients. On analysis of 34 patients who had achieved postoperative biochemical cure, biochemical recurrence-free survival at 5, 10, and 15 years were 90%, 85%, 70% respectively. The log-rank tests indicated that preoperative CT < 500 pg/ml (p = 0.03), normal CEA (p = 0.02), were associated with favorable prognosis. Early thyroidectomy based on CT and CEA levels could be an alternative intervention to prophylactic surgery in the management of gene-mutation carriers of HMTC.

Poster 356 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM FACTORS ASSOCIATED WITH LONG-TERM BIOCHEMICAL CURE AFTER SURGICAL TREATMENT OF HEREDITARY MEDULLARY THYROID CARCINOMA (HMTC) K. Horiuchi, T. Okamoto, K. Haniu, M. Sakurai, E. Nagai, H. Tokumitsu, Y. Yoshida, Y. Omi, A. Sakamoto Endocrine surgery, Tokyo Women’s Medical University, Tokyo, Japan Watchful observation and early thyroidectomy after the onset of the disease demonstrated by an elevated calcitonin (CT) level may be an alternative intervention to prophylactic thyroidectomy for RET proto-oncogene mutation carriers. It is unclear, however, how early the intervention should be recommended to achieve long-term biochemical cure of HMTC. The purpose of this study is to find out factors associated with long-term biochemical cure after surgical treatment of HMTC. A retrospective study on 46 patients with HMTC who underwent initial operation during April 1982 to December 2014 was conducted. For each patient, following variables were reviewed; age, preoperative levels of CEA and CT, tumor size, the extent of neck dissection, and pathological findings of lymph node metastasis. The potential factors were examined for their prognostic significance in relation to biochemical cure by means of the Kaplan-Meier estimates along with the log-rank test. Male: Female ratio was 19:27, and mean age was 36.5 years old (range: 11–70). The mean follow-up duration was 105 months (0– 322). The mean levels of preoperative CT, CEA and CT/CEA ratio were 761 pg/ml (25-40500), 18.6 ng/ml (0.6-785), and 41 (2.5354), respectively. The mean tumor size was 1.3 cm (0-6). Pathological lymph node metastases were seen in 12 (26%) patients. Thirty-four patients achieved biochemical cure following surgery

Poster 357 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM SCREENING FOR THYROID NODULAR DISEASE IN BREST REGION OF BELARUS: 29 YEARS AFTER THE CHERNOBYL CATASTROPHY M. Lushchyk1, V. Drozd1, L. Danilova1, A. Grigorovich2, V. Sivuda2, A. Romanovskyj1, Y. Demidchik1, T. Rogunovich3, V. Saenko3, I.D. Branovan4, N. Takamura3, S. Yamashita3 1 Endocrinology department, Thyroid Disease Unit, Belarusian Medical Academy of PostGraduate Education, Minsk, Belarus; 2 Brest Endocrinology Dispensary, Brest, Belarus; 3Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; 4Project Chernobyl Inc, New York, NY Thyroid cancer is a cancer recommended for early detection. Ultrasound screening play important role in the epidemiological studies aimed early diagnosis of thyroid diseases in high-risk groups of people exposed to radiation during the Chernobyl accident. The aim of our study was to evaluate thyroid nodular diseases and thyroid cancer among exposed population of Brest region of Belarus. Ultrasound screening (US) and ultrasound-guided fine-needle aspiration biopsy (FNAB) of thyroid lesions were done with the help of Hitachi-405 ultrasound scanner. Blood samples were taken and TSH, fT4, TPOAb and TgAb were measured in thyroid nodular disease cases and/or autoimmune thyroiditis in Brest Endocrine Dispensary and Central Research Laboratory of the Belarusian Medical Academy of Postgraduate Education. Serum TSH was measured using a second-generation assay and the result recorded in mU/L. TgAb and TPOAb were classified as either positive or negative, based on institutional reference ranges. The data of last 5 yrs. of clinical and ultrasound screening were analyzed. During 2010–2014 yrs. the total number of examined people who were born during 1968–1986 yrs. reached 21845. Thyroid nodular disease was diagnosed in 4175 (19%) cases. Among those who were less then 18 yrs. old by the moment of the accident the number of US suspicious single nodules reached 2609/4175 (12%), FNAB was done in 672/2609 cases. Results of FNAB of thyroid lesions were - 11 % malignant, 14% indeterminate, and 75% benign. Positive TgAbs ( > 100 IU/l) were found in 234/672 (35%) cases, mean TSH serum concentration were - 3,4 – 0,9 mU/L (mean – SD). The number of patients referred to Republican Center of Thyroid and Neck Tumors reached 72/672 patients (postoperative diagnosis of differentiated papillary carcinoma was approved in 57/72 cases). Positive TgAbs ( > 100 IU/l) were found in 64/72 cases suspicion to malignancy (mean – SD serum TSH concentration - 2,6 – 0,7 mU/L). Ultrasound screening during 25–29 yrs. after the Chernobyl accident still showes a high prevalence of nodular thyroid disease (19%) and cancer (0,29%) in high-risk groups of exposed population of south-western part of Belarus.

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performed analysis to determine the influencing factors for central lymph node metastasis in patients with PTMC. We analyzed retrospectively 622 patients with PTMC underwent thyroid surgery at Chosun University Hospital from January 2002 to December 2012. We reviewed medical records including clinical information, pathologic report. Central lymph node metastasis was found in 119 patients (19.1%) among total 622 patients with PTMC. Lymph node metastasis occurred frequently in patients with following factors; female (p = 0.025), tumor in bilateral thyroid lobe (p = 0.016), more than two in number of tumor (p = 0.035), more than 0.5cm in largest tumor size (p < 0.001) and lymphovascular invasion (p = 0.024). There were no statistically significant differences in age and capsular invasion. In multivariate analysis, we determined significant factors for lymph node metastasis follows as; age at operation (p = 0.045), gender (p = 0.020), tumor size (p < 0.001) and lymphovascular invasion (p = 0.023). We suggest that must perform surgery in spite of PTMC. Moreover, we must consider seriously prophylactic central neck lymph node dissection during surgery in PTMC.

Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE PREVALENCE, CLINICOPATHOLOGIC FEATURES AND SURGICAL OUTCOMES ACCORDING TO THE EXTENT OF THYROIDECTOMY IN DIFFERENTIATED THYROID CANCER SIZED > 1CM AND < 4CM J. Choi, S. Lee, M. Kim, T. KIM, E. Ban, C. Lee, J. lee, S. Kang, J. jeong, K. Nam, W. Chung, C. Park Yonsei university hospital, Seoul, Korea (the Republic of) Recent some guidelines recommend unilateral thyroidectomy for low risk differentiated thyroid cancer (DTC) sized > 1cm and < 4cm. The present study was designed to evaluate the proper extent of thyroidectomy for patients who have differentiated thyroid cancer sized > 1cm and < 4cm. From April 1967 to December 2011, a total of 16,065 DTC patients underwent thyroidectomy in Yonsei University Hospital. Among them, 5,427 (33.7%) patients were classified into for DTC > 1cm and < 4cm and were enrolled in this study. Clinicopathologic features and prognostic results (disease free and specific survival rates) were analyzed by retrospective medical chart review. Mean follow up duration was 57.3 – 58.1 months. In the subtypes of tumors, papillary thyroid carcinoma (PTC) patients were most common cancer (96.9%) and follicular, poorly differentiated carcinoma were 2.7% and 0.1% respectively. Mean tumor size was 1.84 – 0.74cm. Patients had extrathyroidal extension (69.3%), multiplicity (35.0%), bilaterality (26.3%), central lymph node metastasis (35.8%), and lateral neck node metastases (20.2%). A total of 5,427 patients, 4,353 (80.2%) patients underwent total thyroidectomy and 1,043 (19.2%) patients underwent less than total thyroidectomy. Recurrence rate in total thyroidectomic and less than total thyroidectomic group were 3.9% and 10.0% respectively. Less than total thyroidectomic group showed lower the disease free survival (DFS) rate (P = 0.039) and higher disease specific survival (DSS) ( p = 0.035) rate compared with total thyroidectomic group. In multivariate analysis for DFS, tumor size, N stage, and extent of thyroidectomy were independent risk factors. In multivariate analysis for DSS, age, gender, tumor size, N and M stage were independent risk factors. In patients with > 1cm and < 4cm tumor, total thyroidectomy was beneficial in reducing recurrence. However, our study confirmed that risk factors for DSS were not extent of thyroidectomy but traditional prognostic factors such as older age, male sex, large tumor size, lymph node metastasis, and distant metastasis.

Poster 359 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM ANALYSIS OF INFLUENCING FACTORS FOR CENTRAL NECK LYMPH NODE METASTASIS IN PATIENTS WITH PAPILLARY THYROID MICROCARCINOMA Y. Kim Surgery, Chosun University College of medicine, Gwangju, Korea (the Republic of) Papillary microcarcinoma (PTMC) is a small papillary thyroid carcinoma measuring 1cm or less in diameter. Recently, incidence of PTMC has been increased due to an increase in the detection of subclinical disease such as small and low-risk carcinomas with ultrasonography and fine needle aspiration cytology. However, there is central neck lymph node metastasis in patients with PTMC. We

Poster 360 Thyroid Cancer Monday & Tuesday Poster 9:00 AM RETROSPECTIVE ANALYSIS OF CLINICAL AND PATHOLOGICAL FEATURES IN PAPILLARY THYROID MICROCARCINOMA T. Nomura, S. Sugawara, E. Kishino, H. Ogura, M. Yamamoto, W. Saito, Y. Ohta, Y. Koike, T. Yamashita, Y. Yamamoto, K. Tanaka, J. Kurebayashi breast and thyroid surgery, Kawasaki medical school, Kurashiki, Japan It is known that patients with papillary thyroid microcarcinoma (PTM) have a good prognosis. Therefore we may follow up for these patients without operations. But it isn’t a strong evidence that PTM patients is good prognosis without operation. We retrospectively analyzed 245 patients with PTM who were operated from 1976 to 2014 at the Kawasaki Medical School. The relationship between the clinical and pathological factors in PTM patients such as lymph node metastases, extra thyroidal extension, recurrent free survival and overall survival was analyzed. PTM patients were 207 women and 38 men. Age ranged from 16 to 86 years (mean 52 years). The mean duration of follow-up after surgery was 4.6 years (range 6 day-35.2 years). Median tumor diameters were 8mm and 18 patients’ data were unknown. 80 PTM patients (37.3%) had lymph node metastases, 39 patients (16.0%) had extrathyroidal extension. Recurrent free survival within 10 years were 96.6%, overall survival within 10 years were 96.1%. 2 patients died of their metastases, they had lymphnode metastases. Incidental PTM patients had lower lymph node metastases (16.7% vs 41.6%, P = 0.005) and lower extrathyroidal extension (0% vs 21.3%, P = 0.00) than preoperative diagnosed PTM patients. But incidental PTM patients were similar RFS (97.3% vs 96.5%, P = 0.63) and OS (96.6% vs 96.0%, P = 0.53) than preoperative diagnosed PTM patients. Patients with PTM > 5mm had higher lymph node metastases (40.8% vs 16.7%, P = 0.006) and high extrathyroidal extension (21.1% vs 3.3%, P = 0.002) than patients with &5mm. But patients with PTM > 5mm were similar RFS(97.3% vs 100%, P = 0.33) and OS (97.8% vs 91.2%, P = 0.72) than preoperative diagnosed PTM. We should operate for > 5mm PTM patients who are diagnosed before surgery because of the high lymph node metastases and extrathyroid extension.

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Poster 361 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM WORLDWIDE VARIABILITY OF ACCESS TO MKIS FOR REFRACTORY, METASTATIC THYROID CANCER S.R. Perea1,2, N. Armstrong15, B. Barte`s6, M.S. Brose9, R. Elisai11, K. Farnell4, J. Grey7, C. Harmer13, H. Hobrough5, M. Luster14, U. Mallick15, M. McGarry12, L. Moss16, F. Palazzo17, M. Porrey8, F. Pitoia18, M. Schlumberger10, J. Taylor1,19, C. Villar1,3 1 Thyroid Cancer Alliance, Diss, United Kingdom; 2ACTIRA, Buenos Aires, Argentina; 3AECAT, Madrid, Spain; 4Butterfly Thyroid Cancer Trust, Newcastle, United Kingdom; 5Thyroid Cancer Support Group Wales, Cardiff, United Kingdom; 6Vivre sans Thyroide, Paris, France; 7Association for Multiple Endocrine Neoplasm Disorders, Tunbridge Wells, United Kingdom; 8 Schildklier Organisaties Nederland (SON), Amersfoort, Netherlands; 9Otorhinolaryngology: Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA; 10Centre de Lutte Contre le Cancer (CLCC) de Villejuif, Institut Gustave Roussy, Villejuif, France; 11University of Pisa, Pisa, Italy; 12Thyroid Cancer Support Group Ireland, Dublin, Ireland; 13Retired, London, United Kingdom; 14University of Marburg, Marburg, Germany; 15Freeman Hospital, Newcastle Upon Tyne, United Kingdom; 16Velindre Cancer Centre, Cardiff, United Kingdom; 17Hammersmith Hospital & Imperial College, London, United Kingdom; 18Hospital de Clı´nicas - University of Buenos Aires, Buenos Aires, Argentina; 19 British Thyroid Foundation, Harrogate, United Kingdom Advanced thyroid cancer is a rare condition with a poor prognosis. Multikinase inhibitors (MKIs) have some benefits for patients with advanced progressive metastatic and/or symptomatic radioiodine resistant differentiated thyroid cancer (RR-DTC) or advanced medullary thyroid cancer (A-MTC) but patients and physicians report difficulties accessing them. To compare access data to MKIs (mainly sorafenib, vandetanib and cabozantinib), physicians and patient advocates were asked to complete a questionnaire about the availability of MKIs in their country for treating RR-DTC and A-MTC. Data were collected for

A-147 Argentina, England, France, Germany, Italy, Ireland, the Netherlands, Scotland, Spain, the USA and Wales. All 3 drugs have received FDA and EMA approval for RR-DTC and/or A-MTC and others are in development. However, approval is subject to national and regional regulatory agencies and processes, resulting in great international variability in MKIs access. See Table 1. These data represent a snapshot of the present availability of MKIs to advanced thyroid cancer patients and highlight inconsistent results in adjoining countries and regions. Although it would be optimal to inventarise availability of MKIs by analysing official health regulatory sources, these preliminary results may increase awareness of the issues and assist patient organisations, doctors, regulatory authorities and the pharmaceutical industry to work together to improve access.

Poster 362 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM ADHERENCE TO LOW IODINE DIET AND ABLATION SUCCESS RATE IN PATIENTS OPERATED FROM WELL DIFFERENTIATED THYROID CARCINOMAS V. Markovic´1, B. Penic´1, A. Punda1, D. Eterovic´1, A. Pranic´ Kragic´1, Z. Antunovic´2 1 Department of Nuclear Medicine, University Hospital Split and University of Split School of Medicine, Split, Croatia; 2 Department of Physics, Faculty of Science, University of Split, Split, Croatia To investigate the adherence to two-week strict low iodine diet regime and the success of ablation in patients operated from T12N0M0 well differentiated thyroid cancers. This retrospective study was conducted using questionnaire forms and medical records in 135 patients (107 female, 28 male; median age 54 (range, 19–79 years)) operated and ablated with 1,1 GBq of I131 over period 2012–2014. Thirty four patients were on regular diet (group 1), 30 patients were only adviced to hold the low iodine diet (group 2) and 71 patients were given written instructions (group 3, strict regime). Adherence to strict diet regime was poor (53% at the first and 64% at the control hospitalization). The reablation rates were similar: 32%, 27% and 30% for the groups 1, 2 and 3, respectively (P = 0,313). Patients who had reablation had significantly greater preablative Tg concentration compared to patients successfully ablated with single dose (3,0 – 3,5 vs. 1,8 – 2,5 ng/ml), regardless of diet type (multivariate relative risk of reablation for patients having Tg over 3 ng/ml; 1.92 – 0.45 (95% confidence interval)). We did not demonstrate the effect of diet on the outcome of radioiodine ablation, which could in part be due to low adherence. Therefore we advise reminding the patients on starting of two-week low iodine diet by telephone call/SMS. Next, we propose increasing the ablative activity in patients with preablative thyroid remnant Tg concentrations greater than 3,0 ng/ml.

Poster 363 Thyroid Cancer Monday & Tuesday Poster 9:00 AM DIAGNOSIS AND TREATMENT OF PARATHYROID CARCINOMA (SEVEN CASES REPORT AND LITERATURE REVIEW) W. Liu Shanghai Tongren Hospital, Shanghai, China Parathyroid carcinoma (PC) is a rare endocrine malignancy, accounting for less than 1% of cases of primary hyperparathyroidism.It was first described by De Quervain in 1904, but there have since been

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fewer than 1000 cases of this pathology described in the English literature. The clinical manifestations, treatment and prognosis of 7 cases of PC are summarized in our hospital. And discuss the method of diagnosis and treatment of the disease. The overall survival at 5-year and 10-year was 85%-100% and 49–80% in reports.Despite the high survival rate, close to 50% of the rate of recurrences were observed. From January 2005 to December 2014, a total of 7 patients were recruited. Their clinical data, clinical manifestation, examinations and surgical modes were analyzed retrospectively. One patient died after operation beause of severe hypocalcemia.The remaining six patients were followed up for 16–72 months, an average of 37 – 20.03 months. Two patients underwent En bloc resection and one patients underwent parathyroidectomy were followed up until now without recurrence or metastasis.Three patients underwent parathyroidectomy appeared metastasis or recurrence in the follow-up. En bloc resection in initial operation can reduce recurrence and metastasis rate. Aggressive treatment should be considered in initial operation.It can improve the cure rate.

tutions were inconclusive. The patient could not move her neck due to the compressive effect of the mass, consequently affecting her quality of life. There was rapid growth of the mass over the previous 3 months. Fiberoptic laryngoscopy examination revealed mobile vocal folds bilaterally. Using nerve monitoring with an EMG endotracheal tube inserted fiberoptically, the thyroid mass comprising the right lobe and isthmus was resected. The RLN was identified, preserved and stimulated at the end of the procedure. The left lobe was normal in appearance. The final pathological diagnosis was ATC. Repeat fiberoptic laryngoscopy showed normal vocal fold mobility. The patient was offered post-operative chemo-radiation but she and her family declined further treatment. The patient was discharged to a nursing facility. If we extrapolate our findings in the rat model to patients, sectioning of the motor fibres of the RLN is necessary to produce permanent VFP. Identification and preservation of the motor fibres of the RLN during thyroidectomy will result in return of vocal fold motion. RLN monitoring and magnification to preserve the motor fibres of the RLN will aid in improved outcomes after thyroidectomy in ATC.

Poster 364 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM RESILIENCE OF THE RECURRENT LARYNGEAL NERVE IN THYROID SURGERY: A CASE REPORT K. Sundaram 1 Otolaryngology, SUNY Downstate Medical Center, Staten Island, NY; 2Surgery, New York Methodist Hospital, Brooklyn, NY The Recurrent Laryngeal Nerve (RLN) in the rat model is very resilient to crush injuries. Even with severe crush injuries most rat RLNs recover in 42 weeks. The axon profiles were similar in cross section to an adult normal nerve (Tessema et al). This has been observed in our lab as well ( Harris et al. poster at AHNS Translational meeting 2015). Sectioning the RLN in the rat is a definitive way to cause permanent vocal fold paralysis (VFP). It is known that in Anaplastic Thyroid Cancer (ATC), upto 30% of patients could have VFP at the time of initial presentation ( Patel and Shaha). In the remaining cases preservation of the RLN could be aided by use of nerve monitoring and magnification. We present a case of an 89 year old female with a massive goiter, measuring about 12cms in diameter extending from the mandible to the upper chest. Two fine needle aspiration biopsies at other insti-

Anaplastic thyroid carcinoma involving neck and upper mediastinum.

Poster 365 Thyroid Cancer Monday & Tuesday Poster Basic 9:00 AM IN VITRO DETECTION OF AROMATIC COMPOUNDS BY SCENT-TRAINED CANINES TO DISCRIMINATE BETWEEN PAPILLARY THYROID CANCER AND BENIGN THYROID DISEASE IN HUMAN PATIENTS A.M. Hinson1,2, L. Jolly3, A.A. Ferrando4, B.C. Stack1,2, B.M. Wilkerson4, S. Waggoner4, D.L. Bodenner4,2, A.T. Franco3,2 1 Otolaryngology-Head & Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, AR; 2UAMS Thyroid Center, University of Arkansas for Medical Sciences, Little Rock, AR; 3 Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR; 4Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR The objective of the present study was to determine whether the aromatic compounds that allow scent-trained canines to reliably discriminate between PTC and benign thyroid disease could be duplicated in vitro. We also evaluated the tumor cell number threshold that a scent-trained dog could reliably detect within a mixture of PTC and benign thyroid cells. Thyroid tissue was collected during surgery from four patients with PTC (conventional type) and two patients with benign thyroid disease. Cell lines were cultured in DMEM-High Glucose supplemented with 10% fetal bovine serum, 1% penicillin/ streptomycin, and 2mM L-Glutamine. Serial cell dilutions (range 100,000 cells to 10 cells) were prepared in PBS for each cell line. Conditioned culture medium, without FBS, from over-confluent cell lines was also tested. A gloved handler, blinded to the sample status, presented each sample in a conical tube to the canine in a randomized fashion. The handler verbally communicated the canine’s alert to a blinded study coordinator who recorded the response. When presented with - 100 to 1000 cells from PTC cell lines (suspended in 3 cc PBS), the canine indicated the presence of PTC in 16 of 16 cases (100% accuracy). When presented with less than 50 cells, the canine’s alert was correct in only 4 of 10 cases (40% accuracy). By contrast, the canine did not alert on any benign sample presented at any cell concentration between 1,000 and 10,000 cells (3 of 3; 100% accuracy). To determine if the canines were detecting secreted factors from the tumor cells, we presented the canines with conditioned media from the cell lines. The canines gave a positive alert of PTC with 100% accuracy (4 of 4 cases) with the conditioned

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media samples isolated from the PTC cell lines, but did not alert on conditioned media collected from benign cells, or control media. Canines alert on secreted volatiles associated with PTC. PTC cells produce volatile organic compounds that can be detected in vitro by scent-trained canines in a dose dependent manner. Efforts are underway to classify the components underlying the aromatic profile associated with PTC.

Thyroid cancer is one of good prognosis cancer in the head and neck area, but it gets worse in case of lateral neck node metastasis such as N1b stage. Meticulous primary treatment and careful follow up is mandatory in N1b thyroid cancer patients. The purpose of this study is figuring out the risk factor of recurrence in thyroid cancer with lateral neck lymph node metastasis. From 2001 to 2014, thyroid cancer patients who hospitalized in our hospital involved in this study. All the patients who had lateral neck lymph node metastasis (N1b), received total thyroidectomy and ipsilateral modified radical neck. We restrospectively reviewed medical record of these patinets. Total 507 patients involved in this study, Forty-eight (9.5%) patients had recurred, among of them 30(5.9%) had recurred on lateral neck. Age, sex, primary tumor size, extra thyroid extension and tumor maker showed no statistic difference between recurrence and non-recurrence group. Extra capsular spread (ECS) of lymph node and post-operative 1 month thyroglobulin (TG) level showed statistic significant difference in all recurrence ( p = 0.03, p = 0.001). Analysis of cervical recurrence group only was no statistic significance. Meticulous primary treatment and careful post-treatment follow up should be needed in case of N1b thyroid cancer patients with ECS and immediate elevated post-operative TG level.

Poster 366 Thyroid Cancer Monday & Tuesday Poster 9:00 AM THYROTOXICOSIS FROM THYROID CANCER METASTASIS A. Mustafa, A. Manni, A. Pichardo-Lowden Penn State College of Medicine, Milton S. Hershey Medical Center, Division of Endocrinology, Diabetes and Metabolism, Hershey, PA Thyrotoxicosis due to functioning metastasis from thyroid cancer is rare. We report a case with hyper functioning pulmonary and bone metastasis characterized by rapid onset of thyrotoxicosis and long term survival following radioactive iodine administration. A 71 year old male, who underwent a total thyroidectomy for follicular variant papillary thyroid cancer which was already metastatic to the lungs & thoracic spine at presentation. He was euthyroid with a normal TSH of 0.5uIU/ml (0.3-5.1) & a Free T4 of 0.8ng/dl (0.7-1.48). Three months post-operatively he was found to be thyrotoxic (TSH < 0.01uIU/ml, Free T4 2.18ng/dl) despite withdrawal of thyroxine replacement in preparation of radioactive iodine replacement. His total body scan revealed increased uptake in his lungs, two large areas in the thoracic inlet & in the left hemipelvis. His serum thyroglobulin was markedly elevated at 173,130ng/ml. After treatment with 100mCi of radioactive iodine his thyroglobulin decreased to 7,678ng/ml & 3,320ng/ml & he became hypothyroid requiring thyroxine replacement. Thirteen months following his radioactive iodine administration his disease progressed as evidenced by recurrent of thyrotoxicosis (TSH < 0.01uIU/ml, Free T4 7.8ng/dl), & a sharp increase in his serum thyroglobulin to 99,700ng/ml. The total body scan showed persistence of increased tracer uptake in the lung & thoracic inlet area. Therefore he received a second dose of radioactive iodine (59mCi) following the dosimetry protocol. Three months later, he developed hypothyroidism (TSH 21.08uIU/ml) & required thyroxine replacement. However, after 17 months he was found to have a suppressed TSH despite discontinuation of thyroxine treatment. CT scan showed progressive disease in his lung & bone & his thyroglobulin was elevated at 9,653ng/ml. He was scheduled for a total body scan & third radioactive iodine treatment following dosimetry. However, for logistic issues he transferred his care to a local facility where he was followed conservatively. He remains alive 96 months after his thyroidectomy. NA This case is unique for the rapidity of thyrotoxicosis over 3 months despite major debulking surgery & for his long term survival following radioactive iodine therapy.

Poster 367 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM RISK FACTOR OF RECURRENCE IN N1B THYROID CANCER PATIENTS Y. Choi1, S. Kim1, J. Bae2, M. Kim1 1 Otolaryngology-Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea (the Republic of); 2 Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea (the Republic of)

Poster 368 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE FACTORS OF LOCAL & REGIONAL RECURRENCE IN DIFFERENTIATED THYROID CANCER (DTC) PATIENTS Y. Choi1, S. Kim1, J. Bae2, M. Kim1 1 Otolaryngology-Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea (the Republic of); 2 Surgery, The Catholic University of Korea, Seoul, Korea (the Republic of) Recurrence of DTC is classified to three categories. Local recurrence happened in thyroid bed, regional recurrence in cervical lymph node, and distant recurrence in the other distant organs. Distant recurrence is not common in DTC, loco-regional control of tumor is important factor for the prognosis. The purpose of this study is figuring out the factors of local and regional recurrence of DTC. From 2001 to 2014, DTC patients hospitalized in our hospital who recurred after treatment for DTC involved in this study. Restrospectively site of recurrence, primary tumor size, extra thyroid extention, extra capsular spread (ECS), post-operative 1 month thyroglobulin (TG) level, tumor markers, and stage were analyzed. Among 3677 DTC patients who received total thyroidectomy, 120 patients recurred (3.3%). Among 120 recurrence, thirty-one (25.8%) were local recurrence, eighty-two (68.3%) regional recurrence, four (3.3%) were locoregional recurrence and three (2.5%) distant recurrence. We compared local and regional recurrence group. Age and sex, primary tumor size, numbers of primary tumor foci, extra thyroid extention, tumor markers, and stage showed no statistic difference between two groups. But when comparing ECS and TG level between two groups, there was statistic difference (p = 0.04, p = 0.01). Especially regional recurrence group showed higher ECS and TG level. In case of ECS and elevated TG level, the chance of regional recurrence is higher than local recurrence, careful post-operative follow up and check for regional recurrence should be needed in these patients.

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MUC5AC with resultant secondary activation of the EGFR/RAS/ RAF/ERK pathway. Methods: Three patients with aggressive differentiated thyroid cancer (DTC) reported a history of Agent Orange exposure. All 3 patients were male with an age of 56–61 years and Agent Orange exposure through service in Vietnam. Clinical stage at presentation and during follow up was documented, along with all treatments. We also examined their tumor tissues for BRAF, KRAS, HRAS and NRAS mutations and for the PAX8/PPARg and RET/PTC translocations. Results: Two patients were staged as IVa DTC, while the third progressed from stage III to stage IVc. Patients underwent between 25 neck surgeries and received between 200 and 600 mCi radioactive iodine. Two patients subsequently received cervical external beam radiation and one received stereotactic radiation for brain metastases. The tumors of all three patients were positive for the BRAF c.1799T > A mutation (p.V600E). No other mutations or translocations were discovered. Conclusions: While thyroid cancer is not presently listed on the Department of Veterans Affairs list of Agent Orange exposure-related diseases, this small case series suggests that TCDD exposure might lead to highly aggressive thyroid carcinomas. It could be that TCDD increases the likelihood of BRAF mutations, or that it acts synergistically with BRAF mutations to elicit enhanced activation of the MAPK pathway, with resultant accelerated dedifferentiation and tumor spread.

Thyroid Cancer Monday & Tuesday Poster 9:00 AM ACTIONS SPEAK LOUDER THAN FNA: THE COEXISTENCE OF ANAPLASTIC AND PAPILLARY THYROID CANCER B. Addison, S. Thukuntla Endocrinology, University of Texas Medical Branch-Galvston, League City, TX The objective of this presentation is to recognize atypical presentations of papillary carcinomas as a possible indication of a coexistence of anaplastic thyroid cancer. A 50 year-old female came to otolaryngology clinic with complaints of chronic cough, voice changes and dysphagia. She had no history of radiation to the head or neck. She had no past medical or surgical history. Family history was negative for thyroid cancer or thyroid disease. A fiberoptic direct laryngoscopy was performed and was consistent with normal findings with the exception of lack of mobility in the left vocal cord. A CT of the neck was ordered for further evaluation. CT of the neck was consistent with a left thyroid lesion which extended into the midline causing mass effect on the esophagus and trachea. Left vocal cord paralysis was once more noted. Follow-up ultrasound and FNA of the thyroid revealed multiple nodules with the largest on the left at 1.64 x 1.83 x 1.55 cm with evidence of microcalcification. Pathology was consistent with papillary thyroid cancer. The patient had a total thyroidectomy with esophageal repair. Surgical pathology revealed the coexistence of papillary and anaplastic thyroid cancer. The patient was offered clinical trials for therapy options but was lost to follow-up shortly after surgery. Papillary cancers are the most common type of thyroid cancer. The prognosis for an affected patient is often determined by the patient’s age and the behavior of the cancer. Overall, papillary thyroid carcinomas have a good prognosis and high cure rate. Anaplastic thyroid carcinomas are aggressive undifferentiated tumors with a very high mortality. While papillary cancer is often an incidental findings on physical examination, 90% of anaplastic thyroid cancers have evidence of local and distal spread at time of diagnosis. Fine needle aspiration has been proven to be an effective screening tool. However, the coexistence of two pathologies can make diagnosis somewhat difficult and thus alter treatment plans. The ability to recognize unusual presentations of differential thyroid cancers is essential in identifying the coexistence of anaplastic thyroid cancer and providing the appropriate management of care.

Poster 370 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM CASE SERIES OF AGGRESSIVE THYROID CANCER IN PATIENTS WITH HISTORY OF AGENT ORANGE EXPOSURE. V. Bernet1, S.K. Grebe3, J.A. Copland2, K. Cradic3, S. Westphal4, R.C. Smallridge1, K.C. Bible5 1 Endocrinology, Mayo Clinic, Jacksonville, FL; 2Mayo Clinic, Jacksonville, FL; 3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; 4Endocrinology, Mayo Clinic, Scottsdale, AZ; 5Oncology, Mayo Clinic, Rochester, MN Introduction: The herbicide Agent Orange, a defoliant used extensively during the Vietnam War, is known to release 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD has been associated with a 4-fold increase in the risk of thyroid cancer. One potential mechanism to explain its increased thyroid cancer risk is up- regulation of

Poster 371 Thyroid Cancer Monday & Tuesday Poster 9:00 AM ROBOTIC BILATERAL MODIFIED RADICAL NECK DISSECTION FOR THYROID CANCER PATIENT WITH BILATERAL LATERAL NECK LYMPH NODES METASTASIS ; THE FIRST CASE REPORT K. Kang, S. Park, S. Paek, H. Sohn Surgery, Chung-Ang University Hospital, Seoul, Korea (the Republic of) Robotic thyroid surgery is expanding to include more complicated procedures such as modified radical neck dissection (MRND). Nonetheless, bilateral MRND has not been performed using robotic system as far as we know. We would introduce the first bilateral MRND case, reported using a bilateral axillo-breast approach (BABA) to obtain best cosmetic results. A 21-year-old woman visited our clinic with recently developed anterior neck mass. Neck ultrasonography showed 3cm-sized left thyroid mass and multiple suspicious metastatic lymph nodes in bilateral level 3, 4 and 6 area. FNA cytology confirmed papillary thyroid carcinoma with bilateral neck nodes metastasis. The patient underwent total thyroidectomy, bilateral central neck dissection and

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bilateral MRND by BABA under da Vinci robotic system. We modified conventional BABA procedure with vertical maneuver for better access to lower neck area. Operation was successfully performed under da Vinci robotic system. Total operation time was 553 minutes. Pathology was confirmed as papillary thyroid cancer with 27 metastatic lymph nodes out of 53. After surgery, there was no vocal cord palsy, transient hypoparathyroidism or chyle leak. Serum stimulated Tg level was less than 0.15ng/mL and post-RAIA scan showed no abnormal iodine uptake. Thanks to symmetric design of BABA, robotic bilateral MRND is technically feasible, safe, and effective. This procedure would be a good alternative option for those who fear of the operation scar in the neck.

tomy (OT) for the management of patients with papillary thyroid cancer. Medical records from a database of patients who had undergone thyroidectomy with cervical lymph node dissection after being diagnosed with papillary thyroid carcinoma between July 2008 and February 2013 were examined. Clinicopathologic characteristics, surgical outcomes, postoperative morbidities, and follow-up results of the RT and OT groups were investigated. No between-group differences in postoperative complications were noted. Additionally, the incidence of incompleteness in followup studies (1.5% vs. 0.9%; p = 0.661) was comparable between the RT and OT groups. Furthermore, no significant difference in the risk of persistent disease or recurrence between the groups was detected on a multivariate analysis (odds ratio, 2.804; 95% confidence interval, 0.749-10.497; p = 0.126). Although caution should be exercised while selecting patients for RT, RT using BABA may be a technically feasible and safe procedure in terms of surgical completeness.

Poster 372 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM BRAFV600E TEST FOR SUSPICIOUS LATERAL LYMPH NODES IN PAPILLARY THYROID CANCER W. Kim, J. Lee, S. Hwang, J. Jung, T. Kwon, H. Park, J. Jung Surgery, Kyungpook National University, Daegu, Korea (the Republic of) The objective of study was to compare the BRAFV600E test with fineneedle aspiration cytology (FNAC) for lateral lymph node (LN) metastasis in papillary thyroid carcinoma (PTC). A total of 91 patients, including 95 lateral LNs suspicious for PTC metastasis were consecutively entered into the study. We analyzed the accuracy of results for the BRAFV600E test and FNAC for lateral LN metastasis in PTC. Modified radical neck dissection was performed for 34 cases due to lateral LN metastasis. Among these 4 cases with false negative in FNAC, 2 cases were FNAC ( - ), BRAF ( + ), 1 case was FNAC (-), BRAF ( - ), high Tg, and last 1 case was negative in the FNAC, BRAF, Tg. However, we confirmed metastases by frozen biopsies during the operation. BRAF mutation test was helpful and informative in two cases with only BRAF mutation positive The sensitivity of FNAC and the LN-BRAFV600E test was 88.2% and 64.7%, respectively. The specificity and positive predictive value (PPV) were 100% in the two tests. The negative predictive values (NPV) were 93.8% and 83.6%. For samples positive with either the BRAFV600E test or FNAC, the sensitivity, specificity, PPV value and NPV were 94.1, 100, 100 and 96.8%, respectively. In conclusion, the results of this study show that concurrent administration of FNAC and the BRAFV600E test is an supportive diagnostic tool for PTC patients with indeterminate or non-diagnostic suspicious lateral LNs selectively, particularly when they do not have clear diagnostic results from the existing FNAC assay and/ or the Tg test.

Poster 373 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM SURGICAL COMPLETENESS OF ROBOTIC THYROIDECTOMY USING THE BILATERAL AXILLO-BREAST APPROACH: COMPARISON WITH OPEN CONVENTIONAL THYROIDECTOMY H. Kim1, H. Kwak1, S. Jung1, H. Lee1, G. Son1, J. Lee1, J. Bae1, G. Dionigi2 1 Korea University, Seoul, Korea (the Republic of); 2 University of Insubria, Varese, Italy The aim of the current study was to compare the surgical completeness of robotic thyroidectomy (RT) using the bilateral axillobreast approach (BABA) with that of conventional open thyroidec-

Poster 374 Thyroid Cancer Monday & Tuesday Poster Basic 9:00 AM THERMAL INJURY OF THE RECURRENT LARYNGEAL NERVE BY THUNDERBEATTM DURING THYROID SURGERY: RESULTS FROM CONTINUOUS INTRAOPERATIVE NEUROMONITORING IN A PORCINE MODEL H. Kim1, H. Kwak1, S. Jung1, H. Lee1, G. Son1, J. Lee1, J. Bae1, G. Dionigi2 1 Korea University, Seoul, Korea (the Republic of); 2 University of Insubria, Varese, Italy Recurrent laryngeal nerve (RLN) palsy is the most common and serious complication of thyroid surgery. The use of energy-based devices (EBDs) has replaced conventional knot-tying methods in many institutions. However, EBD use proximal to the RLN presents risks related to lateral thermal spread and associated nerve damage. This study aimed to test the safety of THUNDERBEATTM (TB), one of the most recently introduced EBDs, during thyroidectomy. Four piglets weighing 30-40 kg experienced thyroidectomy while continuous electrophysiologic monitoring (C-IONM) occurred, using an electromyography (EMG) endotracheal tube and NIM 3.0 response system. TB was applied at various distances from the RLN, and we assessed the safety of the protocols. Adverse EMG events did not occur at distances > 3 mm from the RLN. Amplitude decreased at 2 mm from the RLN after 8 s. However, immediate loss of signal (LOS) occurred at 1 mm from the RLN, likely due to immediate shrinkage of surrounding tissue after TB application. TB can be used safely at 3 mm from the RLN, but must be used for less than 8 s at more proximal locations. This is the first report assessing the safety of TB, and findings indicate that TB should be used at least 1 mm from the RLN in order to avoid injury.

Poster 375 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE EFFECT OF IMPLEMENTING GENE EXPRESSION CLASSIFIER TO IMPROVE OUTCOMES IN THYROID NODULE CYTOLOGY J.P. Abeykoon1,2, R. Mortada1, F. Dong3, L. Mueller1, E. Ablah3 1 Medicine, University of Kansas School of Medicine, Rochestr, MN; 2 Internal Medicine, Mayo Clinic, Rochester, MN; 3Preventive Medicine and Public Health, University of Kansas School of Medicine, Wichita, KS

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Thyroid nodule cytology is classified into six categories under the Bethesda Classification System. Two of these categories, atypia of undetermined significance (AUS) and suspicious for follicular neoplasm (SFN), are labeled as ‘indeterminate’ diagnosis due to inability to clearly distinguish benign from malignant cytology. Afirma Gene Expression Classifier (AGEC) may help to determine the malignant potential of thyroid nodule among patients with indeterminate cytology. This study aimed to assess whether the implementation of AGEC was associated with decreased proportion of surgical recommendations and lower financial cost. A cross-sectional study included data from electronic medical records at the University of Kansas School of Medicine-Wichita Endocrine Clinic about patients who underwent thyroid nodule fineneedle aspiration between 2004 and 2014. The rate of indeterminate cytology on nodule fine needle aspiration between cohorts before and after AGEC implementation, did not show a significant difference, 23.89% and 19.43% respectively (p = 0.365). Surgical recommendation for patients with indeterminate finding was decreased from 81.5% to 50% ( p = 0.011), before and after AGEC implementation, respectively, and this potentially may have decreased the rate of morbidity and complications linked to thyroid surgery. Primary cost estimate showed implementing AGEC has saved $722/patient in medical evaluation and treatment of a thyroid nodule with indeterminate finding. AGEC implementation appears to decrease the number of unnecessary surgeries, reduce potential surgical complications, and lower financial burden for patients with indeterminate diagnosis of thyroid nodules.

Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM PREVENTIVE AND TREATMENT EFFECTS OF MULTI-GROWTH FACTORS-CONTAINING CREAM ON POST-THYROIDECTOMY SCARS: A SINGLE-BLINDED RANDOMIZED CONTROLLED STUDY S. Shin1, J. Shin1, W. Chung2, K. Nam2, T. Kwon1, J. Lee1 1 Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea (the Republic of); 2 Department of Surgery, Yonsei University College of Medicine, Seoul, Korea (the Republic of) Wound healing is a complex and dynamic process involving hemostasis, inflammation, new tissue formation, and tissue remodeling. This process is regulated by a signaling network involving numerous growth factors, cytokines and chemokines. The aim of this study is to assess the efficacy of multi-growth factors (MGF)-containing cream in the prevention and treatment of post-thyroidectomy scars. Thirty six patients with thyroid carcinoma undergoing thyroidectomy were randomly assigned to the study or control group. Vancouver scar scale (VSS) and objective scar assessment including mexameter, cutometer and corneometer were assessed at baseline, at 2 weeks, at 6 weeks and 12 weeks after application of MGF-containing cream or placebo. The mean VSS score of the study group was lower than the controls at 2 weeks (2.86 – 2.41 vs 3.29 – 1.38, respectively), 6 weeks (2.00 – 1.41 vs 2.43 – 0.98, respectively), and 12 weeks (1.71 – 1.50 vs 1.86 – 0.90, respectively) after application. The mean melanin and erythema indexes of the study group were lower than the controls at 2 weeks, 6 weeks, and 12 weeks. The mean cutometer data of the study group was higher than controls at 6 weeks, and 12 weeks. The mean corneometer data of the study group was higher than controls at 2 weeks, 6 weeks, and 12 weeks. Application of MGF-containing cream improved the erythema, elasticity and water contents of the scar and this might be the reason for improved overall scar quality. Based on these results we suggest the MGF-containing cream as a novel treatment option for postoperative scar prevention.

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Poster 378 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM ASSOCIATION BETWEEN FINE NEEDLE ASPIRATION CYTOLOGY AND FINAL PATHOLOGY IN THE DIAGNOSIS OF THYROID NODULES WITH SURGICAL INDICATIONS M.E. Sevilla Alsina, D. Trabanco, D. Feliciano, D. Bredy Internal Medicine, Hospital Damas, Ponce, PR Fine Nedle Aspiration of Thyroid ( FNA) is broadly used as the preferred test to evaluate thyroid nodules. The clinical importance of this procedure is primarily related to the need of excluding Thyroid Cancer. There are few studies investigating the association between FNA and Final pathology in patients with Thyroid Nodules with surgical indications. There is no evidence from studies in the southern area of Puerto Rico that investigate this association.

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This was a randomized cross-sectional study, 82 medical records were evaluated. Data were obtained for FNA diagnosis, demographics, body mass index, findings on ultrasound and histopatholgy results. In this study the sensitivity of FNA was 73.53% and specificity of 100%. The accuracy of the study was 78%. The study reported a prevalence of 83% malignant tumors in the final pathology and 61% in the FNA. The positive predictive value was 100% and negative 43.75% suggesting that FNA is a good diagnostic test to detect thyroid nodules suspicious for malignancy. FNA of 33 patients were reported with undetermined cytopathology. The measure of agreement and correlaction coefficient showed a moderate agreeement between both studies with a Kappa value of 0.487, suggesting that the results of FNA and final pathology are associated. Of the indeterminate nodules, final pathology reported 15 benign and 18 malignant. This study demonstrated that the FNA is reliable in identifying thyroid nodules in patients with surgical indications.

Lt lower parathyoid gland is showing ICG fluorescence under NIR light in BABA robotic thyroidectomy (yellow circle is indicating parathyroid gland)

Poster 379 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM USE OF INDOCYANINE GREEN FLUORESCENCE FOR PARATHYROID GLANDS PRESERVATION IN BILATERAL AXILLO-BREAST APPROACH ROBOTIC THYROIDECTOMY J. Chung1, H. Kwon2, J. Lee1, S. Kim2, Y. Chai3, J. Choi1, K. Lee2 1 Seoul National University Bundang Hospital, Seongnam, Korea (the Republic of); 2Seoul National University Hospital, Seoul, Korea (the Republic of); 3Seoul National University Boramae Medical Center, Seoul, Korea (the Republic of) Bilateral axillo-breast approach (BABA) robotic thyroidectomy has shown favorable cosmetic and surgical outcomes. With increasing use of BABA robotic thyroidectomy, many efforts have been made to reduce complications related to parathyroid glands and recurrent laryngeal nerves (RLNs). In this study, we focused on preservation of parathyroid by indocyanine green (ICG) fluorescence under nearinfrared (NIR) light. From 2013.12 to 2015.5, among patients who had underwent BABA robotic thyroidectomy due to thyroid cancers, 12 patients were enrolled with informed consents. The patients were given 10mg ICG intravenously after strap muscle dissection. By NIR integrated scope (illuminator: 805nm/filter: 825nm), ICG was excited and emitted fluorescence. Based on the time that fluorescence appeared and disappeared in thyroid and parathyroid, visualization durations with optimal identification time were estimated, with an attempt to find RLNs. Patient demographics and clinico-pathologic characteristics were analyzed together. The elapsed time to thyroid and parathyroid visualization were 211 – 120(s) and 218 – 94(s) with fluorescence duration of 17.6 – 2.6(min) and 20.8 – 6.0(min), respectively. In all cases we could distinguish parathyroid from thyroid. Though earlier enhancement of

thyroid, parathyroid showed more focal and intense fluorescence pattern. RLNs didn’t show ICG fluorescence in contrast to thyroid and parathyroid. Mild transient hypoparathyroidism was reported in one patient, otherwise no recurrent RLN palsy occurred. This study had few limitations in terms of non randomized trial with small cases, subjective measurement of intensity and enhancement patterns. On the other hand there had been no ICG study in BABA robotic thyroidectomy, so this study might present an opportunity to make advancements in this setting. According to results of our study, parathyroid preservation using ICG fluorescence by NIR light is seemed to be feasible and safe in BABA robotic thyroidectomy. RLNs were also easily detected and saved by means of its non-fluorescent property. More randomizedcontrolled studies will be needed to support our conclusion and promote its application in practice.

Poster 380 Thyroid Cancer Monday & Tuesday Poster 9:00 AM THE IMPLICATIONS OF POST-DIAGNOSIS IMAGING ON THYROID CANCER DEATH AND RECURRENCE J.L. Wiebel1, M. Banerjee2, C. Guo2, B. Gay1, M. Haymart1 1 Endocrinology, University of Michigan, Ann Arbor, MI; 2 Biostastics, University of Michigan, Ann Arbor, MI Compounding the rise in differentiated thyroid cancer (DTC) incidence, utilization of post-diagnosis imaging has grown markedly. The effect of this imaging on death and recurrence has not been well studied. Our objective was to determine if undergoing a post-diagnosis imaging test is associated with more secondary treatment and fewer deaths from DTC. We identified 23,669 patients in the Surveillance Epidemiology and End Results (SEER)-Medicare database diagnosed with DTC between 1991 and 2009. CPT codes determined utilization of neck ultrasound, radioiodine scan and PET scan, as well as secondary treatment for DTC: repeat neck surgery, radioactive iodine treatment (RAI) greater than one year after diagnosis or radiation therapy. SEER data was used for deaths due to DTC. Trends over time were assessed with a poisson model. From 1992 until 2009, diagnoses rose from 628 to 2020 (rate ratio (RR) 0.94, p < 0.001), secondary treatment from 101 to 1539 interventions (RR 1.02, p < 0.001), and imaging from 268 to 9576 tests (RR 1.10, p < 0.001); change in death was not statistically significant. In multivariate analysis, undergoing ultrasound increased the likelihood of a second surgery (odds radio [OR] 2.15, 95% confidence interval [CI] 1.93–2.40) and RAI (OR 1.75, 95% CI 1.58–1.95). Radioiodine scan was associated with more surgery (OR 2.97, 95%

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Trends in Differentiated Thyroid Cancer Diagnosis, Post-diagnosis Imaging, Secondary Treatments and Disease-specific death from 1992–2009. CI 2.66-3.31), RAI (OR 21.54, 95% CI 18.52-25.18), and radiation therapy (OR 1.89, 95% CI 1.70-2.10). PET scan correlated with more surgery (OR 2.30, 95% CI 2.06-2.57), RAI (OR 1.79, 95% CI 1.612.00) and radiation therapy (OR 4.06, 95% CI 3.65-4.52). Undergoing neck ultrasound or PET scan did not significantly affect the likelihood of death (OR 1.06, 95% CI 0.92-1.22 and OR 1.08, 95% CI 0.91-1.29, respectively); however, radioiodine scan was associated with a lower mortality (OR 0.61, 95% CI 0.53-0.70). There has been a disproportionate rise in the use of post-diagnosis imaging relative to the number of diagnoses. This marked rise in imaging correlated with increased secondary treatment for DTC but in most cases no clear reduction in mortality. These findings emphasize the importance of curbing unnecessary imaging and tailoring post-diagnosis surveillance to patient risk.

Poster 381 Thyroid Cancer Monday & Tuesday Poster Translational 9:00 AM EBV MAY PLAY A ROLE IN THE DEVELOPMENT OF THYROID NODULES J.F. Almeida3,5, M.A. Marcello3, N.E. Bufalo3, C.L. Rossi1, A.H. Campos2, L.A. Suzuki1, L.P. Amaral3, A. Marques3, L.L. Cunha3, P.P. Arau´jo4, A.J. Tincani4, L.S. Ward3 1 Clinical Pathology, University of Campinas, Campinas, Brazil; 2 Anatomic Pathology, AC Camargo Cancer Center, Campinas, Brazil; 3Laboratory of Cancer Molecular Genetics, University of Campinas, Campinas, Brazil; 4Head and Neck Surgery, Clinics Hospital of University of Campinas, Campinas, Brazil; 5Healthy Science Institute, Paulista University, Campinas, Brazil Human Simplex Virus type 2 (HSV-2), Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) have been associated with various human malignancies and with thyroid autoimmunity. In order to investigate the presence of these viruses in benign and malignant thyroid nodules, we analyzed serum and thyroid tissue from 191 thyroid nodules patients (91 benign and 100 malignant). We also obtained 104 normal thyroid tissues extracted from the contralateral lobe of 104 tumors. We used ELISA to screen the serology of all patients and a real-time quantitative PCR technique to analyze thyroid tissues viral load on antibody-positive patients. In addition, the presence of herpesviruses was confirmed by histological analysis of 21 slides of EBV positive tissues using the expression of LMP-1 by immunohistochemistry (IHQ) and EBER by in situ hy-

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 bridization (ISH). Five out of the EBV positive slides were benign and 16 were malignant. There was no evidence of HSV-2 or CMV DNA, but we found EBV DNA sequences in 29 (16%) thyroid tissue samples. Even though the average viral load was 1068 copies/lg in 15 malignant cases and 374 copies/lg in 7 benign cases, there was no statistically significant difference between groups. We also found seven positive EBV cases out of 104 normal tissues. Viral load was higher in tumors than in their respective normal tissues (mean difference 61 – 202 copies/lg; Wilcoxon, p = 0.0002). None of the samples analyzed by IHQ showed LMP-1 expression into the cytoplasm or into the membrane. ISH analysis revealed 11 positive samples, among them 8 malignant cases, 2 Hashimoto’s disease and 1 goiter. We did not find any association between the presence of EBV and/or its viral load and any clinical or pathological tumor feature. Considering the presence of a high viral load of EBV in thyroid tumors compared to corresponding normal tissues and the expression of EBER mainly in malignant cases, suggest that EBV may play a role in development of thyroid malignancies. Although further studies are needed to better understand the relationship between EBV and thyroid nodules.

Poster 382 Thyroid Cancer Monday & Tuesday Poster Translational 9:00 AM REDUCED EXPRESSION OF HOMEOBOX GENE HOPX IN DIFFERENTIATED THYROID CARCINOMA J.C. Silva Jr.1,2, E.U. de Lima3, T.L. Oliveira1, I.C. da Silva4, C.A. de Lima4, L.L. Sampaio4, L.E. Fonseca Jr.4, V.M. Lima1, M.F. Medeiros1, I.S. Rubio5, H.E. Ramos1 1 Thyroid Study Laboratory, Biorregulation Department, Health and Science Institute, Universidade Federal da Bahia (UFBA), Salvador, Brazil; 2Post-graduate Program in Interactive Processes of Organs and Systems, Health & Science Institute, Universidade Federal da Bahia (UFBA), Salvador, Brazil; 3Genetic Bases of Thyroid Tumors Laboratory, Department of Morphology and Genetics, Universidade Federal de Sa˜o Paulo (UNIFESP), Sa˜o Paulo, Brazil; 4Monte Tabor - Hospital Sa˜o Rafael, Salvador, Brazil; 5 Department of Biological Sciences, UNIFESP, Sa˜o Paulo, Brazil HOPX is a homeobox gene with tumor-suppressing function, whose hypermethylation and consequent reduction of gene expression was studied in several cancer types (lung, esophagus, stomach, pancreas, colorectal and uterus). HOPX gene expression reduction gives more aggressive phenotype and worse prognosis. HOPX acts controlling various oncoproteins (like Cyr61, EphA2, c-Fos, c-Jun, EGR1 and GLUT-3). Objectives: Analysis of clinical-pathologic features and HOPX gene expression profile in Differentiated Thyroid Carcinoma (DTC), comparing with adjacent non-tumor (NT) and benign thyroid samples. Prospective study enrolling 32 patients (26 DTC/6 benign tumors). RNA extraction, conversion in cDNA, gene expression analysis with qPCR method. S8 ribosomal gene was used to normalize expression. Clinical and pathological data was obtained interviewing patients and reviewing electronic medical records. DDcT method was used to calculate gene expression. Wilcoxon’s, ANOVA and Kruskal-Wallis’s tests were used. 96.1% of DTC patients had papillary carcinoma (22 classic, 2 follicular e 1 solid variant). The mean age was 45.5 – 12.7 years old. The mean tumor size was1,02 – 0,68 cm and 80.7% were classified as stage I or II. 30.7% of patients with DTC had extracapsular extension and 38.4% had capsular invasion. 73.08% of DTC samples had decreased HOPXb expression in tumor tissue (T) compared with NT. HOPXb expression was markedly reduced in DTC when compared

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Location of novel SNV, using Ensemble genome browser.

with benign tissues ( p = 0.024). There was a significant reduction (65.6%) of HOPXb gene expression in T compared with NT (3.49 – 8.3 vs. 10.14 – 27.8) ( p = 0.009). In DTC patients without thyroiditis (N = 21), HOPXb reduced expression was also associated with earlier tumor stages (I and II, TNM staging system) compared with advanced stages (III and IV) ( p = 0.02). HOPX reduced expression was also associated with age below 45 years ( p = 0.048). This is the first study showing HOPXb reduced expression in DTC. Association with earlier stages and lower age suggests specific mechanisms controlling HOPX gene expression. It is possible that epigenetic HOPX gene inactivation might be involved. Additional studies may establish the utility of HOPX as prognostic marker in DTC. Support: FAPESB.

Poster 383 Thyroid Cancer Monday & Tuesday Poster Translational 9:00 AM SOMATIC LGALS-3 SINGLE NUCLEOTIDE VARIANT (SNV) THAT FIRSTLY FOUND IN THE KOREAN PAPILLARY THYROID CARCINOMA. J. Yi1, S. Yoo2, S. Lee2, R. Song1, H. Yu1, H. Kwon1, Y. Chai1, S. Kim1, J. Choi1, J. Seo2, K. Lee1 1 Surgery, Seoul National University Hospital, Seoul, Korea (the Republic of); 2Seoul National University, Seoul, Korea, Genomic Medicine Institute (GMI), Medical Research Center, Seoul, Korea (the Republic of) Galectin-3 is known as one of the best marker for differentiated thyroid cancer diagnosis. Compared with large numbers of immunohistochemistry and protein expression study for galectin-3, mutational analysis of LGALS-3 gene had never been reported in thyroid cancer. We identified novel single nucleotide variant (SNV) in LGALS-3 gene in Korean papillary thyroid cancer (PTC) tissue using next generation sequencing technique. We previously performed RNA sequencing for 123 papillary thyroid cancer samples using the Illumina HiSeq 2000. Sequenced reads were aligned to human reference genome (GRCh37) with STAR-2 method. VarScan was used for variant calling. mRNA expression levels were estimated as ‘‘reads per million mapped reads (RPKM)’’. R programming language was used for statistical analysis. SNV that located on chr14:55605006, G > T (pA88S) were found in six PTC. Five had BRAF V600E mutation and one had ETV6NTRK3 rearrangement as a driver mutation. LGALS-3 mRNA expression is higher in SNV group than non-SNV group (203.39 versus 121.63, p = 0.123). In SNV group, up-regulated genes included FCGR2A, CD80, CTLA4, LGALS1, LGALS9, GZMB, CD40, FAS, C1GALT1C1, BARD1, BAX and PRF1 whereas down-regulated genes included LAMP1, CYHR1, PAXIP1, CSNK2A2, SS18L1,

APP, BRAF, GOLGA2, MAP1LC3A, CUBN, TG and TPO. In the linear regression analysis, beta coefficient between LGALS-3 gene expression and other galectin family gene expressions - LGALS-1, LGALS-2, LGALS-7, LGALS-8 and LGALS-12 - were higher in SNV group. Furthermore, RAS family gene expressions - KRAS, NRAS and HRAS - also have higher beta coefficient with LGALS-3 expression in SNV group. BRAF gene expression had negative correlation with LGALS-3. LGALS-3 pA88S SNV was associated with over-expression of other galectins. Increased galectins result in stronger aggregation of transmembrane galectin receptors and enhances intracellular signaling to oncogenic RAS. This SNV may be correlated with high PTC incidence in Korea. Further experimental validation and demographic investigation need to be performed to support this results.

Poster 384 Thyroid Cancer Monday & Tuesday Poster Translational 9:00 AM COPY NUMBER VARIATION RELATED TO MTC PROGRESSION IN A PATIENT WITH MEN 2 AND P.G533C RET MUTATION A.N. Araujo1, D.R. Mazzotti3, R.M. Maciel2, J.M. Cerutti1 1 Morphology and Genetics, UNIFESP, Sa˜o Jose´ dos Campos, Brazil; 2Medicine, UNIFESP, Sa˜o Paulo, Brazil; 3 Psychobiology, UNIFESP, Sa˜o Paulo, Brazil Medullary thyroid carcinoma (MTC) can occur as part of the autosomal dominant hereditary syndrome multiple endocrine neoplasia type 2 (MEN 2). Most cases of MEN 2 syndromes arise from germline mutations in the RET gene. The pathogenesis of MTC suggests that, at least in hereditary cases, RET point mutations causes C-cell hyperplasia (CCH), creating a favorable environment for the development of MTC, and other genetic alterations might be involved in tumor progression. Thus, identifying genetic events associated with MTC progression is critical. Studies have identified associations between DNA copy number variation (CNV) and various diseases, including complex diseases such as cancer. Advances in the study of CNVs make clear the need to assess the contribution that these changes may have on the development of complex diseases. Recently, our group identified CNVs associated with a higher predisposition to lymph node metastasis in a family with p.G533C RET mutation. In this study we aim to investigate whether somatic CNVs may be related to the genesis of MTC in this family with p.G533C RET mutation. To identify the possible candidate regions associated with genesis of MTC both the MTC DNA (case) and peripheral blood (control) were obtained from the index case with MTC and p.G533C RET germline mutation. Case and Control DNA were investigated using the Affymetrix Genome-Wide SNP Array 6.0 platform. The data were analyzed using PennCNV software and the genes present on identified autosomal CNVs were analyzed at Enrichr software, a gene list enrichment analysis tool, to better understand the functional relevance of these genes. We identified 41 CNVs specific to the case (32 losses and 9 gains). Twenty-one of these CNV regions encompass a total of 48 genes.

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Importantly, upon gene evaluation, we found overrepresented Pathways terms associated to galactose metabolism (P = 0.043), type I diabetes mellitus (P = 0.058) and prostate cancer (P = 0.109). The use of paired samples allows indentifying somatic changes that may be associated with tumor progression. However, further analyses are still needed to determine the role of these CNVs in the etiological basis of the MTC in this family with MEN 2 and RET germline mutation.

University of Pennsylvania, Philadelphia, PA; 2Sarah Cannon Research Institute, Nashville, TN; 3University of Colorado, Aurora, CO; 4Massachusetts General Hospital, Boston, MA; 5Loxo Oncology, South San Francisco, CA; 6M.D Anderson Cancer Center, Houston, TX

Poster 385 Thyroid Cancer Monday & Tuesday Poster Translational 9:00 AM BRAF AND RAS MUTATION PATTERNS IN FOLLICULAR VARIANT OF PAPILLARY THYROID CANCER AND ITS CORRELATION WITH HISTOLOGIC SUB-TYPES A. AGARWAL1, N. George1, N. Kumari4, S. Gupta3, S. Agarwal2, S. Muthuswamy2, P. Singh5, N. Krishnani4 1 Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India; 2genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India; 3 Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India; 4 Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India; 5anaesthsia, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India The molecular profile of follicular variant of Papillary thyroid cancer (FVPTC) has been shown to be close to the follicular adenoma/ carcinoma group. However, there are very few studies describing the mutation patterns according to the encapsulated and infiltrative forms of follicular variant. Tissue from paraffin blocks of cancerous tissue (encapsulated and infiltrative cell subtypes of follicular variant of PTC (n = 24) were marked and cut out. The core or shavings were processed for DNA isolation by Qiagen FFP tissue kit. BRAF V600E mutation was analyzed by RFLP PCR method. RAS mutations (KRAS and HRAS) were analyzed by sequencing (ABI 3100). Though there was no difference in age, gender and tumor size, infiltrative carcinomas has a much higher frequency of extrathyroidal extension(16.6% vs4.1%) and nodal metastases (37.5 vs 4.1%) than encapsulated tumors. BRAF mutation 1799T > A was found in none of the encapsulated tumor but in 6 of 24 (25%) infiltrative tumors. HRAS mutations were identified in 2/24(8.33%), but no mutations were identified in the KRAS gene. Both the HRAS mutations are present in the encapsulated papillary thyroid carcinoma follicular variant (2/7; 28.57%).BRAF positivity in classical PTC (n = 60) was 76.6% while no KRas mutation was detected in classical PTC. Molecular signature of Follicular variant of Papillary Thyroid cancer is different from the conventional PTC. Even within the histologic sub-type of FVPTC, encapsulated sub-type has a molecular profile close to the follicular adenoma/carcinoma (absence of BRAF mutation and presence of Ras mutation).

Poster 386 Thyroid Cancer Monday & Tuesday Poster Translational 9:00 AM LOXO-101, A SELECTIVE PAN-TRK INHIBITOR FOR PATIENTS WITH TRK-ALTERATIONS M.S. Brose1, T.M. Bauer2, H.A. Burris2, R.C. Doebele3, A.F. Farago4, A.T. Shaw4, B.B. Tuch5, M.C. Cox5, D.S. Hong6

1

The TRK family of neurotrophin receptors, TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3, respectively), and their neurotrophin ligands regulate growth, differentiation and survival of neurons. Gene rearrangements resulting in mis-expression of fusion products that include the TRK kinase domain have been observed in diverse tumor types and may contribute to tumorigenesis (Vaishnavi, Cancer Discov 5:25, 2015). NTRK1 and NTRK3 fusions with various partner genes have been described in 2-3% of papillary thyroid carcinomas and are mutually exclusive of other known oncogenic mutations (TCGA, 2014 and data on file). LOXO-101 is an orally bioavailable, potent, ATP-competitive inhibitor of TRKA, TRKB, and TRKC. LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members in binding and cellular assays, with 100x selectivity over other kinases, and has shown acceptable pharmaceutical properties and safety in preclinical models. We are performing a Phase 1, multicenter, open-label, 3 + 3 doseescalation study of LOXO-101 to assess safety and tolerability. Data from 15 patients evaluated across 3 dose cohorts were reviewed. LOXO-101 was generally well tolerated with the most common adverse events being Grade 1 and 2 fatigue, dizziness and anemia. Pharmacokinetic assessment demonstrated that maximum plasma concentrations of LOXO-101 were reached 30–60 minutes following dosing. Exposure increased in approximate proportion with dose and was similar on Day 1 and Day 8 of repeated dosing in all subjects, and biologically relevant plasma levels have been achieved. LOXO-101 is well tolerated at doses for which biologically relevant plasma levels are achieved. The activity of LOXO-101 will be assessed in thyroid cancer patients with NTRK gene fusions in ongoing studies.

Poster 387 Thyroid Cancer Monday & Tuesday Poster Translational 9:00 AM MODULATION OF THYROIDAL RADIOIODIDE UPTAKE BY ONCOLOGICAL PIPELINE INHIBITORS AND APIGENIN A. Lakshmanan1, D. Scarberry1, J. Green2, X. Zhang2, S. Selmi-Ruby3, S.M. Jhiang1 1 Physiology & Cell Biology, The Ohio State University, Columbus, OH; 2The Ohio State University, Columbus, OH; 3 Institut National de la Sante´ et de la Recherche Me´dicale, Lyon, France Targeted radioiodine therapy for thyroid cancer is based on selective stimulation of Na + / I- Symporter (NIS)-mediated radioactive iodide uptake (RAIU) in thyroid cells by thyrotropin. Patients with advanced thyroid cancer do not benefit from radioiodine therapy due to reduced or absent NIS expression. To identify inhibitors that can be readily translated into clinical care, we examined oncological pipeline inhibitors targeting Akt, MEK, PI3K, Hsp90 or BRAF in their ability to increase RAIU in thyroid cells expressing BRAFV600E or RET/PTC3 oncogene. Our data showed that (1) PI3Ki GDC-0941 outperformed other inhibitors in RAIU increase mainly by decreasing iodide efflux rate to a great extent; (2) RAIU increase by all inhibitors was extensively reduced by TGF-b, a cytokine secreted in the invasive fronts of

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thyroid cancers; (3) RAIU reduction by TGF-b was mainly mediated by NIS reduction and could be reversed by Apigenin, a plant-derived flavonoid; and (4) In the presence of TGF-b, GDC-0941 with Apigenin co-treatment had the highest RAIU level in both BRAFV600E expressing cells and RET/PTC3 expressing cells. Taken together, Apigenin may serve as a dietary supplement along with small molecule inhibitors to improve radioiodine therapeutic efficacy on invasive tumor margins thereby minimizing future metastatic events.

pressor of Fused (SUFU) and a reference gene (RPS8) was performed. Immunohistochemistry (IHC) for SMO, GLI2 and Sonic Hedgehog (SHH) was performed in tumor samples. We analyzed 40 patients – 22 with persistent disease (PD) and 18 with no biochemical or structural evidence of disease (NED) after having received standard treatment – and 23 thyroid-healthy controls. An ROC curve revealed that SMO mRNA relative expression (RE) could distinguish patients with PD from the NED group (sensitivity 52.6%, specificity 100%). SMO RE was significantly higher in the PD patients when compared to the NED group ( p = 0.017). Thyroid-healthy controls had higher SMO RE than the NED group ( p = 0.038) and it was similar to the PD group. Correlation between SMO RE and serum calcitonin (sCt) was observed (r = 0.534, p = 0.001), as well as with CEA levels (r = 0.515, p = 0.001). Patients with sCt doubling-time (DT) < 24 months had significantly higher SMO RE than those with a DT > 24 months ( p = 0.006). SMO RE was also higher in patients with distant metastases ( p = 0.032). The RE of SUFU, a Hh pathway suppressor, was negatively correlated with the expression of SMO in patients with PD (Fig. 1). GLI1 and GLI2 expression were not informative. IHC of tumor samples from 14/22 PD patients was positive for SHH in both primary tumor and a metastatic lymph node from one patient, who had very high SMO RE. Higher SMO mRNA relative expression in peripheral blood was associated with persistent disease, distant metastases, and with prognostic factors such as sCt DT < 24 months and elevated sCt and CEA levels. Our findings suggest that SMO mRNA expression could be used as a biomarker to detect in real time which patients harbor tumors in which the Hh pathway is aberrantly activated.

Poster 388 Thyroid Cancer Monday & Tuesday Poster Translational 9:00 AM INDIVIDUALIZED ASSESSMENT BY MRNA EXPRESSION OF HEDGEHOG PATHWAY MARKERS IN PERIPHERAL BLOOD OF PATIENTS WITH PERSISTENT MEDULLARY THYROID CANCER S.C. Lindsey1, C.P. Camacho1, M.G. Cardoso3, J.H. Lee1, R. Delcelo2, R.M. Maciel1, M.R. Dias-da-Silva1,3 1 Medicine, Universidade Federal de Sa˜o Paulo, Sao Paulo, Brazil; 2 Pathology, Universidade Federal de Sa˜o Paulo, Sao Paulo, Brazil; 3 Biochemistry, Universidade Federal de Sa˜o Paulo, Sao Paulo, Brazil Patients with advanced medullary thyroid carcinoma (MTC) have an unfavorable prognosis. Hedgehog (Hh) signaling pathway has been shown to be upregulated in MTC. We investigated whether Hh pathway components can be detected in patients with MTC by analyzing circulating mRNA expression, aiming at individualizing the management of MTC. Peripheral blood samples were collected for biochemical analysis and RNA extraction. RT-qPCR for expression of the receptor Smoothened (SMO), transcription factors GLI1 and GLI2, Sup-

FIG. 1: SMO and SUFU mRNA expression in patients with persistent MTC. Analysis of 19 patients with persistent disease revealed that the expression of SMO and of the pathway suppressor SUFU were negatively correlated in a non-linear way. Black dots represent the observed expression of SMO and SUFU for each patient. The continuous line represents the logarithmic curve (r2 = 0.249, p = 0.030).

Poster 389 Thyroid Cancer Monday & Tuesday Poster Translational 9:00 AM VEGF EXPRESSION CORRELATES TO SONOGRAPHIC DOPPLER PARAMETER OF MALIGNANCY IN THYROID NODULES? F.F. Maia1, J. Vassallo2, G.A. Pinto2, E.J. Pavin1, P.S. Matos2, D.E. Zantut-Wittmann1 1 Internal Medicine, Endocrinology, University of Campinas, Sa˜o Paulo, Brazil; 2Pathology, University of Campinas, Campinas, Brazil Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis and a crucial step for cancer progression, even linked to poor outcome and prognosis documented in papillary thyroid carcinoma (PTC). Increased nodular vascularity is considered a highly suspicious feature on ultrasound (US) as per the ATA guidelines. However, the correlation between Doppler US parameter and VEGF expression in thyroid nodules has not been examined extensively. This study aimed to investigate the VEGF expression and it is correlation to nodule hypervascularity in 80 patients (48.1 – 13.8 yrs.) with resected thyroid nodular disease. Thyroid tissues were evaluated by immunochemistry (IHQ) for angiogenesis (monoclonal anti-VEGF antibody: Dako, M 727329-8; diluted 1:100). We used tissue arrays containing 160 thyroid samples, including 12 follicular adenomas (TFA), 33 PTC and 115 nonneoplastic specimens, as follows: 35 adenomatoid nodules (AN), 23 Hashimoto’s thyroiditis (HT) and 57 normal thyroid tissues. The positivity for VEGF was categorized by semi-quantitative method: strong positive, when at least 20% of the cells were clearly stained; weak, 5-20% and negative, < 5%. The hypervascularity via power Doppler examination was defined as peripheral/central flow or predominant central flow. The histopathological findings identified 47 (58.7%) benign and 33 (41.3%) malign thyroid nodules. Sonographic hypervascularity was detected in 28/80 (35%) cases. The majority of malignant cases

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showed mixed and predominant central flow (54.5%) in contrast to 21.2% of benign nodules (P = 0.002; 68.7% accuracy). VEGF stained strong positivity in 77.5% (62/80) of all thyroid nodules. VEGF staining was robust expressed in PTCs (75.8%) than in HT (56.5%) and normal tissue (40.3%); P < 0.05. Solitary or multiple nodules, gender, age over 45 yrs., TSH levels and hypervascularity by Doppler US were not correlated to VEGF expression in this study. The thyroid nodule vascularity determined by Doppler-US contributed to better identify thyroid malignancy in this study. However, VEGF expression was not correlated to thyroid nodule hypervascularity detected by Doppler-US.

1

Poster 390 Disorders of Thyroid Function Monday & Tuesday Poster Clinical 9:00 AM RADIOIODINETHERAPY WITH FIXED-DOSE OF 30MCI (1,110MBQ) IN AUTONOMOUSLY FUNCTIONING NODULES: SINGLE TOXIC NODULE AS A PREDICTIVE FACTOR OF SUCCESS L.B. Pereira1, A.M. Neto1, C.D. Ramos2, M.A. Tambascia1, D.E. Zantut-Wittmann1 1 Endocrinology Division, Internal Medicine Department, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil; 2Nuclear Medicine Division, Department of Radiology, Faculty of Medical Science, Campinas, Brazil Evaluate the efficacy of a fixed 30mCi (1,110MBq) dose of I131 for treatment of hyperthyroidism due to toxic uninodular or multinodular goiter and identify predictors of success. Sixty-one patients with toxic nodular goiter undergoing radioiodinetherapy (RIT) with a fixed dose of 30mCi as therapeutic option and monitored in a tertiary care center have been retrospectively evaluated in the period from to 1999 to 2013. Treatment was considered successful if the patient was euthyroid or hypothyroid without the need for anti-thyroid drugs at least one year after RIT. After RIT, 48 patients (78.7%) met success criteria and 13 (21.3%) remained hyperthyroid. Among the success group, 33 (68.7%) remained euthyroid while the others developed hypothyroidism. There was no statistically significant association of thyroid function after RIT and sex (p = 1.000), echogenicity and thyroid volume evaluated by ultrasound (p = 0.175 and 0.149 respectively), medication used (Propilthiouracil vs. Methimazole; p = 0.182), disease duration up to RIT (p = 0.053), pre-RIT TSH levels (p = 0.450) and pre-RIT 99mTc-pertechnetate uptake (p = 0.036). A higher success rate was seen in patients with a single toxic nodule vs. patients with multinodular goiter (92.3% vs. 55%; p = 0.001). Only single toxic nodule presentation was found to be an independent predictor of RIT success (p = 0.009). The I131 30mCi fixed-dose administration was an effective procedure in patients with single and multiple autonomously functioning nodules. A single toxic nodule was shown to be an independent predictor of therapeutic success.

Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico, Quere´taro, Mexico; 2Unidad de Secuenciacio´n Masiva y Bioinforma´tica, Instituto de Biotecnologı´a. Universidad Nacional Auto´noma de Me´xico (UNAM), Cuernavaca, Mexico Nuclear thyroid hormone (TH) actions are mediated by TH receptors (TRs). T3 is considered the primary bioactive TH because of its high affinity for TRs. However, results from our own group in teleosts and others in mammalian models have shown that, 3,5-T2 (T2) can also regulate gene expression. In fish, the effects of T2 are mediated by a long (L-) TRb1 isoform that contains a 9 amino acid insert in its ligand-binding domain. In contrast, the short (S-) TRb1 lacks this insert and is only activated by T3. In concert, T3 and T2 differentially regulate the expression of S- and L-TRb1, respectively in vivo, and hepatic expression of L-TRb1 is 106-fold higher than that of S-TRb1, reflecting the functional relevance of this signaling pathway. However, our studies have only been performed in liver and no information regarding any other tissue is available. With the aim of expanding our studies on the functional role of the two bioactive iodothyronines to other tissues, we chose to initiate with the cerebellum, a brain structure that shares similar cytoarchitectural organization and neural circuits in all vertebrates and is a TH-responsive tissue. Also, our initial screening showed abundant S- and L-TRb1 expression. We first determined that the exposure (water culture) with 25 nM of T2 or T3 for 12 h was an appropriate treatment to observe clear effects in gene expression in juvenile tilapia cerebellum and liver. Using RNA-seq with the Illumina GAIIx platform, we performed a transciptome analysis focusing in differential expression. Our results show that both, hepatic and cerebellar gene expression are differentially regulated by the two bioactive THs. Thus, T2 predominantly regulates gene expression in liver, as 2,514 and 1,934 genes were found to be regulated by T2 and T3, respectively. Of those, 929 and 349 were T2- or T3- specific, and 1585 were responsive to both thyronines. In contrast, T3 regulated the expression of 147 transcripts in cerebellum, while T2 only regulated 39. Of those, 130 and 22 were T3- and T2-specific, respectively and 17 were regulated by both thyronines. These results show that T3 and T2 exert tissue-specific gene regulation suggesting divergent roles in tilapia cerebellum and liver homeostasis.

Poster 393 Thyroid Hormone Action Monday & Tuesday Poster Basic 9:00 AM CHARACTERIZATION OF IN VIVO METABOLIC AND BEHAVIORAL EFFECTS OF NEW SYNTHETIC TAAR1 AGONISTS IN MOUSE M. Sabatini1, A. Laurino2, G. Nesi1, S. Rapposelli1, L. Raimondi2, R. Zucchi1, G. Chiellini1 1 University of Pisa, Pisa, Italy; 2University of Florence, Florence, Italy

Poster 391 Withdrawn

Poster 392 Thyroid Hormone Action Monday & Tuesday Poster Basic 9:00 AM T3 AND 3,5-T2 DIFFERENTIALLY REGULATE THE EXPRESSION OF GENE SETS IN THE LIVER AND CEREBELLUM OF TILAPIA (O. NILOTICUS) A. Olvera1, G. Herna´ndez-Puga1, P. Navarrete-Ramı´rez1, P. Villalobos1, J. Veronica2, A. Sanchez-Flores2, A. Orozco1

3-iodothyronamine (T1AM) is a chemical messenger, and administration of exogenous T1AM in mice determined significant functional effects, including exploratory behavior, hyperalgesia and hyperglycemia. 3-iodothyroacetic acid is produced in vivo by T1AM oxidative deamination and has been suggested to contribute to its behavioral effects. T1AM is an agonist of trace amine-associated receptor 1 (TAAR1), but it has been reported to affect also other aminergic signaling systems. We have recently synthesized a new structural class of thyronamine analogs, which turned out to be potent agonists for mouse TAAR1. Among them analogs SG-1 and SG-2 were found to be almost equipotent to parent endogenous substances,

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i.e. thyronamine and T1AM, respectively. In the present work we investigated the effects of SG-1, SG-2 and of their potential oxidative deamination products (named SG-5 and SG-6, respectively), on exploratory activity, pain threshold, and plasma glycaemia in mice. CD-1 male mice were injected i.p. with vehicle or test compounds at the dosages of 1.32, 4, or 11 lg/kg (n = 20 in each group). After 15 min plasma glycaemia was measured. After 30 min behavioral tests were performed, to evaluate pain threshold (hot plate test) and exploratory activity (hole board test). Exploratory activity was increased by 1.32 lg/Kg SG-2, while it was decreased by 4 lg/Kg SG-1, and it was not modified by either SG-5 and SG-6. SG-2 and SG-6 decreased the pain threshold in a dose-dependent way, while SG-1 produce biphasic effects (hyperalgesia at 4 lg/Kg and analgesia at 11 lg/Kg) and SG-5 was ineffective. Both SG-1 and SG-2 raised plasma glycaemia, with a potency comparable to the corresponding endogenous thyronamine, while SG-5 and SG-6 did not modify plasma glucose concentration. Synthetic T1AM analogs have different pharmacological profiles, which might be exploited for specific therapeutic applications. The comparison of the functional responses to these compounds with their potency on mouse TAAR1 suggests that the behavioral effects of T1AM and of its analogs cannot be accounted for by TAAR1 stimulation alone.

POMC mRNA poly(A) tail and translation rate are an interesting way by which the organism can compensate the drastic reduction on POMC mRNA expression caused by thyreoidectomy. Therefore, in vivo and in vitro studies led us to conclude that POMC mRNA content is rapidly modulated by T3 through transcriptional and post transcriptional pathways.

Poster 394 Thyroid Hormone Action Monday & Tuesday Poster Basic 9:00 AM T3 RAPIDLY MODULATES PITUITARY/ATT-20 CELLS POMC CONTENT BY TRANSCRIPTIONAL AND POST TRANSCRIPTIONAL PATHWAYS R.M. Pre´vide, P. Bargi-Souza, F. Goulart-Silva, M. Nunes Department of Physiology and Biophysics, University of Sa˜o Paulo, Sa˜o Paulo, Brazil Although many studies have been performed in order to clarify the relationship between thyroid hormones (TH) and the corticotrophic axis activity, this subject has still not been completely understood. Most of these studies were focused on the genomic actions of TH, however, there is an increased amount of evidence that some TH actions can be rapidly triggered by nongenomic mechanisms. In this study we aimed to explore the latter possibility, evaluating the effects of acute T3 treatment on POMC expression in rat pituitaries and in AtT-20 cells. Male Wistar rats were thyroidectomized and after 20 days, they received a single iv injection of saline (Tx + S) or T3 in two different doses: 0,3lg/100g or 100lg/100g (Tx0,3 and Tx100 groups). Animals were euthanized 30 minutes later and pituitaries were removed and submitted to RNA/protein extraction. AtT-20 cells were cultivated in DMEM and 10% FBS depleted of TH for 24 hours and then treated with actinomycin D, or RGD peptide, plus T3 (10 - 9M) for 30 min. Pituitary and AtT-20 cells POMC mRNA content was assessed by qPCR. Pituitary POMC mRNA poly(A) tail lenght and translation rate, as well as POMC and ACTH content were evaluated by RACE-PAT, polysome profile and western blotting, respectively. Our results show that POMC gene expression was greatly reduced in Tx + S rats, and moderately increased in Tx100 rats. No changes on POMC expression were detected, but ACTH content was reduced on Tx100 animals. POMC mRNA poly(A) tail length and translational rate were increased in Tx animals, and rapidly reduced by T3 treatment. AtT-20 cells treated with T3 displayed increased POMC mRNA content, which was partially lost when cells were previously treated with actinomycin D. RGD treatment blocked T3 effect on POMC gene content, thus indicating that this effect was triggered by T3 interaction with the membrane integrin aVb3. The increase on

Poster 395 Thyroid Hormone Action Monday & Tuesday Poster Basic 9:00 AM ELEVATED LEVELS OF ESTRADIOL INHIBIT T3DEPENDENT REGULATION OF ATRIUM CONNEXIN 40 L.C. Faustino2, S. Guedes1,2, N. Rangel1, T. Oliveira1, T.M. Ortiga-Carvalho2, C. Cabanelas2, N.A. Almeida1 1 Universidade Federal Rural do Rio de Janeiro, Rio de Janeiro, Brazil; 2Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil The propagation of electrical activity in the myocardium depends on the current transfer at gap junctions. Connexins 40 (cx40) and 43 are the predominant junctional proteins. In mice, Cx40 is restricted to the atrium and conduction system. Alterations of Cx40 expression or activity are associated with atrial fibrillation. Our group previously demonstrated that atrium Cx40 mRNA is up-regulated by T3. Estradiol (E2) and thyroid hormones (TH) play important regulatory functions in a wide variety of biological processes, including cardiac function. Several evidences have shown that actions of E2 and TH can be integrated. Here, we aimed to investigate the possible interaction among TH and E2 in atrium cx40 gene regulation. Female mice were subjected to ovariectomy (OVX) and then, treated with a low (2 ug) and a high dose (20 ug) of estradiol benzoate (EB) for 15 days. In another experiment, OVX mice received daily sc injections of T3 (50 ug/100 g BW) and EB (2 ug and 20 ug). We treated A7r5 cells (smooth muscle cells from rat thoracic aorta) with low and high doses of T3 and EB (10 - 8 M and 10 - 6M) for 24h. Results / Discussion: First, we observed that high doses of EB down-regulated cx40 mRNA in vivo and in vitro (A7r5 cells and rat atrial cardiomyocytes). In A7r5 cells, both low and high doses of T3 up-regulated cx40 mRNA. The transcriptional activity of cx40 promoter was inhibited by 10–6 M of EB in A7r5 cells while 10–6 M of T3 increased cx40 promoter activity in HeLa cells. Interestingly, when A7r5 cells and mice were co-treated with high doses of EB and T3, EB inhibited T3-induction of cx40 mRNA, indicating that high levels of E2 interfere with T3-dependent regulation of cx40 both in vivo and in vitro. Our data indicate, for the first time, a cross-talk between E2 and T3 regulating atrium cx40 expression. It is possible that T3 and E2 receptors compete for the same hormone response element. We propose the following, when E2 levels are low and T3 is present: T3, bound to its receptor, increases cx40 transcription. When E2 levels are high, the complex ER-E2 displaces TR-T3 from the DNA, inhibiting cx40 expression directly and indirectly avoiding upregulation by T3.

Poster 396 Thyroid Hormone Action Monday & Tuesday Poster Basic 9:00 AM THE EFFECT OF THYROID HORMONE ON THE EXPRESSION OF KISSPEPTIN IN HYPOTHALAMUS AND ITS RELATED MECHANISMS G. Chen, Lin, W. Endocrinology, Fujian Provincial Hospital, Fuzhou, China

A-160 To study how the chronic injection of T3 by intracerebroventricular cannulation affects the KISS1 gene transcription level and the kisspeptin expression. Explore the pathways and related mechanisms of how T3 intervenes the reproductive function by observing the effect of rapamyci. Please find it in tables. Please find it in tables. 1. In vitro, thyroid hormone that applied to GT1–7 cells can change the expression of KISS1 gene and kisspeptin in GT1-7 cell. 2. Different concentrations of thyroid hormone on kisspeptin GT1-7 cells had different influence. Either too high or too low concentration of T3 can reduce the expression of kisspeptin. when the concentration of T3 was 200 ng/ml the expression of kisspeptin in GT1-7 cells was the highest . 3. In vivo, instantaneous lateral intraventricular injection of T3 can increase the expression of KISS1 gene and kisspeptin in the hypothalamus..4.In vivo, continued chronic lateral intraventricular injection of T3 can significantly increase body weight in mice, Rapamycin can reverse this kind of effect. 5. T3 chronic lateral intraventricular injection can inhibit hypothalamic KISS1 gene and kisseptin expression. Rapamycin can’t reverse this impact, but can make the influence of TO on the sex hormone levels in mice improved. The influence of thyroid hormone in gonad axis is related with kisspeptin. mTOR may play a pivotal role in the interaction between the thyroid axis and gonad axis. Methods and Results: 1. In vitro experiment: We cultivated GT1-7 cells in vitro and prepared T3 solutions with concentration of 2000ng/ml, 200 ng/ml, 20 ng/ml, 0 ng/ml respectively. GT1-7 cells were treated with different concentration of T3 solutions for 24 hours, then collected. We used Realtime PCR to test the gene expression of KISS1 and western blot to detect kisspeptin expression in GT1-7 cells which were treated with different concentrations of T3. So as to figure out the optimal concentration of T3 that can stimulate the expression of kisspeptin in GT1-7 cells. 2. In vivo experiment: acute experiment: 12 mice were randomly divided into control group (N group) and T3 injection group (T group). We performed instantaneous injection of NaOH and T3 respectively by mouse stereotaxic instrument, and observed the expression of KISS1 mRNA and kisspeptin in hypothalamus of mice. We also used immunohistochemical method to compare the differences of the expression of kisspeptin in the arcuate nucleus area between these two groups. Chronic experiment: 24 mice were randomly divided into four groups. Each group contains 6 mice. Group N was set as a normal control group with no intracerebroventricular cannulation and no injection of drugs; With the help of the mouse stereotaxic instrument we implanted catheter into the lateral ventricle and connected the catheter with ALZET capsule osmotic pump which was embedded ubcutaneously. With this set Group IN was treated with chronic injection of NaOH for 7 days. Group IT was treated with chronic injection of T3 for 7 days. Group IR was treated with chronic injection of T3 and rapamycin for 7 days. During the dosing days we take vaginal smears of every mouse to know their estrus cycles. We measured their weights before and after the experiment to observe the effects of drug injection on their body weights. We got the blood of the mice and tested the serum thyroid stimulating hormone (TSH), free thyroid hormones (FT4), luteinizing hormone (LH), and estrogen(E) to compare the effects of different drug intervention in mice. We used realtime PCR to test KISS1 gene mRNA expression and used western blot to measue kisspeptin expression. We also compared hypothalamic arcuate nucleus kisspeptin protein expression among these different treatments groups with immunohistochemical staining. Results: 1. In vivo experiment results: T3 can change KISS1 mRNA and kisspeptin expression in GT1-7 cells. The influence of T3 on the expression

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 of KISS1 gene and kisspeptin expression is a y"Uy" shape curve. Both of the doses that were too low or too high would supressed the expression of KISS1 gene and kisspeptin. The best concentration of T3 on the expression of kisspeptin in GT1-7 cells were 200 ng/ml. In vivo experiment results: acute experiment: Intracerebroventricular injection of T3 instantaneously can increase KISS1 mRNA and kisspeptin expression in mice. The difference was significant (P < 0.05). Immunohistochemical results were consistent with the results of KISS1 gene and kisspeptin expression. Chronic experiments: One week after lateral ventricle catheter intervention, Compared with Group IN, the mice in Group IT had better appetite and their weights increased significantly, while the mice in Group IR reduced their weights significantly with reduced feeding. The difference was statistically significant (P < 0.05). There were no significant difference among these groups in estrus cycles, pathological results of ovaries and uterus. The TSH, FT4 and LH levels in Group IT were significantly lower than the control group, but the level of E was higher than that of the control group. (P < 0.05). Compared with Group IN, Group IT decreased the expression of KISS gene and kisspeptin in hypothalamus. The immunohistochemical results of kisspeptin in hypothalamic arcuate nucleus suggested the same trend, The difference was statistically significant (P < 0.05). Compared with Group IN, Group IR mice decreased the expression of KISS1 gene and kisspeptin in hypothalamus too. (P < 0.05). There is no significant difference between Group IT and Group IR.

Poster 397 Thyroid Cancer Monday & Tuesday Poster 9:00 AM METASTATIC ONCOCYTIC NEOPLASM OF THYROID PRESENTING AS UNKNOWN PRIMARY WITHOUT NEOPLASIA ON TOTAL THYROIDECTOMY N.C. Thomas, A. Manni Penn State Milton S Hershey Medical Center, Hershey, PA Distant metastases are observed in about 10% of differentiated thyroid cancer (DTC) patients; isolated liver metastases in 0.5%. DTC can also present as metastatic disease of unknown primary. We report the first case of a patient with isolated liver metastases from DTC presenting as unknown primary, without evidence of cancer in the thyroid despite a total thyroidectomy. We report the case of a 75-year-old man with incidentally discovered liver mass which on biopsy was shown to be an oncocytic neoplasm. Immunohistochemistry (IHC) was most consistent with thyroid primary. Tumor cells stained for Thyroglobulin (Tg), TTF-1 and PAX-8. Serum TSH was 0.88 uIU/mL and Tg was 285 ng/mL. Ultrasound of thyroid showed multiple subcentimeter nodules. FNA of a 6 mm hypoechoic nodule with irregular borders and microcalcifications was benign with no BRAF mutation. PET scan revealed intense FDG uptake in the liver and abdominal lymph nodes but not elsewhere including the thyroid. Transarterial chemoembolization (TACE) was done with shrinkage of tumor and 75% decline in Tg. Total thyroidectomy did not reveal any evidence of oncocytic nodules despite careful review. There are only 12 cases of isolated liver metastases from DTC reported in the literature. In each case a focus of DTC was identified in the thyroid, though it required re-examination of past thyroidectomy slides in patients who had been previously diagnosed with follicular adenoma. This is the first case report of thyroid cancer presenting as metastatic disease of unknown primary without evidence of DTC in the thyroid despite a total thyroidectomy. Tissue staining for Tg was instrumental in identifying thyroid as the primary. Remarkable reduction in Tg after

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shrinkage of the tumor mass with TACE was confirmatory. Radioiodine whole body scan will aid in detecting residual or metastatic thyroid cancer, if iodine-avid, and facilitate adjuvant ablation. Ectopic thyroid or teratoma remains a possibility. This case highlights the possibility of unique metastatic deposits of DTC even without biopsy-proven DTC in the thyroid in the right clinical setting. We were able to clinch a diagnosis of DTC in this patient with IHC positive for Tg and dramatic response in Tg to TACE.

The independent skeletal effect of thyrotropin (thyroid stimulating hormone, TSH) was suggested in animal studies. However, clinical data on the association between bone loss and variations in TSH level is controversial. This study aimed to investigate the relationship between TSH and bone mineral density (BMD). A cross-sectional study with 37,431 subjects (4,379 cases with subclinical thyroid dysfunction and 33,052 cases with euthyroidism) aged over 35 years was conducted. We performed thyroid function test and measured BMD at lumbar spine, femur neck, and total hip. The level of TSH and T3 correlated positively in women (r = 0.076, P = 0.001) and did not correlated in men. Both in men and women, the level of TSH correlated positively and T3 correlated negatively with BMD at all skeletal sites in age and body mass index adjusted analyses. The BMD increased steadily with increasing categories of TSH from subclinical hyperthyroid to subclinical hypothyroid range in subjects with T3 level of the highest tertile (119.5200.0 ng/dL), but no longer significant in subjects with lower plasma T3 level. The variations in TSH within the subclinical range were positively correlated with BMD in healthy men and women. The negative impact of T3 on BMD appears to be compensated by increasing TSH in subjects with upper normal range of plasma T3 level.

Poster 398 Thyroid Hormone Action Monday & Tuesday Poster 9:00 AM MYXEDEMA COMA IN A PATIENT WITH SUBCLINICAL HYPOTHYROIDISM PRESENTING WITHIN TWO WEEKS OF STARTING SUNITINIB N.C. THOMAS1, A. Jang2, A. Melvin2, N. Raja-Khan1 1 Endocrinology, Penn State Milton S Hershey Medical Center, Hershey, PA; 2Penn State Milton S Hershey Medical Center, Hershey, PA Hypothyroidism can range from subclinical hypothyroidism (SH) to myxedema coma, an endocrine emergency seen in patients with longstanding severe hypothyroidism. Recently a case of myxedema coma was reported in a patient with SH. We report a case of myxedema coma with SH that developed within 2 weeks of starting Sunitinib. A 65-year-old patient with metastatic renal cell carcinoma was started on Sunitinib after checking Thyroid stimulating hormone (TSH) and Free T4 (FT4). Within 2 weeks she began to have weakness, reduced oral intake and confusion and by the day of admission was stuporous with temperature of 35.8C. Home medications included opiates and Valproate. TSH was elevated at 63.40 uIU/mL (0.47-4.68) but free T4 was 1.13 ng/dL (0.78-2.19) and free T3 was 4.0 pg/dL (2.8-5.3). Given the markedly elevated TSH, altered mental status and defective thermoregulation we suspected myxedema coma and started her on intravenous T4 and T3 with a dramatic improvement in symptoms within 12 hours. Adrenal insufficiency was ruled out. MRI brain ruled out intracranial pathology. She was back to baseline within 3 days and T3 was discontinued. The term myxedema coma is largely a misnomer as most patients are not comatose. Classic clinical picture is that of decompensated hypothyroidism with altered mental state and defective thermoregulation Sunitinib-induced hypothyroidism is due to upregulation of type 3deiodinase; tissue levels of T3 are low despite normal circulating levels. In our patient the rapid rate of decline in tissue T3 levels from normal allowed less time for compensatory mechanisms, unlike in patients with long standing hypothyroidism. This may have contributed to the precipitous decline in clinical status even though FT4 and FT3 were still within reference range. Moreover, in myxedema coma thyroid hormone levels correlate poorly with disease severity or outcome. We should maintain a high index of suspicion for myxedema coma even with disparate FT4 and FT3 levels suggestive of SH in a patient on Sunitinib or other tyrosine kinase inhibitors especially in the first few weeks of starting them. The rapidity of decline in FT4 and FT3 levels may contribute to the severity of hypothyroidism.

Poster 399 Thyroid Hormone Action Monday & Tuesday Poster Clinical 9:00 AM THE PROTECTIVE EFFECT OF THYROTROPIN AGAINST BONE LOSS IS ASSOCIATED WITH PLASMA TRIIODOTHYRONINE LEVELS T. Kim, J. Jang, S. Kim, J. Chung Internal Medicine, Samsung Medical Center, Seoul, Korea (the Republic of)

Poster 400 Thyroid Hormone Action Monday & Tuesday Poster Clinical 9:00 AM TWO CASES OF RESISTANCE TO THYROID HORMONE BETA (RTHb) CAUSED BY TWO NOVEL MUTATIONS T. Pappa1, A. German2, J. Kerrigan3, S. Refetoff1 1 Department of Medicine, Thyroid Unit, The University of Chicago, Chicago, IL; 2Bnei Zion Medical Center, Technion, Haifa, Israel; 3 East Tennessee Children’s Hospital, Knoxville, TN Mutations in thyroid hormone receptor beta (THRB) gene have been identified in the majority of cases expressing the RTHß phenotype. We report RTH caused by two novel THRB gene mutations. Family 1: A 10-year-old male presented with persistent tachycardia and attention deficit disorder (ADD). Thyroid function testing (TFT) revealed high total and free thyroid hormone (TH) levels and unsuppressed TSH (Fig.1). The thyroid gland was enlarged on ultrasound and 123I scan showed diffuse increased activity. His father also had ADD and a similar thyroid profile. Paternal grandfather was Native American/Irish and grandmother Dutch/German. Famiy 2: The proposita presented at age 9 with restlessness and tachycardia. She had goiter and tremor. Both free T4, TT3 and TSH were elevated. Briefly treated with antithyroid drugs and propranolol, she underwent ablation with 131I and is currently on combined L-T4/T3 treatment. At age 35, she gave birth to a full term, normal-weight male with increased heart rate (130-160bpm) and a similar thyroid profile (Fig.1). The father is Hungarian Ashkenazi and mother Sepharadic Israeli/Greek/Turkish. In family 1, the proband and his father were heterozygous for a single nucleotide substitution (c.736C > G), changing amino acid 246 from leucine to valine (p.L246V) (Fig.1). In family 2, the proposita and her son were heterozygous for a single nucleotide substitution (c.1367T > G) replacing leucine at position 456 with serine (p.L456S). Both her parents were normal. Testing a polymorphic silent variant in codon 245, we showed that the mutant allele was inherited by her father (Fig.1). Based on PolyPhen-2 algorithm, both mutations are expected to be probably damaging (scores 0.62 and 1 respectively).

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MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 to the Tg. There were no false negatives (FN), but there were 10 false positives (FP) with Tg < 10. In 3 of these latter patients absence of metastases (MTS) was confirmed in histology and 1 presence of nodal micrometastases. The positive predictive value was 55% and 100% negative. 6 aspirations nondiagnostic (14.64%) 5 corresponded to acellular fluid-filled cysts, 4 with wash Tg + in which he was confirmed by biopsy metastatic papillary cystic carcinoma and 1 with negative Tg was hygroma biopsy. One adenopathy nondiagnostic with Tg > 10 ng / ml resulted metastasis of papillary carcinoma in the biopsy. The positive predictive value was 100% and 100% negative. Thyroglobulin in washout of needle is a complement of FNA for diagnostic and follow-up DTC mainly in cystic nondiagnostic acellular lymphadenopathy. False positives Tg < 10 ng / ml in washout of needle should be interpreted in relation to blood / wash thyroglobulin ratio.

Poster 402 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM NEW TRENDS IN THYROID PATHOLOGY N.M. Monteros Alvi1, M. Galindez2, M. Nallar3, L. Van Cauwlaert3, V. Cerioni2, R. Marquez4 1 Patologia, Hospital On˜Ativia, Salta, Argentina; 2 Endocrinologia, Hospital On˜Ativia, Salta, Argentina; 3 Cirugia, Hospital On˜Ativia, Salta, Argentina; 4 Estadistica, Hospital On˜Ativia, Salta, Argentina Pedigrees of the two RTH families. Abnormal values are shown in bold; low values are in blue and high values in red. Two novel THRB gene mutations associated with RTHß are reported. The characteristic thyroid profile along with clinical features should raise suspicion for RTH. Early diagnosis will prevent ablative treatments that further complicate long-term management.

Poster 401 Thyroid Hormone Action Monday & Tuesday Poster Clinical 9:00 AM USEFULNESS OF THYROGLOBULIN MEASUREMENT IN FINE NEEDLE ASPIRATION BIOPSY OF CERVICAL NODULE N.M. Monteros Alvi1, G. Iban˜ez2 1 Patologia, Hospital On˜ativia, Salta, Argentina; 2 Laboratorio De Endocrinologia, Salta, Argentina The value of Thyroglobulin (Tg) in washout of fine needle aspiration biopsy (FNAB) of cervical nodule may be applicable to the initial diagnosis of metastatic or follow-up of differentiated thyroid carcinoma (DTC). Our objective was to determine the predictive value of Tg in washout of FNA cervical nodule. Prospective study of 41 patients with FNAB as initial diagnostic method of cervical lymphadenopathy or in monitoring DTC. Tg in washout of needle was measured with 411 Cobas Chemiluminescence (Roche). Cutoff value used of Tg: 2 ng/ml. The predictive value (PV + /-) of Tg was determined correlating the cytology in diagnostic FNAB. In nondiagnostic FNAB samples the VP was determined by biopsy. 6 cases were initial diagnosis and 35 nodules in monitoring DTC. In the first group 5 were cystic lymph nodes, in the second 27 lymph nodes were solid, 2 cystic and 6 solid nodules in surgical bed. Tg range: < 0.2 to 12,567 ng/ml. . Negative average Tg = 0.73 ng/ml and Tg positive = 861.79 ng/ml. Diagnostic cytology punctures were 35 (85.36%), 11 true positives (TP) and 14 true negatives (TN) relative

Several studies have shown an increase incidence of thyroid cancer in recent years. It remains unclear whether those trends reflect a true occurrence of disease but also may be due to changes in pathological diagnosis criteria. The aim of the study was to determine changes in histopathology diagnosis in patients that underwent thyroidectomy due to Nodular Thyroid Disease of any cause for a period of 34 years. Retrospective descriptive study -analytic- with a total of 4184 thyroidectomies performed at Dr. Arturo On˜ativia’s Hospital in Salta, Argentina, from January 1979 to December 2013. The surgical specimens were analyzed by a trained pathologist and were divided in 3 categories: benign, malignant and neoplasms of uncertain malignant potential, the incidence of each category was determined and were divided arbitrary in three periods: I) 1979-1989; II) 1990-2000, III) 2001-2013. The incidence of benign/malignant disease was in each period: I) 87.8% vs. 12.2%; II) 72.7% vs. 27% III) 69.5% vs. 29, 6 %. Differentiated papillary and follicular carcinoma (results in each period) respectively: I) 59.5% vs. 24.5%; ll) 69% vs. 19%; III) 82% vs. 10%. Neoplasms of uncertain malignant potential were only observed in period III (0.9%). From the total of papillary carcinomas, the incidence of microcarcinomas was in each period: I)17%, II) 15%; III) 24%; with a incidental/non incidental percentage ratio of 64%/36% in the last period. The diagnosis of Nodular Thyroid Pathology has changed in the last 30 years. We observed an increased incidence of cancer, mainly due to a raising amount of papillary subtype. From these, we found an increased incidence of incidental microcarcinomas. We also observed a decrease incidence of follicular carcinoma and in the last period the diagnose of follicular tumors of uncertain malignant potential arose. From all analysed data we could presume that the appearance of new, more sophisticated diagnostic techniques such as ultrasonography (US) and fine needle aspiration biopsy (FNAB) has changed the management of thyroid diseases over the lapse of time studied. In addition such advances facilitated earlier diagnosis of thyroid cancer and tumors such as follicular tumors of uncertain malignant potential which have low malignant progression.

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Poster 403 Thyroid Hormone Metabolism & Regulation Monday & Tuesday Poster Basic 9:00 AM THE ROLE OF CAR IN THE FASTING INDUCED INCREASE OF LIVER TYPE 3 DEIODINASE IN MICE. E. de Vries1, H.C. van Beeren1, M.T. Ackermans2, E. Fliers1, A. Boelen1 1 Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands; 2Clinical Chemistry, Academic Medical Center, Amsterdam, Netherlands Profound changes occur in the hypothalamus-pituitary-thyroid (HPT) axis during fasting ultimately leading to lower serum thyroid hormones (TH). It has been shown in rodent liver that enzymes involved in the clearance of TH such as type 3 (D3) deiodinase, sulfotransferases (Sults) and UDP-glucuronosyltranferases (UGTs), are activated during fasting, possibly contributing to the decrease in serum TH concentrations. The constitutive androstane receptor (CAR) might play a role in this activation as the upregulation of Sults and UGTs during fasting is CAR dependent and CAR - / - mice display a blunted serum T4 and T3 decrease during fasting. However, the role of CAR in the fasting-induced D3 increase is unknown. The aim of the present study was to clarify the role of CAR in the fasting induced increase of liver D3. To this end we used CAR-/- mice and their wild type (WT) littermates and fasted these mice for 24 hours. We measured hepatic expression and activity of type 1 deiodinase (D1) and D3 as well as expression of other TH metabolizing enzymes. In addition, both serum and hepatic thyroid hormone concentrations were measured. Fasting increased UGT1a1, Sult1a1, Sult1d1 and D1 mRNA expression which was partly dependent on CAR. D3 mRNA expression increased in WT but not in CAR - / - mice upon 24 hours of fasting, however basal D3 expression was higher in CAR - / - mice. The fasting induced alterations in D3 activity were different in CAR - / mice compared to WT. Serum and hepatic T4 and T3 concentrations decreased equally in both CAR - / - and WT mice upon fasting. However, basal hepatic T3 concentration was lower in CAR-/- mice consistent with higher basal D3 expression. In conclusion, CAR is involved in the regulation of liver D3 expression during fasting, and possibly in the regulation of D3 under basal conditions. However, the fasting induced decrease in serum TH concentrations is not mediated by CAR.

Poster 404 Thyroid Hormone Metabolism & Regulation Monday & Tuesday Poster Basic 9:00 AM LONG-TERM EFFECTS OF POSTNATAL OVERNUTRITION ON THYROID HORMONE METABOLISM AND FUNCTION IN RATS P.C. Lisboa, E.P. Conceic¸a˜o, E.D. Oliveira, E.G. Moura Physiology, State University of Rio de Janeiro, Rio de Janeiro, Brazil Early overnutrition (EO) during lactation leads to obesity, leptin resistance and lower thyroid hormones (TH) levels at adulthood. To know the biological significance of this thyroid hypofunction, we studied the long-term effects of postnatal EO on the function of hypothalamic-pituitary-thyroid (HPT) axis as well as on the TH metabolism and action. To induce EO, litter size was reduced to 3 pups per litter (SL group) on the 3rd day of lactation. In controls (NL group), litter size was adjusted to 10 pups per litter. Rats were euthanized at PN180. TRH content and in vitro TSH were evaluated. D1 and D2 activities were measured in different tissues. Mitochondrial alpha-glycerol-3-

A-163 phosphate dehydrogenase (mGPD) activity, UCP1 and TRb1 content were evaluated. SL group presented lower hypothalamic TRH, intra-pituitary and released TSH, despite unchanged plasma TSH. Also they showed lower D1 activity in thyroid, skeletal muscle and white adipose tissue (WAT) and higher D2 activity in hypothalamus, pituitary, brown adipose tissue and WAT, which are in accordance to its hypothyroid status. Despite the lower TH, thyroid, heart and testis D2 activities were unchanged, suggesting that other factors, which were programmed by postnatal EO, are more important regulators of these enzymes than TH, at least, in these tissues. Hepatic D1, mGPD and TRb1 were unchanged in SL rats, suggesting that the TH conversion and cellular action were preserved in the liver, even with lower TH. UCP1 in BAT and TRb1 in WAT were decreased that can contribute to a lower catabolic status. Our data evidence that postnatal EO change thyroid function in adult life in a tissue-specific way, helping to understand the obesogenesis in this model.

Poster 405 Thyroid Hormone Metabolism & Regulation Monday & Tuesday Poster Basic 9:00 AM SILVER NANOPARTICLES EXPOSURE IN RATS DISRUPTS HYPOTHALAMUS-PITUITARYTHYROID AXIS R.R. Conceic¸a˜o1, R. Marino Romano2, J.S. Souza1, M.M. Kizys1, K.C. Oliveira1, R.M. Maciel1, M.R. Dias da Silva1, G. Giannocco3,1, M.A. Romano2, M.I. Chiamolera1 1 Laboratorio de Endocrinologia Molecular e Translacional, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; 2 Laboratorio de Toxicologia Reprodutiva, Departamento de Farmacia, Universidade Estadual do Centro Oeste, Guarapuava/ Parana´, Brazil; 3Departamento de Ciencias Biologicas, Universidade Federal de Sao Paulo, Diadema, Sao Paulo, Brazil Silver nanoparticles (AgNPs) are clusters of silver atoms with diameters that can range from 1 to 100 nm, they have growing applications in medical field, food industry and textile sector due to its great antibacterial potential. Although previous studies have showed the effect of AgNP in the gonadal axis by decreasing reproductive parameters, its disrupting role in the hypothalamic-pituitary-thyroid (HPT) axis is unknown. Therefore, the aim of this study was to evaluate the influence of AgNPs exposure on thyroid hormone levels and HPT axis. Male Wistar rats in the post-natal day (PND) 21 were randomly split into three groups that received the following doses of AgNPs: 0 (G0, group control), 15 (G15) and 30 (G30) lg/kg, during 25-day exposure period from PND23 to PND58, then sacrificed at PND102. TSH, total T3 and T4 were assessed by commercial kits. Total RNA was extracted from pituitary and liver tissues. Genes related to thyroid hormone metabolism and transport Dio1, Dio2, Dio3, Mct8 have their gene expression analyzed by RT-qPCR. Serum TSH concentration was lower in G30 than in G0 (p < 0,05), while T3 value increased in G15 when compared to other groups (p < 0,001). Regarding the thyroid metabolism, we found decreased liver mRNA expression levels of Dio3 (p < 0,01) and Dio1 (p < 0,01) in both G15 and G30 group. In pituitary, Mct8, Dio3 and Dio1 gene expression were decreased in G15 and G30 (p < 0,05), but Dio2 only in G30 (p < 0,05). In summary, AgNPs exposed animals presented hormonal profile resembling thyroid hormone excess, likely due to disruption in gene expression of iodotironine deiodinases and thyroid hormone transporter.

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Poster 406

these patients normalized the TSH 3 and 6 months after surgery. The mean TSH level before gastric bypass, 3 and 6 months after were respectively: 2.38 IU/L, 1,77 IU/L, 1,99 IU/L. TSH levels at 6 months were inversely correlated with the excess body weight loss. The greater reduction in the excess body weight loss, the lower TSH levels. (p 0,070). Nevertheless BMI correlates directly with TSH levels six months after the surgery (p 0.004). The normalization of TSH levels after weight loss was also described in other studies, suggesting an adaptive process of the thyroid function to the increased resting energy expenditure in obese state (3). We could demonstrate that TSH decreased with fast weight loss within 3 months after gastric bypass and there is a positive correlation between greater excess body weight loss with lower TSH levels.

Thyroid Hormone Metabolism & Regulation Monday & Tuesday Poster Basic 9:00 AM BROMOCRIPTINE (DOPAMINERGIC AGONIST) INJECTION IN THE PUPS AT THE BEGINNING OF LACTATION INDUCES THYROID DYSFUNCTION IN ADULT RATS E.G. Moura, J.C. Carvalho, E.D. Oliveira, P.C. Lisboa Physiology, State University of Rio de Janeiro, Rio de Janeiro, Brazil We found that maternal treatment with bromocriptine (BRO, a dopaminergic agonist) at the end of lactation, used to decrease milk production, programmed for hypothyroidism in the adult offspring. Since BRO is transferred through the milk, we evaluated its direct effects on the pups. Male offspring were treated with BRO (0.1 mg / once daily) or vehicle from first to tenth day of lactation. Body mass, food intake, thyroid function and prolactinemia were analyzed. Offspring were killed in adult life (PN180). At 21 days-old (weaning), BRO animals showed lower body mass (- 11%) and food intake ( - 11%). At PN180, BRO animals presented normal body weight and visceral adiposity but lower food intake ( - 5%) and hypoprolactinemia ( - 66%). This group had lower content of hypothalamic TRH ( - 58%), pituitary TSH ( - 32%), and plasma T3 ( - 30%). These alterations were followed by reduced UCP-1 ( - 34%) expression in BAT as well as lower mGPD ( - 81%) activity and type 1 deiodinase (Dio1) expression ( - 49%) in the liver. No changes were detected in type 2 deiodinase (Dio2) expression or thyroid hormone receptors. For the first time, we demonstrated that neonatal BRO treatment programs to hypothalamic hypothyroidism in the adult offspring, suggesting that imprinting factors that increase the dopaminergic tonus in this period has deleterious consequences during development.

Poster 407 Thyroid Hormone Metabolism & Regulation Monday & Tuesday Poster Clinical 9:00 AM THYROID FUNCTION IN MORBIDLY OBESE POPULATION AND IMPROVEMENT AFTER WEIGHT LOSS INDUCED BY LAPAROSCOPIC ROUX-EN-Y GASTRIC BYPASS G.A. de Carvalho, C. Mesa Junior, P. Granzotto, R. Strobel, C. Martins Internal Medicine, Clinical Hospital of the Federal University of Parana, Curitiba, Brazil TSH seems to be positively related to the degree of obesity and weight loss seems to induce a reduction in the TSH levels and T3Total. TSH is the first regulatory mechanism of total energy expenditure and T3 regulates energy metabolism and thermogenesis (1). So we proposed this observational study to determine the prevalence of subclinical hypothyroidism in the obese population, which were subjected to gastric bypass and evaluate how thyroid hormones and TSH levels change after weight loss. Preoperative and follow-up data of 56 obese patients were retrospectively collected in a database of patients undergoing laparoscopic RYGBP in a service in Curitiba- Brazil. The patients had BMI > 35 kg/m2, age between 18 and 65 years. Fasting glucose, insulin, total cholesterol, HDL, triglycerides, LDL, TSH, free T4, total T3 levels were analyzes before, 3 and 6 months after gastric bypass. The prevalence of metabolic syndrome was 50%. The prevalence of subclinical hypothyroidism was 7,14% (4 patients), and 03 of

Poster 408 Thyroid Imaging Monday & Tuesday Poster Clinical 9:00 AM INITIAL AND FOLLOW-UP ULTRASONOGRAPHIC FEATURES INFLUENCING VOLUME REDUCTION AND PREDICTING ADDITIONAL ABLATION SESSION IN RADIOFREQUENCY ABLATION OF BENIGN NON-FUNCTIONING THYROID NODULES J. Sung1, K. Kim1, D. Lee2 1 Department of Radiology, Daerim St. Mary’s Hosital, Seoul, Korea (the Republic of); 2Department of Internal Medicine, Daerim St. Mary’s Hospital, Seoul, Korea (the Republic of) We planned this study to find out ultrasonographic (US) features affecting the volume reduction rate (VRR) and predicting additional ablation to prevent recurrence after radiofrequency (RF) ablation of benign non-functioning thyroid nodule. We retrospectively analyzed US images of 149 thyroid nodules from 139 patients [M:F = 13:126, 43.0 – 11.5 years (range, 18–71 years)] that were treated with RF ablation from Jan. 2011 to Dec. 2011 and followed up more than 12 months. We evaluated nodule volume before ablation and at the 1st and the last follow up, VRR at the 1st and the last follow up, solidity of the nodule, the degree of abutting the medial thyroid capsule (0; none, 1; minimal, 2; < 1/4; 3; 4/1*1/2, 4; > 1/2), ratio of peripheral remnant viable tissue to the entire circumference of the nodule (0; none, 1; minimal, 2; < 1/4; 3; 4/ 1*1/2, 4; > 1/2), and nodule vascularity (0; none; 1; peripheral only, 2; peripheral and central less than 50%, 3; peripheral and central more than 50%) at initial study and 1st follow up. We reviewed the difference of above features according to VRR at last follow up [VRR1 ( < 75%); 21, VRR2 (75*95%); 60 and VRR3 ( > 95%); 68 nodules) and number of ablation sessions (1; 107 and more than 2; 42 nodules). The mean 1st and last follow up periods were 3.2 – 6.1 and 26.9 – 11.3 months, respectively. Initial volume was 15.3 – 21.6ml in VRR1, 11.4 – 13.5ml in VRR2, and 5.8 – 6.8ml in VRR3. The degree of nodule solidity was 86.4 – 13.7% in VRR1, 82.9 – 21.0% in VRR2, and 75.1 – 27.0% in VRR3. The degree of abutting the medial thyroid capsule was 2.1 – 1.3 in VRR1, 1.8 – 1.4 in VRR2, and 1.3 – 1.2 in VRR3. Ratio of peripheral remnant viable tissue to the entire circumference of the nodule on 1st follow up US was 1.3 – 1.2 in 1 session group and 3.2 – 0.9 in more than 2 session group. Nodule vascularity on 1st follow up US were 0.3 – 0.6 in 1 session group and 1.2 – 0.6 in more than 2 session group. The lower VRR tended to be occurred in the larger initial volume, with the less cystic component and in the more abutting position to medial thyroid capsule. Additional RF ablation should be considered when ablated thyroid nodule turned to have large amount of peripheral viable tissue and increased nodule vascularity at follow up US.

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Poster 409 Thyroid Imaging Monday & Tuesday Poster Basic 9:00 AM THE INCIDENCE OF THYROID MALIGNANCY IN PATIENTS WITH SONOGRAPHICALLY BENIGN APPEARING HYPOFUNCTIONING NODULES K. Xia, A. Chong, I. Jong, S. Ramdave, G. Soo, D. Nandurkar Diagnostic Imaging, Monash Medical Centre, Melbourne, VIC, Australia A hypofunctioning (cold) nodule on scintigraphy is associated with an increased risk of malignancy. This study assesses if the risk of malignancy in cold nodules can be stratified according to the presence of sonographic features and therefore determine the need for cytopathological correlation. A retrospective audit correlating the sonographic and histological findings of hypofunctioning nodules on Tc-99m pertechnetate scintigraphy was performed. Patients with cold nodules on scintigraphy carried out at our institution between January 2005 and February 2015 were identified. The presence or absence of specific sonographic features (marked hypoechogenicity, irregular margins, microcalcifications, hypervascularity, taller than wide) was established for each nodule. These findings were correlated with fine needle aspirate cytology results. The sonographic features and histology for benign and malignant nodules were compared using Fischer’s exact test. A total of 53 cold nodules were examined with 21 nodules with suspicious ultrasound findings and 32 nodules with no suspicious ultrasound findings. In the nodules with no suspicious ultrasound findings, two had malignant histology including papillary carcinoma and follicular with micropapillary carcinoma (2/32) and 30 nodules were benign (30/32). There is a significant association between no suspicious ultrasound features and benign histology (p < 0.0001) using an unpaired t-test, with a negative predictive value of 0.94 (0.79 - 0.99). In the nodules with suspicious ultrasound findings, 3 cancers were detected (3/21), one follicular and two papillary thyroid carcinomas. There was a strong association between marked hypoechogenicity and malignant histology (p = 0.02) but no statistically significant correlation between other sonographic features and malignant histology. The rate of malignancy in cold nodules is low in the absence of suspicious ultrasound features. There was a statistically significant association between no suspicious sonographic findings and benign histology in our study. This suggests that ultrasound can be used to stratify a cold thyroid nodule before invasive procedures are performed.

Poster 410 Thyroid Imaging Monday & Tuesday Poster Clinical 9:00 AM EVALUATION OF THE QUALITY OF THYROID US REPORTS B.K. Mitchell, K. Bedillion Pineview Surgery, Morgantown, WV By age 45, approximately 1/3 of the population in the United States have a thyroid nodule by US examination, and 50% by age 65. In contrast, only 1.1% develop thyroid cancer (http://seer.cancer.gov/ statfacts/html/thyro.html). Because of massive discrepancy between the presence of nodules and the presence of cancer, precise evaluation is essential prior to biopsy or surgery. Based on standards set by the American College of Radiology and American Institute of Ultrasound Medicine for thyroid ultrasound reports, quality criteria were established. Community and university hospital reports were reviewed and graded based upon the presence

of information established as part of a quality report. Images were reviewed for data not reported. Management recommendations (biopsy, follow up US, appropriate or inappropriate RAI scanning) were recorded. Clinical information (TSH level, history of radiation exposure, family history of thyroid malignancy) impacting decision making was evaluated. See Table. The location, size, number and echogenicity of nodules and overall gland echogenicity was reported in 50–73% of reports, and image analysis revealed that nodule size, vascularity and echogenicity were generally imaged, but not reported. Focal versus diffuse process was noted in 39% of reports. Vascularity of the gland, and nodules and margins were reported in 10 to 20% of reports. Lymph nodes were rarely imaged or reported. Reports commented on calcifications (present or absent) in 27% of reports overall (50% for University reports). Clear management guidance was generally lacking and unnecessary studies were frequently recommended (only 36% advised for or against biopsy) (92% of University studies). The majority of Thyroid US reports lack adequate data (60% contain less than 50% of categories). A standardized reporting template may decrease cost and improve care by preventing inappropriate interventions and surgery, following ATA guidelines. Analogous American College of Pathology templates for TNM reporting and BIRADS breast imaging are standard of care. A TIRADS or TQRS (Thyroid US Quality Reprting System) should be adopted and updated to coincide with ATA guidelines.

Poster 411 Thyroid Imaging Monday & Tuesday Poster Clinical 9:00 AM CLINICAL EVALUATION OF REAL-TIME TISSUE ELASTOGRAPHY FOR THYROID FOLLICULAR CARCINOMA DETECTION N. Fukunari, T. Nishikawa, M. Nakano, S. Aida Surgery, Showa University Yokohama Northern Hospital, Yokohama, Japan The newly developed high resolution ultrasonography has a diagnostic accuracy exceeding 90% in papillary carcinoma. However, in the case of follicular carcinoma, neither conventional US imaging nor aspiration biopsy cytology can deliver satisfactory results. This paper focus on the evaluation of the clinical usefulness of colorDoppler (CD) imaging and Elastography for the differential diagnosis of thyroid nodules, especially follicular tumors. The diagnosis and management of follicular cancer of the thyroid gland remains a controversial topic. The aim of this study was to evaluate the clinical usefulness of Elastography for the differential diagnosis of thyroid follicular lesions. 232 follicular tumors were examined by Real-time Tissue Elastography (RTE). Papillary cancers, other types thyroid malignancies or hot nodules were excluded

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from this study. The images of thyroid follicular lesions were recognized as four typical patterns as follows: Pattern 1(P1): nodule is relatively homogenous and colored with light green. Pattern 2(P2): the center of nodule is colored with green and its periphery is colored with blue. Pattern 3(P3): nodule is mixed-colored with light green and red. Pattern 4(P4): the whole tumor is displayed in blue. All the follicular tumors were surgically and histopathologically diagnosed finally. In this series, 109 hyperplastic nodules, 45 follicular adenomas and 78 follicular cancers (56 Minimally invasive, 22 Widely invasive) were found. Of the 78 follicular cancers, 65 cases were classified as P2, which was occupied 91.5% in P2. Assuming Pattern 2 to be malignant and others to be benign, 148 of 154 benign tumors and 65 of 78 follicular cancers were accurately diagnosed, yielding a sensitivity of 87.2%, a specificity of 96.1%, Positive Predictive Value of 91.5% and Negative Predictive Value of 91.9%. Elastography can be a useful tool for the differential diagnosis of the thyroid follicular tumors and has a possibility to improve the diagnostic sensitivity and specificity, especially in case of intranodular hyper-vascular tumors better than that of CD studies. A combination with CD and Elastography enable to play more important role of follicular cancer detection.

Poster 412 Thyroid Imaging Monday & Tuesday Poster Clinical 9:00 AM THE UTILITY OF PREOPERATIVE ULTRASOUND EVALUATION OF THE CERVICAL LYMPH NODES IN PATIENTS WITH SUBCENTIMETER PAPILLARY THYROID CANCER S.I. Noureldine1, M. Al-Jumaily1, J. Bishop2, R.P. Tufano1 1 Otolaryngology - Head and Neck Surgery, Johns Hopkins University, Baltimore, MD; 2Pathology, Johns Hopkins University, Baltimore, MD The American Thyroid Association (ATA) guidelines recommend that a neck ultrasound should be performed in patients with suspicious thyroid nodules to guide a complete resection of the primary tumor as well as a compartment-oriented dissection of affected lymph nodes as necessary. However, subcentimeter papillary thyroid cancers (PTCs) are considered to be indolent tumors that rarely progress to clinically significant disease. Herein, we aim to identify the utility of preoperative neck ultrasound in patients with subcentimeter PTC. We performed a retrospective analysis of a cohort of 1008 PTC patients who underwent thyroidectomy at a university-based tertiary care center, between January 2002 and April 2014. Patients with subcentemeter intrathyroidal tumors diagnosed as PTC or suspicious for PTC on fine needle aspiration (FNA) biopsy were analyzed. All

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 patients underwent preoperative neck ultrasound as a standard of care. Overall, 130 (13%) patients were found to have subcentemeter intrathyroidal tumors diagnosed as PTC (n = 103) or suspicious for PTC (n = 27) on FNA biopsy. Average nodule size was 0.8 – 0.2 cm. Neck ultrasound identified suspicious and indeterminate lymphadenopathy in 23 (17.7%) and 16 (12.3%) patients, respectively. Twenty-two of those patients underwent FNA biopsy of the identified lymph nodes. Four were found to have metastatic PTC to the lymph nodes of the central compartment, and 1 was found to have metastatic PTC to both central and lateral neck compartments preoperatively. Intraoperative inspection did not identify any additional cases of metastatic regional disease. On histopathology, all 5 patients were found to have regional metastases ranging from 0.2 to 1.9 cm in size. On average follow-up of 91 weeks, only 2 patients, who initially underwent total thyroidectomy without neck dissection, developed regional metastases and required surgical intervention. Although the vast majority of subcentimeter PTC follows a relatively indolent course, regional metastases can, and occasionally do, exist at initial presentation regardless of tumor size. Neck ultrasound is useful in identifying those cases in which thyroidectomy over an active surveillance management approach is preferred.

Poster 413 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM MAGNETIC RESONANCE IMAGING-GUIDED HIGHINTENSITY FOCUSED ULTRASOUND AS A PROMISING NON-INVASIVE INTERVENTION FOR THE TREATMENT OF HEAD AND NECK TUMORS S.I. Noureldine1, A. Partanen2, N. Ellens3, C. Burdette4, K. Farahani3, R.P. Tufano1 1 Otolaryngology - Head and Neck Surgery, Johns Hopkins University, Baltimore, MD; 2Phillips, Baltimore, MD; 3 Radiology, Johns Hopkins University, Baltimore, MD; 4 Acoustic MedSystems, Chicago, IL Surgery is commonly performed for the treatment of various benign and malignant tumors of the head and neck region. Unfortunately, complications are not rare and there is an unmet need for a minimally or non-invasive alternative. High-intensity focused ultrasound (HIFU) could possibly be an outpatient non-invasive alternative to surgery. Focused ultrasound waves are used to heat and coagulate tissue deep inside the body, while magnetic resonance imaging (MRI) guidance enables accurate treatment planning and therapy. We aimed to assess the feasibility of using MR-HIFU to obtain localized ablation of the thymus and thyroid tissue in an animal model, without adversely affecting neighboring structures. Two 70 lbs. pigs underwent targeted ablation (sonication) using the Sonalleve clinical 3T MR-HIFU system (Philips Healthcare, Vantaa, Finland). MRI was used for treatment planning, guidance, real-time multi-planar thermometry, as well as for post-treatment evaluation of efficacy. Both animals were euthanized after the procedure and the ablated tissue was harvested and fixed with formalin prior to macroscopic and histologic examination. Intraoperative inspection of neighboring structures was performed to confirm their integrity. MR-HIFU enabled multi-planar temperature monitoring at the targeted treatment cells as well as surrounding tissue. This permitted safe, spatially accurate, and controlled ablation of the thyroid and thymus. Post-ablative contrast-enhanced MRI elucidated the ablated regions and on histological assessment, acute coagulative necrosis suggestive of acute thermal injury was observed at these targeted treatment cells that was limited to the ablated tissue. No damage to

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 the deep vessels, trachea, esophagus, or muscles was observed, and no skin burns occurred. The results of this preliminary study confirm the feasibility of using extracorporeal MR-HIFU to ablate a defined area within the thymus and thyroid tissue, without affecting neighboring structures. Further studies are needed to confirm the safety, oncological control, and functional outcomes of this therapy.

Poster 414 Withdrawn

Poster 415 Thyroid Imaging Monday & Tuesday Poster Clinical 9:00 AM SHEAR WAVE ELASTOGRAPHY INDEX (SWEI); A TOOL TO DIFFERENTIATE BETWEEN MALIGNANT AND BENIGN THYROID NODULES F.N. Baig1, S.Y. Liu2, H. Law1, S. Yip1, M. Ying1 1 Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong; 2Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, HongKong, Hong Kong Shear wave elastography (SWE) has been widely used in the assessment of various soft tissues. However, limited literature information is available about the application of SWE in differentiating benign and malignant thyroid nodules. The objectives of the present study are to determine if shear wave elastography index (SWEI: Emaximum and Emean) is feasible for differentiating benign and malignant thyroid nodules, and to investigate the optimal cut-off value of SWEI for such purpose. We conducted a prospective sonographic assessment on patients presenting with nodular goiter using both grey scale ultrasound (GSU) and SWE by a single thyroid ultrasonographer. For each thyroid nodule, SWEI was measured and compared with fine-needle aspiration cytology (FNAC)/histological results. SWEI was evaluated as a prognostic factor to distinguish between benign and malignant thyroid nodules. Of the 86 thyroid nodules studied (16 males and 70 females, mean age 52.3 – 1.5 yrs.), 21 (24.4%) were proven malignant lesions. For SWEI, the mean Emaximum (95 – 9.6 KPa) and mean Emean (30.2 – 3.1 KPa) of malignant nodules were significantly higher than those of benign nodules (mean Emaximum = 59 – 3.7 KPa and mean Emean = 21.6 – 1.2 KPa) (both p < 0.05). Using cytological/histological findings as gold standard, receiver operating characteristic (ROC) curves revealed 71.4% sensitivity and 80% specificity at a cut-off of 74 KPa for SWEI (Emaximum), and 81% sensitivity and 64.6% specificity at a cut-off of 23 KPa for SWEI (Emean). SWE provides useful quantitative information in the assessment of thyroid nodules. Our study suggests 74 KPa as the threshold value if maximum value for elasticity index is used and 23 KPa as the cutoff if mean value is considered. GSU in conjunction with SWEI can achieve better diagnostic confidence in differentiating malignant and benign thyroid nodules.

Poster 416 Thyroid Imaging Monday & Tuesday Poster Clinical 9:00 AM THE RELATIONSHIP BETWEEN ULRASONOGRAPHIC TYPES AND PATHOLOGIC FEATURES OF CALCIFICATION B. Kim3,1, C. Lee2, Y. Kim3, S. Yang4, J. Kim4, S. Jun5, S. Oak1, S. Kwon1, Y. Choi1 1 Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea (the Republic of); 2Department of Internal

A-167 Medicine, St. Mary’s Medical Center, Busan, Korea (the Republic of); 3Dpartment of Pathology, Kosin University College of Medicine, Busan, Korea (the Republic of); 4Department of General Surgery, Kosin University College of Medicine, Busan, Korea (the Republic of); 5Department of Nuclear Medicine, Kosin University College of Medicine, Busan, Korea (the Republic of) Ultrasonographic(USG) microcalcification is well known to be highly associated with papillary thyroid carcinoma. However, there are only few data about pathologic features of calcification what we could see by ultrasonography. So the aim of this study is to evaluate the relationship between USG types and pathologic features of calcification. A total 411 nodules diagnosed as papillary thyroid cancer with or without USG calcification was reviewed pathologic features. We divided USG calcification into two types as microcalcification and macrocalcification. And we also divided pathologic calcification into three types as psammomma body, stromal calcification and ossification. A morphology of any type calcification was classified into three types as irregular, linear, mass type. 61.1% (n = 251) had no USG calcification and 38.9% (n = 160) had any types of USG calcification. The nodules with USG calcification had significantly higher pathologic calcification than without USG calcification (71.6% vs 38.2%, p < 0.001). Among the nodules with USG calcification, 41.3% (n = 66) had microcalcification type and the others (n = 94) had macrocalcification. USG microcalcification type had larger portion of psammomma body feature than macrocalcification (28.8% vs 17.0%). On the contrary to this, ossification feature was observed in only 6.1% of microcalcification and in 19.1% of macrocalcification. Microcalcification had more irregular shape (24.2 vs 21.3%) and smaller than 0.1cm size of pathologic calcification (81.4% vs 47.8%). We finded pathologic calcification types were different according to USG calclfication types. Therefore it is possible there are different pathophysiologic mechanisms according to USG calclfication types.

Poster 417 Withdrawn

Poster 418 Thyroid Imaging Monday & Tuesday Poster Clinical 9:00 AM ULTRASOUND FINDINGS OF THYROID GLAND IN TYPE 1 DIABETES MELLITUS ¨ ren, E. Cagiltay, E. Tunc¸, A. Keskin N. O Izmir Military Hospital, Izmir, Turkey The prevalence of autoimmune thyroiditis is reported to be significantly higher among young patients with type 1 diabetes. Ultrasound studies of the thyroid gland have shown that as well as gland enlargement, parenchymal hypoechogenicity are present in patients with autoimmune thyroiditis. Furthermore, the significance of ultrasound abnormalities of thyroid gland is discussed controversially. The aim of this study was to investigate the sonographic involvement patterns of autoimmune thyroiditis in type 1 DM. 45 young adult male patients with type 1 DM and 46 young adult male with same age as a control group were included in the study. Gland volume, parenchymal heterogenity, nodules were assessed on ultrasound. Thyroid parenchymal heterogenity were detected in 51% (N = 23) of type 1 DM group while it was % 2 (N = 1) in control group. Pathcy parenchymal heterogenity was % 30 (N = 7), diffuse micronodular parenchymal heterogetnity was 70 % (N = 16) in DM group. Thyroid nodules were detected 22% (N = 10) in DM group while it was 6 %

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(N = 3) in controls. Mean thyroid volume was 4.98 mL in DM group while it was 5.21 mL in control group. Thyroid parenchymal heterogenity is the most important sonographic finding in patients with type 1 DM and it should be always kept in mind while performing thyroid sonography of young adult males.

animals. Goats often have large goiters. Selenium deficiency, impairs T4 to T3 conversion and iodine conservation. Water from wells contaminated with toxins including arsenic, mercury and strontium, also contribute to thyroid disease. Iodine deficiency contributes to high rates of pregnancy loss, preterm labor, stillbirth, and neonatal goiter. Nepalese have some of the largest goiters. While neurological cretinism is more common in the world, goitrous cretinism is more common in Himalayan countries such as Nepal. The highest prevalence of thyroid disease is seen in the subjects over the age of 50. Hypothyroidism occurs in 18% of people in some regions of Nepal. Also, hyperthyroidism is more common, occurring in almost 14% of some regions of Nepal. Some studies report that hyperthyroidism is almost as common as hypothyroidism. Most goitrous subjects were euthyroid (58.59%); hyperthyroidism affected (27.38%). Though women still have more thyroid disease than men, the percentage difference is not as great as in other areas of the world. One researcher reported similar prevalence of subclinical hypothyroidism in women and men, alluding to a dominant effect of iodine deficiency being more important than autoimmunity. Men and women with goiters had a similar prevalence of thyroid dysfunction. Iodine deficiency affects iodination. Goats in Nepal show higher MIT/DIT and T3 /T4 ratios. Water contaminants contribute to thyroid disease. Mercury acts as a selenium antagonist. Arsenic interferes with TR binding, transcription, and signaling and increases risk of simple diffuse goiter. Decreasing thyroid disease in Nepal, includes not only supplementation with iodine, but also supplementation with selenium. In addition, avoiding contaminated well water, by using rain water and installing plumbing, is important for improving general health including thyroid disease.

Poster 419 Thyroid Imaging Monday & Tuesday Poster Clinical 9:00 AM VARIOUS COMPLEMENTARY ASSAYS FROM US-GUIDED FINE NEEDLE ASPIRATION BIOPSY SPECIMEN IN THE DIAGNOSIS OF THYROIDAL OR PERITHYROIDAL LESION : HOW TO AND WHEN J. Hwang3, J. Yoon2, Y. Lee3, J. Woo3, S. Hyun3, H. Hong3, H. Kim3, H. Kim3, Y. Park1 1 Family Medicine, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea (the Republic of); 2 Radiology, Yonsei University College of Medicine, Seoul, Korea (the Republic of); 3Radiology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea (the Republic of) Although Ultrasound(US)-guided fine-needle aspiration biopsy (FNAB) with cytological evaluation is the most reliable tool in diagnosis of thyroid and perithyroidal lesions, 10–40% of nodules are diagnosed as indeterminate by cytology. We would describe currently feasible complementary assays from FNA specimen for enhancing the accuracy of FNA diagnosis and discuss appropriate indications. We would depict cases using various feasible complementary assays from US-guided FNA specimen and discuss appropriate indications. 1) Washout Thyroglobulin (Tg) measurement in the wash out fluid from FNA for metastatic lymph node or locoregional recurrence in patients with papillary thyroid cancer (PTC) 2) Washout Calcitonin (CT) measurement in the wash out fluid from FNA for suspect medullary thyroid carcinoma (MTC). 3) Tb(Tuberculosis)PCR (Polymerase Chain Reaction) for diagnosing tuberculous lymphadenopathy or abscess 4) Washout PTH (Parathyroid Hormone) measurement in the wash out fluid from FNA for parathyroidal lesion. US-FNAB Tg or CT are valuable tools in the identification of primary PTC or MTC and its neck LN metastases or recurrences. USFNAB PTH enhances the accuracy of diagnosis of parathyroid lesions, while Tb-PCR facilitate early diagnosis and allows appropriate therapy. Understanding currently feasible complementary assays from FNAB specimen in the diagnosis of thyroid/perithyroidal lesions is important because various complementary assays from FNAB specimen can improve diagnostic accuracy of US-FNAB cytology, and can be easily adopted in clinical practice.

Poster 420 Thyroid Nodules & Goiter Monday & Tuesday Poster Basic 9:00 AM THYROID DISEASE IN NEPAL BEFORE THE EARTHQUAKE L. Greene New York University School of Medicine, New York, NY Before the earthquake, Nepal was one of the poorest nations in the world, with 26.5% of its population, or 190 million people suffering from disorders due to iodine deficiency. Glaciation erosion depletes iodine and selenium in soil, leading to deficient iodine in plants and

Poster 421 Thyroid Nodules & Goiter Monday & Tuesday Poster 9:00 AM ABUNDANT MEGAKARYOCYTES IN FINE-NEEDLE ASPIRATES OF THE THYROID: A REPORT OF TWO CASES Y.M. SASAI1, T. Maeda1, A. Suzuki2, M. Hirokawa2 1 Moriguchi keijinkai hospital, Moriguchi, Japan; 2 Kuma hospital, Kobe, Japan Megakaryocytes (MGK) may be observed in fine-needle aspirates (FNA) in extrahematopoietic organs. On thyroid aspiration cytology, few reports describing MGK have been documented. MGK may be misinterpreted as multinucleated giant cells or malignant cells, and the presence may lead us erroneous diagnoses. Patient 1: A 73 year-old female with diabetes mellitus who received a computed tomography (CT) scan, was detected a low-density area in the right lobe of the thyroid. An ultrasound (US) examination revealed a cyst in the right lobe of the thyroid. Hyperechoic small dotlike lesions were scattered throughout both lobes. US-guided FNA was performed for the hyperechoic small dot-like lesions in the left lower lobe. Patient 2: A 58 year-old male had a recent history of a proctectomy for rectal carcinoma, stage I. He received neither chemotherapy nor radiotherapy after the operation. CT scan detected a low-density area in the right lobe of the thyroid. US-guided FNA was performed for the nodule. Both of them had normal thyroid function and didn’t have severe hematologic disorders. Ultrasound-guided aspiration cytology for each thyroid lesion revealed numerous multilobulated giant-sized cells with the nuclei showing smudgy chromatin patterns. Immunocytochemically, these giant cells were positive for CD42b. Then these cells were confirmed to be MGK.

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We should be aware that abundant MGK can appear in FNA of the thyroid even in patients without severe hematologic disorders, and the immunocytochemical staining using antibody for CD42b is useful in avoiding erroneous diagnoses.

Poster 422 Thyroid Nodules & Goiter Monday & Tuesday Poster 9:00 AM AN INTRATHYROIDAL PARATHYROID ADENOMA MASQUERADING AS MALIGNANCY IN PREGNANCY G.T. Miller, L. Reynolds Endocrinology, University of Kentucky, Lexington, KY Intrathyroidal parathyroid adenomas are uncommon, accounting for < 1% of parathyroid adenomas causing primary hyperparathyroidism. A 32-year-old woman at 27 weeks gestation was referred after her serum calcium was found to be elevated on routine prenatal labs. Her ionized calcium was 6 mg/dL (4.6–5.3) and intact total PTH was 78 pg/mL (12–72). Her symptoms were chronic fatigue, short-term memory loss, and occasional inability to think clearly. A cervical US was undertaken, revealing a heterogeneous left-sided nodule measuring 2.67 cm L · 0.88 cm AP · 1.48 cm T with grade 3 vascularity, smooth borders, and lack of microcalcifications. A 1 cm distinct hypoechoic area was also noted within the nodule. No parathyroid adenomas or abnormal lymph nodes were seen. An US-guided FNA biopsy of the nodule showed abundant colloid and markedly atypical follicular groups suspicious for papillary thyroid carcinoma in a background of chronic lymphocytic thyroiditis. A PTH stain showed two distinct populations: follicular groups suspicious for papillary carcinoma which stained PTH negative, and a second, rare population of small cells which stained PTH positive. Needle washing from the aspirate of the hypoechoic area revealed a PTH level of 82 pg/mL. At this institution, cytology with atypical follicular groups suspicious for papillary thyroid cancer is generally confirmed as papillary cancer on surgical specimens. Concern about fetal and maternal complications from hypercalcemia led to a decision to proceed with surgery at 34 weeks gestation. Therefore, an uncomplicated total thyroidectomy was performed, resulting in undetectable PTH levels intraoperatively. Surgical pathology revealed a 1.8 cm left lobe intrathyroidal parathyroid adenoma and no evidence of malignancy. The patient delivered a healthy infant at term. This case report highlights the difficulty of confirming the diagnosis of intrathyroidal parathyroid adenoma on cytological biopsy specimens. Needle washing analysis for PTH can be helpful, but in this case, the cytological findings led to more extensive surgery than necessary.

inoculation during invasive procedures, such as FNA or central venous line placement. In most cases, treatment of thyroid abscesses includes surgical resection. 39-year-old woman who presented with odynophagia, anterior neck pain and swelling, and fever for 2 days. She had a history of multiple medical problems including gastric bypass complicated by short gut syndrome requiring supplemental fluids and electrolytes via a tunneled line, and history of multinodular goiter status post left thyroid lobectomy, with benign pathology. FNA of residual right thyroid nodule 7 months before presentation was benign. Upon examination, she had a palpable right thyroid nodule, with edema, tenderness, erythema, and warmth. CT neck showed a hypodense 2.7-cm right thyroid mass with extensive fat stranding. FNA yielded purulent material, gram stain showed 2 + gram positive cocci in pairs consistent with coagulase negative staphylococcus epidermidis, and anaerobic culture showed propionibacterium species. After 8 weeks of treatment with IV daptomycin and ertapenem, she recovered uneventfully with decrease in the size of the lesion within the right thyroid lobe. Repeat FNA yielded negative gram stain and culture. On further questioning, the patient admitted that her husband had been accessing her port at home for unknown reasons. Infected thyroid nodule believed to be due to hematogenous spread due to transient bacteremia after manipulation of a central venous port. The separation in time between the FNA and the infection made FNA-related infection extremely unlikely. Treatment achieved without resection of the thyroid nodule. We describe a case with a favorable outcome without invasive surgery.

Poster 424

Thyroid Nodules & Goiter Monday & Tuesday Poster 9:00 AM THYROID ABSCESS IN AN IMMUNOCOMPETENT PATIENT WITH MULTINODULAR GOITER P. Escalona1, Z. Chen2, J. Kung1 1 Endocrinology, Tufts Medical Center, Boston, MA; 2 Internal Medicine, Tufts Medical Center, Boston, MA

Thyroid Nodules & Goiter Monday & Tuesday Poster 9:00 AM A CASE OF A PRIMARY HYPERPARATHYROIDISM OF DOUBLE PARATHYROID ADENOMA WITH INTRATHYROID PARATHYROID ADENOMA Y. Takae, A. Nakajo, H. Arima, M. Hirata, Y. Shinden, N. Hayashi, Y. Nomoto, Y. Eguchi, Y. Kijima, S. Natsugoe Department of Digestive Surgery,Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences Kagoshima University, Kagoshima, Japan

Thyroid abscesses are uncommon but associated with significant risk of rapid progression and potential airway compromise. They often occur in patients who have preexisting disorders of the thyroid gland, such as nodules or cancer; anatomic defects, such as pyriformis sinus fistulae; or immunocompromised status. They may arise from hematogenous or lymphatic spread or by direct spread from infections in the neck or oropharynx. Rarely, they result from trauma or direct

Ectopic Intrathyroid parathyroid adenoma is a rare lesion, and its location is usually detected by ultrasound and MIBI scintigraphy. We present a case study of double parathyroid adenoma including ectopic intrathyroidal parathyroid adenoma requiring differential diagnosis from carcinoid tumor. A 56-year-old male was pointed out a hypercalcemia (serum calcium = 16.0mg/dl) and renal dysfunction (serum Cre 1.21mg/dl)

Poster 423

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by medical checkup. Primary hyperparathyroidism was suspected due to the high intact-PTH level (967pg/ml). A cervical ultrasound sonography showed a nodule with cystic degeneration like nodular goiter in the thyroid left lobe, and a solid nodule considered as a parathyroid tumor located beneath the thyroid right lobe. Fine needle aspiration cytology (FNAC) was performed on a nodule in the left lobe of thyroid gland, which resulted in benign category. A 99-Tc Sestamibi scintigraphy were positive in both nodules. The patient underwent left hemithyroidectomy and right lower single gland parathyroidectomy. Left thyroid nodule showed the carcinoid tumor pattern in HE staining and immunostaining but PTH staining was positive. We could have diagnosed double parathyroid adenoma with ectopic intrathyroidal parathyroid adenoma using the algorithm of head and neck endocrine tumors. A nodule at the lower thyroid right lobe was parathyroid adenoma. Despite of the difficulty of the HE stain findings, we could have reached correct diagnosis using the algorithm of head and neck endocrine tumors. In the case of hyperparathyroidism with high calcium level, we have to keep in mind the multiple parathyroid adenoma including ectopic lesions.

peated FNAB, that is higher than 7,4%, rates were significantly different. There were no difference between second and third study. As far as real count of BRAF’s diagnostic ‘‘failure’’ was 0,34% and more than half of those patients were already indicated for operation, repeated FNAB is still most reliable and is true ‘‘low cost’’ and fast method of reassessment of Bethesda 1 group patients.

Poster 426 Thyroid Cancer Monday & Tuesday Poster Clinical 9:00 AM THE SIZE OF THE TUMOR AND THE PRESENCE OF INVASION OF THE CAPSULE ARE NOT SIGNIFICANT RISK FACTORS IN FOLLICULAR VARIANT OF PAPILLARY CARCINOMA A. Semenov, N. Timofeeva, R. Chernikov, I. Sleptsov, V. Makarin, A. Uspenskaya, I. Chinchuk, K. Novokshonov, U. Karelina, E. Fedorov, S. Vorobjev, A. Kulyash, Y. Malugov, A. Bubnov, Y. Fedotov endocrine surgery, SPbSU clinic, Saint-Petersburg, Russian Federation

Poster 425 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM THE EFFECTIVENESS OF REPEATED FINE NEEDLE ASPIRATION BIOPSY AFTER AN INCONCLUSIVE CYTOLOGICAL FINDINGS A. Semenov1, V. Makarin1, R. Chernikov1, I. Sleptsov1, N. Timofeeva1, S. Vorobjev2, A. Kulyash2, A. Uspenskaya1, I. Chinchuk1, U. Karelina1, K. Novokshonov1, E. Fedorov1, Y. Malugov1, A. Bubnov1 1 endocrine surgery, SPbSU clinic, Saint-Petersburg, Russian Federation; 2Pathology, SPbSU clinic, Saint-Petersburg, Russian Federation The role of repeated fine-needle biopsies in the selection of patients for surgical treatment is regularly criticized. Many groups believe that it is advisable to perform core needle biopsies, or performing genetic studies. However, the cost of these techniques is much higher, the ability to perform them is not supported by many health systems. Indication for FNAB was a thyroid nodule of ‡ 1 cm or of a less size with clinical or ultrasound features of malignancy. In case of multinodular goiter each nodule was punctured and examined separately. 3929 cases (8%) were noninformative out of 49419 FNAB of thyroid nodules performed in North-West Regional Endocrine Center during 2010–2012 years. Among these technical mistakes occurred in 69 cases (1.7%), and insufficient amount of follicular epithelial cells was in 3861 (98.3%) of cases. Repeated FNABs were performed to all patients with nondiagnostic primary results of FNAB (Bethesda 1) in one month after the first one. During the second FNAB we placed cell material into 4 slides instead of 2 slides like for the first time. In case of nondiagnostic second report, third study was scheduled after another month, and performed with 8 slides with material. In 3760 (96%) of cases became informative after repeated FNAB. 168 (4%) cases remained nondiagnostic (about 67,5% of them were operated before third biopsy because of other indications, usually malignant or suspicious tumor in other nodule or toxic goiter). Malignant tumors (Bethesda 6) were revealed in 1,8%, that is significantly lower than among primary FNAB (3%), Follicular neoplasia was found in 409 (10,9%) of cases of re-

Follicular variant of papillary carcinoma (FVPTC) is 40% of all malignant findings after surgery for Bethesda 4 nodules. The main extent of the suregery in these patients - hemithyroidectomy, no matter of the size of the tumor. The nessesity to reoperate to complete thyroidectomy causes a lot of issues. We studied 356 cases of FVPTC out of 1501 papillary carcinomas, who were operated in 2007–2012 in the University clinic of SaintPetersburg State University (Nothern-western center of endogrine surgery). Treatment and observation of the patients was perfomed in accordance with the recommendations of the ETA for the diagnosis and treatment of differentiated thyroid cancer. Only 7 patients (2,0%) had distant metastases among 356 patients with FVPTC. The lymph node metastasis were revealed in 42 (11.8%) cases. Among them 25 (7,0%) patients had N1b lesion. Thus, 84% of patients with N1b metastases were identified before the first operation. It should be noted that all patients with distant metastases had lymphogenic metastases. As T-criteria (in AJCC TNM classification) is based on the tumor size and the presence of extrathyroidal invasion. We compared the average tumor size in patients with and without metastases. We did not reveal significant differences in tumor size. The frequency of invasion extrathyroidal reached 71,4% of patients with distant metastases, however, in the group without regional and distant metastases remained at the level of 37.4%. A key criterion for staging according to AJCC is the age of the patient. The mean age of patients with distant metastases was of 34.6 – 9.2 years, which is significantly lower than the age of patients without metastases to 49.2 – 14,1 years. Neither the size of tumor, nor the presence of thyroid capsule invasion in case of follicular variant of papillary thyroid carcinoma are sufficient indication for completion of thyroidectomy. While conventional ultrasound examination and lung CT can successfully reveal patients with more aggressive disease.

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015

Poster 427 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM THE IMPACT OF MOLECULAR MARKER TEST RESULTS ON SURGICAL MANAGEMENT OF CYTOLOGICALLY INDETERMINATE THYROID NODULES P. Valderrabano1, K.J. Otto1, J. McCaffrey1, M.E. Leon2, B.A. Centeno2, B. McIver1 1 Head and Neck, and Endocrine Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 2Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Oncogene panels (OP) might have a beneficial impact on management of indeterminate thyroid nodules, by identifying cancers prior to surgery, reducing the need for completion thyroidectomy. We sought to evaluate how use of OP influences our surgical management. In this retrospective, IRB approved study we reviewed 828 indeterminate thyroid nodules evaluated at our institution since October 2008. We compared the surgical management of 482 (58%) patients with a single nodule biopsied after excluding: 332 (40%) nodules of patients that had multiple nodules biopsied; 11 (1%) with obvious malignancy (proven lateral neck lymph node metastasis [LNM, n = 9] or presurgical vocal cord paralysis [n = 2]); and 3 (0.3%) with unclear cytology-histology correlation. Ninety-three nodules (19%) were evaluated with OP (miRInform in 45 and ThyroSeq V2 in 48) while 389 (81%) were not (Controls). Resection rate was significantly lower in OP than in Control group (40% [n = 37] vs. 65% [n = 251], p < 0.01). Of the 37 OP resected nodules, 14 (38%) had a mutation identified (M + ). The overall prevalence of malignancy (PoM) was 32% (32% in the OP and 31% in the Control group (NS)). The PoM amongst the OP nodules was 43% for M + (PPV 43%) and 26% for mutation negative (M - ) nodules (NS). OP nodules were more likely treated by total thyroidectomy (TT) (51% vs. 26%, p < 0.01) and central lymph node dissection (CLND) (24% vs. 11%, p = 0.02). M + nodules were responsible for these differences (TT and CLND rates of 86% and 57% in M + nodules, compared to 30% and 4% in M - nodules, p < 0.01). However, the PoM among patients treated with TT or CLND in the OP vs. the control groups were NS. LNM were identified in 10% (20/213) of lymph nodes resected by formal CLND. Fewer LNM were found in the OP patients (2% vs. 13%, p = 0.02). Due to malignancy 25 patients required completion thyroidectomy, 2 (5%) in the OP and 23 (9%) in the control group (NS). OP evaluation led to fewer, but more aggressive surgeries without increasing the yield of malignancy, or decreasing the rate of completion thyroidectomies. Molecular testing results need cautious interpretation while additional, independent clinical validation studies are done.

Poster 428 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM PERCUTANEOUS LASER ABLATION OF AUTONOMOUSLY FUNCTIONING THYROID NODULES IN PATIENTS WITH HYPERTHYROIDISM OR SUBCLINICAL HYPERTHYROIDISM: CLINICAL CASES BASED ON 17 PATIENTS I. Song1, H. Yoon1, J. Bae2, J. Oh3 1 Internal medicine, Raphael hospital, Daegu, Korea (the Republic of); 2Pathology, Raphael hospital, Daegu, Korea (the Republic of); 3 Nuclear medicine, Raphael hospital, Daegu, Korea (the Republic of) Benign thyroid nodules can be safely and effectively treated using minimally invasive therapy under image-guidance. Although the use of

A-171 percutaneous laser ablation (PLA) in relieving compressive symptoms of large nodules has been well studied, little is known regarding the effectiveness of PLA in the treatment of autonomously functioning thyroid nodules (AFTNs). Overt/subclinical hyperthyroidism with an AFTN may cause harmful effect on bone and heart and has been effectively treated using radioactive iodine and surgery. Post-treatment hypothyroidism, patients’ reluctance to use radioactive iodine, and some inevitable complications of surgery, however, remain challenging. A retrospective analysis was performed on 17 patients (16 female and 1 male; mean age of 50.5 – 13.6 years old) who were diagnosed as having hyperthyroidism or subclinical hyperthyroidism with AFTNs and were treated with PLA in our clinic between 2010 and 2012. Initial nodule volume, post-ablation volume, side effects, serum thyroidstimulating hormone (TSH), free tri-iodothyronine, and free thyroxine (fT4) were reviewed. All were identified as hot nodules in 99mTc pertechneate scintigraphy prior to treatment. PLA was performed under real-time ultrasound-guidance and with an output power of 2.5W. We try to achieve complete ablation of nodule periphery by using 20G Chiba needle and optic fibers(400um plane-cut quartz fiber). Normalization of serum TSH was achieved in 14 out of 17 patients(3/3 with hyperthyroidism, 11/14 with subclinical hyperthyroidism) in the first PLA session and the three remaining patients reached euthyroid status after the second PLA session. None of the patients developed hypothyroidism. Mean thyroid nodule volume reduction was 78.9% (7.33 – 5.92ml to 1.55 – 1.47ml) six months after PLA (p < 0.001). No significant post-treatment complications were reported. PLA is a safe, effective treatment modality in treating small to middle sized AFTN; particularly, the procedure appears to be more effective when complete ablation of the nodule periphery can be achieved.

Poster 429 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM FACTORS ASSOCIATED WITH LONG-TERM RISK OF THYROID CANCER IN NODULES WITH A NON-DIAGNOSTIC FINE NEEDLE ASPIRATION BIOPSY A.E. Espinosa De Ycaza1, K. Marshall3, D. Dean1, M. Castro1, V. Fatourechi1, M. Ryder1,2, J. Morris1,2, M. Stan1 1 Division of Endocrinology, Mayo Clinic, Rochester, MN; 2 Medical Oncology, Mayo Clinic, Rochester, MN; 3 Department of Medicine, Mayo Clinic, Rochester, MN Due to the large variability in the rates of malignancy associated with non-diagnostic thyroid nodules following fine needle aspiration (FNA), (between 2 and 20%); there is no clear consensus on their management. The aim of this study was to identify the prevalence of thyroid cancer and the factors associated with malignancy in such patients. In this retrospective cohort study, 699 nodules (from 655 patients) with an initial non-diagnostic ultrasound guided (US) FNA between 2004 and 2010 were included. Diagnosis of thyroid cancer in the index nodule was confirmed by review of the pathology report at time of surgery. Nodules were considered to be benign if there was surgical confirmation of benign histology (n = 103), if a repeat FNA or core biopsy was benign (n = 199), if a nodule was stable in size by US at least 3 years after initial biopsy (n = 41), or if there was no reported diagnosis of thyroid cancer after ‡ 3 years in the participants contacted by mail (not followed at our institution, n = 95). The overall non-diagnostic rate was 11.2%. There were 453 nodules with non-diagnostic FNA that had follow up information available to determine benign or malignant outcome. The mean age was 58.6 years, 73.5% were women, and nodule size at time of FNA was 2.2 – 1.3 cm. The prevalence of thyroid cancer was 3.3% (15/453, Figure 1). In survival analysis, age and the presence of calcifications

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MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015 Median baseline volume of the nodules was 21,7 ml, IQR 14,333,3). A significant volume reduction was observed since the first month after RFA (median volume 11,3 ml, p < 0,001 vs baseline), but the most significant reduction was recorded at 1 year follow-up (median volume 7,3 ml, p < 0,0001 vs baseline, p < 0,001 vs 1 month). After 2 year follow-up a further slight shrinkage was seen (median 6,5 ml), though not significant vs 1 year (p 0,54). The overall volume reduction at 2 year follow-up was 71,1% vs baseline (p < 0,0001). RFA was safe and well tolerated in all patients without any significant side effect. Thyroid function was not affected by RFA. This trial shows good efficacy of RFA in reducing volume of benign nonfunctioning solid thyroid nodules; data on a longer follow-up are needed to confirm long-term efficacy. RFA may represent a valid therapeutic approach in patients with TNs not receiving conventional treatments.

Poster 431 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM COMPARISON OF POSTOPERATIVE PAIN AFTER CONVENTIONAL AND ENDOSCOPIC THYROIDECTOMY : DOES HIGH VOLUME MAKE A DIFFERENCE ? A.D. Rao1,2, T. Luong2, N. Son2, P. Hiep2 1 Surgery, Khoo Teck Puat, Singapore, Singapore; 2Surgery, National Hospital of Endocrinology, Hanoi, Viet Nam were significant predictors for the diagnosis of thyroid malignancy (HR: 0.83, 95%CI: 0.71 - 0.99 for every 5 years increase in age and HR: 4.34, 95%CI: 1.56 - 12.4 for the presence of calcifications) while initial nodule size, solid nodule, and hypoechogenicity were not. In this large cohort of patients with non-diagnostic FNAs of thyroid nodules, the prevalence of thyroid cancer was lower than the known prevalence in all thyroid nodules. Younger age and the presence of calcifications were predictors of malignancy in these nodules. Therefore repeat biopsy of a non-diagnostic nodule should be considered in young individuals and/or in the presence of nodule calcifications. Otherwise a conservative approach can be considered.

Poster 430 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM LONG-LASTING SHRINKAGE OF THYROID NODULES AFTER RADIOFREQUENCY ABLATION. A 2 YEARS PROSPECTIVE STUDY F. Garino1, M. Deandrea1, A. Mormile1, G. Magliona1, R. Garberoglio2, F. Riganti2, P.P. LIMONE1 1 A.O. Ordine Mauriziano di Torino, Torino, Italy; 2 ‘‘Sedes Sapientiae’’ Clinic, Turin, Italy Percutaneous radiofrequency thermal ablation (RFA) was reported as an effective tool for the management of benign thyroid nodules (BTNs) but long term follow-up on standardized procedures are lacking at present time. The aim of this study was to prospectively evaluate the volume reduction of nonfunctioning medium/large sized thyroid nodules after a single session of RFA. 69 patients with non-functioning thyroid nodules were enrolled at Mauriziano Hospital and Sedes Sapiaentiae Clinic. In all patients malignancy was ruled out by repeated fine-needle aspiration cytology. All patients were evaluated clinically, biochemically, and by US at baseline and 1, 6, 12 and 24 months after RFA, performed with ‘‘moving-shot’’ technique.

Endoscopic thyroidectomy has been described as ‘‘minimal access’’ but ‘‘maximally invasive’’ on account of postoperative pain. Many previous studies have shown more pain after endoscopic thyroidectomy when compared with conventional open thyroidectomy. This can be attributed to the more extensive subcutaneous dissection inherent with endoscopic thyroidectomy or duration of surgery in inexperienced hands. Previous experience with other minimally invasive procedures has shown an inverse relationship between experience and duration of surgery which translates into better clinical parameters including postoperative pain. This may have limitations with endoscopic thyroidectomy in lieu of the extensive subcutaneous dissection. This study aimed to compare pain scores in a tertiary high volume unit. 60 random patients who underwent conventional total thyroidectomy (n = 30) and endoscopic total thyroidectomy (n = 30, bilateral axillary breast approach with gas insufflation) by the same surgeons for benign pathologies were evaluated for postoperative pain at initial recovery, 6 hours and 24 hours after surgery. Patients were allocated to either group based on protocol rather than surgeon preference to eliminate selection bias. Anaesthesia and postoperative analgesic protocol were the same with similar instructions for rescue analgesia. Pain was compared between the two groups using the visual analogue scale and the amount of rescue analgesic. The mean duration of operation was 65 – 13 minutes and 71 – 14 minutes (p = 0.35) in the conventional and endoscopic groups respectively. The postoperative mean pain score at initial recovery was 4 – 0.9 vs 4.5 – 1.3 (p = 0.093) in the conventional and endoscopic groups respectively. The mean pain scores at 6 and 24 hours were 2.6 – 0.9 vs 3.5 – 1.3 (p = 0.055) and 2 – 0.9 vs 2.6 – 1.2 (p = 0.066) respectively. No significant differences were observed between the two groups in terms of postoperative rescue analgesia (p = 0.33). In experienced high volume centers, transaxillary endoscopic thyroidectomy does not result in more postoperative pain or use of analgesic when compared with conventional thyroidectomy in spite of the extensive subcutaneous dissection and longer duration of surgery.

MONDAY, OCTOBER 19–TUESDAY, OCTOBER 20, 2015

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Poster 432

Poster 433

Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM EFFICACY OF RADIOFREQUENCY ABLATION (RFA) IN CLINICAL, MORPHOLOGICAL AND FUNCTIONAL CONTROL OF LARGE, SOLID, SYMPTOMATIC AND BENIGN THYROID NODULES: PRELIMINARY OUTCOMES OF A SPANISH MULTICENTER STUDY AFTER THE FIRST MONTH OF FOLLOW-UP. M. Sambo Salas1, M. Prieto3, X. Serres7,4, G. Cuatrecasas2, L. Ocan˜a5, J. Reverter10, J. Mesa6, J. Galofre8, J. Larrache9, T. Martin11, A. Torres11, C. Familiar12, M. Sanabria12, S. Merino13, T. Ganado13 1 Endocrinology and Nutrition, Hospital General Universitario Gregorio Maran˜o´n,, Madrid, Spain; 2Centro Me´dico Teknon,, Barcelona, Spain; 3Radiology, Hospital General Universitario Gregorio Maran˜o´n,, Madrid, Spain; 4Radiology, Hospital Vall d’Hebron, Barcelona, Spain; 5Hospital Universitario Virgen de la Victoria, Malaga, Spain; 6Hospital Vall d’Hebron, Barcelona, Spain; 7Radiology, Centro Me´dico Teknon, Barcelona, Spain; 8 Clı´nica Universidad de Navarra, Pamplona, Spain; 9Radiology, Clı´nica Universidad de Navarra, Pamplona, Spain; 10Hospital Germans Trias i Pujol, Badalona, Spain; 11Hospital Virgen Macarena, Sevilla, Spain; 12Hospital Universitario Clı´nico San Carlos, Madrid, Spain; 13Radiology, Hospital Universitario Clı´nico San Carlos, Madrid, Spain

Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM COMPARING DIAGNOSTIC RATES OF LIQUID-BASED CYTOLOGY USING SUREPATH VERSUS TRADITIONAL SMEARS FOR REPORTING THYROID CYTOLOGY X. Liu1, D. Cui1, H. Fan1, L. Jiang1, L. Wei1, H. Chen1, Q. Yao2, Y. Wu2, R. Rong2, Z. Zhang2, X. Wang1, E.S. Cibas3, E.K. Alexander4, T. Yang1 1 Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 2Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 3Department of Pathology, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA; 4Thyroid Unit, Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA

Radiofrequency ablation (RFA) using ‘‘moving shot’’ technique is a radioguided, minimally invasive and percutaneous alternative that has shown to be fast and effective for the management of benign compressive or hyperfunctioning thyroid nodules (TN). Nevertheless, there are no multicenter clinical trials or studies with combined endpoints, nor demonstrated reproducibility in our population or in large volume TN This is a 6 month follow-up multicenter prospective study involving 9 hospitals Aim: To determine the effect of RFA in clinical, morphological and functional control of large, solid, symptomatic and benign TN in patients not candidates for surgery or radioiodine ablation. The project is still ongoing, so we present preliminary data. To date we have ablated in 8 centers, 29 TN, with a mean maximum diameter of 4.1 – 1.03 cm (range 2.4–7) and a mean initial volume (V = pabc/6) of 24.4 – 20.88 mL (range 3.69–77.64) in 28 symptomatic patients (82.1 % women, mean age of 52.1 years, 35.7% with MNG, mean compressive symptom score (CSS) of 4.1; 23 of them euthyroid, 4 with subclinical hyperthyroidism and 1 with overt hyperthyroid). Complete ablation in one session was possible in 69% of cases. The main causes of incomplete ablations were: great size (3 cases), proximity to the ‘‘danger triangle’’ (3) and slight edema in pre-thyroid soft tissues (2). No major complications were reported during the procedure. Only 6 patients referred mild transient pain, 3 slight swelling in the soft tissues, 2 had transient cough and 1 suffer vasovagal symptoms. After 24–48 hours, no serious side effects were reported: 1 patient had slight bruising on the skin, 2 referred mild pain and 1 cough. After 1 month (results of 21 patients), all side effects disappeared and the the TN experimented a significant decrease in volume: mean of 43.61 – 16.2 % (16.6 SD – 14.61 mL; range 1.87–64.9, p = 0.0001). There has been no cases of new-onset clinical or subclinical hypothyroidism and patients with previous hyperthyroidism remains controlled with less treatment. Patients had a significant decrease of mean CSS (0,8 SD – 1,16, p = 0,0001). Preliminary outcomes already confirm the effectiveness and safety of RFA in the management of TN.

Liquid-based cytology (LBC) is increasingly used for interpretation of thyroid nodules aspirates. Controversy exists about the diagnostic value of LBC compared to traditional smears. Most prior studies of LBC were performed using ThinPrep system. Few studies have ever compared the efficacy of SurePath with traditional smears. We performed a prospective comparison of LBC using SurePath with traditional smears in 230 thyroid nodules from 224 patients. Four needle sticks constituted a single nodule FNA, with 2 passes used for traditional smears while the other 2 passes were rinsed with CytoRich Red collection fluid and SurePath slides developed. A group of cytopathologists separately read all samples, and all slides were reported using the Bethesda system for reporting thyroid cytology. The diagnostic rate was compared between the smear group and SurePath group using McNemar test. The mean nodule size was 1.7 – 1.1 (0.4–10.0) cm. Patient age averaged 47 – 14 (17–79) years, and the population was 82% female. The diagnostic rate for all solid nodules was 77.1% in smear group, which was significantly higher than 59.7% in the SurePath group (P < 0.001). No significant difference was seen for mixed solid/cystic (P = 0.238) or mostly cystic nodules (P = 0.453). The diagnostic rate using a combination of traditional smear and SurePath in solid nodules was 84.0%. This was significantly higher than 77.1% in smear only group (p = 0.002). When excluding nodules less than 1 cm, the diagnostic rate of smear for solid nodules was 82.3%, which was significantly higher than 63.3% in SurePath group (P = 0.004). The diagnostic rate of combination of smear and SurePath was 88.6% for solid nodule, which was higher than 82.3% in smear only group without statistical significance (P = 0.063). Traditional smear preparation demonstrated a superior diagnostic adequacy compared to SurePath processing following direct comparison. However, a combination of both SurePath and smear may yield the most favorable diagnostic rate compared to either process separately.

Poster 434 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM LOW PARATHYROID HORMONE LEVELS ACTUALLY DO NOT PREDICT THE NEED FOR CALCIUM SUPPLEMENTATION AFTER TOTAL THYROIDECTOMY S. Kahan, A. Najafian, A. Mathur, E.B. Schneider, M. Zeiger Endocrine Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD Hypocalcemia is a known complication of total thyroidectomy. The presence of a low postoperative parathyroid hormone (PTH) level

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has been suggested as an absolute indicator of the need for calcium supplementation however, appropriate prior study designs and conclusions are lacking. The aim of this study was to examine whether low PTH alone on postoperative day one is associated with the need for calcium supplementation. A retrospective review of consecutive patients who underwent a total or completion thyroidectomy by a single surgeon from June 2014 through April 2015 was performed. The decision to treat with calcium supplementation was based solely on the presence of an ionized calcium level < 1.13 mmol/L on postoperative day one (normal 1.13–1.32 mmol/L). The diagnostic indices of a low PTH level ( < 10.0 pg/mL) on postoperative day one to predict the need for calcium supplementation were examined. Ninety-two patients underwent total thyroidectomy, of which 25(27%) had PTH 10 pg/mL on postoperative day one, only 12% required supplemental calcium on discharge. The sensitivity and specificity of a PTH 40mm or compressive complaints) and the rest by cytological abnormalities. 28% of the nodules revealed to be malignant (4.79 % of total). In this study it was found that about 1/3 of nodules increased in size and 4,79% revealed to be malignant, even with a previous benign cytology. Our results favour a monitoring and a FNAC repetition of the nodules during follow-up, an usual practice in our department.

Poster 440 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM ASSOCIATION BETWEEN HELICOBACTER PYLORI INFECTION AND THE PRESENCE OF THYROID NODULES IN THE EUTHYROID KOREAN POLULATION D. Yi, S. Oh, H. Lee, Y. Kang, S. Son Internal medicine, Pusan National University Yangsan Hospital, Yangsan, Korea (the Republic of) There is positive correlation beetween H. pylori infection and autoimmune thyroid diseases. And chronic thyroiditis is one of the major cause of nodule formation. In this study, we investigated association between H. pylori infections and the presence of thyroid nodules. We reviewed medical records of subjects who underwent annual health screening at our hospital from February 2013 to March 2015. Euthyroid patients with available results of thyroid ultrasound and CLO test were included. Subjects with a history of thyroid disorders and thyroid hormone replacement were excluded. 120 (48.0%) subjects had thyroid nodules, and 143 (57.2%) were diagnosed with H. pylori infections. The thyroid nodules group had a higher prevelance of H. pylori infections than the control group (P = 0.008). The prevalence of H. pylori infection showed no relationship with serum free FT4 and TSH level. The prevalence of thyroid nodules was higher in patients with H. pylori infection com-

Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM RELATIONSHIP OF VITAMIN D AND INTRAOPERATIVE PARATHYROID HORMONE LEVEL IN COMPLETION AND TOTAL THYROIDECTOMY B.R. Lawson1, A. Hinson1, D.L. Bodenner1,2, B.C. Stack1 1 Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, AR; 2Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR Intraoperative parathyroid hormone testing has been adopted by head and neck endocrine surgeons for various applications. Among these is stratification for appropriate same-day discharge in patients undergoing completion and total thyroidectomy. In our high-volume surgical practice, we have noted a curious increase in postoperative hormone levels compared to baseline in some patients. This counterintuitive phenomenon of hormone increase in surgically manipulated glands prompted further investigation. Our objectives are two-fold: 1) to quantify how frequently intraoperative parathyroid hormone levels increase, and 2) to explore a possible relationship between secondary hyperparathyroidism due to vitamin D deficiency and elevation in intraoperative parathyroid hormone levels. One-hundred fifty three consecutive patients undergoing completion and total thyroidectomy at a tertiary academic center were included for analysis. All patients had baseline, 10- and 20-minute post-excision PTH levels as well as perioperative vitamin D levels analyzed by the same laboratory. Institute of Medicine criteria were employed for vitamin D stratification (normal, insufficient, deficient). Continuous data were analyzed using Fisher’s exact test, and categorical data were analyzed using chi-square contingency tables. A total of 42 patients (27.5%) had an intraoperative parathyroid hormone elevation. There was no statistically significant difference in frequency of hormone elevation based on vitamin D status (p = 0.451). When parathyroid hormone rose, it did so by an average of 33.7 ng/dL (52.2%). However there was no significant difference in the quantitative hormone increase based on vitamin D levels (p = 0.399). While elevation in intraoperative parathyroid hormone levels after completion and total thyroidectomy is an unexpected phenomenon, our data indicate that it occurs in over one-fourth of cases. Based on this initial analysis, immediate increase in postoperative parathyroid hormone is not attributable to secondary hyperparathyroidism caused by vitamin D deficiency.

Poster 442 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM THE EFFECT OF ONE AND TWO SESSIONS OF US-GUIDED HIGH-INTENSITY FOCUSED ULTRASOUND (HIFU) TREATMENT ON THYROID NODULE VOLUME AND THYROID FUNCTION R. Kovatcheva1, J. Vlahov1, J. Stoinov2, K. Zaletel3 1 Thyroid and Metabolic bone diseases, University Hospital of Endocrinology, Sofia, Bulgaria; 2Endocrine Surgery, University Hospital of Endocrinology, Sofia, Bulgaria; 3Medical Center Ljubljana, Ljubljana, Slovenia

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Thyroid nodules can be detected by ultrasound (US) with a prevalence of 19–67% and in most of them, surgery is not the treatment of choice. High-intensity focused ultrasound (HIFU) is a new, noninvasive thermo-ablative method, developed to reduce thyroid nodule size. Our aim was to assess the long-term efficacy and safety of a single and repeated US-guided HIFU treatment of benign solid thyroid nodules. In our prospective study, 20 euthyroid patients (mean age, 44.5 years) with benign solitary or dominant thyroid nodule were treated with US-guided HIFU system (EchoPulse, Theraclion) under conscious sedation. Twelve patients (group 1) received one treatment and 8 patients (group 2) received second treatment after 3-month follow-up. Nodule volume was established at baseline, 3 and 12 months after the final treatment. Thyroid function was assessed at baseline and 12 months after the final treatment. Adverse events were evaluated. Written informed consent was acquired from all patients. The mean energy applied per nodule volume did not significantly differ between group 1 and 2 (3.5 – 1.4 kJ/mL and 4.1 – 1.6 kJ/mL, respectively). Starting from 5.04 – 2.82 ml (group 1) and 4.83 – 2.93 ml (group 2), the mean volume decreased significantly at 12-month follow-up (2.35 – 2.44 ml, p = 0.003, and 2.63 – 1.85 ml, p = 0.017, respectively) with a maximal volume reduction of 95.4% and 66%, respectively. The mean volume reduction did not differ significantly between group 1 and 2 (55.7% – 27.2 and 50% – 21, respectively). In all treated patients, the mean TSH was significantly higher 12 months after the final treatment (2.26 – 1.08 mIU/L compared with 1.7 – 0.97 mIU/L before HIFU, p = 0.013), but still within normal ranges. After the first treatment transient subcutaneous oedema and mild skin redness were observed in 2 patients, and after the second treatment one patient developed Horner syndrome, which resolved 6 months later. In non-functioning benign thyroid nodules, the effect of one and two consecutive HIFU treatments is comparable. Although TSH slightly increases after HIFU ablation, the long-term thyroid function remains normal.

which were resected by surgery had their cytological results compared with histopathological reports. The study evaluated 977 thyroid nodules (585 patients). Patients median age was 51 years (16–83), 90% women, and 41,5% (243/585) patients were submitted to surgery. Nodules cytologies were classified as category I in 11% (108), category II in 59.6% (583), III in 7.1% (70), IV in 8.5% (84), V in 5.1% (50); VI in 8.3% (82). Malignancy rate was 25.7% for category I, 5.48% II, 11.5% III, 20.7% IV, 71.7% V, 97.3% VI. Sensitivity of 93%, specificity of 63.3%, PPV of 57.4% and PNV of 94.4%. The indications of surgery in nodules category I, with malignant histological results, were the presence of other nodule with suspicious cytology (5/9) or large nodules, above 5cm (4/9). From all of malignant lesions 66,6% were papillary microcarcinoma. Our results are concordant with what is described by the Bethesda system classification, however, with higher malignancy rates in category I. Therefore, presence of Bethesda I thyroid nodule in a multinodular goiter with nodules larger than 5cm or with suspected cytology should be carefully evaluated due the possible occurrence of multifocal tumors. The other Bethesda categories presented similar data to other series in literature.

Poster 443 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM BETHESDA CLASSIFICATION AND CYTOLOGICALHISTOLOGICAL CORRELATION OF THYROID NODULES IN A BRAZILIAN THYROID DISEASE CENTER K. Reuter1, M. Mamone1, E. Ikejiri1, C.P. Camacho1, C.C. Nakabashi1, C. Janovsky1, J.H. YANG1, F. Vanderlei3, D. Andreoni1, R.M. Maciel1,2, R. Padovani1,4, R.M. Biscolla1,2 1 Endocrinology, Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil; 2 Fleury Medicina e Sau´de, Sa˜o Paulo, Brazil; 3Head and Neck Division, Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil; 4Santa Casa de Sa˜o Paulo, Sa˜o Paulo, Brazil Since 2009 the Bethesda System for Reporting Thyroid Cytopathology Results has been used by some reference centers to classify thyroid nodules cytology in six categories, presenting their malignancy rates and suggesting their respective approaches. Some reference centers validated this classification by the evaluation of their own malignancy rates in each Bethesda category. In Brazil, there are no studies about the Bethesda classification, and if the malignancy rates reported in literature could be applied to our population. The aim of this report is to evaluate the performance of Bethesda classification in a Brazilian thyroid nodule reference center, and to correlate cytological and histopathological results in patients submitted to surgery. Data records related to fine needle aspiration biopsy results were retrospectively analyzed in nodules greater than 1cm and/or nodules with suspect characteristic by thyroid ultrasonography. Nodules

Poster 444 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM RADIOFREQUENCY ABLATION AS A TREATMENT OPTION OF THYROID PSEUDO-ANEURYSM S. Jung1, A. Jeon1, H. Byun1, J. Baek2, J. Sung3, J. Sim4 1 Radiology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea (the Republic of); 2Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea (the Republic of); 3Radiology, Daerim St. Mary’s Hospital, Seoul, Korea (the Republic of); 4Radiology, Withsim Clinic, Gyeonggi, Korea (the Republic of) Although most of the pseudo-aneurysms(P-As) are developed after arterial puncture during the angiography or trans-vascular intervention, P-As may be occurred after biopsy. Ultrasound-guided compression is a choice of treatment. We introduce radiofrequency ablation (RFA) as a treatment option of the thyroid P-A developed after thyroid biopsy. Eight P-As are developed after thyroid biopsy (fine-needle aspiration : core needle biopsy = 3:5) in eight patients (M:F = 3:5, mean age, 51.5 years, age range 29–72 years) at four institutions. Biopsy was performed for thyroid mass (benign:malignant nodule = 6:2). All

A. After three hours compression, internal flow is again noted within the pseudo-aneurysmal sac. B. After RFA, high echoic thrombi is demonstrated at the aneurysmal sac without internal flow(short thick errow). High echogenicity is seen in aneurysmal root, RFA site (long arrows).

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PAs were diagnosed by Doppler ultrasonography. They were treated with observation, compression, RFA, or combination. RFA was performed when P-A was incompletely treated by only compression. Treatment status was confirmed with Doppler ultrasonography. All eight P-As were completely treated with observation (n = 1), only compression (n = 3) and combination of compression and RFA (n = 4). Mean diameter of the P-As was 8.1mm (range, 4–12mm). Mean compression time was 37.7minutes and 85minutes in treatment cases with only compression and RFA after compression, respectively. RFA was performed with 0.5 or 1cm electrode. Its mean power and mean duration were 20W (range, 10–50W) and 29.3 seconds (range, 5–87 seconds), respectively. There was no RFA procedure related complication. RFA may be a safe and simple treatment option of the thyroid P-A developed after thyroid biopsy in cases that cannot be controlled by simple compression. on, respectively. RFA was performed with 0.5 or 1cm electrode. Its mean power and mean duration were 20W (range, 10–50W) and 29.3 seconds (range, 5–87 seconds), respectively. There was no RFA procedure related complication.

Poster 446

Poster 445 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM ETHANOL ABLATION OF CYSTIC THYROID NODULES: LARGE SIZE IS ASSOCIATED WITH TREATMENT FAILURE H. Kang, J. Yoon, H. Kim Internal Medicine, Chonnam National University Medical School, Gwangju, Korea (the Republic of) The aims of this study were to evaluate the efficacy and safety of ultrasound-guided percutaneous ethanol ablation for benign thyroid cystic nodules and to find the clinical factors associated with the outcome of therapy. We examined 46 patients with benign thyroid cystic nodules (25 pure cysts and 18 cystic dominant nodules) confirmed by fine-needle aspiration cytology. After removal of cystic fluid, 99% ethanol was injected into the cystic cavity under ultrasound (US)-guidance. Follow-up US was performed 2 weeks later to evaluate early response. Late response was evaluated at 6–36 months after the therapy. Effective response (ER) was defined as volume reduction more than 50% with improved symptom or the absence of any residual cystic lesion; partial response (PR), as volume reduction at 25–50%; no response (NR), as volume reduction less than 25% or volume expansion. Cure was defined as the absence of any residual cystic lesion or reduction in nodule volume more than 50% compared to initial volume of the cystic nodule. In early response, ER, PR, NR were 67.4% (31/46), 30.4% (14/ 46), and 2.2% (1/46), respectively. Initial volume of 12.0 – 7.8ml (3.4-41.3) was significantly reduced to post-ethanol ablation therapy of 5.4 – 6.2ml (0–33.0) [55% volume reduction, p < 0.001], and to final volume of 4.4 – 5.4ml (0-23.3) [63% volume reduction, p < 0.01]. Cure was obtained in 31 of 40(77.5%) patients after one treatment session. Six patients needed additional ethanol injection therapies. Baseline cystic nodule volume had influence on the outcome (p = 0.04), the chance of success decreased with increasing cystic nodule volume. Eleven patients (23%) had transient (lasting less than 5 minutes) mild local pain. US-guided ethanol ablation is thought to be a safe, highly effective therapeutic method for cystic thyroid nodules. In large cystic nodules, other treatment modalities should be considered, because large initial volume of the cystic nodule is the factor associated with the failure of therapy.

Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM 131I 30 MCI (1,110 MBQ) FIXED DOSE AS AN ATTRACTIVE THERAPEUTIC ALTERNATIVE IN NONTOXIC NODULAR GOITER V.P. Miguel1, C.M. Riguetto1, V.P. Souza1, J.P. Miguel3, A.M. Neto1, F.F. Maia1, E.J. Pavin1, C.D. Ramos2, D.E. ZantutWittmann1 1 Internal Medicine, Endocrinology Division, Faculty of Medical Sciences University of Campinas, Miguelo´polis, Brazil; 2Nuclear Medicine Division, University of Campinas, Campinas, Brazil; 3 Otorhinolaryngology, division of Neck Surgery, Holy House of Limeira, Limeira, Brazil The best treatment for nontoxic multinodular goiter (NTG) remains controversial and depends on size, severity of compressive symptoms, clinical conditions and patients choice. The goal of treatment is to decrease goiter size by surgery or radioiodine therapy (RIT). In our service, patients not candidate for surgery are referred to conventional RIT with a fixed dose of 30 mCi (1,110 MBq). Our aim was to analyze clinical and laboratorial outcomes of patients with NTG after a fixed dose of 131I 30 mCi. We retrospectively evaluated RIT outcomes in patients with NTG followed from February 2011 to July 2014, all with TSH and free thyroxine within reference values and treated with 30 mCi of 131I. Thyroid function and volume (by ultrasound, US) were assessed before and one year after RIT. Eighteen patients were treated during the period, 17 (94.4%) females, median age at diagnosis 49.5 years (interquartile range 31.7–61 years). At initial evaluation, median TSH was 1.26 uUI/ml (0.60–1.73) and FT4 was 1.29 ng/dl (1.07–1.45). The pre RIT US showed a median volume of 68 cm3 (56.4-99.4,range 31.3–295.3 cm3). Median technetium-99m uptake in 20 minutes was 0.5% (0.23–0.70). Contrasted cervical radiography showed cervical compression in 14 (85.7%) patients. RIT was chosen due to surgery refusal in 43.8%, advanced age in 31.3%, comorbidities in 12.5% and previous thyroidectomy in 12.5% of patients. We did not find information for RIT indication for two patients. Median time between diagnosis and RIT therapy was 16.5 years (6.2–24). Thyroid volume by US after RIT was 49.5 cm3 (27.4–71.1). Median volume reduction was 30.6% (10.7-42.8). Thyroid volume was assessed after a median of 15 months. Thyroid function tests one year after RIT were within the reference values in 87.5% of patients, with median TSH and FT4 of 2.01 (1.42–4.62) and 1.28 (1.09–1.41), respectively. Ninetytwo percent of patients (n = 13) were satisfied with final result. A substantial reduction in thyroid volume accompanied by a low incidence of hypothyroidism and a high satisfaction rate makes the use of conventional RIT with a fixed dose of 30mCi an attractive therapeutic alternative in selected cases of NTG.

Poster 447 Thyroid Nodules & Goiter Monday & Tuesday Poster 9:00 AM PREVALENCE OF THYROID NODULES IN AN ADULT BULGARIAN POPULATION SAMPLE A. Shinkov, A. Borissova, J. Vlahov, L. Dakovska University Hospital of Endocrinology, Medical University of Sofia, Sofia, Bulgaria Thyroid nodules are common and different series report prevalence up to over 40% depending of the studied cohorts. The aim of the study was to explore the prevalence of thyroid nodules in a random adult sample of the population and to compare the gender, age and thyroid function characteristics of the subjects with and without nodules.

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Material and methods: Two thousand and twenty two subjects were included, 1073 female and 949 male, age range 20–88 years. All subjects filled an interview and underwent thyroid ultrasound. Body weight, height and TSH, FT4 and TPO Ab were measured. Nodules 5 mm or more were registered and their number - single or multiple and the echo structure - solid, cystic or mixed were recorded. Results: Nodules were found in 24.3% of the subjects, in 32.1% of the females and 15.7% of the males, p < 0.001. We found nodules in 22% of the subjects who reported no history of thyroid disorder. Nodules were found in 41% of those reporting history of thyroid surgery and 23.9% of those without such history, p = 0.04. In 61.9% the nodules were single and in 38.1% - multiple. Multiple nodules were more prevalent in the females (43%) than in the males (26.7%), p = 0.001. Of all nodules, 67.7% were solid, 9.7% were cystic and in22.6% the structure was mixed. The nodule prevalence both single and multiple increased with the age of the subject. TSH was lower (2.24 vs. 2.97. p < 0.001) and FT4 was higher (11.3 vs. 10.9, p = 0.011) in the subjects with nodules. Conclusions: We found nodules in a fourth of the population with a higher prevalence in the females, increasing with the age in both genders. Subjects with previous thyroid surgery had higher frequency of nodules as well.

There are several discrepancies in the management of thyroid nodules(TN). The aim of this study was to evaluate various approaches to TN by different specialists and medical centers in Turkey. The questionnaire designed and conducted for ITC 2010 by R.Paschke, was conducted to 400 Turkish Physicians, from different disciplines and institutions; including 264 general surgeons, 58 endocrine surgeons and 78 endocrinologists. Different institutions were; Education and Research State hospitals (n = 110), University hospitals (n = 122), State hospitals (n = 84) and Private hospitals (n = 84 ). The case was a 35 years old male patient (TSH:0.5 mIU/L), ultrasound (US) revealed a 1.3 cm right nodule(RN) and 1.8 cm left nodule (LN). The next information, Turkish physicians would like to acquire was FNAC (38.5%) followed by scintigraphy + FNAC (25.5%), US details (24.5%) and scintigraphy alone(11.5%). Routine calcitonin measurement was advised by 33.5% of specialists, mainly endocrinologists (51%). Subsequently, US and scintigraphy were detailed as; intranodular flow, microcalcification for the solid, normoactive RN and solid hypoechoic, cold for the LN. FNAC for both nodules was recommended by 68.5%, RN only 15%, LN only 7.5% of specialists. Thirty six (9 %) specialists recommended surgery without FNAC, mainly by general surgeons (n = 32). Further on, RN was defined as indeterminate and LN as benign cytologically. Malignancy risk for the indeterminate RN was questioned; 16% of the specialists gave 30–40% risk, 40% gave 20% risk and 44% gave less than 10% risk. When the FNAC results were changed as benign for both nodules, and two new nodule formation at the following two years was described; 62% of specialists recommended surgery and 38% recommended follow-up with or without LT4. Surgery was recommended by 43% of endocrinologists, 32% of general and 14% of endocrine surgeons. Specialists from private hospitals recommended surgery more frequent than Research State, and University Hospitals (37%, 27%, 23% respectively). Approach to thyroid nodules is controversial among different specialists and institutions in Turkey. Private hospital setting seems to increase the surgical rate.

Poster 448 Thyroid Nodules & Goiter Monday & Tuesday Poster Clinical 9:00 AM DIAGNOSTIC AND THERAPEUTIC APPROACH TO THYROID NODULES FROM DIFFERENT SPECIALISTS OF TURKEY M.F. Erdog˘an1, B.I. Aydogan1, S. Demirer2, Y. Erbil3 1 Department of Endocrinology and Metabolism, Ankara University Faculty of Medicine, Ankara, Turkey; 2Department of General Surgery, Ankara University Faculty of Medicine, Ankara, Turkey; 3 Department of General Surgery, Istanbul University Faculty of Medicine, Istanbul, Turkey

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Wednesday, October 21, 2015 Oral 449 Autoimmunity Wednesday Oral Basic 4:30 PM DISCOVERING NOVEL SMALL MOLECULES WHICH ABROGATE TSH RECEPTOR SIGNALING R. Latif1, R.B. Realubit2, C. Karan2, T.F. Davies1 1 Medicine, Icahn School of Medicine at Mount Sinai & James J Peters VA Medical Center, New York, NY; 2Sulzberger Columbia Genome Center, Columbia University Medical Center, New York, NY Pathological activation of the TSHR is caused by thyroid stimulating antibodies in Graves’ disease or by genomic mutations which enhance the constitutive activation of the receptor signaling unit influencing both associated G protein and non-G protein signaling. Selective small molecule antagonists represent novel therapeutic compounds for the treatment of such abnormal TSHR signaling. Neumann et al (Endocrinology 2014,155:310-314) have previously reported a small molecule antagonist identified by sequential chemical modification of a TSHR agonist. In contrast, we have developed a unique high throughput TSH inhibition assay using a transcriptional based luciferase response to TSH (20lU) in TSHR expressing CHO cells optimized to a 384 format. This assay yielded a Z’ score of 0.3–0.7 and we chose a mean signal threshold of > 50% inhibition. We first screened *40K compounds from the Enamine diversity library at 16.7lM final concentration resulting in 273 positive hits (hit ratio 0.6%). A secondary confirmation screen against TSH (20lU) and forskolin (5lM) - a post receptor activator of adenylyl cyclase - confirmed 14 TSHR-specific candidate molecules. The most potent 4 molecules inhibited up to 40% of TSH stimulation under these experimental conditions with only minimal inhibition of forskolin stimulation. The potency of the lead molecule, MS-K14, had an IC50 of 12.3lM and a unique chemical structure. A parallel analysis using the Cell Titer-Fluor Cell viability assay (Promega) showed these lead inhibitors to be non-cytotoxic molecules. In conclusion, we have identified new small molecule TSHR inhibitors that have serious potential to be developed as therapeutic antagonists. (Supported by NIH - DK069713).

Oral 450 Autoimmunity Wednesday Oral Basic 4:45 PM CONTRASTING DISEASE SPECTRUM IN PRECLINICAL MODELS OF GRAVES’ ORBITOPATHY IN BALB/C AND C57BL/6 MICE S. Moshkelgosha1, U. Berchner-Pfannschmidt1, S. Diaz-Cano2, B. Edelmann1, G. Go¨rtz1, M. Horstmann1, A. Noble3, W. Hansen1, J. Banga1,3, A. Eckstein1 1 Molecular Ophthalmology, University Duisburg-Essen, Essen, Germany; 2Department of Pathology, King’s College Hospital NHS Trust, London, United Kingdom; 3Faculty of Life Sciences & Medicine, King’s College London, London, United Kingdom Amongst the multiorgan complications of Graves’ hyperthyroid disease is Graves’ Orbitopathy (GO), characterised by orbital muscle inflammation, adipogenesis and fibrosis, leading to painful protrusion (proptosis) of the eyes. BALB/c mice are susceptible to experimental Graves’ disease, where we have recently modelled the orbital heterogeneity as seen in GO patients, by close field muscle electroporation of hTSHR A-subunit plasmid. To understand the immunological basis of GO, it is important to evaluate the GO model in other inbred strains, especially C57BL/6 (B6) mice where variety of

transgenic and gene knockout animals are available. However, B6 mice are generally resistant to induction of Graves’ disease. Parallel immunization of TSHR A-subunit plasmid following by electroporation in female B6 and BALB/c mice was conducted. For all animals antigen specific T cell response, antibody levels and orbital histology were examined. The results showed 65% B6 mice significantly positive for thyroid stimulating antibodies, although only 15% developed hyperthyroidism. Examination of ex vivo T cell responses to hTSHR antigen showed 8/11 BALB/c mice with significant T cell stimulation, whilst responses in B6 mice were generally attenuated. In addition to differences in T cell response, B6 mice showed characteristic signs of orbital pathology which were dramatically distinct from that observed in BALB/c animals. Orbital pathology in BALB/c mice was characterised by orbital muscle inflammation and adipogenesis, but the large Harderian gland remained normal. In contrast the orbital tissue in B6 mice was characterised by pigment-laden dendritic cells and melanocytosis. Importantly, Harderian gland abnormalities included multifocal chronic inflammation and infiltration of CD3 + T cells. Perifascicular atrophy and adipose tissue infiltration was also apparent in the extraorbital muscles. In summary, these results indicate despite poor ex vivo T cell response to TSHR antigen, B6 mice are susceptible to induction of experimental GO, accompanied with distinct orbital pathology from the well characterised BALB/c mice. The two models hold great promise for studying GO pathogenesis.

Oral 451 Autoimmunity Wednesday Oral Basic 5:00 PM TSH RECEPTOR ANTIBODIES TO THE CLEAVAGE REGION (C-TSHR-ABS) INDUCE ENDOPLASMIC RETICULUM STRESS MEDIATED BY REACTIVE OXYGEN SPECIES (ROS) S.A. Morshed1,2, R. Ma1,2, R. Latif1,2, T. Davies1,2 1 Endocrinology, Icahn School of Medicine at Mount Sinai, Bronx, NY; 2Thyroid Research Unit, James J Peters VA Medical Center, Bronx, NY The endoplasmic reticulum (ER) is composed of protein chaperones that catalyze protein folding and sensors that detect the presence of misfolded proteins which may be induced by cellular stress. Activation of the unfolded protein response (UPR) either resolves the stress or initiates apoptosis. Mitochondria are an important source of ROS which contributes to cellular stress but the effect of ROS on the ER has been elusive. We have shown previously that C-TSHR-Abs (sometimes referred to as neutral antibodies) induce ROS production and ER stress resulting in thyrocyte cell apoptosis if unopposed. Using fluorometry, live-cell imaging, immunohistochemistry, Incell Western, and immunoblotting of thyrocyte (FRTL-5) cultures, we found that C-TSHR-Abs activated ROS in a dose- and timedependent manner and which paralleled the induction of ER stress (as evidenced by changes in CHOP, IRE1a and PD1) and protein folding responses (Erp44 and grp78). C-TSHR-Abs also caused mitochondrial DNA damage as detected by anti-8-Hydroxydeoxyguanosine. The induced ROS/ER stress in turn activated the Cyto-C/Bax/RIPK/ PERP apoptotic signaling cascades. A known inhibitor (phenyl butyric acid) suppressed ER stress ( > 50%) but not total ROS ( < 10%), whereas a NADPH oxidase (Diphenyleneiodonium chloride) inhibitor showed a robust inhibition of total ROS ( > 80%) and simultaneously suppressed ER stress ( > 70%).

WEDNESDAY, OCTOBER 21, 2015 These data indicate that thyroid cell ER stress was directly induced by ROS. Such results disclose that apoptosis is triggered by ROS-mediated activation of ER stress. Targeting ROS and ER stress by a cocktail of inhibitors may help reduce thyroid inflammation in patients with autoimmune thyroid disease. (Supported by DK069713).

Oral 452 Autoimmunity Wednesday Oral Basic 5:15 PM COOPERATIVE INHIBITION OF ORBITAL FIBROBLAST ACTIVATION BY SIMULTANEOUS TREATMENT WITH TSH RECEPTOR AND IGF1 RECEPTOR SMALL MOLECULE ANTAGONISTS C.C. Krieger, R.F. Place, S. Neumann, M. Gershengorn NIDDK, NIH, Bethesda, MD Severe Graves’ ophthalmopathy (GO) is characterized by excessive hyaluronan (HA) secretion by activated orbital fibroblasts. We have previously shown that bi-directional cross-talk between TSH and IGF1 signaling pathways can be a major contributor to the upregulation of HA production. The monoclonal GD-IgG, M22, activated both signaling pathways without directly stimulating the IGF1 receptor (IGF1R), suggesting that IGF1R effects are dependent on TSH receptor (TSHR) signaling. A maximally effective dose of TSHR small molecule antagonist, NCGC00242364 (S2-7) alone abolished M22 stimulation of HA secretion whereas a maximally effective dose of IGF1R antagonist Linsitinib (Lins) inhibited HA secretion by 44%. We hypothesize that interdependence between TSHR and IGF1R is the product of a post-receptor convergence of the TSH and IGF1 signaling pathways, and that simultaneous inhibition of both receptors will lead to amplified inhibition of M22-mediated HA secretion. Orbital fibroblasts from four GO patients (GOFs) were activated with M22 in the presence of S2-7 and Lins. HA secretion by GOFs in cell culture was used as a measure of GOF activation and assessed with a modified ELISA. The effectiveness of combination treatments was evaluated using varying doses of S2-7 and Lins, and additivity was determined via fixed-ratio isobolograms. The half-maximally effective doses (EC50s) of TSHR signaling with or without IGF1 were determined by assays for cAMP and Western blots for phosphoextracellular signal-regulated kinases 1/2 (ERK1/2). We found a ten-fold shift in the dose-response for ERK2 phosphorylation by TSH in the presence of IGF1. As ERK2 phosphorylation marks ERK activation, this finding is consistent with the idea that ERK2 mediates TSHR/IGF1R interaction. Thus, the synergistic effect of TSH plus IGF1 on HA secretion is mediated by receptor cross-talk at ERK2 phosphorylation. Linsitinib and S2-7 have additive effects in combination, illustrating that receptor cross-talk translates to the pharmacological profiles of these drugs. These data show that IGF1R inhibitors are most effective in combination with TSHR antagonists. Combination treatments may allow for lower doses of both drugs in therapy of GO.

Oral 453 Thyroid Cancer Wednesday Oral Basic 4:30 PM SIMULTANEOUS SUPPRESSION OF BRAFV600E AND HISTONE DEACETYLASE SYNERGISTICALLY RESTORES ROBUST THYROID GENE EXPRESSION AND RADIOIODINE UPTAKE IN THYROID CANCER CELLS W. Cheng, M. Xing Laboratory for Cellular and Molecular Thyroid Research, Johns Hopkins University School of Medicine, Baltimore, MD

A-181 Use of BRAFV600E inhibitors to target the BRAFV600E/MAP kinase (MAPK) pathway to restore thyroid gene expression and radioactive iodine (RAI) avidity for treatment of otherwise RAI-refractory thyroid cancer has become an attractive therapeutic option that is being tested clinically. The therapeutic responses, however, seem to be modest. Given the demonstration that histone deacetylation at the gene promoter of sodium/iodide symporter (NIS) by histone deacetylase (HDAC) is a mechanism in the silencing of thyroid genes by the MAPK pathway, we hypothesized that simultaneously suppressing BRAFV600E and HDAC could be a novel, more effective, and practically easily achievable strategy for such RAI treatment. We tested the effects of the BRAFV600E inhibitor PLX4032 (Vemurefenib) and the HDAC inhibitor SAHA, both of which have been approved for clinical use, alone or in combination, in inducing the expression of thyroid iodine-handling genes and RAI uptake in thyroid cancer cell lines. PLX4032 induced the expression of thyroid genes, such as those for NIS and thyroid-stimulating hormone (TSH) receptor, and RAI uptake preferentially in BRAFV600E thyroid cancer cell lines compared with BRAFWT cells and SAHA showed an effect in a geneticindependent manner in both BRAFV600E and BRAFWT thyroid cancer cells. A robust synergistic effect was observed in BRAFV600E thyroid cancer cells when the two inhibitors were simultaneously used. TSH further enhanced the effects of PLX4032 and SAHA on thyroid gene expression and RAI uptake. Abundant NIS expression in the cell membrane under these conditions, which plays the most important role in RAI uptake in thyroid cells, was confirmed by immunofluorescent microscopy. Simultaneously suppressing BRAFV600E and HDAC using clinically applicable PLX4032 and SAHA together with TSH treatment synergistically restores robust thyroid gene expression and RAI uptake in BRAFV600E thyroid cancer cells. This represents a novel and potentially effective strategy to prepare for RAI ablation treatment of otherwise RAI-refractory BRAFV600E thyroid cancer.

Oral 454 Thyroid Cancer Wednesday Oral Basic 4:45 PM FOLLICULAR THYROID CANCER AND UNCOUPLING OF MTOR - AMPK PATHWAYS S.C. KARI1, L. KIRSCHNER1,2 1 MOLECULAR VIROLOGY IMMUNOLOGY AND MOLECULAR GENETICS, OHIO STATE UNIVERSITY, Columbus, OH; 2Division of Endocrinology, Ohio State University, Columbus, OH Thyroid cancer affects about one percent of the population, and has seen rising incidence in recent years. Follicular thyroid cancer (FTC) comprises 10–15% of all thyroid cancers. FTC is aggressive and often metastasizes, leading to secondary complications, and increased risk of cancer deaths. Mechanistic target of rapamycin (mTOR) has recently emerged as central regulator of cell metabolism with a key role in cell proliferation and cancer development. Our investigation of human FTC tissue samples demonstrated mTOR activation and increase in p-CREB as a measure of Protein Kinase A (PKA) activity. We therefore generated a mouse model of FTC with PKA activation (due to knockout of the PKA regulatory gene, PRKAR1A), and showed the tumors faithfully replicating the human FTC results, with activation of mTOR and p-CREB. mTOR signaling was analyzed using western blot of tumor tissue and FTC-133 thyroid cancer cell line. Briefly, total protein was harvested, quantified, and analyzed by western blotting. Examination of mouse tumors revealed mTOR activation along with that of AMP-dependent kinase (AMPK- Thr 172 activating site). AMPK is an energy sensor, and normally a negative regulator

A-182 of mTOR pathway, through phosphorylation of TSC-2 and Raptor, and dephosphorylation of PRAS-40. However, in the tumors, phosphorylation of TSC-2 and Raptor at AMPK sites was absent, and phospho-PRAS40 was expressed. The present literature suggests PKA activating mTOR through p70S6K1. Similarly LKB1, the major AMPK kinase is a known substrate of PKA. AMPK enhances fatty acid oxidation (FAO), downregulates PI3/AKT and ERK pathways, and reduce glucose dependence. Experiments are currently underway to study altered FAO. We are presently characterizing the molecular pathway linking PKA to mTOR and AMPK activation, and to FTC development. Our data is consistent with the hypothesis that PKA activates both the mTOR and AMPK pathways independent of each other, and these two metabolic pathways are uncoupled in FTC, with AMPK activation leading to switch in cellular metabolism towards enhanced FAO. This study has potentially important implications in understanding the role of cellular metabolism as a driving force leading to FTC development.

Oral 455 Thyroid Cancer Wednesday Oral Translational 5:00 PM IL-12 IMMUNOTHERAPY OF BRAFV600E-INDUCED PAPILLARY THYROID CANCER IN A MOUSE MODEL M. Zou1, R. Parhar2, F. Al-Mohanna2, E. Baitei1, A. Assiri3, B. Meyer1, Y. Shi1 1 Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 2Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 3Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Papillary thyroid cancer (PTC) accounts for more than 80% thyroid malignancies and BRAFV600E mutation is frequently found in more than 40% PTC. Interleukin 12 (IL-12) is a proinflammatory heterodimeric cytokine with strong antitumor activity. It is not known whether IL-12 immunotherapy is effective against BrafV600E-induced PTC. In the present study, we investigated the effectiveness of IL-12 immunotherapy against BrafV600E-induced PTC in TPO-BrafV600E mice.TPO-BrafV600E mice were created for thyroid-specific expression of BrafV600E under the control of thyroid peroxidase (TPO) promoter, and spontaneous PTC developed at about 5 weeks of age. The mice were subjected to 2 treatment regimens: (1) weekly intramuscular injection of 50 mg plasmid DNA expressing a single chain IL-12 fusion protein (scIL-12/CMVpDNA), (2) daily intraperitoneal injection of mouse recombinant IL-12 protein (mrIL-12, 100 ng/day). The role of T cells, natural killer (NK) cells, and transforming growth factor beta (TGF-b) in IL-12 mediated antitumor effects was determined by a 51Cr release cytotoxicity assay. Tumor size and weight were significantly reduced by either weekly intramuscular injection of scIL-12/CMVpDNA or daily intraperitoneal injection of mrIL-12, and tumor became more localized. Survival was significantly increased when treatment started at one week of age as compared to that at the 6 weeks of age. Both NK and CD8 + T cells were involved in the cytotoxicity against tumor cells and their anti-tumor activity was significantly reduced in tumorbearing mice. TGF-b also inhibited the anti-tumor activity of NK and CD8 + T cells. The immune suppression was completely reversed by IL-12 treatment and partially recovered by anti-TGF-b antibody. Both IL-12 gene therapy and recombinant protein therapy are effective against PTC. Given that the immune response is significantly suppressed in tumor-bearing mice and can be restored by IL12, the current study supports the application of IL-12 as an adjuvant therapy for thyroid cancer

WEDNESDAY, OCTOBER 21, 2015

Oral 456 Thyroid Cancer Wednesday Oral Basic 5:15 PM MURINE FOLLICULAR THYROID TUMORS RECRUIT A TUMOR MICROENVIRONMENT ENRICHED WITH MYELOID AND LYMPHOID DERIVED IMMUNE CELLS L. Jolly1, N. Massoll2, A.T. Franco1 1 Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR; 2Pathology, University of Arkansas for Medical Sciences, Little Rock, AR The tumor microenvironment (TME) is comprised of many cell types, including immune-derived cells, which promote tumorigenesis in a variety of solid malignancies. However, the role of immune-derived cells in thyroid cancer progression remains largely unexplored. The objective of this study was to identify the cell types recruited to the thyroid TME a murine model of FTC that progresses to PDTC (HrasG12V/Pten-/-/TPO-Cre). Single cell suspensions of HrasG12V/Pten-/-/TPO-Cre thyroid tumors or wildtype thyroids were prepared, incubated with immune cell marker antibodies, and analyzed via FACS in order to identify populations of tumor associated immune cells. Cytokine profiles from tumor cells were also determined. FACS analysis revealed that HrasG12V/Pten-/-/TPO-Cre thyroid tumors were comprised of 68.5 – 11.79% CD45 + (immune) cells, compared to only 17.6% in wildtype thyroids. We further defined the immune compartment of thyroid tumors and found that 53.1 – 10.9% of CD45 + cells were myeloid-derived. Within this myeloid compartment, 60.1 – 16.8% of the cells were identified as non-classical macrophages and 19 – 7.6% as myeloid-derived suppressor cells, suggesting an immunosuppressive TME. We next evaluated whether T cells were recruited to the TME of HrasG12V/Pten-/-/TPO-Cre tumors. Of all T cells, 0.2% were identified as cytotoxic T-cells, whereas 54.7% were identified as CD4 + T cells. 73.9% of CD4 + T cells were also positive for CD25, which is indicative of an immune suppressive regulatory T cell phenotype. Cytokine analysis of conditioned medium revealed increased secretion of SDF-1, I-TAC, CCL2, and MCSF in stable tumor cell lines derived from HrasG12V/ Pten-/-/TPO-Cre thyroid tumors, which may provide a mechanism by which immune cells are recruited to the TME. We also report increased secretion of KC, the murine homolog of IL-8, which is also increased in the serum of thyroid cancer patients. We propose that Hras-driven murine thyroid tumors recruit an immune suppressive TME. We hypothesize this tumor-promoting TME allows the progression of FTC to PDTC. Modulation and therapeutic strategies directed towards this TME may provide novel therapeutic opportunities for the treatment of Ras-driven thyroid cancers.

Oral 457 Disorders of Thyroid Function Wednesday Oral Clinical 4:30 PM THYROID FUNCTION AND SUDDEN CARDIAC DEATH: A POPULATION-BASED COHORT STUDY L. Chaker2,1, M. van den Berg3, M. Eijgelsheim2, A. Hofman3, B. Stricker3, R. Peeters1,2 1 Thyroid Center, Erasmus Medical Center, Rotterdam, Netherlands; 2 Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands; 3Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands The association between thyroid function and several cardiovascular disease has clearly been established, but no studies to date have assessed the relation with sudden cardiac death (SCD). Therefore we aimed to determine the association between thyroid function and SCD.

WEDNESDAY, OCTOBER 21, 2015

A-183 Center of Drug Research, Pharmaceutical Biotechnology, LudwigMaximilians-University, Munich, Germany

Participants ‡ 45 years from the Rotterdam Study with thyroxinestimulating hormone or free T4 (FT4) measurement were eligible. We conducted age- and sex-adjusted Cox-models for the association of TSH and FT4 with the risk of SCD, in all subjects and also restricting to euthyroid subjects (defined by TSH 0.4-4.0 mIU/L). Multivariable analyses additionally adjusted for heart rate and several cardiovascular risk factors. We stratified by age and sex and performed sensitivity analyses restricting to witnessed SCDs and subjects with normal FT4 (11-25 pmol/L). Absolute risks were calculated in a competing risk model by taking death by other causes into account. We included 10,318 participants with median follow-up of 9.1 years (interquartile range 3.8–11.1) and 261 incident SCD events. In the multivariable analyses, the highest tertile of FT4 had a higher risk of SCD in the full range (HR 1.35, 95% CI, 1.01–1.83) and normal range thyroid function (HR, 1.40, 95% CI, 1.02–1.95), compared to the reference. Stratification by age or sex and sensitivity analyses did not alter risk estimates. Absolute 10-year risks increased with increasing FT4 levels from 1% to almost 4% in euthyroid participants, within the normal range of FT4. Higher FT4 levels are associated with increased relative and absolute risks of SCD, even in euthyroid subjects. FT4 levels might be used for risk stratification in the general population, but the additional benefit of adding thyroid function to prediction models or screening modules for SCD still has to be determined.

Oral 458 Iodine Uptake & Metabolism Wednesday Oral Translational 4:45 PM SYSTEMIC NON-VIRAL CMET/HGFR-TARGETED GENE DELIVERY USING THE THERANOSTIC FUNCTION OF THE SODIUM IODIDE SYMPORTER (NIS) S. Hacker1, S. Morys3, A.K. Levacic3, C. Schug1, N. Schwenk1, J. Carlsen2, C. Zach2, E. Wagner3, C. Spitzweg1 1 Department of Internal Medicine II, University Hospital of Munich, Munich, Germany; 2Department of Nuclear Medicine, University Hospital of Munich, Munich, Germany; 3Department of Pharmacy,

The sodium iodide symporter (NIS) in its role as well characterized reporter and therapy gene represents an outstanding tool to target different cancer types allowing non-invasive imaging of functional NIS expression by 123I-scintigraphy and therapeutic application of radioiodine. Based on its overexpression on the surface of the vast majority of cancer types, the cMET/HGF-receptor serves as an ideal target for tumor-selective targeting of gene delivery vehicles using a cMET-receptor binding peptide (cMBP) as ligand. In the current study, we used sequence defined polymers as nonviral gene delivery vehicles comprising polyethylene glycol (PEG) and cationic (oligoethanoamino) amide cores coupled with a cMBP to target the cMET/HGF-receptor in a human hepatocellular cancer (HuH7) mouse model. These polymers were complexed with human NIS-DNA (polyplexes) and were tested for transduction efficiency and receptor-specificity in vitro and in vivo. Flow cytometry revealed high (90%) cell surface cMET-expression on HuH7 cells. In vitro iodide uptake studies demonstrated high transduction efficiency and cMET-specificity of polyplexes coupled with cMBP (cMBP-polymer/NIS) compared to polyplexes without ligand (alanin-polymer/NIS). Based on these results, we used a HuH7 xenograft mouse model to investigate tumor recruitment and biodistribution of cMBP-polymer/NIS. 123I-scintigraphy 48h after intravenous polyplex application showed high tumor-selective iodine accumulation (5–9% ID/g 123I, biological half-life of 3,1 h), while injection of control vectors did not result in specific iodine uptake. Tumor-selective NIS transgene expression after c-METtargeted NIS gene delivery was also confirmed by typical clusters of NIS-specific immunoreactivity in the tumors, while non-target organs were NIS negative. In conclusion, our data demonstrate the great potential of cMETtargeted sequence-defined polymers for tumor-selective NIS gene delivery as elegant tool for tumor-specific radioiodine therapy of cMET expressing tumors

Oral 459 Thyroid Hormone Action Wednesday Oral Translational 5:00 PM DIVERSE GENOTYPES AND PHENOTYPES OF T3 RECEPTOR TRa MUTATIONS A.V. Gucht1, K. Demir2, M. Meima1, D. Chrysis3, E. Visser1, E. Levtchenko4, P. van Trotsenburg5, T. Visser1, R. Peeters1 1 Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands; 2Division of Pediatric Endocrinology, Dr. Behcet Uz Children’s Hospital, Izmir, Turkey; 3 Department of Pediatric Endocrinology, University of Patras Medical School, Patras, Greece; 4Department of Pediatric Nephrology, University Hospital Leuven, Leuven, Belgium; 5 Department of Pediatric Endocrinology, Emma Children’s Hospital, Academic Medical Center Amsterdam, Amsterdam, Netherlands Recently, TRa1 mutations have been identified in patients with the socalled RTHa syndrome, characterized by growth retardation, variable motor and cognitive defects, macrocephaly, and abnormal thyroid function tests. So far, 9 families have been described with TRa1 mutations. We hypothesized that the phenotype of the different TRa mutations correlates with the effect of the mutations on receptor function. Our objective was to identify additional RTHa patients and to evaluate the consequences of the novel TRa mutations together with the effect of LT4 treatment. Patients were assessed clinically and biochemically before and during L-T4 treatment. In addition, we studied the influence of the

A-184 mutations using cells co-transfected with wild-type and/or mutant TRa1 and a TR-dependent promoter-reporter construct. In addition to the previously described F397fs406X mutation (P1) we identified 5 novel mutations: C380fs387X (P2), D211G (P3), A263S (P4), R384H (P5), G207E (P6). All six mutations are located in the ligand binding domain (LBD) of TRa1. The localization pattern is similar to that of mutations in TRb in patients with RTHb, which appear in three clusters within the LBD of TRb. All patients had low serum (F)T4 and rT3, increased T3 and normal TSH levels. The patients also shared common characteristics comprising growth retardation and a delayed motor and mental development; however, the severity varied from mild (mutations D211G, A263S, R384H, G207E) to severe (mutations F397fs406X, C380fs387X). In 2 of the 3 patients evaluated, LT4 treatment appeared to have beneficial effects on growth and motor development. In addition, the effect of the mutation on the T3 sensitivity of the receptor varied from reduced (mutations D211G, A263S, R384H, G207E) to completely abolished (mutations F397fs406X, C380fs387X). We identified 5 novel mutations in TRa1, resulting in RTHa phenotypes with varying degrees of severity. Noteworthy, the severity of the clinical phenotype appears to be associated with the type and localization of the mutation in TRa. RTHa patients with mild mutations, especially when diagnosed at a young age, seem to benefit from LT4 treatment.

Oral 460 Thyroid Nodules & Goiter Wednesday Oral Clinical 5:15 PM RADIOFREQUENCY VERSUS ETHANOL ABLATION FOR TREATING PREDOMINANTLY CYSTIC THYROID NODULES: A RANDOMIZED CLINICAL TRIAL H. Park, J. Baek, Y. choi, J. Lee Radiology, Asan Medical Center, Seoul, Korea (the Republic of) Although radiofrequency ablation (RFA) appears to be superior to ethanol ablation (EA) for treating predominantly cystic thyroid nodules (PTCNs) in previous retrospective studies, the best treatment modality for PCTNs is still unclear because there does not appear to have been any study comparing the abilities of the two modalities.Therefore, the purpose of our study was to compare single-session RFA and EA for treating PCTNs primarily regarding tumor volume reduction. This single-blind, randomized trial was approved by the Institutional Review Board of two centers and informed consent was obtained from all patients before enrollment. Fifty patients with a single PCTN were randomly assigned to be treated by either RFA (25 patients) or EA (25 patients) from two hospitals. The primary outcome was the tumor volume reduction ratio (%) at the sixmonth follow-up; the superiority margin was chosen as 13% (RFA minus EA). Analysis was performed primarily in intention-to-treat

WEDNESDAY, OCTOBER 21, 2015 manner. The secondary outcomes were therapeutic success rate, improvement of symptomatic and cosmetic problems, and the number of major complications. The analysis was performed in an intention-to-treat manner. The mean volume reduction was 87.5% – 11.5 for RFA (n = 22) and 82.4% – 28.6 for EA (n = 24) (P = .710; mean difference [95% CI], 5.1% [ - 8.0 to 18.2]), indicating no significant difference. Regarding the secondary outcomes, therapeutic success (P = .490), mean symptom (P = .205) and cosmetic scores (P = .710) showed no difference. There were no major complications in both groups (P > .99). The therapeutic efficacy of RFA is not superior to that of EA; therefore, EA might be preferable as the first-line treatment for PCTNs.

Oral 461 Thyroid Cancer Wednesday Oral Translational 4:30 PM MULTI-GENE NEXT GENERATION SEQUENCING (THYROSEQ) ASSAY ON LOCALLY INVASIVE T4 WELL DIFFERENTIATED THYROID CANCER U. Duvvuri1, M. Grimes2, L. Mady1, R. Ferris1, D.G. Winger3, S. Chiosea4, R. Seethala4, M. Nikiforova4, Y. Nikiforov4 1 Otolaryngology, University of Pittsburgh, Pittsburgh, PA; 2Medicine- Endocrinology, University of Pittsburgh, Pittsburgh, PA; 3 Statistics, University of Pittsburgh, Pittsburgh, PA; 4Pathology, University of Pittsburgh, Pittsburgh, PA Locally invasive well differentiated thyroid cancer (WDTC) poses a treatment dilemma because it frequently involves the critical structures. These tumors presumably arise from smaller lesions, and gain mutations as they progress. Delineating the mutational signature of these advanced tumors may allow us to develop a prognostic gene signature than can be used to stratify smaller WDTCs in the preoperative setting. The aim of this study was to characterize the mutational landscape of T4 WDTC. We identified a cohort of T4 WDTC that did not have any histopathologic areas of anaplastic cancer or poor differentiation. All patients were treated with curative intent and had a minimum of 3 year follow-up. Pathology reports and slides were re-assessed. These tumors were subjected to molecular testing using the ThyroSeq v2.1 panel. The panel included 14 genes analyzed for point mutations and 42 types of gene fusions that occurring in thyroid cancer. In addition, 7 genes were assessed for expression in order to evaluate the cell composition of the samples. These data were then compared to Thyroseq v2.1 data obtained from a consecutive series of 102 WDTC of T1-3. Of 26 patients with T4 WDTC, successful sequencing data was obtained in 25 patients. The incidence of any molecular alteration was 96% (24/25). The most common mutation was BRAFV600E (76%). The second most frequent mutations were TERT mutations in 56% of patients: TERT C228T in 36% (9/25) and C250T in 20% (5/ 25). Interestingly, TERT/BRAFV600E co-mutations were identified in 48% (12/25). In contrast, only 4% of T1-3 tumors (5/103) demonstrated TERT/BRAFV600E co-mutations (p < 0.001). In the advanced tumor cohort, the presence of TERT/BRAFV600E comutations was associated with a statistically significant increased risk of recurrence when compared to tumors without co-mutations (58.3% vs 18.3% p = 0.04). The results of the study demonstrate that locally advanced WDTC exhibit a high rate of mutations (96%), and an unusually high rate of BRAF and TERT mutations and their combination. These data support the notion that co-existing BRAF/TERT mutations or other multiple mutations may be associated with aggressive tumor behavior.

WEDNESDAY, OCTOBER 21, 2015

Oral 462 Thyroid Cancer Wednesday Oral Clinical 4:45 PM DISCOVERY STAGE OF GENOME WIDE ASSOCIATION STUDY FOR PAPILLARY THYROID CANCER IN KOREA Y. Hwangbo1, H. Son3, S. Yang3, E. Lee2, S. Kwak1, Y. Song1, S. Moon1, S. Cho1, J. Moon1, K. Yi1, D. Park1, J. Kim3, Y. Park1 1 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea (the Republic of); 2Center for Thyroid Cancer, National Cancer Center, Goyang-si, Korea (the Republic of); 3Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea (the Republic of) Genome-wide association studies (GWAS) are widely used in human genetics to identify genes associated with various cancers. Several susceptibility loci of differentiated thyroid cancer were identified in previous GWAS (FOXE1, NKX2-1/MBIP, DIRC3, NRG1). We conducted discovery stage of GWAS for papillary thyroid cancer (PTC) in Korea. One-stage case-control GWAS on PTC was performed in Korean population of 415 cases and 8,842 controls. About 3.58 million genotyped or imputed markers were evaluated to identify putative genetic variants associated PTC after adjusting age and sex. Case-control comparisons identified 26 candidate association signals at P < 1.5 x 10 - 5. Most strong association was observed at 1p21.2 in 87kb 3’ of LPPR4. Remained 25 associations included previously identified locus; FOXE2 and NRG1. Lead SNPs in NKX2-1/MBIP and DIRC3 showed borderline associations with P = 1.6 · 10 - 4. We also found signals with borderline significance (P < 5 · 10 - 4) located intron of TSHR and INSR, which are known genes involved in growth of thyroid cancer. We find candidate susceptibility loci for PTC in one-stage GWAS, and replication study are needed to confirm these associations in independent populations.

Oral 463 Thyroid Cancer Wednesday Oral Translational 5:00 PM PROGRAMMED DEATH LIGAND 1 EXPRESSION CORRELATES WITH AGGRESSIVE METASTATIC PAPILLARY THYROID CARCINOMA R. Ralhan1,2, S. Chowdhury1, J. Veyhl1, A. Alenzi 1, C. MacMillan1,3, P.G. Walfish1 1 Endocrine Division, Department of Medicine, Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Toronto, ON, Canada; 2Department of Otolaryngology, University of Toronto, Toronto, ON, Canada; 3Department of Pathology, University of Toronto, Toronto, ON, Canada Overexpression of programmed death ligand 1(PD-L1) on tumor cells is associated with poor prognosis in some human cancers and is correlated with the response to anti- PD-1 / PD-L1 drugs. The aim of this study was to evaluate PD-L1 expression in papillary thyroid carcinoma (PTC) with varying aggressiveness and correlate with clinical outcome to determine whether PD-L1 represents a therapeutic target in refractory aggressive or metastatic PTC that could be amenable to checkpoint blockade immunotherapy. In a retrospective study approved by the Mount Sinai Hospital Research Ethics Board, immunohistochemical analysis of PD-L1 was carried out in fifty PTCs of varying aggressiveness using formalin fixed and paraffin embedded tissue sections, a rabbit monoclonal anti PDL-1 antibody (E1L3N)XP, (Cell Signalling Technologies, Cat-13684), Vectastain Elite ABC Reagent and diaminobenzidine, and counterstained with hematoxylin. The immunostaining was scored in the subcellular compartments -

A-185 plasma membrane and cytoplasm of tumor cells and tumor microenvironment based on percentage of stained cells and staining intensity. The protein expression was correlated with available relevant long term clinical data and disease outcome. Results/Discussion. Kaplan Meier analysis showed that patients with PD-L1 membrane positive tumor cells had significantly shorter median disease free survival (DFS = 9.75 months) as compared to those with PD-L1 negative tumor cells (DFS = 166.5 months; p < 0.001); PD-L1 immunopositivity in tumor infiltrating lymphocytes also correlated with reduced DFS (33months, p = 0.023). The patients with both PD-L1 positive tumor cells and microenvironment had shorter DFS of 33.9 months as compared to those with no detectable expression (166.5 months, p = 0.017). Our findings suggest that PD-L1 expression in tumor cells and adjacent microenvironment correlates with aggressive metastatic PTC and shortened survival and could justify the potential application of anti PD-1/PD-L1 immunotherapy for such refractory patients.

Oral 464 Thyroid Cancer Wednesday Oral Clinical 5:15 PM TERT PROMOTER MUTATION MAY BENEFIT TO THE HIGH RISK PATIENTS OF DIFFERENTIATED THYROID CANCER FOR THE PREDICTION OF MORTALITY AND RECURRENCE Y. Song1, J. Lim1,2, K. Jung1,3, Y. Hwangbo1, S. Moon1, J. Moon1,4, D. Park1, Y. Park1 1 Seoul National University College of Medicine, Seoul, Korea (the Republic of); 2National Medical Center, Seoul, Korea (the Republic of); 3Eulji University Hospital, Seoul, Korea (the Republic of); 4 Seoul National University Bundang Hospital, Seoul, Korea (the Republic of) The impact of TERT promoter mutation on poor outcomes in thyroid cancer has recently described. It is important to define which subset of patients with differentiated thyroid cancer (DTC) could be benefit from the TERT promoter mutation test for the prognostication clinically applicable. A total of 551 patients with DTC who underwent thyroidectomy between 1993 and 2012 in Seoul National University Hospital were included. Median follow-up duration was 4.8 years (interquartile range 3.4 to 10.6 years). The overall prevalence of TERT promoter mutation was 4.5%. This mutation was found more frequently in patients with the tumors harboring BRAF or RAS mutation (4.8% or 11.3%, respectively) or in the high-risk patients defined by the ATA high-risk group or the TNM stage III-IV group (9.1% or 12.9%, respectively). Coexistence of TERT mutation in the BRAF or RAS mutated-tumors conferred an incremental impact on recurrence or mortality as well as several aggressive clinicopathologic features. Moreover, even after adjustment of clinicopathologic cofactors, the presence of TERT promoter mutations significantly increased the risk of both recurrence and thyroid cancer-specific mortality among the ATA high-risk group (for recurrence, hazard ratio [HR], 4.90; 95% confidence interval [CI], 1.84 - 13.05; P = .001; for mortality, HR, 17.52; 95% CI, 2.11 145.52; P = .008) or among the TNM stage III-IV group (for recurrence, HR 3.18, 95% CI 1.12 - 9.06; P = .030, for mortality, HR, 9.50, 95% CI, 2.15 - 41.86; P = .003). TERT promoter mutation test strengthened the prognostic predictability of the ATA or TNM staging system, as well as those of BRAF or RAS mutation. Thus, it could benefit to DTC patients for the prediction of mortality and recurrence, especially for the high risk patients.

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Short Oral Communication 465 Autoimmunity Wednesday Short Oral Communication Basic 4:00 PM POSSIBLE ROLE FOR THYROTROPIN RECEPTOR VARIANT (TSHRV) AS A BINDING PROTEIN FOR TSHR LIGANDS IN GRAVES’ ORBITOPATHY (GO)? L. Zhang1, M. Draman1, F. Grennan-Jones1, P.N. Taylor1, I. Muller1, I. Ladas1, S. Evans2, B. Skippen2, D. Morris2, C.M. Dayan1, M.E. Ludgate1 1 School Of Medicine, Cardiff University, Cardiff, United Kingdom; 2 Department of Ophthalmology, University Hospital of Wales, Cardiff, United Kingdom Thyrotropin receptor (TSHR) autoantibodies, including thyroid stimulating antibodies (TSAB) contribute to GO pathogenesis. We hypothesise that the TSHR 1-8 exon variant (TSHRV) could act as a binding protein for TSHR ligands and modulate their activity. If present in orbital fibroblasts (OF) TSHRV could participate in GO pathogenesis. We studied expression of full length (TSHR) and variant (TSHRV) in primary human orbital fibroblasts (OF) from GO (n = 5) versus non-GO (n = 5) and ex vivo orbital fat tissues GO (n = 9) versus non-GO (n = 5). Transcripts were measured by QPCR in ex vivo samples and OF in basal conditions (D0) and following adipogenic differentiation (D15). Western blot analysis was performed using an antibody specific for TSHRV. To assess TSHRV function, cAMP induced by TSH 5mu/ml or monoclonal TSAB (M22) 0.2ng/ ul was measured directly in OF at different time points in adipogenesis using RIA. A luciferase bioassay (cells express TSHR and cAMP-responsive luciferase) compared responses to TSH/M22 in conditioned medium (CM) from differentiated OF or control human fibroblasts, to determine whether the TSHRV is secreted as a binding protein for TSHR ligands such as TSH or TSAB. After differentiation, TSHRV levels in OF from GO were significantly higher than non-GO (p = 0.039). Ex vivo analysis of fat samples (TSHR/TSHRV) did not show any differential expression between GO and Normal. TSHRV western blot revealed a positive signal at 46kDa in lysates from both normal and GO OF. TSH/M22 induced 4-/2-fold increases in cAMP respectively in normal OF. In GO, TSH/M22 responses were substantially lower, and were inversely correlated with the ratio of TSHRV:TSHR transcripts (Spearman correlation: TSH r = - 0.55, p = 0.23, M22 r = 0.87, p = 0.03). In the bioassay, TSH/M22 induced light was lower in CM from differentiated GO OF compared to CM from normal OF, suggesting that secreted TSHRV had reduced the effects of TSH/M22. TSHRV transcripts are more abundant than full length TSHR in OF and during adipogenesis are significantly higher in GO than nonGO. TSHRV may be secreted and provide a binding protein for TSHR ligands and thus alter intracellular TSHR signalling.

Short Oral Communication 466 Autoimmunity Wednesday Short Oral Communication Basic 4:06 PM BETA1/2-ADRENERGIC AND M2R MUSCARINIC AUTOANTIBODIES AND THYROID HORMONE FACILITATE INDUCTION OF ATRIAL TACHYARRHYTHMIAS IN THE RABBIT T.A. Murphy, H. Li, X. Yu, D.C. Kem Medicine, OUHSC and OKCVAMC, Oklahoma City, OK We previously described a significant association of activating autoantibodies (AAb) in Graves’ subjects with atrial fibrillation (AF). We demonstrated these AAb facilitated ex vivo production of ectopic atrial beats capable of triggering tachyarrhythmias. We have now examined

WEDNESDAY, OCTOBER 21, 2015 the impact of combined B-adrenergic (BAR) and muscarinic (M2R) receptor activating autoantibodies (AAb) alone and with addition of thyroid hormone (T4) on induction of atrial tachyarrhythmias and AF. We have also examined the impact of AAb and T4 induced changes in the atrial substrate that facilitates establishment of AF. Seven rabbits were immunized with B1AR + M2R ECL2 peptides. After 6 weeks, they were given T4 (50 mg/kg/qod) IM for 2 weeks. Four others were treated with T4 alone. Under anesthesia,the right jugular vein was dissected and cannulated with a 4 Fr. multi-electrode catheter; and passed into the right atrium under electrographic control to record atrial potentials. Arrhythmias were induced with intra-cardiac repetitive burst pacing. Electrophysiological studies were performed on anesthetized rabbits at 0 weeks, 6 weeks postimmune and 8 weeks post-immune + T4. Five B1AR-AAb + M2R-AAb + T4 animals completed the whole study and demonstrated burst-induced sustained atrial fibrillation (AF). AF induction was blocked acutely by B1AR + M2R 2nd ECLL-aa decoy peptides. The measured effective refractory period (ERP) was decreased significantly in the post immune state, and was acutely reversed by IV decoy peptide. Thyroid hormone decreased the ERP. Decoy peptide therapy reversed the AAb impact on ERP. In a separate group of 4 animals, T4 alone facilitated induction of sinus and junctional tachycardias but not AF. This study demonstrates B1AR + M2R-AAb and T4 lower ERP, an index of atrial substrate susceptibility to induction of tachyarrhythmias in additive fashion. Both AAbs and T4 potentiate the vulnerability of the heart to atrial tachyarrhythmias. AAb related tachyarrhythmia induction notably was blocked by decoy peptide therapy despite continued hyperthyroidism. This study has established a model of thyroid + AAb-associated AF and helps fulfill Witebsky’s postulates for an autoimmune-associated disease.

Short Oral Communication 467 Autoimmunity Wednesday Short Oral Communication 4:12 PM THE STUDY OF THE CHANGES AND MECHANISMS OF MICRORNA-326 IN IODINE-INDUCED AUTOIMMUNE THYRODITIS MODEL OF NODH-2H4 MICE L. yu-shu, Z. Hong-jin, Z. Shan Endocrinology and Metabolism, The First Affiliated Hospital of China Medical University, Shenyang, China The abnormals of cellular immunity is a significant part of Autoimmune thyroiditis (AIT). As an important member of microRNAs, microRNA-326 take part in the progress and development of the disease by regulate cellular immune responses. The main aim of our study is to investigate the temporal and spatial distribution of microRNA-326, the dynamic changes of Th1/Th2/Th17 cell in NOD$H-2h4 mice with iodine-induced AIT, analyze the relationship between them. Explore the potential effect and mechanism of microRNA-326 on iodine induced AIT. The mice were divided into control and iodine-treated (HI) groups. The percentage of Th1, Th2, Th17 cells in splenic mononuclear cells were observed after the mice were sacrificed. The expression of cytokines IFN-c, IL-4, IL-17a and microRNA-326 in spleen were measured by RT-PCR. Polarized Th17 cells were divided into microRNA-326 inhibition group, miRNA-326 transfection control group, the blank group. The percentage of Th17 cells, the expression of microRNA-326, Ets-1, IL-17a were also measured. Number of Th17 cells, the expression of IFN-c mRNA, IL-17 mRNA and microRNA-326 in spleen of HI group were higher than in control group after feeding NaI solution for 8 weeks; the number of Th2 cells, expression of Ets-1 protein had the same change after feeding NaI solution for 12 weeks. There were positive relationships between the expression of miR-326 and the titers of serum TgAb, the level of IFN-c

WEDNESDAY, OCTOBER 21, 2015 mRNA and IL-17a mRNA expression, respectively. In spleen of HI group, there were negative relationships between the protein expression of Ets-1 and the expression of IL-17a mRNA, the expression of miR-326. The expression of Ets-1 protein in miRNA-326 inhibitor group increased significantly compared with that of negative control group and blank control group; There was no significant difference between miRNA-326 inhibitor group and negative control group, blank control group in the level of IL-17a, Th17 cells account. MicroRNA-326 may inhibit the expression of Ets-1,and then play an important role in the occurrence and development of autoimmune thyroiditis finally.

Short Oral Communication 468 Autoimmunity Wednesday Short Oral Communication Basic 4:18 PM THE EXPRESSION OF FCcRIIB ON B CELLS IN PATIENTS WITH HASHIMOTO’S THYROIDITIS Y. Liu, Y. Gong, R. You, Y. Zhang, N. Yu, C. Qu, Y. Huang, H. Zhang, G. Lu, Y. Gao, Y. Gao, X. Guo Peking University First Hospital, Beijing, China Thyroglobulin antibody and anti-thyroid peroxidase antibody are diagnostic hallmarks of Hashimoto’s thyroiditis (HT), and they are produced by terminal B cells. The activation of B cells is regulated by inhibitory receptor FccR II B. The aim of our study was to investigate the expression levels of FccR II B in patients with HT, and the regulated factors for FccR II B expression on B cells were also studied. Blood samples from 56 newly diagnosed HT patients and 21 healthy control subjects were collected. 100ul of whole blood was stained with relevant antibodies, the percentage of B cell subsets as well as the levels of FccR II B was analyzed by flow cytometry. Peripheral blood mononuclear cells were isolated and cultured with CD40 antibody (a-CD40), a-Igs F(ab’)2(a-Ig)and IL-4 for 48 hours, then FccR II B was tested by flow cytometry. The percentage of CD27-IgD-IgM- B cells and plasma cells from HT patients was significantly higher than that of healthy donors (P < 0.05). The mean fluorescence intensity (MFI) levels of FccR II B on CD27-IgD-IgM- / CD27 + IgD-IgM- / CD27 + IgD + IgM + B cells and plasmablasts from HT patients were significantly lower than those of healthy donors (P < 0.05). With a-Ig or(and) IL-4 treatment, a-CD40 significantly decreased the MFI levels of FccR II B on CD27-IgD + IgM + / CD27-IgD-IgM- / CD27 + IgD + IgM + / 27 + IgD-IgM- B cells, plasmablasts and plasma cells (P < 0.05, respectively), along with the reduced percentage of FccR II B on CD27-IgD + IgM + / CD27-IgD-IgM- / CD27 + IgD + IgM + / CD27 + IgD-IgM- B cells (P < 0.05, respectively).

A-187 The percentages of B cell subsets were different between HT and healthy groups. The down-regulation of FccR II B was mediated by a-CD40 and was potentiated by a-Ig and IL-4. It indicated that FccR II B on B cells might be involved in the pathogenesis of HT.

Short Oral Communication 469 Autoimmunity Wednesday Short Oral Communication Basic 4:24 PM SPHK1/S1P/S1PR1 AXIS MAY ACT AS NOVEL THERAPEUTIC TARGET FOR AUTOIMMUNE THYROIDITIS C. Han, X. Xia, X. Shi, Z. Shan, W. Teng Department of Endocrinology and Metabolism, The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases,The First Hospital of China Medical University, Shenyang, China Sphingosine-1-phosphate(S1P) is a pleiotropic bioactive sphingolipid metabolite that is formed intracellularly via SphK1 and SphK2, two closely related sphingosine kinases. There is growing evidence that S1P is involved in inflammations and autoimmune diseases. Although FTY720, one of the most effective S1P receptor 1 (S1PR1) antagonists, has been identified clinically for certain autoimmune diseases, but the relationship between S1P and autoimmune thyroiditis has not been well investigated. 1. The expressions of SphK1 and SphK1 in thyroid tissue were measured by WB and IHC in Hashimoto Thyroiditis (HT) patients and normal controls (NC). In addition, SphK1 and SphK1 expressions were also measured in spontaneous autoimmune thyroiditis (SAT) NOD.H2h4 mice and control (CON)mice 2.The content of S1P was measured by HPLC/MS in human and mice thyroid tissue and serum; 3.The molecular mechanism of S1P stimulate primary cultured CD4 + T cells of NOD.H2h4 mice was investigated; 4.The severity of SAT was measured in FTY720 treated mice. 1. Sphk1 had higher expression in HT patients and SAT mice than NC and CON mice groups. 2. The concentration of S1P was higher in both thyroid tissue and serum of HT patients and SAT mice when compared to control groups. 3. S1P mediates Tyr-705 phosphorylation of STAT3 via S1PR1, through up-regulation of JAK2 tyrosine kinase activity; moreover, S1P mediates Ser-727 phosphorylation of STAT3 by up-regulating AKT and mTOR activities. 4. FTY720 ameliorates the severity of thyroiditis in SAT mice significantly. FTY720 treatment decreases the degree of phosphorylation of STAT3 (Tyr-705 and Ser727) in CD4 + T cells. Th1, Th17 and Tfh differentiation was reduced in SAT mice after FTY720 treatments were administered. S1P was elevated in autoimmune thyroiditis via highly expressed Sphk1. FTY720 reduced the phosphorylated STAT3, which could be stimulated by the elevated S1P in CD4 + T cells. FTY720 ameliorated the severity of thyroiditis in NOD.H2h4 mice by reducing the activity of STAT3 via S1PR1.In together, Sphk1/S1P/S1PR1 may be a promising therapeutic target for autoimmune thyroiditis.

Short Oral Communication 470 Thyroid Nodules & Goiter Wednesday Short Oral Communication 4:00 PM DO THE RECENT AMERICAN THYROID ASSOCIATION GUIDELINES ACCURATELY GUIDE THE BIOPSY ACCORDING TO THE NODULE SIZE? A RETROSPECTIVE REVIEW M. Anwar1, M. Alshehri1, F. Murad1, Z. Al-Qurayshi1, T. Mallik2, T. Thethi1, E. Kandil1 1 Surgery, Tulane University School of Medicine, New Orleans, LA; 2 Ochsner Medical Center, New Orleans, LA

A-188 The risk of malignancy in smaller thyroid nodules has sparked a widespread argument among clinicians for the need of biopsy in subcentimeter nodules. However the role of nodule size to determine the prognosis and outcomes in thyroid cancer patients remains questionable. In this study, we tried to determine whether the nodule size can serve as an indicator for performing cytologic evaluation according to recent American Thyroid Association (ATA) guidelines. A retrospective review was done of all the patients with thyroid nodules who presented to a single surgeon over 6 years. Data on patients’ demographics, nodule size, ultrasonographic features, and histopathologic findings of operative specimens was collected. Each patient with malignant pathology was risk-stratified using ATA risk score for a recurrent disease and MACIS score for prognostic outcomes. We identified 912 thyroid nodules of which 154 (16.9 %) were malignant and 758 (83.1 %) were benign. According to the ATA risk score, 114 (74%) had low risk, 31 (20%) had intermediate risk, and 8 (5.2%) had high risk of recurrence. There was no difference in prognosis according to the MACIS score and disease recurrence as per the ATA risk score for patients with £1 cm vs. >1 cm nodules (P = 0.76 and 0.72 respectively). The ATA (intermediate + high) risk of recurrence (adjusted for gender) was not significantly higher in nodules >1cm than £1 cm (OR 1.32; 95% CI 0.33, 5.20. P = 0.69). In the 13 malignant cases with nodule size £1 cm; 2 had extrathyroid extension, 2 had capsular invasion, 5 had lymphovascular invasion, and 6 had positive BRAF mutation (P > 0.05). Calcifications on ultrasound and certain histopathologic features like extrathyroid extension, capsular & lymphovascular invasion, aggressive histology, BRAF mutation, and positive surgical margins were associated with high risk of disease recurrence and of a poor prognosis. Thyroid nodules with extrathyroid extension, aggressive histology, positive surgical margins, capsular or lymphovascular invasion are associated with poor outcomes and increased risk of recurrence. Recent ATA recommendations to follow smaller nodules without cytologic evaluation may not be justified in the light of identical outcomes and disease recurrence risk as for larger nodules. However, additional prospective studies are warranted for further investigations.

Short Oral Communication 471 Disorders of Thyroid Function Wednesday Short Oral Communication 4:06 PM EFFECTIVENESS OF LEVOTHYROXINE THERAPY TARGETING A THYROTROPIN LEVEL LOWER THAN 2.5 MU/ L DURING THE FIRST TRIMESTER IN PREVENTING MISCARRIAGE: A PROSPECTIVE STUDY AT A SINGLE INSTITUTION S. Kobayashi1,2, J.Y. Noh2, N. Watanabe2, A. Yoshihara2, I. kurihara1, K. Ito2, H. Itoh1 1 Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; 2Ito Hospital, Shibuya-ku, Japan The American Thyroid Association 2011 guidelines recommend initiating levothyroxine therapy in subclinical hypothyroidism patients to achieve a thyrotropin level of lower than 2.5 mIU/l in the first trimester and lower than 3.0 mIU/l in the second and the third trimesters. However, the outcome of pregnancy when the thyrotropin levels are controlled in this manner have not been reported in the Japanese population. We enrolled the patients with thyroid diseases, excluding those with Graves’ disease who were taking anti-thyroid drug or potassium iodide, when they are pregnant. Levothyroxine therapy was intiated or the dose of levothyroxine was adjusted to achieve a thyrotropin level lower than 2.5 mIU/l in the first trimester and lower than 3.0 mIU/l in the second and the third trimesters, each time the patient visited the hospital.

WEDNESDAY, OCTOBER 21, 2015 The pregnancy outcomes of 420 patients who visited the hospital during the first trimester were analyzed. The median patient age was 34 years (range, 21–46 years). Forty-eight percent of patients were diagnosed with Hashimoto’s disease; 17.9%, with TgAb or TPOAb negativity and/or thyroid nodules;16.2%, with Graves’ disease in remission; 11.6%, with Graves’ disease with radioiodine therapy or surgery; 7.4%, with thyroid tumor after surgery; 0.7%, with TSBAbpositive hypothyroidism. The pregnancy outcomes were as follows: miscarriage 14.3%, preterm delivery 5.7%, postterm delivery 0.2%, perinatal mortality 0.2%, and full-term birth 79.5%. In total, 82 patients visited the hospital twice until 10 weeks of pregnancy. The rate of miscarriage rate did not differ between patients with thyrotropin levels lower than 2.5 mIU/l at the first visit (median gestational age 3.6 weeks (3–6.7 weeks)) and patients with thyrotropin levels of 2.5 mIU/l or higher (8.0% vs 12.3%, p = 0.7152). The rate of miscarriage was significantly lower in patients with thyrotropin levels lower than 2.5 mIU/l at the second visit (median gestational age, 8 weeks (6.1– 9.9 weeks)) than in patients with thyrotropin levels of 2.5 mIU/l or higher (6.1% vs 31.3%, p = 0.0121). Intensive levothyroxine therapy to achieve thyrotropin levels lower than 2.5 mU/l during first trimester is effective in prevention of miscarriage.

Short Oral Communication 472 Disorders of Thyroid Function Wednesday Short Oral Communication Clinical 4:12 PM LONGITUDINAL EVALUATION OF A GERIATRIC POPULATION - RELATIONSHIP BETWEEN DEPRESSIVE SYMPTOMS AND SUBCLINICAL HYPOTHYROIDISM DEFINED BY AGE-ADJUSTED CRITERIA FOR SERUM TSH L.B. Teixeira1, M.L. Nascimento1, M. Aroeira1, D.S. Chachamovitz1, M. Vaisman1, C. Paixa˜o Junior2, P.F. Teixeira1 1 UFRJ, Rio de Janeiro, Brazil; 2UERJ, Rio de Janeiro, Brazil Aging is associated with increases in serum TSH. The association between Subclinical Hypothyroidism (SCH) and depressive symptoms in the elderly subjects has not been proved in several studies. However, until now, none applied age-specific reference range to determine the upper limit of serum TSH, in order to adequately classify SCH in such population. The present study aimed to evaluate the association between SCH (considering specific TSH cutoff for age) and depressive symptoms (DS) in the geriatric population monitored in specific outpatient clinic of a tertiary hospital. This was an observational longitudinal study, in which assessments of patients ( ‡ 65 years old) were performed at baseline and after 12 to 24 months of follow-up. In both instances the subjects were evaluated with: Clinic interview, chart review and measurements of serum thyrotropin (TSH) and FT4. Geriatric Depression Scale (GDS) of 15 items was used in those with score of the Mini Mental State Examination (MMSE) ‡ 13 and the Cornell Scale for those with MMSE 5.8 mUI/L for individuals aged 65-79 years and >6.7 mUI/L for those aged ‡ 80 years). Two hundred forty nine patients were evaluated. Improvement of DS tended to occur more frequently in patients that developed SCH throughout the time (62.5% vs 31.5%; p = 0.07). Furthermore, the presence of SCH was independently associated with improvement of DS in multivariate analysis (p = 0.04; OR: 7.30 [1.06 to 50.13]) adjusted by diabetes, smoke habitus, periphery arterial disease, age >85yo, stroke, acute myocardial infarct, loss cognition, excess pharmacy use, reduced functionality, fall syndrome and anti depressive use. Baseline serum FT4 was positively associated with variations in Cornell scale (rs = + 0.331;p = 0.04) and the incident depressive syndrome (independent from scale) was associated with

WEDNESDAY, OCTOBER 21, 2015 higher overall levels of FT4 at the end of study (1.12 vs 1.09; p = 0.02). It was concluded that the presence of SCH, defined by specific levels of TSH for age, had a favorable impact in depressive symptoms of elderly patients. Furthermore, serum FT4 had a negative impact in different studied outcomes related to DS.

Short Oral Communication 473 Disorders of Thyroid Function Wednesday Short Oral Communication Clinical 4:18 PM BIOCHEMICAL PARAMETERS IN A SUBGROUP REQUIRING T4 PLUS T3 REPLACEMENT TO REVERSE SYMPTOMS OF HYPOTHYROIDISM G.M. Pepper1,2, P. Casanova1,2, K. Reynolds1,2 1 University of Miami, Jupiter, FL; 2Palm Beach Diabetes and Endocrinology, Jupiter, FL Individuals with hypothyroidism may report persistent symptoms typical of thyroid hormone deficiency despite peripheral thyroid hormone levels in the normal range. One possible explanation proposed by Bianco et al is tissue specific variation in deiodinase conversion of levothyroxine (LT4) to triiodothyronine (T3) resulting in normalization of TSH levels before peripheral T3 levels are optimized. To investigate this we analyzed thyroid functions of hypothyroid patients with satisfactory and unsatisfactory clinical responses to LT4. Those in the latter group also achieved substantial clinical benefit after conversion to a product containing LT4 and T3 (Armour Thyroid). We retrospectively reviewed T4, T3 and TSH levels in three groups of adults; 1. Good responders (GR); clinically euthyroid on LT4, N = 67. 2. Poor responders (PR), persistent symptoms of hypothyroidism on LT4 who reported substantial improvement after conversion to Armour Thyroid, N = 57. 3. Normal controls (NC), N = 54 Tukey-Kramer’s test indicated mean T4/T3 ratio significantly greater in GR (10.3 – 1.9) than PR (9.3 – 2.5) and NC (8.5 – 2.0); p < 0.01. T3 levels were significantly higher in PR (1.0 – 0.25 ng/dl) than GR (0.87 – 0.18 ng/dl) and NC (0.9 – 0.17 ng/dl), p < 0.01. LT4 levels were similar in PR (9.0 – 1.8 ng/dl) and GR (8.8 – 1.6 ng/dl) but both significantly higher than NC, p < 0.01. TSH levels were significantly lower in PR (1.09 – 1.16 lIU/mL) than NC (1.52 – 0.75 lIU/ mL), P < 0.01 but no different than GR (1.23 – 0.74 lIU/mL) Peripheral T3 levels in PR would be expected to be lower than GR if tissue specific variation in deiodinase activity was the explanation of poor clinical response to LT4 replacement in primary hypothyroidism. Here, T3 levels in PR were higher than GR while TSH levels were similar. An alternate explanation for these findings would be relative T3 resistance in PR.

Short Oral Communication 474 Disorders of Thyroid Function Wednesday Short Oral Communication Clinical 4:24 PM QUICK VISION IMPROVEMENT OF SEVERE GRAVES’ OPHTHALMOPATHY WITH A PARENTERAL PPAR-GAMMA ANTAGONIST AND COX-2 INHIBITOR - SODIUM DICLOFENAC W. Bloise, L. Y. Mimura, J. P. Moura Endocrinology, Sa˜o Paulo University, Shool of Medicine, S*so Paulo, Brazil Decrease of vision is a serious complication of Graves’ ophthalmopathy (GO), that is treated usually by massive corticosteroids or orbital decompression, with weighty adverse effects. The objective is

A-189 to report a fast and substantial improvement of vision attained by parenteral sodium diclofenac in severe GO patients. Patient findings: Five patients with severe Graves’ ophthalmopathy, with age ranging from 40 to 61 years old, 2 females, were admitted complaining of blurred vision and one almost blind accompanied by a supporter. The visual acuity was evaluated on the most affected eye by the Snellen chart at admission and 7 days after the parenteral therapy. Intramuscular 75 mg of sodium diclofenac was administered every 12 hours during 7 days, followed by oral sodium diclofenac 50 mg every 12 hours in different periods of time. After 7 days improvement of vision was reported by all patients. In 4 individuals the intial acuity vision of the most affected eye were: 0,9- 0,4-0,3-0,7(?). After 7 days were 1,0- 0,7- 0,8-0,7(?). Cataract impaired the evaluation of the increased vision of the patient with Snellen 0,7(?). The almost blind patient whose Snellen in both eyes were 0,1, remained at the Snellen level but came to the hospital by herself using the public way of locomotion and recognizing the colors. Normal vision was shown by 3 patients after the end of the treatment. One whose acuity after the first 7 days increased from 0,3 to 0,7 is not adherent to the follow-up.The almost blind individual was directed to orbital decompression but receiving oral diclofenac. No adverse effects was shown. Consent was obtained by all participant patients. Seven days of parenteral 75 mg of sodium diclofenac by intramuscular injection each 12 hours is an effective safe and less expensive option for the initial management of severe GO with impaired vision.The authors enphazise the quick and substantial improvement of vision with this target therapy. A prospective and controlled study is needed to substantied the results of this preliminary report.

Short Oral Communication 475 Thyroid Hormone Metabolism & Regulation Wednesday Short Oral Communication Basic 4:00 PM NEW INSIGHTS INTO THYROID HORMONE (TH) MECHANISM OF ACTION IN DENDRITIC CELLS (DCS): CHARACTERIZATION OF TH TRANSPORT AND METABOLISM N. Gigena1, V.A. Alamino1, M. Montesinos1, M. Nazar1, R.A. Louzada2, S.M. Wajner3, A.L. Maia3, A.M. Masini-Repiso1, D.P. Carvalho2, G.A. Cremaschi4, C.G. Pellizas1 1 Centro de Investigaciones en Bioquı´mica Clı´nica e Inmunologı´a (CIBICI-CONICET) - Facultad de Ciencias Quı´micas - Universidad Nacional de Co´rdoba, Co´rdoba, Argentina; 2Instituto de Biofı´sica Carlos Chagas Filho - Universidade Federal do Rı´o de Janeiro, Rı´o de Janeiro, Brazil; 3Hospital de Clı´nicas de Porto Alegre - Universidade Federal do Rı´o Grande do Sul, Porto Alegre, Brazil; 4Laboratorio de Neuroinmunomodulacio´n y Oncologı´a Molecular. Instituto de Investigaciones Biome´dicas (BIOMED-CONICET). Universidad Cato´lica Argentina, Buenos Aires, Argentina DCs are specialized antigen (Ag) presenting cells that induce adaptive immune responses. We reported TH receptor (TR) b1 expression in murine DCs and triiodothyronine (T3)-dependent stimulation of DC maturation and ability to develop a Th1-type response through an Akt, NF-kB and TRb1-dependent mechanism. Moreover, T3 increased DC capacity to stimulate a cytotoxic T-cell response that was exploited in a DC-based antitumor vaccination protocol. The effects of THs in target tissues are influenced by their entry into the cell (Transport) and by regulation of their intracellular levels (Metabolism). However, these events have not been characterized at DC level. Therefore, the objective of this work was to evaluate: 1) TH Transport, by: 1.a. the expression of monocarboxylates (MCT) Type 8 and 10, Organic Anion Transporter Polypeptide (OATP) 1C1,

A-190 neutral amino acid transporter (LAT) 1 and 2); 1.b. ability of DC to transport THs inside DCs; 2) TH Metabolism, by: the expression and activity of iodothyronine deiodases (D1, D2 and D3); and 3) Regulation of TH Transport and Metabolism by T3 Mice bone-marrow derived DCs were treated with T3 (5nM) for 18 h. mRNA and protein expressions were evaluated by RT/qPCR and western blot. The identity of amplified mRNAs was confirmed by Genetic Sequencing. Uptake assays using [125I-T3] or [125I-T4] were performed to evaluate TH transport. TH cellular metabolism was evaluated through D2 and D3 described enzymatic activity assays, using [125I-T4] and [125I-T3] respectively 1.a. DCs express MCT-10 and LAT-2, 1.b. THs are actively transported by DCs; 2. DCs express D2 and D3 and exhibit both enzymatic activities; and 3) Treatment of DCs with physiological levels of T3: 3.a. regulates positively the expression of MCT-10 and LAT-2, 3.b. increases TH transport into the cell, 3.c. augments the expression and activity of D3, 3.d. does not alter the expression of D2, however inhibits D2 enzymatic activity Our findings describe TH Transport and Metabolism in DC, which broaden the knowledge of TH action in DCs and the directioning of adaptive immunity. These results may also provide tools for the manipulation of desired tolerogenic/inflammatory immunity, under different pathological conditions

Short Oral Communication 476 Thyroid Hormone Metabolism & Regulation Wednesday Short Oral Communication Basic 4:06 PM EFFECT OF N-ACETYLCYSTEINE ON SERUM T3 LEVELS AND HEART FUNCTION IN A RAT MODEL OF LOW T3 SYNDROME S.M. Wajner1,2, T.E. Lehnen1,2, M.V. Santos1, A. Lima1, T. Serrano1,2, B. Schaan1,2, A.L. Maia1,2 1 Universidade Federal do rio Grande do Sul, Porto Algre, Brazil; 2 Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil Oxidative stress-related changes on deiodinase function have been implicated in the low T3 syndrome while the administration of the antioxidant N-acetylcysteine (NAC) prevents the thyroid hormone derangement in myocardial infarction (MI) patients. Upregulation of type 3 deiodinase (D3) has been shown in a rat MI (coronary occlusion) model. Here we investigated whether NAC could prevent MI-related myocardial dysfunction as well as the D3 role in this process. Male Wistar rats submitted to left anterior coronary artery occlusion received NAC (10mg/kg, 12/12h for 48h; n = 20) or placebo (NaCl; n = 20). Sham-operated (SO) rats were used as controls (n = 10). Heart function was evaluated by echocardiography after 10 or 28 days post-MI; animals were then euthanized, blood samples were collected and hearts removed. Decreases in T3 levels occurred in MI-placebo animals at 10 (108.8 to 89.2ng/dL; P < 0.01) or 28 days (108.5 to 95.3ng/dL; P < 0.03) after MI. In contrast, no significant decreases in T3 levels occurred in MI-NAC group (105.6 to 101.3ng/dL; P = 0.8, and 109 to 106.8ng/dL; P = 0.08, respectively). Although the groups show similar extension of infarcted area (*50%) and troponin levels (P = 0.7), the ejection fraction was higher in MINAC at 10 (76 vs 58%, P < 0.001) or at 28 days (76 vs 57% P < 0.001). The final left ventricle diastolic volume (FLVDV) was maintained in MI-NAC group (0.36 to 0.36ml P < 0.001) but not in MI-placebo animals (0.36 to 0.6ml; P < 0.001) at 10 days. After 28 days FLVDV was lower in MI-NAC group than in MI-placebo animals (0.57 vs 0.84ml; P < 0.001). D3 expression was significantly increased in both groups, as compared with SO animals (P < 0.001). Interestingly, D3 levels in myocardial peri-infarcted

WEDNESDAY, OCTOBER 21, 2015 tissue were *20 fold higher in MI-placebo, as compared with MI-NAC group (P < 0.001). Increased myocardial infarcted D3 expression persisted *10 fold higher after 28 days in the MIplacebo but not in MI-NAC group (P < 0.001). NAC treatment prevented T3 decreases and was associated with improved cardiac parameters of ventricular function after MI in a rat model of low T3 syndrome.

Short Oral Communication 477 Thyroid Hormone Metabolism & Regulation Wednesday Short Oral Communication Basic 4:12 PM THE ROLES OF AMDHD1 GENE, A DIRECT TARGET GENE OF THYROID HORMONE, DURING ADULT INTESTINAL STEM CELL DEVELOPMENT M. Okada, Y. Shi, T. Miller NIH, Bethesda, MD The thyroid hormone (T3)-dependent frog metamorphosis resembles mammalian postembryonic development and offers a unique opportunity to study how adult stem cells are developed, largely due to the ability to manipulate the externally developing frog embryo. In particular, the remodeling of the intestine during metamorphosis mimics neonatal intestinal maturation in mammals when the adult intestinal epithelial self-renewing system is established. We have been using intestinal metamorphosis to investigate how the organ-specific adult stem cells are formed during vertebrate development. A tissue-specific microarray analysis of intestinal gene expression during metamorphosis has identified a number of candidate stem cell genes, including AMDHD1. Spatiotemporal expression profile of AMDHD1 gene was analyzed by qPCR and in situ hybridization. Molecular mechanisms underlying the regulation of AMDHD1 gene by thyroid hormone was analyzed by ChIP assay. AMDHD1 transcripts are upregulated in the epithelium but not the rest of the intestine when adult stem cells are forming in the epithelium. More importantly, in situ hybridization analysis reveal AMDHD1 mRNA is localized to the developing adult epithelial stem cells of the intestine. In addition, T3 activates AMDHD1 gene expression directly at the transcription level through T3 receptor binding to the AMDHD1 gene in the intestine. Histidine ammonialyase gene, another gene in histidine catabolic pathway, is also similarly regulated by T3 in the intestine. These results together suggest that histidine catabolism plays a critical role in the formation and/or proliferation of adult intestinal stem cells during metamorphosis. Our findings suggest that T3 activates AMDHD1 gene exclusively in the developing adult epithelial stem cells within the intestine and AMDHD1 likely in turn plays a role to promote the formation and/or proliferation of the adult stem cells during metamorphosis.

WEDNESDAY, OCTOBER 21, 2015

Short Oral Communication 478 Thyroid Hormone Metabolism & Regulation Wednesday Short Oral Communication Basic 4:18 PM EXPORT OF IODOTYROSINES BY HUMAN MCT8 AND MCT10 E.C. Lima de Souza, C. Zevenberger, R. Peeters, E. Visser, T. Visser Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands MCT8 and MCT10 are highly homologous and highly effective thyroid hormone (TH) transporters. Despite this high homology, MCT10 also transports aromatic amino acids, whereas MCT8 seems to be specific for iodothyronines. The iodotyrosines MIT and DIT are intermediates in TH biosynthesis, showing structural resemblance with iodothyronines. Therefore, we decided to investigate if in addition to the iodothyronines T4, T3, rT3 and 3,3’-T2 (T2), MCT8 and MCT10 may also transport MIT and DIT. COS1 cells were transiently transfected with human MCT8, MCT10, LAT1 or LAT2, and incubated for 5–60 minutes at 37 C with 10 nM 125I-labeled T3, T4, rT3, T2, and 10 lM MIT or DIT in PBS. qRT-PCR was performed to evaluate expression of LAT1 and LAT2. We found that MCT8 transports iodothyronines with preference for T4*T3 > rT3*T2, while MCT10 shows preference for T3*rT3 > T4*T2. We also show for the first time that MCT8 and MCT10 facilitate cellular export of MIT and DIT. Export of MIT by MCT8 is inhibited by T4 and T3, however the same is not observed for DIT. Uptake of MIT and DIT by COS1 cells appears to be mediated by LAT1. Both LAT1 and LAT2 are capable of transporting MIT and DIT. We found that uptake of MIT and DIT by COS1 cells is inhibited by the specific LAT inhibitor BCH. RT-qPCR analysis shows that COS-1 cells express LAT1, but not LAT2. Also in COS1 cells overexpressing LAT1 or LAT2, co-transfection with MCT8 or MCT10 results in a marked reduction in cellular accumulation of MIT and DIT, in agreement with efficient efflux of MIT and DIT by MCT8 and MCT10. We demonstrate effective cellular uptake of MIT and DIT by LAT1 and LAT2, and effective cellular efflux of these iodotyrosines by MCT8 and MCT10.

Short Oral Communication 479 Thyroid Hormone Metabolism & Regulation Wednesday Short Oral Communication Basic 4:24 PM DIFFERENT EFFECTS OF PTU AND MMI ON THYROIDSPECIFIC GENE EXPRESSION A. Yoshihara1,2, M. Sue1, K. Oda1,2, Y. Ishido2, Y. Luo2, N. Hiroi1, K. Suzuki2 1 Faculty of Medicine, Toho university, Tokyo, Japan; 2Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University, Tokyo, Japan Propylthiouracil (PTU) and methimazole (MMI) are widely used for treatment for Graves’ disease. They share the similar inhibitory effect on thyroid hormone biosynthesis by interfering with thyroid peroxidase (TPO)-mediated oxidation of iodine. However, their possible effects on other thyroid-specific functional molecules have not been comprehensively studied. The effects of PTU and MMI on thyroid-specific gene expression were evaluated in thyroid FRTL-5 cells. The mRNA expression was analyzed by DNA microarray and real-time PCR, whereas the protein expressions were further analyzed by western blotting. In the presence of thyroid stimulating hormone (TSH), both PTU and MMI suppressed thyroid transcription factor 1 (Nkx2-1),

A-191 monocarboxylate transporter 8 (Slc16A2), the putative transporter of thyroid hormone (TH) from thyrocytes into circulation, and iodotyrosine deiodinase (Dehal1), the essential enzyme for recycling of iodine after Tg proteolysis. However, the suppressive effect of PTU on NKx2-1, Slc16A2 and Dehal1 was completely abolished in the absence of TSH, suggesting that the effect of PTU requires TSH. On the other hand, MMI still suppressed Dehal1 expression in the absence of TSH. The expression of sodium/iodide symporter (NIS; Slc5a5), the transporter of iodine on the basolateral membrane of thyrocytes, was significantly stimulated by PTU. The current study showed that the suppressive effects of PTU and MMI in thyrocytes are not only TPO-mediated catalytic reactions, but also extends to the suppression of thyroid-specific functional genes expression, e.g. Nkx2-1, Slc16a2, and Dehal1. Moreover, the current study suggests that PTU and MMI may use different mechanisms to regulate Dehal1 expression, and TSH may play essential and differential roles in mediating PTU and MMI signals in thyrocytes. Potential PTU or MMI-induced suppression of TH efflux and/ or iodide recycling in thyrocytes should be further examined by functional studies.

Short Oral Communication 480 Thyroid Hormone Action Wednesday Short Oral Communication Basic 4:00 PM MULTI-OMICS CHARACTERIZATION OF A HUMAN THYROTOXICOSIS MODEL M. Pietzner1, B. Engelmann2, T. Kacprowski2, J. Golchert2, A. Dirk4, G. Homuth2, E. Hammer2, M. Nauck1, H. Wallaschofski1, T. Mu¨nte3, N. Friedrich1, U. Vo¨lker2, G. Brabant4 1 Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany; 2Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany; 3Department of Neurology, University of Lu¨beck, Lu¨beck, Germany; 4Department of Internal Medicine I, University of Lu¨beck, Lu¨beck, Germany In a variety of clinical conditions the standard approach based on TSH and free thyroid hormone measurement fails to classify thyroid hormone (TH) status. Other biochemical markers as well as SHBG are insufficient to overcome this drawback. In search for new markers we applied an untargeted metabolome and proteome approach in a model of experimental thyrotoxicosis in humans. Sixteen young healthy males were given 250lg levothyroxine (LT4) per day for eight weeks. Plasma was sampled before treatment, after four and eight weeks of treatment, as well as four and eight weeks after treatment. Metabolite and protein levels were determined by mass spectrometry. Mixed-effect linear regression models with serum free thyroxine (FT4) as exposure and metabolite/protein levels as outcome were evaluated. To compile a bio-molecule signature discriminating between thyrotoxicosis and euthyroidism, a random forest was trained and validated in a two-stage cross-validation procedure. Despite no obvious clinical symptoms we observed profound molecular alterations. About one third of the metabolites and proteins were significantly positively (2/3) or negatively (1/3) associated with serum FT4. In line with known TH action, lipid and amino acid metabolism were profoundly altered. Additionally, new strong, positive associations were detected for c-glutamyl amino acids. Functional characterization of significantly affected proteins highlighted not only established TH-affected pathways, e.g. coagulation cascade and apolipoproteins, but also novel associations were found related to the complement system. Robust and good (AUC = 0.86) discrimination between thyrotoxicosis and euthyroidism was achieved with a signature of 15 metabolites/proteins.

A-192 Our results emphasize the power of untargeted OMICS approaches to reveal novel pathways of TH action. Furthermore, we demonstrate that such studies have the potential to identify new molecular signatures, beyond TSH and FT4, for diagnosis and treatment of thyroid disorders.

Short Oral Communication 481 Thyroid Hormone Action Wednesday Short Oral Communication Basic 4:06 PM THYROTROPIN-RELEASING HORMONE (TRH) REGULATES COLD-INDUCED ADAPTIVE THERMOGENESIS IN BROWN ADIPOSE TISSUE A. Ozawa, T. Watanabe, T. Tomaru, S. Ishii, N. Shibusawa, M. Mori, T. Satoh, M. Yamada 1. Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan Thyrotropin-releasing hormone (TRH) in the hypothalamic paraventricular nucleus (PVN) controls the hypothalamic-pituitarythyroid (H-P-T) axis. A rapid and transient increase of TRH has been reported to be required for the acute increase in the level of thyroid hormone in response to cold-exposure. Brown adipose tissue (BAT) is the primary site of thermogenesis in small mammals, and the thermogenic capacity of BAT is primarily due to expression of mitochondrial uncoupling protein 1 (UCP1). Thyroid hormones are considered as key regulators of energy expenditure through the activation of UCP1. In this study, we examined the roles of TRH in the cold-induced activation of the H-P-T axis and also in regulating the thermogenic activity of BAT. We exposed TRH-deficient mice (TRH-/-), exhibited characteristic tertiary hypothyroidism, to 4C for 240 min. Blood samples and BAT were obtained at various time points. Serum TSH, free T4 and corticosterone were measured at each time points. An expression level of mRNA from BAT was detected using Real-time PCR method for UCP1 and related factors. (1) The rectal temperature decreased to 20C in TRH-/-, but showed no significant change in wild-type mice (WT). The replacement of thyroid hormone with T4, to achieve euthyroid status in TRH-/(TRH-/- + T4), reversed this decrease partially, but significantly. (2) The increase in the serum TSH at 90 min after cold exposure and thyroid hormones levels at 120 min observed in WT was abolished in TRH-/- + T4. The level of corticosterone was not significantly changed at any points in each genotype. (3) A marked increase of UCP1 of BAT was detected in WT after cold exposure, but not in TRH-/- + T4. A significant increase of PGC-1, Dio2 and FGF21, those are considered as activators for UCP1, was also disappeared in TRH-/- + T4. TRH is involved in the rise of TSH and thyroid hormone in response to cold stress. TRH is also involved in adaptive thermogenesis in BAT other than via the H-P-T axis. The transcriptional program of adaptive thermogenesis in BAT via prolonged sympathetic stimulation induced by cold exposure requires TRH.

Short Oral Communication 482 Thyroid Hormone Action Wednesday Short Oral Communication Basic 4:12 PM THYROID HORMONE UPTAKE AND EFFLUX PROFILES DIFFER AT THE L-TYPE AMINO ACID TRANSPORTER 2 K.M. Hinz, D. Neef, G. Krause Leibniz-Institut fuer molekulare Pharmakologie (FMP), Berlin, Germany Thyroid hormones (THs) traverse the cell membrane by transporter proteins, amongst others also by the L-type amino acid transporter

WEDNESDAY, OCTOBER 21, 2015 Lat2, which is expressed in diverse tissues. Previously we showed that Lat2 is involved in the uptake of mainly T2 and to a somewhat lesser extent of T3 but neither in uptake of rT3 nor T4. Initial structure-function-studies localized sensitive amino acids of Lat2 for TH uptake by homology model driven mutations. However the complete molecular mechanism of TH traversing remained unclear. We want to clarify i) why T4 is not imported, ii) which substrates are exported out of the cell by Lat2 and iii) the associated molecular determinants. We investigate transport characteristics of homology model guided mutations of Lat2 and TH-substrate features for murine Lat2. Using the Xenopus laevis oocytes as expression system we analysed the uptake and efflux of TH-derivatives by Lat2 variants. Here we highlight two amino acids Y3.36 and F6.46 at either side of a central traversing channel within the transmembrane domain of Lat2. Five side chain shortening mutations showing increased T2 uptake widened this channel of Lat2 differently. However, only one mutation Y3.36A made the uptake of T4 possible, indicating that the large side chain of Y3.36 impedes the uptake of bulky T4 in Lat2. Reverse effect was observed for side chain enlargement F6.46W showing an increased T2, but a decreased uptake of amino acids Leu and Phe. A potential iodine/ aromat interaction seems to play a role for TH transport at this position. Both amino acids are imported and exported as well by Lat2. Notably mutation N3.39S increased the efflux of Phe and Leu. Unexpected results are observed for the efflux of THs by Lat2. Although T2 is imported by Lat2 no T2 efflux is observed. The characterized different TH uptake and efflux profiles for Lat2 are important contributions to reveal determinants of the molecular traversing mechanisms. Just one residue obstructs the T4 uptake. The results are of importance regarding the growing interest in T2 that can also trigger cellular responses, since Lat2 imports mainly T2 and T3.

Short Oral Communication 483 Thyroid Hormone Action Wednesday Short Oral Communication Basic 4:18 PM TRIIODOTHYRONINE (T3) MAY PREVENT FASTINGINDUCED SKELETAL MUSCLE ATROPHY IN VITRO AND IN VIVO C. Mangialardo1, I. Cammarata1, V. Russi1, M. Santaguida3, C. Virili3, V. Moresi4, M. Centanni1, C. Verga Falzacappa1,2 1 Medico-surgical sciences and biotechnologies, Sapienza, University of Rome, Rome, Italy; 2Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy; 3Experimental Medicine, Sapienza University of Rome, Rome, Italy; 4Anatomy, Histology, Forensic Medicine and Orthopedic, Section of Histology, Sapienza University of Rome, Rome, Italy Skeletal muscle atrophy is a weakening condition that may ensue from prolonged muscle disuse, cancer cachexia, anorexia etc. Functional and morphological features may include decreased muscle fiber cross- sectional area and protein content, reduced force, and increased fatigability. Adequate intracellular T3 concentration warrants healthy muscle homeostasis, while both hyper- and hypothyroidism lead to muscle weakness, hypotrophy and atrophy. However, it is still unknown whether T3 may have an effect on muscle atrophy. Aim of the study was to analyze the effects of T3 treatment on muscle atrophy in vitro and in vivo. In vitro muscle atrophy was induced in C2C12 derived myotubes either by serum starvation or by TNFalpha treatment [100 ng/ml] for 48h, in the presence or the absence of T3 [100 nM]. The cross sectional area measurements were evaluated on May Grunwald Giemsa stained samples. In vivo 8 wks male BALB/c mice were fooddeprived for 48 hours, to induce muscle atrophy, and simultaneously

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treated with intraperitoneal injections of either T3 [100 lg/kg BW] or vehicle [NaCl 0.95%], as a control. A strong reduction in diameters was observed in both starved(40 – 2 %) and TNFalpha- (65 – 7 %) treated myotubes, while T3treated myotubes showed no such a reduction (25 – 5 %). Moreover, T3-treatment prevented starvation-induced Atrogin1 expression, an atrophy marker gene. These in vitro data on myotubes were confirmed in vivo. In Balb-c mice, despite T3 treatment, starvation led to a 20 – 3 % reduction in the whole body weight. Upon starvation, Tibialis anterior (TA) weight was reduced (17 – 5 %) in untreated mice, while in T3-treated mice no significant (8 – 4%) TA weight reduction was observed. Morphometric analyses confirmed an even variation in myofiber size in this muscle (- 25 – 4% stv vs ctrl, - 2 – 1,5 % stv T3 vs ctrl). In summary, our data showed a protective effect of T3 treatment in starvation-induced muscle atrophy, both in vitro and in vivo.

These results reinforce the critical role of T3 in the regulation and maintenance of immune homeostasis since T3-activated DCs favor the promotion of adaptive immunity towards a pro-inflammatory profile. Our findings may be exploited to manipulate the immunogenic potential of DCs to positively regulate the development of protective immunity or negatively control the generation of autoimmune diseases.

Short Oral Communication 484

The nature of thyroid stem cells and thyroid cancer stem cells is poorly understood. In order to address this question, a side population (SP) cells-derived thyroid cell line (SPTL) was established from mouse thyroid side population cells. When GFP-tagged SPTL cells were directly injected into the thyroid glands of immunocompromised mice, or intravenously administered through the tail vein after partial thyroidectomy, some SPTL cells were found in thyroid follicles. These data demonstrated that SPTL cells can contribute to thyroid regeneration, suggesting their ability as thyroid stem/ progenitor cells. Total RNAs were prepared from SP and MP (main population, non-SP) cells right after sorting, and SPTL cells. The RNA-seq libraries (5 ng) were subjected to sequencing on a Hiseq 2000 (Illumina, San Diego, CA). SPTL and SP cells shared 584 and 940 commonly up- and downregulated genes among those having fold changes ‡ 2 (log2FC ‡ 1) with an FDR £ 0.01. The commonly up-regulated genes included Sca1 while commonly down-regulated genes included Tg, Tshr, Tpo, Nkx2-1, Pax8, and Foxe1. Signal Transduction Pathway Association analysis revealed that the most up- and down-regulated signal transduction pathways were those related to TGF-beta and epithelialmesenchymal transition (EMT). The expression of EMT-related genes such as Tgfb2, Tgfb3, Snai1, Snai2, and Vim was higher in SP/ SPTL cells as compared to MP cells, while the expression of Cdh1, the epithelial marker, was lower in SP/SPTL cells. Our results were compared with the mRNA profiles using microarray analysis of 59 thyroid tumors (11 ATC and 48 PTC as reported in Hebrant et al, PLoS One, 2012). The commonly up-regulated genes in SP/SPTL cells and ATC included SAIL2, TWIST1, and VIM, while the commonly down-regulated genes were TSHR, TPO, NKX2-1, and FOXE1. The gene expression patterns were similar between SP/ SPTL cells and ATC. The SPTL cells could provide a useful tool to study thyroid adult stem/progenitor cells as well as thyroid cancer-initiating cells, and to understand the mechanisms that separate the differentiation process to become thyroid from the pathway to develop thyroid cancers.

Thyroid Hormone Action Wednesday Short Oral Communication Basic 4:24 PM FURTHER INSIGHTS INTO THYROID HORMONE (TH) ACTION AT THE INITIATION OF ADAPTIVE IMMUNITY: TRIIODOTHYRONINE (T3) TILTS THE BALANCE TOWARDS A PRO-INFLAMMATORY PROFILE V.A. Alamino1, M. Montesinos1, N. Gigena1, A. Blidner2, A.M. Masini-Repiso1, G.A. Rabinovich2, C.G. Pellizas1 1 Centro de Investigaciones en Bioquı´mica Clı´nica e Inmunologı´a (CIBICI-CONICET) and Departamento de Bioquı´mica Clı´nica, Facultad de Ciencias Quı´micas, Universidad Nacional de Co´rdoba, Co´rdoba, Argentina; 2Laboratorio de Inmunopatologı´a, Instituto de Biologı´a y Medicina Experimental (IBYME-CONICET) and Departamento de Quı´mica Biologica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires., Buenos Aires, Argentina We reported TH receptor b1 expression in mice dendritic cells (DCs), the main antigen (Ag)-presenting cells, and T3-dependent stimulation of DC maturation and ability to develop a Th1-type response. Moreover, T3 reduced DC apoptosis, and increased DC ability to stimulate a cytotoxic Ag-specific response and Ag crosspresentation. In agreement, T3 stimulated DC-based immunotherapy reduced the incidence of B16 melanoma establishment and growth in affected mice, prolonging their survival. Besides, regulatory T (Treg) and T helper (Th) 17 cells are lymphocyte subsets with opposing actions: Th17 are key effector cells, while Treg are essential cells for immunologic tolerance. Hence, their balance has been implicated in the development of inflammatory, autoimmune and neoplastic processes. Here, we aim to disclose the effect of T3-stimulated DCs in the homeostasis between these pro-inflammatory/regulatory profiles Mice bone marrow derived DCs were pulsed with T3 (5nM) for 18 h. Intracellular and secreted cytokine production was assayed by flow cytometry and ELISA, respectively. The ability of DC to stimulate allogenic splenocytes was assessed in a mixed lymphocyte reaction and the expression of different profiles markers was analyzed by flow cytometry T3 stimulated DC production of the Th17-skewing cytokines IL-6, IL-23 and IL-1b. In accordance, allogenic splenocytes co-cultured with T3-matured DCs secreted higher levels of IL-17. The augmented IL-17 production was mainly derived from cd T cells, although Th17 cells were also involved. On the other hand, T3 reduced the expression of programmed death-ligand-1 (PD-L1) in DCs, an inhibitory molecule associated with immune tolerance. In agreement, T3-treated DC decreased the frequency of Treg cells, revealed by a reduction of CD4 + CD25 + FoxP3 + cells

Short Oral Communication 485 Thyroid Cancer Wednesday Short Oral Communication Basic 4:00 PM SIMILARITY OF GENE EXPRESSION PROFILES BETWEEN THYROID STEM CELLS AND ANAPLASTIC THYROID CARCINOMA M. Iwadate Laboratory of Metabolism, National Cancer Institute, Bethesda, MD

Short Oral Communication 486 Thyroid Cancer Wednesday Short Oral Communication Basic 4:06 PM INHIBITION OF SRC SIGNALING PROMOTES AN INCREASED RELIANCE ON THE MITOGEN ACTIVATED PROTEIN KINASE PATHWAY IN PAPILLARY AND ANAPLASTIC THYROID CANCER T.C. Beadnell, K.E. Wuensch, S.M. Riffert, R. Schweppe Medicine, UC Denver, Aurora, CO

A-194 Src plays an important role in thyroid cancer growth, invasion, and metastasis. To further understand how to effectively target Src, we previously generated 2 BRAF- (BCPAP & SW1736) and 2 RASmutant (C643 & Cal62) cell lines resistant to the Src inhibitor, dasatinib, and observed increased MAPK pathway activation in both BRAF- and RAS-mutant resistant cell lines, and the drug-resistant c-SrcT341M mutation in the RAS-mutant cell lines. These data indicate that Src inhibition promotes increased signaling through the MAPK pathway as a common mechanism of resistance. Here, we hypothesize that MEK inhibition can overcome resistance to targeted inhibition of Src with dasatinib. The effects of Src and MAPK pathway inhibition were tested using in vitro growth and apoptosis assays and an in vivo xenograft model. Consistent with increased MAPK activity in the dasatinib-resistant (DasRes) cells, here we show the growth of the DasRes cell lines exhibit enhanced sensitivity (3- to 39- fold) to the MEK1/2 inhibitor, trametinib, in the presence of dasatinib. Western blot analysis in the BRAF-mutant DasRes cells, indicated that Src and MEK1/2 inhibition is important for increased MEK1/2 inhibitor sensitivity. Whereas, in the RAS-mutant DasRes cells, trametinib sensitivity is likely through dasatinib mediated paradoxical c-Src activation and phosphorylation of pY925-FAK, a Grb2 binding site, which promotes MAPK activation. In vivo, MEK1/2 inhibition resulted in an initial inhibition of tumor growth in the RAS-mutant Cal62 parental tumors (5.26 fold; p-value = 0.0031). However, the parental tumors became refractory to trametinib after 30 days. In contrast, the DasRes Cal62 tumors exhibited a 5.5-fold greater inhibition of final tumor volume in response to trametinib (DR vs P; p = 0.0009), with complete responses in 3 out of 8 DasRes tumors. Finally, up-front dasatinib and trametinib treatment resulted in strong synergistic inhibition of growth (CI = 0.1-0.3) and increased apoptosis (4- to 19fold) in vitro. Prolonged inhibition of Src reprograms thyroid cancer cells to become more reliant on the MAPK pathway, providing further rational for this combination therapy and a potential mechanism for Src and MEK1/2 inhibitor synergy.

Short Oral Communication 487 Thyroid Cancer Wednesday Short Oral Communication Basic 4:12 PM NOVEL THERAPIES IDENTIFIED IN PATIENT DERIVED THYROID CANCER XENOGRAFTS. L.A. Marlow1, J.C. Hall1, A.C. Mathias2, L.K. Dawson2, W.F. Durham2, K.A. Meshaw2, R.J. Mullin2, D. Small2, A. Synnott2, D. Milosevic3, B.C. Netzel3, S.K. Grebe3, M. Ryder4, P. Weinberger5, R.C. Smallridge1,4, J.A. Copland1 1 Cancer Biology, Mayo Clinic, Jacksonville, FL; 2Charles River Discovery Services, Morrisville, NC; 3Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; 4Endocrinology, Mayo Clinic, Rochester, MN; 5Otolaryngology, Georgia Reagents University, Augusta, GA The success of clinical trials designed on the basis of pre-clinical models has been minimal for patients with radioiodine resistant aggressive thyroid cancer. There is a dire need to develop improved pre-clinical models for these tumors that have the capability to translate more reliably from bench to bedside, thus allowing improved selection of novel therapeutic agents. Patient-derived xenograft (PDX) models are purported to most closely replicate a patient’s response to therapy due to preservation of tumor heterogeneity and microenvironment. Thus, we have developed a panel of pre-clinical thyroid cancer PDX models by implanting patient tumor tissue into immunocom-

WEDNESDAY, OCTOBER 21, 2015 promised mice characterizing the models and testing therapeutics. Each model is characterized and compared to the originating patient tumor tissue by short tandem repeat (STR) analysis for DNA fingerprinting, immunohistochemistry (IHC) for thyroid markers, and for oncogenic driver mutations. We have developed ten PDX models that include follicular variant papillary thyroid carcinoma (FVPTC), insular thyroid carcinoma (ITC), poorly differentiated papillary thyroid carcinoma (PDTC), squamous cell thyroid carcinoma (SCTC), and anaplastic thyroid carcinoma (ATC). Each model demonstrates its own unique responses to radiation; cytotoxic therapies (doxorubicin, cisplatin, paclitaxel) or molecular targeted therapies such as tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib, erlotinib), BRAF inhibitor (dabrafenib), MEK inhibitor (trametinib), farnesyl transferase inhibitor (tipifarnib), and proteasome inhibitor (carfilzomib). Furthermore, in a HRAS mutant ATC PDX model, remarkable responses are seen with combination therapy sunitinib plus paclitaxel. We expect that this might provide the rationale for some of these therapeutic strategies to move forward towards clinical trials.

Short Oral Communication 488 Thyroid Cancer Wednesday Short Oral Communication Basic 4:18 PM DEVELOPMENT OF AN ORAL SMALL MOLECULE TSH RECEPTOR AGONIST FOR DIAGNOSIS OF RESIDUAL/ RECURRENT THYROID CANCER S. Neumann2, M. Cullen2, E. Eliseeva2, R.F. Place1, M. Gershengorn2 1 Nova Therapeutics LLC, Pasadena, CA; 2National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD Radioactive iodine (RAI) thyroid scans are commonly used to diagnose residual/recurrent thyroid cancer. Currently, the only approved drug to stimulate RAI uptake (RAIU) is thyrotropin alfa (ThyrogenTM); a recombinant form of human TSH (hTSH). It is administered via intramuscular injection over 2 consecutive days by a trained healthcare provider prior to RAIU. While effective, an orally available equivalent would offer benefits to both clinicians and patients by providing a noninvasive route of drug administration. In 2009, we identified the first small molecule agonist capable of stimulating RAIU in mice by selectively targeting an allosteric site in the transmembrane domain of the TSH receptor (TSHR). Herein, we share our latest advancements on the path toward developing a new drug for thyroid cancer. We have performed a series of methods including (but not limited to): (i) stereochemical purification of a lead candidate TSHR agonist in conjunction with dose response analyses and time course studies to define in vitro drug profiles; (ii) molecular modeling to visualize enantiomer binding to the TSHR transmembrane pocket; and (iii) excipient solubility screens in conjunction with oral delivery, T4 measurement, and RAIU analysis in mice with comparison to thyrotropin alfa (utilizing a converted human equivalent dose). We have identified a new molecular enantiomer (referred to as E2) with improved drug-like properties including superior in vitro potency and in vivo efficacy in comparison to other drug candidates. We have also surveyed several excipient formulations in order to facilitate safe oral delivery of E2. In addition, we have identified a translatable oral dosing schedule capable of facilitating RAIU in mice equivalent to thyrotropin alfa. E2 represents the next step toward developing a new oral drug for patients with thyroid cancer to stimulate RAIU with possible clinical (e.g. noninvasive delivery allowing for easier self-administration by

WEDNESDAY, OCTOBER 21, 2015 patients) and economical (e.g. manufacturing costs and reduced clinical visits as a consequence of circumventing IM injection) benefits over the current standard of care.

Short Oral Communication 489 Thyroid Cancer Wednesday Short Oral Communication Basic 4:24 PM GENISTEIN-A POTENTIAL THERAPEUTIC FACTOR FOR HIGH RISK PAPILLARY THYROID CARCINOMA WITH BRAFV600E MUTATION Z. Liu1, K. Kakudo2, C. Zhang1, X. Cui1 1 Department of Pathology, Shandong University School of Medicine, Jinan, China; 2Department of Pathology, Kinki University Faculty of Medicine, Otoda-cho, Japan Genistein is the main component of isoflavones, which has been reported to have anticarcinoma effect in different carcinomas but not in thyroid carcinoma. Clinically, patients of PTC with BRAFV600E mutation have a higher rate of recurrence and metastasis but little is known on its additional treatment. This study focuses on the antitumor role of Genistein in papillary thyroid carcinoma and tries to provide an additional method for the treatment of high risk group thyroid carcinoma. BHP10-3 harboring with RET/PTC 1 rearrangement and BCPAP harboring BRAFV600E mutation were treated with gradient concentration of Genistein. The morphological changes of the tumor cells were evaluated microscopically. Cellular proliferation, cycle and apoptosis were determined by MTS proliferation assay, Annexin-V apoptosis assay and cell cycle assay by Flow Cytometry, respectively. The expression of proliferation markers cyclinD1, cyclinA2 and cyclinB1 were demonstrated by qRT-PCR and Western blotting. Genistein inhibits the proliferation of both cell lines (P < 0.001). This reduction was associated with G2/M phase arrest (P < 0.001) and apoptosis (P < 0.01). Genistein induces the apoptosis of both cell lines (P < 0.001). The anti-proliferation and apoptosis inducing effects are more obvious in BCPAP cell line harboring BRAFV600E mutation. In conclusion, our data provide the preliminary evidence that Genistein has the anti-tumor effect in the range of 2.5 and 80lg/ml in papillary thyroid carcinoma cells. This may provide a potential therapeutic method for high risk papillary thyroid carcinoma with BRAFV600E mutation.

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Short Oral Communication 490 Thyroid Cancer Wednesday Short Oral Communication Translational 4:00 PM GENETIC BACKGROUND AND PROTEIN PROFILING RELATED TO TELOMERASE ACTIVATION IN MEDULLARY THYROID CARCINOMA N. Wang, H. Kjellin, M. Ba¨ckdahl, J. Zedenius, D. Xu, J. Lehtio¨, C. Larsson Karolinska Institutet, Stockholm, Sweden Medullary thyroid carcinoma (MTC) is a rare but aggressive type of thyroid cancer originating from the thyroid C-cells. Telomerase is a ribonucleoprotein complex, which plays a critical role in telomere maintenance and cancer biology. In our previous study we observed activation of telomerase in approximately 50% of MTCs which showed a strong association with shorter patient survival. However TERT promoter mutations were not revealed. To determine the background of telomerase activation, TERT copy numbers and TERT promoter methylation were quantified in 42 MTCs(39 sporadic and 3 MEN2) and normal thyroid references. Quantitative Real time PCR based copy number assay was used to explore the copy number status of TERT in our cohort of MTCs. Methylation of the TERT promoter was quantified using Pyrosequencing. Protein expression profiling was performed by LC-MS/ MS. Five of the 21 sporadic MTCs with telomerase activation demonstrated TERT copy number gain, while all other cases demonstrated two copy numbers for TERT. Increased methylation index (MetI) for CpG methylation at the TERT promoter was found in 37/ 39 sporadic MTCs (MetI 12-90%) as compared to normal thyroid (MetI 6–8%) (P < 0.0001). MetI correlated positively with TERT gene expression (r = 0.432, P = 0.006) and negatively with telomere length (r = - 0.343, P = 0.032) and was associated with the presence of a RAS mutation (P = 0.031). MTC cases with MetI > 52% had shorter survival as compared to cases with MetI £ 52%. The effect of telomerase activation on protein expression profiles was then assessed. A total of 4,321 proteins were identified and quantified including 240 that were differentially expressed between MTCs positive and negative for telomerase activation. The findings suggest that TERT copy number gain and increased promoter methylation are associated with telomerase activation in MTC. Quantification of TERT methylation could be considered as a prognostic marker in MTC.

Short Oral Communication 491 Thyroid Cancer Wednesday Short Oral Communication Translational 4:06 PM IMMUNE MARKERS IN MEDULLARY THYROID CANCER (MTC) AND THEIR CLINICAL SIGNIFICANCE R. Dadu1, J. Rodriguez Canales2, I.I. Wistuba2, W. Tian2, H. Lui2, E. Grubbs3, G. COTE1, G. Ray5, M.D. Williams4, M. Cabanillas1 1 Endocrine Neoplasia and HD, MD Anderson cancer Center, Houston, TX; 2Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; 3Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; 4Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; 5Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX Recent studies have uncovered that a dysfunctional immune response is associated with primary and metastatic cancer. We sought to determine if immune response is associated with tumor pathology and clinical outcomes in MTC.

A-196 Immunohistochemistry of 8 immune markers was performed on FFPE MTC sections (Table 1). Slides were analyzed choosing 5 random areas in the tumor center (TC) and tumor periphery (TP). The final score was expressed as average score of the 5 areas. The immune cell markers were evaluated as density [number of positive cells/area regardless of intensity]. PD-L1 expression was evaluated using H-score [% of positive cells with membrane staining combined with staining intensity]. PD-L1 H score > 1 was considered positive. Spearman’s correlation, Wilcoxon rank and Kruskall-Wallis tests were used for comparisons. Table 1 provides baseline characteristics and the detailed results of our immune marker analysis for 48 primary MTC tumors. For individual cases, the immune cell populations were the same in the TC and TP. There was no evidence of variable marker expression based on RET/RAS mutation or calcitonin/CEA. Presence of cytotoxic (CD8 + ), memory (CD45Ro + ) and regulatory T cells (FoxP3 + ) in TC correlated with absence of metastases at diagnosis. Positive PDL1 expression in the TC was present in 13/48 (27%) of MTC tumors and correlated with tumor infiltrating lymphocytes. PD-L1 expression in the TP (likely macrophage, analysis of CD68 marker is ongoing) correlated with favorable pathology (absence of: extrathyroidal extension, invasion into adjacent structures, positive margins and lymphovascular invasion) and absence of metastases at diagnosis. At the time of this analysis, immune marker expression did not correlate with OS. Median OS was not reached (median follow up time 70 months, range: 3–260). Disease free survival analysis is ongoing. This is the first study to analyze the TC/TP expression of immune markers in a large MTC cohort. Immune surveillance is associated

WEDNESDAY, OCTOBER 21, 2015 with decreased metastatic potential and favorable pathologic features in MTC and thus may play a role in stabilizing disease. PD-L1 expression on tumor cells indicates that a subset of patients may benefit from immune-based therapies.

Short Oral Communication 492 Thyroid Cancer Wednesday Short Oral Communication Translational 4:12 PM PROGNOSTIC MARKERS AND RESPONSE TO VANDETANIB THERAPY IN SPORADIC MEDULLARY THYROID CANCER PATIENTS V. Tiedje2, S. Ting1, R. Walter1, K. Worm1, J. Badziong2, D. Zwanziger2, K.W. Schmid1, D. Fu¨hrer2 1 Institute of Pathology, University Hospital Essen, Essen, Germany; 2 Department of Endocrinology and Metabolism, University Hospital Essen, Essen, Germany Medullary thyroid carcinoma (MTC) occurs sporadically in 75% of patients. Metastatic disease is associated with significantly poorer survival. For progressive, metastatic disease currently two tyrosine kinase inhibitors are approved. The aim of this study was to identify i) prognostic markers for progressive MTC and b) oncogenic factors associated with response to vandetanib therapy. Clinical courses of 32 patients with sporadic MTC of different tumor stages (n = 10 pN0cM0, n = 9 pN1cM0, n = 14 pN1p/cM1) were compared with genetic profiles of the patients’ primary tumor tissue. Analysis for RET-proto-oncogene mutations was performed by Sanger- and Next-Generation-Sequencing. The mRNA expression (mRNA count) of 33 tyrosine kinases was measured by nCounter NanoString analysis. 10/32 patients, all pN1p/cM1, received vandetanib treatment. Somatic RET mutations were found in 21/32 MTC. The highest risk RET918 mutation was found in 8/14 MTC of pN1p/cM1 patients and moderate risk mutations (codon 620, 630 and 768, respectively) in primary tumour tissues of two pN0cM0, one pN1cM0 and one pN1p/ cM1 patient. BRAF (p = 0.019), FGFR2 (p = 0.007), FGFR3 (p = 0.044) and VEGFC (p = 0.042) mRNA expression was significantly lower in MTC of pN1cM0/pN1pcM1 compared to pN0cM0 patients, whereas PDGFRA (p = 0.026) mRNA expression was significantly higher in MTC of pN1cM0/pN1pcM1 compared to pN0cM0 patients. Among the 10 vandetanib treated patients, 5 showed partial response, all harbouring the RET918 mutation. mRNA expression of FLT1 (p = 0.039), FLT4 (p = 0.025) and VEGFB (p = 0.042) was significantly higher in primary tumour tissues of patients responding to vandetanib therapy. In this study, we identified molecular markers in primary tumour tissue of sporadic MTC associated with the development of metastases (both lymph node and organ metastases) as well as response to vandetanib therapy.

Short Oral Communication 493 Thyroid Cancer Wednesday Short Oral Communication 4:18 PM THYROIDPRINT: A NEW AND SIMPLE GENETIC CLASSIFIER THAT ACCURATELY RULES-OUT MALIGNANCY IN INDETERMINATE THYROID NODULES H.E. Gonzalez1, S. Vargas1, R. Martinez1, S. Urra1, A. Solar2, E. Bruce1, N. Mena1, F. Cruz3, S. Loyola3 1 Department of Surgical Oncology, Pontificia Universidad Catolica de Chile, Santiago, Chile; 2Department of Anatomic Pathology, Pontificia Universidad Catolica de Chile, Santiago, Chile; 3 Department of Radiology, Pontificia Universidad Catolica de Chile, Santiago, Chile In most of the world, diagnostic surgery continues to be the most frequent treatment option for indeterminate thyroid cytology given

WEDNESDAY, OCTOBER 21, 2015 the lack of access to a test that allows to avoid surgery. We present a new and simple diagnostic test based on qPCR that accurately rulesout the presence of cancer in indeterminate thyroid nodules. A broad histo-cytological spectrum of samples (benign 150– malignant 67) were prospectively collected, including 68 surgical specimens (22 malignant - 46 benign) and 149 FNAs (Bethesda: II: 83, III: 10, IV: 22, V: 10 and VI: 24). The gold standard for Bethesda II samples was the cytology report and for surgical specimens and FNAs (Bethesda III, IV, V and VI) the surgical biopsy report. The gene expression of a panel of 10 genes was determined by qPCR. A Training Set based on the gene expression data of 132 samples (biopsies 68–FNAs 64) was used to develop several gene classifiers trained by lineal (LDA) or non-lineal (NLDA) discriminant analysis. Classifier performance was further improved by a propietary software that identified and correctly classified samples with atypical (outlier) gene profiles (Outlier Classification System–OCS). The remaining samples (85 FNAs, benign 60 - malignant 25) were used as an independent Testing Set to identify the best classifier. Three prototype classifiers were developed in the Training Set, showing AUC between 0.82–0.92, sensitivity 83%–93% and specificity 52%–77%. The OCS improved classifier performance to AUC between 0.92–0.97, sensitivity 90%–95% and specificity 43%–83%. In the independent Testing Set, only one classifier named ThyroidPrint based on a 10-gene panel showed consistent performance, with of AUC 0.94, sensitivity 92.0%, specificity 83.3%, negative predictive value of 96.2% and positive predictive value of 69.7% (pre-test 29.4%). ThyroidPrint combines optimal NPV (96%) with high specificity (83%), safely ruling out malignancy while significantly reducing the number of false positive cases. The technical simplicity and optimal performance of ThyroidPrint may offer a promising and accessible solution to improve the diagnosis of indeterminate thyroid nodules and signifiacntly reduce the rate of diagnostic surgery.

Short Oral Communication 494 Thyroid Cancer Wednesday Short Oral Communication Translational 4:24 PM ETV6-NTRK3 FUSION ONCOGENE WAS IDENTIFIED IN SPORADIC ADULT PAPILLARY THYROID CARCINOMA A.U. Bastos, G. Oler, J.M. Cerutti Morphology and Genetics, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil Papillary Thyroid Carcinomas (PTC) is the most common type of thyroid cancer. Somatic alteration of genes coding proteins involved in the MAPK pathway, including point mutation of BRAF and RAS genes and rearrangements of RET are the most common alterations found in PTC. The Cancer Genome Atlas (TCGA) identified both known and novel somatic mutations in PTCs that included single nucleotide variants, small insertions and deletions, gene fusions, and copy-number alterations. Although point mutations in BRAF and RAS genes were the most prevalent genetic events, recurrent kinase fusions were found in a high proportion of samples. Fusions involving RET, NTRK3 and BRAF kinases were the most frequent, being RET/PTC1, RET/PTC3 and ETV6-NTRK3 fusion transcripts detected at a higher frequency across multiple PTC samples. We here determined the prevalence of ETV6-NTRK3 fusion transcript in a series of PTC previously screened for BRAF, KRAS, NRAS, HRAS, RET/PTC1 and RET/PTC3 somatic mutations. A series of 118 sporadic adult PTCs was screened for the presence of ETV6-NTRK3 by standard RT-PCR. The cDNA generated from PCCL3 cells expressing the fusion transcript was used as a positive control. ETV6-NTRK3-positive samples were sequenced to confirm the findings.

A-197 ETV6-NTRK3 fusion transcript was identified in about 6% (n = 7) of PTC. ETV6-NTRK3 fusion transcript was exclusively found in the follicular variant of PTC. Most patients with ETV6-NTRK3 were under the age of 45. Although ETV6-NTRK3 was initially identified in pediatric thyroid carcinoma, we here confirmed this event in PTC from adults. While point mutations were the most common alteration found in these series of PTC, fusion oncogenes were detected at higher prevalence than the reported in the TCGA network.

Short Oral Communication 495 Thyroid Cancer Wednesday Short Oral Communication 4:00 PM PRESENTING FEATURES OF THYROID LYMPHOMA: THE MAYO CLINIC EXPERIENCE A. Sharma1, S. Jasim1, C.C. Reading2, T. Habermann3, K. Ristow3, V. Fatourechi1, M. Stan1 1 Endocrinology, Diabetes, Nutrition, Mayo Clinic, Rochester, MN; 2 Radiology, Mayo Clinic, Rochester, MN; 3Oncology, Mayo Clinic, Rochester, MN Thyroid lymphoma is a relatively rare disease. Primary thyroid lymphoma accounts for 1 - 5% of all thyroid malignancies and less than 1% of all lymphomas. Fine needle aspiration (FNA) is usually the first line in tissue diagnosis for thyroid masses. Radiologic features may increase one’s index of suspicion for thyroid lymphoma. Retrospective analysis of all patients between 2000–2014 with a tissue biopsy positive for thyroid lymphoma in the Mayo Clinic Lymphoma Database was conducted. Data were extracted from the electronic medical record, pathology was reviewed by a cytopathologist and imaging reviewed by an expert radiologist. 75 subjects had biopsy proven thyroid lymphoma with 70.7% being considered primary thyroid lymphoma (disease confined to the neck). Median age at diagnosis was 67 years (range 20 - 90). 50.7% were male, and 54.7% had a history of Hashimoto’s thyroiditis. Symptoms included neck mass (88%), dysphagia (45.3%) and hoarseness (37.3%). 57 subjects had an ultrasound before treatment. The typical appearance was of a solid, hypoechoic mass with mildly increased vascularity, no internal calcifications and variable edge characteristics (from well-defined to ill-defined). The median volume was 64.1 cm3 (IQR 29.8–130.9 cm3). 65 subjects had FNA as their first diagnostic procedure. 69.2% of FNA biopsies were abnormal and 40% indicated a specific lymphoma subtype. The diagnosis was confirmed in 46.7% by core biopsy, 9.3% incisional biopsy, 25.3% thyroidectomy (partial or total) and 13.3% lymph node biopsy. Histologic subtypes included diffuse large B-cell (DLBCL) 73.3%, follicular lymphoma 5.3%, MALT 10.7%, MALT/DLBCL 2.6%, Tcell 2.6% and Hodgkin’s lymphoma 1.3%. Average SUVmax reported was 21.8 (range 10.6–31.6). Rapidly enlarging thyroid masses with compressive symptoms should raise suspicion for thyroid lymphoma. Radiologically they generally present as a large, unilateral, thyroid centered mass, hypoechoic by US, expanding into adjacent soft tissues and with marked FDG avidity on PET. FNA can be suggestive of the diagnosis in most cases, but more tissue is required for subtype confirmation.

Short Oral Communication 496 Thyroid Imaging Wednesday Short Oral Communication Clinical 4:06 PM CORE NEEDLE BIOPSY AS A FIRST-LINE BIOPSY METHOD FOR INITIALLY DETECTED THYROID NODULE: A COMPARATIVE STUDY USING PROPENSITY SCORE MATCHING H. Lim1, S. Jung2, J. Shin3, S. Hahn3

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Radiology, Soonchunhyang University Seoul Hospital. Soonchunhyang University College of Medicine, Seoul, Korea (the Republic of); 2Radiology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea (the Republic of); 3Radiology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea (the Republic of) Core needle biopsy (CNB) has been suggested as a complementary tool for the diagnosis of thyroid nodules with previous inconclusive fine needle aspiration (FNA) result, and reported as a safe and accurate biopsy method. However, there were few reports that evaluated the role of CNB as a first-line biopsy method for thyroid nodule. The purpose of this study was to evaluate the role of CNB as a firstline diagnostic method for initially detected thyroid nodules. A total of consecutive 2898 initially detected thyroid nodules, which were evaluated with ultrasound-guided FNA or CNB, were included. A propensity score matching analysis was performed to reduce the effects of selection bias, and 631 CNB group and 631 FNA group were finally enrolled. We compared diagnostic performance, inconclusive results, and complication between CNB and FNA group. We also compared nodule characteristics between CNB-nondiagnostic group and FNA-non-diagnostic group. After matching, CNB showed significantly lower non-diagnostic result rate (1.4 % vs 8.1 %), lower indeterminate result rate (5.1 % vs 8.1 %) than FNA group (P < 0.001, and P = 0.031, respectively). Thyroid nodules with calcification, posterior location, or small diameter ( < 1 cm) showed significantly lower non-diagnostic rate on CNB compared with FNA. There was no difference in diagnostic performance between FNA and CNB group according to experience degree. Complication rate of CNB (3.6 %) was larger than FNA (1.6 %) (P = 0.022). CNB showed good diagnostic performance and lower inconclusive results than FNA. CNB is a useful fist-line biopsy method for initially detected thyroid nodule.

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Short Oral Communication 498 Thyroid Nodules & Goiter Wednesday Short Oral Communication Clinical 4:18 PM REMOTE ACCESS ROBOTIC FACELIFT THYROIDECTOMY: A MULTI-INSTITUTIONAL EXPERIENCE W.S. Duke1, F.C. Holsinger2, E. Kandil3, J. Richmon4, M. Singer5, D.J. Terris1 1 Otolaryngology, Georgia Regents University, Augusta, GA; 2 Otolaryngology, Stanford University, Stanford, CA; 3Surgery, Tulane University, New Orleans, LA; 4Otolaryngology, Johns Hopkins University, Baltimore, MD; 5Otolaryngology, Henry Ford Health System, West Bloomfield, MI Robotic facelift thyroidectomy (RFT) was developed as an alternative to transaxillary thyroidectomy. Advantages of this approach include a more direct route to the central neck with less serious potential complications. Early favorable results led to this confirmatory multi-institutional experience. Prospectively collected data on consecutive patients undergoing RFT in five North American academic endocrine surgical practices were compiled. Surgical indications, operative times, final pathology, nodule size, complications, and postoperative management (drain use and length of hospital stay) were evaluated. A total of 102 RFT procedures were undertaken in 88 patients. All but one of the patients (98.9%) were female and the mean age was

WEDNESDAY, OCTOBER 21, 2015 41.9 – 13.1 years (range, 12 to 69 years). The indication for surgery was nodular disease in 92.2% of cases; 7.8% were completion procedures performed for a diagnosis of cancer. The mean size of the largest nodule was 1.9 cm (range, 0 to 5.6 cm). The mean total operative time for a thyroid lobectomy was 162 minutes (range, 82 to 265 minutes). No permanent complications occurred. There were 4 cases (3.9%) of transient recurrent laryngeal nerve weakness, 3 cases (2.9%) of transient asymptomatic biochemical hypocalcemia, and 4 (3.9%) hematomas. There were no conversions to an anterior cervical approach. The majority of patients were managed on an outpatient basis (76.9%) and without a drain (65.7%). RFT is feasible and safe in selected patients. Distinct differences in this North American population (compared with most Asian robotic transaxillary thyroidectomy series) are the larger mean thyroid nodule size and the low rate of malignancy. This approach affords several advantages over the transaxillary approach, including a more limited extent of dissection, the potential for drainless outpatient surgery, and avoidance of complications such as brachial plexus injury. RFT can continue to be offered to carefully selected patients as a way to avoid a visible cervical scar.

Short Oral Communication 499 Thyroid Cancer Wednesday Short Oral Communication Clinical 4:24 PM ONCOGENIC MUTATIONS IN THYROID CARCINOMA AND THEIR POWER TO DETECT MALIGNANCY IN DIVERSE THYROID NEOPLASMS R.T. Kloos1, M. Pagan2, K. Travers2, E. Tom2, M. Wong2, G. Fedorowicz2, J. Anderson2, S. Kim2, C. Lin2, R. Monroe3, P.S. Walsh2, J. Huang2, G.C. Kennedy2 1 Medical Affairs, Veracyte, Inc, South San Francisco, CA; 2Research & Development, Veracyte, Inc., South San Francisco, CA; 3CLIA, Veracyte, Inc., South San Francisco, CA Thyroid carcinomas harbor oncogenic driver mutations. The TCGA Research Network expanded the number of mutations detected in papillary thyroid carcinomas (PTC). We investigated the prevalence of mutations in diverse subtypes of thyroid neoplasia beyond PTC. We evaluated FNAs (n = 83) collected preoperatively and diagnosed post-surgically by a panel of experts as malignant (PTC, mPTC, FVPTC, PTC-TCV, MTC, WDC-NOS, HCC, FC) or benign (BFN, FA, HCA, HTA, LCT). We also evaluated surgical tissues (n = 139) with histopathology truth, and a consecutive series of indeterminate FNAs without histopathology from our CLIA lab (n = 110). Samples were subjected to genome-wide NGS and analyzed for 265 variants in 56 genes, comprising previously published markers such as BRAF, PIK3CA, RAS, TSHR, and a higher frequency subset detected by TCGA including ARID1B, EIF1AX, PPM1D and others. Overall 41/104 (39%) histopathology malignant samples were found to harbor a known mutation, while 15/92 (16%) of the histopathology benign samples were also mutated. In FNAs, mutations were detected in 12/40 malignant samples (30% sensitivity) and in 4/ 43 histopathology benign samples (91% specificity). The most frequently mutated subtypes were PTC (18/39, 46%), FVPTC (12/32, 38%) and FA (12/21, 36%). Frequently mutated genes in malignant samples included BRAF 22/104 (21%), and NRAS 12/104 (12%). Collectively, we estimated that TCGA mutations (n = 265) would achieve a positive predictive value (PPV) ranging from 73%-75%, and a negative predictive value (NPV) of 52%-58% across all subtypes, with a maximum sensitivity of 43% in PTC, PTC-TCV, and FVPTC (combined). Mutation frequency in cytology indeterminate CLIA FNA was 15/110 (14%). While the genomic landscape of all thyroid neoplasm subtypes will inevitably be elucidated, caution should be used in the early adoption

WEDNESDAY, OCTOBER 21, 2015 of published mutations as the sole predictor of malignancy in thyroid. The largest set of such mutations known to date has the power to detect only a fraction of thyroid carcinomas in preoperative FNAs.

Short Oral Communication 500 Thyroid Cancer Wednesday Short Oral Communication Translational 4:00 PM DUAL INHIBITION OF HDAC AND PI3K-AKT PATHWAYS HAS POTENT ANTI-CANCER ACTIVITY IN THYROID CANCER CELLS S. Kotian, V. Neychev, K. Gaskins, S. Gara, L. Zhang, N. Nilubol, D. Patel, E. Kebebew Endocrine Oncology, NCI, Bethesda, MD Aggressive thyroid cancers display genetic heterogeneity with disruptions in many regulatory pathways, and monotherapy has shown limited efficacy. Targeting multiple altered pathways simultaneously, may prove to be a more effective strategy for developing effective agents for thyroid cancer therapy. Histone deacetylases (HDACs) are an important class of enzymes that regulate key factors involved in cellular growth, differentiation, and survival. Aberrant expression of HDACs is found in several cancers. We analyzed gene expression data from the Cancer Genome Atlas database on thyroid cancer and found several HDACs (HDAC2, HDAC4, HDAC6 and HDAC10) that were associated with aggressive thyroid cancer and decreased overall survival. The PI3K-AKT pathway is also activated in aggressive thyroid cancer. Thus, we hypothesized that dual inhibition of these pathways could circumvent the limitations posed by single agent drugs. We, therefore, investigated the effect of CUDC-907 (a dual inhibitor of HDACs and PI3KAKT) in thyroid cancer cells. We found that CUDC-907 significantly inhibited cellular proliferation in 6 thyroid cancer cell lines in a dose-dependent manner, arrested cells in G2/M with decreased levels of the checkpoint regulator cyclin B1 and increased p21. CUDC-907 treatment induced apoptosis with increased caspase 3/7 activity and decreased Bcl-2 (anti-apoptotic) levels. CUDC-907 treatment also decreased cellular migration and invasion, which was associated with decreased Ncadherin expression. These anticancer effects of CUDC-907 were associated with decreased levels of HDAC2, HDAC4, p-ERK1 and p-AKT1, and hyper-acetylation of histone H3 confirming effective targeting of the deregulated pathways in the thyroid cancer cells. Based on our results, the strategy of dual inhibition of HDAC and PI3K/AKT pathways, using one agent, is a promising therapeutic strategy for advanced thyroid cancer.

Short Oral Communication 501 Thyroid Cancer Wednesday Short Oral Communication Clinical 4:06 PM KNOWLEDGE OF PATHOLOGICALLY VS. CLINICALLY NEGATIVE LYMPH NODES IS ASSOCIATED WITH REDUCED USE OF RADIOACTIVE IODINE POST-THYROIDECTOMY FOR LOW RISK PAPILLARY THYROID CANCER E. Ruel1, S. Thomas4, M. Dinan5, J.M. Perkins1, S.A. Roman2, J.A. Sosa2,3 1 Endocrinology, Duke University Medical Center, Durham, NC; 2 Surgery, Duke University Medical Center, Durham, NC; 3Duke Cancer Institute, Durham, NC; 4Biostatistics, Duke University, Durham, NC; 5Duke Clinicial Research Institute, Durham, NC Cervical lymph node metastases are common in papillary thyroid cancer (PTC). Clinically negative lymph nodes confer uncertainty

A-199 about true lymph node status, potentially prompting postoperative radioactive iodine (RAI) administration even in low risk patients. We examined the association of clinically (C0) vs. pathologically negative (P0) lymph nodes with utilization of RAI for low risk PTC. Using the National Cancer Database 1998–2011, adults with PTC who underwent total thyroidectomy for Stage I/II tumors 1-4 cm were evaluated for receipt of RAI based on C0 vs. P0 status. Cut point analysis was conducted to determine the number of P0 nodes associated with the greatest decrease in the odds of receipt of RAI. Univariate and multivariate analyses predicting RAI use were conducted for all patients and patients < 45 years. 64,980 patients met study criteria; 39,778 (61.2%) were C0 vs. 25,202 (38.8%) P0. 24,850 (62.5%) C0 vs. 15,492 (61.5%) P0 patients received RAI. Patients with P0 nodes were more likely to have negative surgical margins and multifocal disease (all p < 0.001). Mean number of negative nodes reported in surgical pathology specimens was 4; ‡ 5 pathologically negative nodes provided the best cut point associated with reduced RAI administration (OR 0.91, CI 0.85-0.97). After multivariable adjustment, P0 patients with ‡ 5 nodes examined were 11% less likely to receive RAI compared to C0 patients across all ages (OR 0.89, p < 0.001), and 14% less likely to receive RAI if aged < 45 years (0R 0.86, p = 0.001). Patients with fewer than 5 P0 nodes did not differ in RAI use compared to C0 controls. Pathological confirmation of negative lymph nodes in patients with PTC appears to influence the decision to administer RAI if ‡ 5 negative lymph nodes are removed in a surgical specimen. It is possible that fewer excised lymph nodes may be viewed by clinicians as incidentally resected, and thus not representative of the true nodal status of the central neck.

Short Oral Communication 502 Thyroid Nodules & Goiter Wednesday Short Oral Communication Clinical 4:12 PM SHALL WE TEMPORARILY HOLD ANTIPLATELET AND ANTICOAGULANT AGENTS BEFORE PATIENTS UNDERGO FNA OF THYROID NODULES? H.S. Bajaj1, E. Sharma2, B. Singh1, J. Jaura1, A. Chadha1, D. Markandey1, Y. Wu3 1 LMC Diabetes & Endocrinology, Brampton, ON, Canada; 2University of Guelph, Guelph, ON, Canada; 3School of Public Health, University of Hawaii, Manoa, HI Current guidelines and clinical practice recommendations do not suggest holding antiplatelets/anticoagulants (Blood thinners - BT) prior to fine needle aspirations (FNA) of thyroid nodules. Evidence looking at the role of these drugs (eg. Aspirin and Warfarin) in causing blood aspirate and their subsequent effect on diagnostics remains inconclusive. The aim of this study was to investigate the correlation, if any, between antiplatelet and anticoagulant medication and diagnostic yield with FNA cytology. This is a retrospective cohort analysis comparing FNA cytology of patients with and without BT. We assessed 547 available cytology reports read by a single cytopathologist; amongst 556 patients - all of whom had ultrasound-guided (US) FNA procedure performed by a single endocrinologist certified in neck ultrasound from November 2009 to May 2014. A total of 46 patients were on aspirin therapy and one was on warfarin. The average age of the cohort was 54 years with 457 being female and 99 male. Cytology was standardized into five categories based on the Bethesda classification: 74.6% of the samples were benign; 15.7% were nondiagnostic; 4% were reported as suspicious for malignancy or as malignant; 2.9% were indeterminate; and 2.7% showed atypia of undetermined significance. Logistical regression comparisons for anticoagulant use among the cohort, with

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adjustment of the confounders in a multivariate modeling, were carried out using R version 3.1.2. The nondiagnostic rate was 13.8% among the 509 patients on no BT treatment, whereas 34% out of the 47 individuals on BT had nondiagnostic cytology (odds ratio = 2.99, p-value = 0.0012). After adjusting for confounding variables including cystic ultrasound features and cystic aspirate on FNA, these results remained statistically significant. The use of aspirin was independently associated with nondiagnostic FNA cytology (Table). Antiplatelet/Anticoagulant medications may significantly increase the nondiagnostic rate of FNA cytology. A routine recommendation to hold these drugs temporarily prior to US-guided FNA procedure should be considered, if deemed medically safe in an individual patient.

Short Oral Communication 503 Thyroid Cancer Wednesday Short Oral Communication Clinical 4:18 PM THE INTERNATIONAL ANAPLASTIC THYROID CANCER TISSUE BANK AND DATABASE PROJECT (INATT) L. Moss Clinical Oncology, Velindre Cancer Centre, Cardiff, United Kingdom Anaplastic thyroid cancer (ATC) is very difficult to research due to rarity (*80 cases/year in UK) and associated short prognosis (average 2–6 months with 1year). This combination makes randomised clinical trials notoriously difficult. iNATT has been developed to facilitate research opportunities by providing a source of tissue, blood and clinical data. iNATT is hosted by the Wales Cancer Bank, funded by Thyroid Cancer Support Group Wales and sponsored by Velindre NHS Trust. It opened to recruitment in the UK in October 2013. All patients with ATC are eligible and can be approached at any stage in their cancer journey. Patients are asked to donate surplus thyroid cancer tissue along with an optional EDTA blood sample and clinical data. The project is expected to run for at least 5 years. Research proposals are invited from academia and industry and are reviewed by the iNATT Steering Committee comprising scientists and clinicians. The project is inclusive and simple, to optimise recruitment. Cinical data fields include mode of presentation, treatment interventions and survival plus details on tracheostomy

WEDNESDAY, OCTOBER 21, 2015 and enteral feeding. Outcome data is collected at 6, 12, 18 months then annually. Consent can be taken in person as well as via telephone, videolink and Skype. Ethical approval has been granted to allow use of tissue from deceased patients where it is felt the patient would have wished to participate had they known about the project and the family are in support. iNATT is supported by the National Cancer Research Institute Thyroid Cancer Subgroup in the UK. A good geographical spread of participating centres has been developed and international centres are now being encouraged to join. Feedback from patients and their relatives has been very positive. iNATT breaches a gap between the current lack of effective therapies and the need to develop randomised clinical trials. It has the potential to improve our understanding of the aetiology and progression of this disease and ultimately aid the development of new therapies. International collaboration will increase the rate of sample collection and any interested parties are encouraged to contact the chief investigator.

Short Oral Communication 504 Thyroid Cancer Wednesday Short Oral Communication Clinical 4:24 PM INCIDENCE OF NON THYROIDAL PRIMARY MALIGNANCY (NTPM) AND THE ASSOCIATION WITH I-131 TREATMENT IN PATIENTS WITH DIFFERENTIATED THYROID CANCER (DTC) D. Hirsch1,2, A. Gorshtein1,2, E. Robenshtok1,2, I. Shimon1,2, C. Benbassat1,2 1 Endocrinology, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel The risk of Non Thyroidal Primary Malignancy (NTPM) associated with I-131 treatment (RAI) in DTC patients is an important concern. Yet, data regarding the incidence of NTPM following RAI are conflicting. Our aim was to investigate the incidence of NTPM and the association with RAI treatment in a cohort of DTC patients treated at a single tertiary medical center. We cross-matched data of 1945 patients form the Rabin Medical Center Thyroid Cancer Registry with data from the Israeli National Cancer Registry for diagnosis of NTPM. Medical records were reviewed. SPM was defined as new malignancy diagnosed at least 2 years after DTC diagnosis. Mean follow-up was 9.3 years. (a) A total of 410 NTPMs were identified in 370/1945 (19%) DTC patients (females 266/370, mean age 53.9 – 15). Of these, 174 (42.4%) were defined as SPM. (b) Of 1937 patients with data, 1570 (81.1%) received RAI treatment and 367 (18.9%) did not. The rates of SPM in the two groups were 132 (8.4%) and 42 (11.4%), respectively. (c) First and cumulative RAI doses in those with/ without SPM were 103 – 49 vs 115 – 46 mCi and 186 – 172 vs 166 – 131 mCi, respectively. SPM rates after cumulative dose 100mCi were 49/437 (11.2%) and 65/663 (9.8%), respectively. (d) The hazard ratio of SPM in patients after RAI treatment compared to untreated patients, adjusted for age and gender, was 0.79 (95% CI 0.6-1.1) and 1 (95% CI 0.9-1), respectively, and no correlation was found between first or cumulative RAI dose and the diagnosis of SPM (g) The common sites for NTPM (and SPM) were breast in 101 patients (50), gastrointestinal 44 (18), melanoma 33 (11), hematologic 53 (20), prostate 26 (16), lung 23 (16), urinary tract 38 (18), parotid 8 (3). NTPM in DTC patients is not uncommon and antecede DTC in most cases. Our data do not support a carcinogenic effect of RAI.

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015

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Wednesday, October 21–Thursday, October 22, 2015 Poster 505 Autoimmunity Wednesday & Thursday Poster Basic 9:00 AM MULTICENTER STANDARDIZATION OF A TSH RECEPTOR STIMULATING ANTIBODY BIOASSAY T. Diana1, Y. Li2, M. Lehmann1, M. Kanitz1, H. Kim2, P. Olivo2, G.J. Kahaly1 1 Johannes Gutenberg University Medical Center, Mainz, Germany; 2 Quidel Corp, San Diego, CA Subsequent to a monocenter calibration of an FDA-cleared TSHreceptor (TSHR) stimulating antibody (TSAb) bioassay with an international standard (IS), verification and validation were tested across an American and a German lab. TSAb was measured using CHO cells expressing a chimeric TSHR. The second IS (NIBSC code 08/204,113 mIU per Ampoule, monoclonal TSAb, M22) was applied for calibration. All samples were prepared in one lab and distributed for testing. For verification, two users per lab measured the IS dose-response curve and 13 subject samples (3 high, 3 moderate, and 3 low TSAb positive as well as 4 normal controls) with 3 cell lots over 3 days. Validation of the bioassay was achieved by measurement of the same patient serum with one cell lot and one user per lab over 20 consecutive days. The IS dose-response curve was generated using two-fold concentrations from 0.3125 to 200 mIU/L. Specimen-to-reference ratio (SRR%) values of the standard curve were mean – SD: 45 – 11, 49 – 12, 58 – 15, 75 – 16, 124 – 33, 185 – 45, 280 – 54, 392 – 95, 465 – 100, 558 – 128 and 614 – 181. Overall CV% was 19-26%. For conversion, the linear IS calibration curve from 5 to 80 mIU/L was used. Calibration curves showed high R2 values > 0.95. Measurements of low TSAb positive samples were 5–25 mIU/L. CV% values were 11–21% and 16-21% in the two labs, respectively. Moderately high TSAb samples ranged from 25–80 mIU/L while the CV% values were 20–25% and 19–24%, respectively. High positive TSAb samples were above the linear range ( > 80 mIU/L) of the calibration curve and required further 1:2 dilution steps for conversion. Inter-cell-lot variance was prominent with CV% values of 2–8% and 4–20% in the low and moderate TSAb areas, respectively. Furthermore, CV% values of the validation measurements were 9–22% and 16–24%, respectively. Across both laboratories, CV% values were 14–23% and 36–39% for low and moderately positive TSAb samples. The multicenter standardization of the TSAb bioassay shows a steady performance and allows conversion of the SRR% values in IU. This will significantly facilitate comparison of results with conventional TSHR binding immunoassays and between laboratories performing TSHR bioassays.

Poster 506 Autoimmunity Wednesday & Thursday Poster Translational 9:00 AM THYROID BLOCKING ANTIBODIES ARE HIGHLY PREVALENT IN AUTOIMMUNE THYROID DISEASE T. Diana, J. Krause, M. Kanitz, G.J. Kahaly Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany Functional TSH receptor (TSHR) autoantibodies are causative for the pathogenesis of autoimmune thyroid diseases (AITD). Since role and prevalence of TSHR blocking autoantibodies (TBAb) are poorly

defined, we looked for both presence and clinical relevance of TBAb in a large collective of AITD patients and healthy controls. Serum blocking and stimulatory (TSAb) autoantibodies were measured with two cell-based bioassays that utilize Chinese Hamster Ovary cells expressing a chimeric TSHR and a cAMP response element-dependent luciferase. Blocking activity was defined as percent inhibition of luciferase expression relative to induction with bovine TSH alone (cut-off >40% inhibition). Results of TSAb activity were reported as percentage of specimen-to-reference ratio (SRR%, cutoff >140%). A total of 1808 subjects were investigated. All 302 healthy euthyroid controls were TBAb (–15.05 – 30.8% inhibition) and TSAb (SRR% 53 – 16) negative. In contrast, TBAb were present in 124/ 1506 (8.2%) patients with AITD. Of these 124 (115 female) TBAb positive patients, 80/706 (11.33%) and 44/800 (5.5%) had Hashimoto’s thyroiditis (HT) and Graves’ disease (GD), respectively. Mean serum TBAb values differed in HT (65.78 – 23.16% inhibition) versus GD (79.97 – 17.95%, p = 0.0008). Ten patients with AITD (one with thyroid-associated orbitopathy) were both TBAb (51.9 – 10.5% inhibition) and TSAb (SRR% 173.6 – 23) positive. A total of 62/124 (50%) TBAb positive patients showed values >70% inhibition, 11/124 (8.9%) 61–70%, 17/124 (13.7%) 51–60%, and 34/ 124 (27.4%) patients showed inhibition values of 40–50%. All serum TBAb levels >50% inhibition were reproducibly confirmed and thyroid binding inhibitory immunoglobulin positive (TBII, automated binding ECLIA assay) while 20–25% of TBAb levels with 40– 49% inhibition showed variable results. Serum TBAb levels showed 74.25 – 23% inhibition in 68/124 (54.8%) hypothyroid patients (baseline serum TSH 21 – 41.6 mU/L), 68.47 – 22.3% inhibition in 27/124 (21.7%) euthyroid patients (TSH 1.75 – 1.16mU/L), and 59.77 – 17.57% inhibition in 4/124 (3.2%) thyrotoxic patients (TSH 0.03 – 0.03 mU/L). Serum TBAb are highly prevalent in AITD patients, foremost in those with HT.

Poster 507 Autoimmunity Wednesday & Thursday Poster Basic 9:00 AM THE EFFECTS OF GLUCOCORTICOID INCREASING FACTORS ON THE PATHOGENESIS OF AUTOIMMUNE THYROID DISEASES S. Zhao Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China., Tianjin, China Glucocorticoid increasing factors (GIFs) can regulate endocrinology system through hypothalamus-pituitary-adrenal axis. The feedback loop GIF-HPA plays an important role in the pathogenesis of autoimmune thyroid diseases. We aim to observe the effects of the level of GIFs in the serum on the GIF-HPA feedback loop and on the induction of EAT, in addition, to further understand the pathogenesis of AITD. EAT was induced by immunization with thyroglobulin in EAT susceptible (Lewis) and unsusceptible (Wistar) rats. The pathological changes in thyroid, the levels of cortisol and GIFs (IL-1b, IL-6) and the titers of TPOAb in the serum were determined at different time, i.e, 3–4 hours after the first immunization, 8–12 hours after the first immunization and two weeks after the last immunization.

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Both the incidence of EAT and the level of infiltration of lymphocytes in thyroid of Lewis rats were much higher than those of Wistar rats. At the time of 3–4 hours after the first immunization, the levels of cortisol of Lewis rats just showed a mild increasing and no more changes could be seen at later time. Of Wistar rats, the levels of cortisol increased remarkably and even were two folds of the baseline at the time of 8–12 hours after first immunization. The pattern of the dynamic changes of the levels of GIFs (IL-1b, IL-6) in both rats were consistent with that of the changes of cortisol respectively. The titers of TPOAb in the serum of Lewis rats were much higher than those of Wistar rats. Both the low production of GIFs and the discrepancy showed in the GIF-HPA feedback loop are possibly responsible for the different susceptibility of EAT. IL-1band IL-6 could influence the onset of AITD via GIF-HPA feedback loop.

Poster 508 Autoimmunity Wednesday & Thursday Poster Basic 9:00 AM IS THYROID AUTOIMMUNITY LINKED WITH VITAMIN D DEFICIENCY IN PREGNANCY? EVIDENCE FROM A COMMUNITY-BASED CROSS-SECTIONAL STUDY FROM NORTH INDIA S. Sethi1, S. Singh2, D. Raut3, N. Roy1, A. Mandal4 1 Community Medicine, Vardhman Mahavir Medical College and Safdurjung Hospital, New Delhi, India, New Delhi, India; 2National Organ and Tissue Transplant Organisation, New Delhi, India; 3 Family Welfare Training and Research Centre, Mumbai, India; 4 Pathology, Vardhman Mahavir Medical College and Safdurjung Hospital, New Delhi, India, New Delhi, India Presence of maternal thyroid antibodies is one of the leading causes of thyroid dysfunction in pregnancy. Recent studies have suggested an association between Vitamin D Deficiency (VDD) and thyroid autoimmunity (TAI), however there is paucity of literature exploring this relationship in pregnant women. The current study was thus designed as a cross sectional study to determine the prevalence of hypothyroidism, TAI and VDD among pregnant women, and to explore the association between Vitamin 25(OH)D and Anti-TPO Antibody (TPOAb) levels. Complete enumeration method was used to select pregnant women residing in six villages of Delhi. Singleton pregnancies were included with no known history of any chronic medical or surgical disorders. An interviewer administered questionnaire was used to collect socio-demographic and clinical history. Clinical examination and blood sample collection was done. Vit. 25(OH)D was measured by Electrochemiluminescence and TPOAb by ELISA. VDD was defined as Vit. 25(OH)D upper limit of normal and cortisol post SST at cut-off value). Unconjugated hyperbilirubinemia can occur in severe pernicious anemia due to ineffective erythropoiesis as seen in our patient. Pancytopenia is sometimes present in severe megaloblastic anemia and in many case series from the Indian Sub-continent megaloblastic anemia is among the most frequent causes of pancytopenia. It is due to increased apoptosis of the hematopoietic cell precursors. A diagnosis of evolving APS II was made as the patient had autoimmune hypothyroidism, evolving adrenal insufficiency and pernicious anemia. Patient was given 75ug of Levothyroxine and Intramuscular Cyanocobalamin 1000 ug every 3 days for 6 doses. After 3 weeks of treatment, the laboratory parameters improved: Hb 8.1%; TLC 7300/ cc; Platelet: 160,000/cc and Total Bilirubin 1.6mg/dl. He was ad-

vised intramuscular Cyanocobalamin 3 monthly lifelong. He was advised stress dose of glucocorticoids and monitoring of serum cortisol on a regular basis as his adrenal insufficiency seemed to be evolving. Anti-21 hydroxylase antibody was not done as this was not available. This case shows that in APS II, sometimes the obvious symptoms of hypothyroidism and adrenal insufficiency may be absent, as the disease is insiduous in onset and progression. A high index of suspicion is needed in subtle or atypical presentations.

Poster 512 Autoimmunity Wednesday & Thursday Poster Clinical 9:00 AM PREVALENCE OF THYROID AUTOANTIBODIES IN CHILDREN AND ADOLESCENTS WITH THYROID NODULES: THE FUKUSHIMA HEALTH MANAGEMENT SURVEY Y. Ito1, S. Suzuki2,3, T. Fukushima2,3, S. Midorikawa3, T. Matsuzuka4, T. Ohhira3, M. Abe3, S. Yamashita3, A. Ohtsuru3, S. Suzuki2, H. Shimura1,3 1 Department of Laboratory Medicine, Fukushima Medical University, Fukushima-shi, Japan; 2Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima-shi, Japan; 3 Radiation Medical Science Center for the Fukushima Health Management Survey, Fukushima Medical University, Fukushima-shi, Japan; 4Department of Otolaryngology, Fukushima Medical University, Fukushima-shi, Japan Fukushima Prefecture has started Thyroid Ultrasound Examination Program as a part of Fukushima Health Management Survey after the accident of the Fukushima Dai-ichi Nuclear Power Plant. Antithyroglobulin (TgAb) and anti-thyroid peroxidase (TPOAb) antibodies were measured in the confirmatory examinations in this program for participants with thyroid nodules more than 5.0 mm and cysts more than 20.0 mm in diameter. Although autoimmune

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thyroiditis is the most common thyroid disorder in the pediatric age range, prevalence of thyroid autoantibodies in the pediatric population has not been well known. The aim of this study was to assess the prevalence of thyroid autoantibodies and its relationship with sonographic findings in children and adolescents with thyroid nodules in Fukushima. This study was a cross-sectional study between October 2011 and March 2014. 1747 children and adolescents (597 males and 1130 females) were subjected to this study. The age of subjects ranged from 2 to 21 years, and the median age was16 years. Serum TgAb and TPOAb were determined by electro-chemiluminescence immunoassays. TgAb, TPOAb, and either antibody were positive in 13.7%, 9.7%, 16.3% of the subjects, respectively. There were significant differences in prevalence of TgAb, TPOAb, and either antibody between male and female subjects. However, age-dependent increase in positivity ratio of TgAb or TPOAb was not observed. 32.6% and 33.3% of subjects with positive TgAb or TPOAb exhibited sonographic features suggesting diffuse thyroid disorders, respectively. In addition, the prevalence of TgAb in subjects who were classified as malignancy or suspicious for malignancy was significantly higher than that with other classifications. However, there was no significant difference in positivity of TPOAb. Results in this study suggest the prevalence of thyroid autoantibodies in children and adolescents with thyroid nodules are comparable to those in adult population. It was suggested that approximately one third of autoantibody-positive subjects exhibited diffuse histological alterations. Association between TgAb and thyroid cancer was also shown in the pediatric population.

Poster 513 Autoimmunity Wednesday & Thursday Poster Clinical 9:00 AM THE PRESENCE OF THYROID-STIMULATION BLOCKING ANTIBODY PREVENT HIGH BONE TURNOVER IN UNTREATED PREMENOPAUSAL PATIENTS WITH GRAVES’ DISEASE S. Moon1, S. Cho1, J. Bae1, Y. Hwangbo1, Y. Song1, J. Moon1, K. Jung1, Y. Kim1, M. Moon1, K. Yi1, J. Chung3, Y. Park1, D. Park1, B. Cho2 1 Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul, Korea (the Republic of); 2Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea (the Republic of); 3Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Korea (the Republic of) Osteoporosis-related fracture is one of the complications of Graves’ disease. This study hypothesized that the different actions of thyroidstimulating hormone receptor (TSHR) antibodies, both stimulating and blocking activities in Graves’ disease patients might oppositely impact on bone turnover. Newly diagnosed premenopausal Graves’ disease patients were enrolled (n = 93) and divided into two groups: patients with TSHR antibodies with thyroid-stimulating activity (stimulating activity group, n = 83) and patients with TSHR antibodies with thyroidstimulating activity combined with blocking activity (blocking activity group, n = 10). From stimulating activity group, patients who had matched values of free T4 and TSH binding inhibitor immunoglobulin (TBII) to blocking activity group were further classified as stimulating activity-matched control (n = 11). Bone turnover markers, BS-ALP, Osteocalcin, and C-telopeptide were significantly lower in blocking activity group than stimulating activity or stimulating activity-matched control groups. TBII level showed positive correlations with BS-ALP and osteocalcin levels in stimulating activity group, while it showed negative correlation with osteocalcin level in blocking activity group.

In conclusion, the activation of TSHR antibody-activated TSH signaling contributes to high bone turnover, independent of the actions of thyroid hormone, and thyroid-stimulation blocking antibody has protective effects on bone metabolism in Graves’ disease.

Poster 514 Autoimmunity Wednesday & Thursday Poster Clinical 9:00 AM A NEW BIOASSAY FOR THYROID-STIMULATING ANTIBODIES (AEQUORIN TSAB) IN GRAVES’ OPHTHALMOPATHY Y. Hiromatsu1, N. Araki3, H. Eguchi1, J. Tani1, Y. Teshima2, K. Mitsuzaki1 1 Division of Endocrinology and Metabolism, Kurume University School of Medicine, Kurume, Japan; 2Department of Ophthalmology, Kurume University School of Medicine, Kurume, Japan; 3 Diagnostic Division, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan Graves’ ophthalmopathy (GO) is an autoimmune disorder characterized by the autoimmunity against thyroid-stimulating hormone (TSH) receptor in the orbit. The TSH receptor antibody (TRAb) are used for the diagnosis and assessment of GO. Recently a novel assay for thyroid-stimulating antibody (TSAb) has been introduced using a frozen Chinese hamster ovary cell line expressing the TSH receptor, cyclic adenosine monophosphate (cAMP)-gated calcium channel and aequorin (aequorin TSAb). The aim of the study is to evaluate the roles of the aequorin TSAb in GO. We studied 136 Japanese patients with GO (22 euthyroid and 8 hypothyroid Graves’ disease) in our hospital. TRAbs were measured by the 1st generation TRAb (TRAb1st, TRAb Cosmic III kit, Cosmic Co, Japan), the 2nd generation assay (hTRAb, DYNO test TRAb Human ‘Yamasa’, Yamasa Co., Japan) and the conventional TSAb kit ‘Yamasa’, (Yamasa) and the new aequorin TSAb assay (Otsuka Pharmaceutical Co., Japan). The informed consents were obtained from patients and the institutional approval was obtained from the Kurume University School of Medicine. The aequorin TSAb, conventional TSAb, TRAb1st and hTRAb were positive in 125/136 (92%), 110/136 (81%), 81/130 (62%) and 93/114 (82%), respectively. In hyperthyroid Graves’ disease those were positive in 98/106 (98%), 96/106 (91%), 78/101 (77%) and 84/ 93 (90%), respectively. In patients with euthyroid Graves’ disease those were positive in 19/22 (86%), 9/22 (41%), 1/21 (5%), and 6/17 (35%), respectively. In hypothyroid Graves’ disease those were positive in 8/8 patients (100%), 5/8 (63%), 2/8 (25%), and 3/4 (75%), respectively. The aequorin TSAb levels were significantly related to TRAb1st (r = 0.4172 P < 0.0001), hTRAb (r = 0.2592, P < 0.0001) and the conventional TSAb (r = 0.4665, P < 0.0001), but not for CAS. The aequorin TSAb assay was more sensitive than the conventional assays, especially in euthyroid Graves’ disease. This novel TSAb assay may be promising clinical implication for GO.

Poster 515 Autoimmunity Wednesday & Thursday Poster Clinical 9:00 AM EFFECT OF PATIENT SERA ON TYPE 2 5¢-DEIODINASE ENZYME ACTIVITY USING HUMAN THYROID, SKELETAL AND EYE MUSCLE TISSUE FRACTIONS IN HYPERTHYROID GRAVES¢ OPHTHALMOPATHY I. Molnar1, A. Szentmiklosi2, E. Somogyine-Vari1 1 Immunoendocrinology and Osteoporosis Centre, EndoMed, Debrecen, Hungary; 2Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 Ophthalmopathy manifests mainly in hyper- or hypothyroid Graves¢ disease highlighting the importance of type 2 5¢-deiodinase enzyme activity, which is responsible for T4 conversion to T3. The effect of patient sera on type 2 5¢-deiodinase activity was investigated using human thyroid, skeletal and eye muscle tissue fractions, in Graves¢ disease. The patient groups consisted of 52 patients with Graves¢ disease (15 without ophthalmopathy and 37 were hyperthyroid) and 33 patients with cardiac diseases (hypertension, ischemia) served as control. Eye muscle thickness were measured in 22 patients with ophthalmopathy. Type 2 5¢-deiodinase activity was investigated using 125I-T4 after blocking type 1 5¢deiodinase activity with propyltiouracil. Type 2 5¢-deiodinase activity was significantly lower in thyroid tissue fraction than in eye muscle one in hyperthyroid Graves’ ophthalmopathy (3.99 – 5.79 vs 7.66 – 11.19 pmol/mg/min, P < 0.05), whereas this value was 5.05 – 1.28 pmol/mg/min in control patients (P < 0.0001). The transition from hyperthyroidism to euthyroidism resulted in elevation of type 2 5¢-deiodinase activity in all tissue fractions in Graves¢ ophthalmopathy (P < 0.17 for thyroid, P < 0.015 for skeletal and P < 0.015 for eye muscle) and did not in those without ophthalmopathy. In hyperthyroidism, eye muscle type 2 5¢deiodinase activity correlated positively with eye muscle thickness (P < 0.001, r = 0.284), and negatively with FT3 serum levels (P < 0.005), as well as with the presence of thyroid peroxidase antibodies (P < 0.037). The thyrostatic therapy increased the type 2 5¢deiodinase activity in all tissue fractions, but the increase was significantly higher in eye muscle tissue fraction than those in controls (7.58 – 1.45 vs 18.29 – 14.21 pmol/mg/min, P < 0.04). The absence of antibodies to TSH receptor and thyroglobulin was associated with a relevant increase in 5¢-deiodinase activity of all tissue fractions with concomitantly decreased FT4 levels in Graves¢ ophthalmopathy. Conclusion:The higher type 2 5¢-deiodinase activity in eye muscle tissue seems to be involved in eye muscle enlargements via the thyroid hormone metabolism which is reflected by lower FT4 or FT3 serum levels in Graves¢ ophthalmopathy.

Poster 516 Autoimmunity Wednesday & Thursday Poster 9:00 AM CERTAIN HLA ALLELES ARE ASSOCIATED WITH GRAVES’ DISEASE (GD) IN PATIENTS IN WHOM HYPERTHYROIDISM IS PRECEDED BY STRESSFUL EVENTS (SE) R. Vita, D. Lapa, F. Trimarchi, S. Benvenga Department of Clinical & Experimental Medicine, University of Messina, Messina, Italy There are no studies on HLA alleles in GD patients whose initial or recurrent hyperthyroidism is preceded by ‡ 1 SE. We have enrolled 58 Caucasian GD patients (36 F, 22 M) in whom ‡ 1 SE preceded by £ 12 months the onset and the exacerbations [EXA, on antithyroid drugs (ATD)] or relapses (REL, off ATD), if EXA/REL occurred. Based on outcomes observed over a follow-up of ‡ 5 years (median 13, range 5–27) after ATD withdrawal, 3 groups were formed: remission (REM, patients with neither EXA nor REL; n = 15, 25.9%), EXA ( ‡ 1 EXA; n = 6, 10.3%) and REL ( ‡ 1 REL; n = 37, 63.8%). We performed serological HLA typing in all GD patients and in 130 Caucasians healthy controls. Differences between rates were analyzed with the v2 test or the exact Fisher’s test. Two HLA class I and three class II alleles were more frequent in patients compared to controls: B8 (13.8% vs. 3.1%, P = 0.006), Cw7 (63.8% vs. 32.3%, P = 0.0001), DR3 (17.2% vs 7.7%, P = 0.03), DR4 (27.6% vs. 10.8%, P = 0.002) and DQ2 (36.2% vs. 24.6%, P = 0.03).

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In contrast, two HLA class I alleles were less frequent: B14 (1.9% vs. 16.1%, P = 0.005) and Cw8 (1.7% vs. 10.8%, P = 0.04). Among GD patients, the following alleles were over or under-represented, depending on outcome. Cw7 was more frequent in the EXA (83.3%) and REL (72.2%) groups than in the REM group (40%, df = 2, P = 0.05). Both A28 and DR6 were more frequent (33.3% and 50%, df = 2, P = 0.007 and P = 0.05) in the EXA group than in the REL (3.1% and 15.6%) and REM (0% and 6.7%) groups. The Cw6 allele was more frequent in the REM group (40% vs. 0% of the EXA and 11.1% of the REL group, df = 2, P = 0.02), while B7 allele was more frequent in both the REM and EXA groups (26.7% and 33.3%) than in the REL group (3.1%, df = 2, P = 0.03). Among the 37 relapsers, B53 was detected only in those with ‡ 2 relapses (3/14, 21.4%), but in none of those with only one (0/23, P = 0.05). In conclusion, in patients with stress-related GD both class I and class II molecules are pathogenetically important. In addition, HLA typing may be helpful for predicting the outcome after ATD withdrawal.

Poster 517 Autoimmunity Wednesday & Thursday Poster 9:00 AM THE RATES OF CHRONIC LYMPHOCYTIC THYROIDITIS (CLT) DIAGNOSED AT FINE NEEDLE ASPIRATION CYTOLOGY (FNAC) OF THYROID NODULES IN EASTERN SICILY SHOW INTERPROVINCE AND INTRAPROVINCE GEOGRAPHICAL DIFFERENCES, MOSTLY ASSOCIATED WITH POLLUTION A. Latina2, R. Vita1, F. Di Bari1, T. Vicchio1, A. Bonanno3, A. Ieni3, G. Tuccari3, S. arena4, S. Benvenga1,2 1 Department of Clinical & Experimental Medicine, University of Messina, Messina, Italy; 2Interdepartmental Program of Molecular & Clinical Endocrinology and Women’s Endocrine Health, University Hospital, University of Messina, Messina, Italy; 3Department of Human Pathology ‘‘Gaetano Barresi’’, Section of Pathology, University of Messina, Messina, Italy; 4ASP 8 Siracusa, Department of Internal Medicine, Section of Endocrinology and Metabolic Diseases, Umberto I Hospital, Siracusa, Italy In a recent study (EJE, 2015) from the southernmost province of Sicily (Siracusa [SIR]) and spanning the years 2006–12, the rate of CLT at a FNAC service of an Endocrine Unit was greater in patients living in the petrochemical complex (PC) area compared to the control area (SIR city; 138/490 nodules [28.2%] vs. 157/833 [18.8%], P = 0.0001). In a FNAC service of an Oncology Unit from the northernmost province of Sicily (Messina [ME]), the CLT rate for years 2008–10 was 7.3% (Hormones, 2013), increasing to 11% in 2011 (unpublished). To compare SIR with ME more reliably, starting in September 2014 we wished to evaluate prospectively the CLT prevalence at our FNAC service in the Endocrine Unit of ME. Here we present data on the first 169 nodules punctured. Overall, the CLT rate was 32% compared to 22.3% of SIR (295/ 1323, P = 0.005). The CLT rate in ME city was 34.1% (31/91; P = 0.0006 vs. of 18.8% of SIR city). In the ME province area containing a PC and thermoelectrical power plant (TPP), the CLT rate was 40% (8/20; P = 0.25 vs. 28.2% of the equivalent area in SIR). Just west of this area, there is another area close to a garbage dump (GD), and in this area the CLT rate was 47.1% (8/17; P = 0.09 vs. the said 28.2% of SIR). Continuing moving west, the rate fell to 25% (4/16) in the hills/mountains and 22.2% (2/9) in the coast, but then increased again to 60% (3/5) in the westernmost coastal town of S.S. di Camastra, the major ceramic industry (CI) of northern Sicily. CLT was absent (0/8) in the eastern, Ionic Sea side of the ME province. In the Eolian islands, CLT rate was 1/2. If the described trends held upon

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accruing the cohort, ME province would have a very high prevalence of CLT at FNAC, in agreement with nonFNAC-based studies (Thyroid, 2008; PlosOne, 2013). The rate of CLT in areas of PC is 1.4X higher in ME province for the likely coexistence of a TPP, while the 1.7X or 2.1X higher CLT rate observed in areas of pollution associated with GD or CI suggests that such pollution is an even stronger environmental trigger of CLT. The 1.2X higher rate of CLT in ME city compared to the polluted area of SIR province suggests that environmental factors other than petrochemical pollution are being active in ME city.

Poster 518 Autoimmunity Wednesday & Thursday Poster 9:00 AM TYPE OF FISH CONSUMED AND SERUM THYROID AUTOANTIBODIES (TGAB, TPOAB) IN PREGNANCY AND EARLY POSTPARTUM (PP) S. Benvenga1, M. Vigo3, D. Metro2, R. Granese4, R. Vita1, M. Le Donne4 1 Department of Clinical & Experimental Medicine, University of Messina, Messina, Italy; 2Department of Biomedical, Morphological and Functional Sciences, University of Messina, Messina, Italy; 3 Department of Pediatric, Gynecological, Microbiological and Biomedical Science, University o Messina, Messina, Italy; 4Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, University of Messina, Messina, Italy Certain pollutants may trigger autoimmunity. One such pollutant is mercury, which accumulates in large, top predator fish. Fish consumption (FC) or supplementation with omega-3 fatty acids (x-3 FA) were reported to cure and/or prevent autoimmune disorders. However, a PubMed search upon entering ‘‘fish consumption and thyroid autoimmunity’’ returned no articles. We hypothesized that stable consumption of the x-3-rich oily fish (OF) was associated with a more favorable profile of serum TgAb and TPOAb compared with stable consumption of swordfish (SwF). As we are studying thyroid autoimmunity in women starting from gestation, we have elected to test this hypothesis in pregnant women. Here we present data on serum TgAb and TPOAb, that we prospectively measured in pregnancy (1st, 2nd trimester) and PP (day 4), in 236 thyroid disease-free, non-smoker women with stable dietary habits. Based on FC, women were divided into 4 groups: A (n = 48; SwF), B (n = 52; OF), C (n = 68; SwF + other fish, not necessarily OF), D (n = 68; fish other than SwF and OF). Major endpoints were positivity rates and serum levels of the two Ab. FC averaged 8 times a month in all 4 groups. The estimated monthly content (EMC) of x-3 FA in the fish consumed was the greatest in group B (13.2 – 5.4 g), which is higher (P < 0.001) than in each of the other groups (A = 6.3 – 2.1; C = 6.0 – 2.8; D = 5.1 – 3.8). In contrast, the EMC of mercury was the highest in group A (1000 – 300 lg), and the lowest in group B (26 – 12, P < 0.001). Groups A and B also differed for the EMC of lead (65 – 23 lg vs. 46 – 21, P < 0.001). At all three time points, positivity rates for serum TgAb or TPOAb were the highest in group A (25%, 16.7%, 12.5%, or 25%, 12.5%, 12.5%), and the lowest in group B (0%, 0%, 0%, or 0%, 0%, 0%), with intermediate rates in groups C and D. Similarly, serum levels of either TgAb and TPOAb were the highest in group A, the lowest in group B, and intermediate in groups C and D. In conclusion, we validated our hypothesis that consumption of the x-3 rich OF impacts favorably, but consumption of the mercuryrich SwF impacts unfavorably, on serum TgAb and TPOAb. As these Ab are markers of autoimmune-related PP problems, our data suggest a dietary prophylaxis of such problems.

Poster 519 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM THE MICROPAPILLARY/HOBNAIL PATTERN VARIANT OF PAPILLARY THYROID CARCINOMA (PTC) AT A SINGLE PATHOLOGY INSTITUTION: GREATER RATE, SMALLER SIZE AND MILDER SHORT-TERM COURSE COMPARED WITH TWO PREVIOUS SERIES OF LITERATURE. A. Ieni1, V. Barresi1, S. Benvenga2, G. Tuccari1 1 Departmert of Human Pathology, University of Messina, Messina, Italy; 2Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy Typically, PTC has a good prognosis with a 10-yr survival greater than 90%. However, rare variants of PTC exist, which feature tall or columnar cells. These rare subtypes are referred to as aggressive PTC variants, in that they portend an unfavorable clinical course. Recently, a micro-papillary pattern with hobnail appearance (MPHA) in PTC has been indicated as associated with poor prognosis, but this suggestion is based only on a few cases. A total of 295 consecutive PTC cases were reviewed. Of these, 242 (82%) were females, while 53 (18%) were males (F:M ratio = 4.7:1), with a mean age of 50 yrs (range 14–92). The corresponding histologic sections (at least 6 for each case) were stained with haematoxylin and eosin and reviewed independently by two pathologists to reach a consensus on the identification and quantification of the MPHA. Of the 295 PTC, 124 (42.5%) were codified as follicular variant, 104 (35%) as classic, 34 (11.5%) as sclerosing, 15 (5%) as tall cells, 10 (3.4%) as Warthin-like, and 8 (2.6%) as MPHA variant. In this last group, the F:M ratio was 6:2 (3:1), and mean age was 55 yrs. In 4/8 cases (50%) the MPHA-PTC was localized in the left thyroid lobe, and only in 1/8 (12.5%) it was bilateral. Coexisting lesions were only of two types: hyperplastic nodules (6/8 = 75%) or chronic lymphocytic thyroiditis (CLT; 2/8 = 25%). Pending more observations for this very rare entity, our rate of MPHA-PTC (2.7%) is 2X or 4X greater than that of the two previous series described from North America + North Italy (24/3535 [0.7%, P = 0.0002]) or Mexico (7/496 [1.4%], P = 0.19). Moreover, its prognosis, at least in the short term, appears to be milder compared to these two previous cohorts. Probably, the milder course in our cohort is due not only to the lower rate of the vascular invasion (50% vs. 71% (P = 0.40) but also to the smaller size of the MPHA-PTC nodule (median: 14.5 mm vs. 25; m – SD: 17.7 – 7.8 vs. 29.5 – 17.2, P = 0.067). Further investigations should also explore the significance of the coexistence with other benign lesions.

Poster 520 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM THE RATE OF CHRONIC LYMPHOCYTIC THYROIDITIS (CLT) / HASHIMOTO’S THYROIDITIS (HT) AT FINE-NEEDLE ASPIRATION (FNA) OF THYROID NODULES VARIES DEPENDING ON ULTRASOUND AND CYTOLOGICAL CLASS OF RISK OF HE NODULES S. Arena2, R. Baratta1, A. Latina3, S. Benvenga4,3 1 Department of Clinical and Experimental Medicine, Endocrinology Unit, Garibaldi-Nesima Hospital, Catania, Italy, Catania, Italy; 2 A.S.P. 8 Siracusa Department of Internal Medicine, Section of Endocrinology and Metabolic Diseases, Umberto I Hospital, Siracusa, Italy; 3Interdept. Program of Molecular & Clinical Endocrinology and Women’s Endocrine Health, University Hospital,

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 Messina, Italy; 4Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy The prevalence of HT varies considerably worldwide, and it appears to continue increasing most likely for environmental issues. This variability was confirmed for CLT diagnosed at FNA, and it may also depend on differences between different cohorts concerning the ultrasound (US) and FNA cytological characteristics of the thyroid nodule. We wished to analyse the relationship of CLT with such US and cytological class of risk. We investigated 2,376 thyroid nodules in 1,932 consecutive patients (females = 1,514; males = 418). US characteristics investigated were maximum diameter, echotexture (isoechoic, n = 1,681; hypoechoic, n = 695) and microcalcifications (MC). Using the THY coding of our country, FNA stratification was into low risk (THY2 + THY3A, n = 1,928) or high risk of malignancy (THY3B + 4 + 5, n = 448 or THY3B + 4 + 5 = 448). THY3A and THY3B correspond to the AUS/ FLUS and follicular neoplasm categories of the Bethesda system. Uniand multivariate logistic regression analysis were performed. CLT was detected in 23.6% of the 2.376 nodules, females: 26.1% and males: 14.0% (P < 0.0001). CLT rate was greater in the hypoechoic than isoechoic nodules (34.0% vs 19.4%, P < 0.0001). CLT + ve nodules were smaller than the CLT-ve ones (15.5 – 6.5 vs 17.5 – 8.4 mm, P < 0.0001). MC were significantly (P < 0.01) higher in CLT + ve (33.3%) than in CLT-ve nodules (23.1%). CLT rate was greater in the FNA high risk category compared to the low risk (28.3% vs. 22.6%, P < 0.01). Except for MC (P = 0.20), multivariate logistic regression analysis confirmed the associations (P range = 0.001- < 0.0001). In conclusion, the inter-series variability of frequency of CLT at FNA may well depend from differing composition of the cohorts based gender, US characteristics (size, echogenicity, MC) and cytological class of risk of the nodules. The greater is representativity of females, smaller, hypoechoic, microcalcified and cytologically highrisk nodules, the greater will be the rate of CLT.

Poster 521 Autoimmunity Wednesday & Thursday Poster 9:00 AM THYROID RECEPTOR ANTIBODY (TRAB) AT DISCONTINUATION OF ANTI-THYROID DRUG THERAPY AS A PREDICTOR OF RELAPSE OF HYPERTHYROIDISM IN GRAVES’ DISEASE - A PROSPECTIVE ANALYSIS K.E. Stewart, C. Addison, V. Tsatlidis, S. Razvi Diabetes and Endocrinology, Queen Elizabeth Hospital, Gateshead, United Kingdom Clinicians and patients need a marker to predict the risk of relapse in Graves’ thyrotoxicosis. Thyroid receptor antibody (TRAb) at cessation of anti-thyroid drug (ATD) treatment has been postulated to be useful. Consecutive patients (n = 187) with Graves’ thyrotoxicosis, who were treated with ATDs for 12–18 months, and who were followed up for at least 12 months after ATD cessation were analysed prospectively. Patients were classified as relapse-free if serum TSH level was ‡ 0.4 mU/L at least 12 months post ATD cessation and having relapsed if TSH £ 0.4 mU/L and had raised thyroid hormone levels at any point post ATD cessation. Demographic, clinical and biochemical data were recorded. Cox regression analysis was performed to predict the variables that best predicted relapse. ROC analysis was also performed to measure area under the curve (AUC). Over a follow-up period of (mean – SD) 32 – 16 months 43% of patients relapsed. TRAb levels at the point of ATD cessation were the only predictor of relapse, independent of age, gender, smoking status, presence of orbitopathy and thyroid hormone concentrations. For each unit increase in TRAb at ATD cessation there was a 11% increase in risk of relapse, HR 1.11 (1.08–1.14), p < 0.001. ROC analysis showed

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that the AUC for TRAb at ATD cessation in predicting relapse was moderate 0.67 (0.60-0.75) p < 0.001. Younger age and duration of treatment with ATD predicted lower TRAb levels at ATD cessation. Graves’ disease is common and treatment with ATDs offers the best chance for patients to be free of a lifelong tablet burden. Clinicians are currently unable to predict accurately the risk of relapse in patients opting for ATD therapy. Our data shows that TRAb levels at ATD cessation provide the best estimate of predicting risk of relapse in Graves’ patients. This has the potential to personalise the management of individual patients in the future.

Poster 522 Autoimmunity Wednesday & Thursday Poster Clinical 9:00 AM SERUM LEVELS OF SELENIUM AND OTHER 18 KINDS OF TRACE ELEMENTS IN PATIENTS WITH GRAVES’ OPHTHALMOPATHY AND GRAVES’ DISEASE L. Shanshan, P. Sichen, W. Zhaojun, W. Teng, L. Yu-shu the first affiliated hospital of China Medical University, Shenyang, China Trace elements are closely related with health. We analyzed the serum levels of selenium and other 18 kinds of trace elements (including As, Ba, Cd, Cr, Cs, Mn, Pb, Ti, U, Ga, Ni, Sr, Cu, Zn, Fe, Co, V and Rb) in patients with GO and GD to investigate the relationship between trace elements and diseases. We recruited 243 patients from our out-patient clinic, First Hospital of China Medical University. 65 patients were GD hyperthyroidism without GO (GD group); 55 GD patients had normal thyroid function without GO (eGD group); 57 patients with GO had normal thyroid function (GO group); and 66 healthy controls were from medical examination center (con group). ICP-MS method were used to measure the serum levels of trace elements. Among the 19 kinds of trace elements, 9 of them could be detected (including Se, Fe, Rb, Cs, Sr, Cu, Zn, Co and V), and 7 of them (including Se, Cs, Sr, Cu, Zn, Co and V) had statistical differences among groups. GD group and GO group (no matter with or without ophthalmopathy) had lower serum level of Cs, Se, Zn, and V compared with con group (p < 0.05). Only GO group had lower serum level of Cu and Co compared with con group (p < 0.05) ; Only GD group had lower serum level of Sr compared with con group (p < 0.05); GD group had lower serum level of Sr and Zn compared with eGD group (p < 0.05). Serum Se levels were same in GD and GO groups. By comparing mean serum Se levels in positive and negative group of the thyroid autoantibodies (including TPOAb, TgAb and TRAb), no significant differences were seen (P > 0.05) in both GD and GO patients. Serum selenium levels and trace elements Cs, Zn and V levels are lower in patients with GD (with or without GO) compared with control. Those trace elements may play a role in patients with GD and GO.

Poster 523 Autoimmunity Wednesday & Thursday Poster Clinical 9:00 AM QUALITY OF LIFE AND COGNITIVE FUNCTION IN PATIENTS WITH GRAVES DISEASE DURING HYPERTHYROID, EUTHYROID AND HYPOTHYROID TREATMENT PHASES: RESULTS FROM A PRELIMINARY STUDY C.M. Riguetto, A.M. Neto, V.P. Miguel, V.P. Souza, M.A. Tambascia, D.E. Zantut-Wittmann Endocrinology Division, Internal Medicine Department, Faculty of Medicine of University of Campinas, Campinas, Brazil

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Thyroid hormones play an essential role in regulating mood and cognition. Since Graves’ disease (GD) is associated with poor quality of life and complaints of cognitive dysfunction, especially in the thyrotoxic phase, we aimed to analyze quality of life and prevalence of cognitive dysfunction in patients with GD, during the three phases of hyperthyroidism, hypothyroidism and euthyroidism. A cross-sectional study was conducted on 55 patients with GD. Investigation consisted of four questionnaires: Medical Outcome Study 36-item Short-Form Health Status Survey (SF-36), Graves’ ophthalmopathy quality of life (GO-QoL), Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE). Serum samples for measurement of TSH, free thyroxine and free triiodothyronine were collected in all patients at the moment of quality of life and cognitive assessment. Median age, school time and disease duration were 44 years (interquartile range 37–51), 8 years (5–11) and 5 years (3–7), respectively. Forty-four (80%) were female, 28 (50.9%) had Graves’ Ophthalmopathy, but only 8 (14.5%) active; median visual functioning and psychosocial function total scores were 92.85 and 50, respectively. Thirty-eight patients (69.1%) were euthyroid, 10 (18.2%) hyperthyroid and 7 (12.7%) hypothyroid during assessment. Cognitive function with MMSE and MoCA showed no differences between groups. Median MMSE/MoCA total scores in euthyroid, hyperthyroid and hypothyroid patients were, 29.0 (27.0–30.0)/25.0 (21.0–27.0), 30.0 (25.5–30.0)/25.5 (19.25–27.25) and 29.0 (29.0–30.0)/22.0 (20.0–25.0), respectively. In SF-36, the hyperthyroid group showed lower scores in most domains compared to the euthyroid and hypothyroid groups. Hyperthyroid patients showed statistically significant differences in physical functioning (85 vs. 100; p = 0.015) and limitations in physical aspect (50 vs. 100; p = 0.049), when compared to the hypothyroid group. A preliminary study in a small group of patients with GD showed significant differences in quality of life, but not in cognitive dysfunction evaluation, between hyperthyroid and hypothyroid patients.

Poster 524 Autoimmunity Wednesday & Thursday Poster Clinical 9:00 AM PAPILLARY THYROID MICROCARCINOMA CO-EXISTS WITH HASHIMOTO’S THYROIDITIS: IS REAL-TIME ELASTOGRAPHY STILL USEFUL? Y. Li, W. Yan, Q. Wu, B. Hu Department of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai; Shanghai Institute of Ultrasound in medicine, Shanghai, China Hashimoto’s thyroiditis (HT) is a very common autoimmune thyroid disease and according to reports of surgery samples of differentiated

thyroid carcinomas, 10*58% of them were accompanied by HT. Ultrasound elastography (UE) is a new method to facilitate conventional US by evaluating the elasticity of tissue.In our study, we will recruit nodules smaller than 10 mm with or without HT. We will focus on the performance of real-time elastography in differentiating PTMC combined with HT. Conventional ultrasound scan (US) and ultrasound elastography (UE) were performed on 558 nodules smaller than 10 mm before surgery by Dr. WANG. Serum concentrations of thyroid peroxidase antibody (TPO-Ab) (normal range 60 U/ml) were measured. Continuous variables were analyzed by independent t test. Receiver operating characteristics (ROC) curve analysis was applied to calculate the cut-off values of SR and ES. The comparison of AUCs is performed by Z test. 482 nodules were diagnosed as PTMC and there are 181 nodules co-existed with HT. SR measurements were lower in PTMC co-existed with HT when comparing those without HT.

a: SR of papillary thyroid carcinoma without HT is 4.18(upper), whereas SR of papillary thyroid carcinoma with HT is 2.3. b: SR of nodules with HT is negatively correlated to TPO-Ab titer. c: Taking the data from all of the 558 nodules as integrity, the best cut-off of diagnosing malignancy was SR > 2.58, ES > 3. d: Taking the data from 181 nodules with HT as integrity, the best cut-off of diagnosing malignancy was SR > 2.10, ES > 3. e: The diagnostic value of SR and ES were higher than conventional US (z = 1.058, 6.899, p < 0.001) and diagnostic value of SR > 2.58 was also higher than ES > 3 (z = 0.474, p < 0.001). f: In the nodules co-existed with HT, the diagnostic value of SR > 2.1 were higher than ES > 4 and conventional US (z = 3.595, 4.876, p < 0.001), and cut-off of SR > 2.1 did not show significant enhance of diagnostic value compared to SR > 2.58 (z = 0.439, p = 0.8903 > 0.001)

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 (7.292 – 6.581 vs 11.319 – 13.155, p < 0.000). Taking the data from all of the 558 nodules as integrity, the best cut-off of diagnosing PTMC was SR > 2.58. When taking the data from 181 PTMC with HT as integrity, the best cut-off was SR > 2.10. The diagnostic value of SR > 2.1 were higher than ES > 3 and conventional US (z = 3.595, 4.876, p < 0.001), but cut-off of SR > 2.1 did not show significant enhancement of diagnostic value compared to SR > 2.58 (z = 0.439, p = 0.8903 > 0.001) in PTMC with HT. There is a negative relation between SR and titer of TPOAb(r = -0.650, p < 0.0001). Although SR measurements were lower in PTMC co-existed with HT when comparing with those without HT, using a regular ES and cut-off of SR measurement would not influence the diagnosing performance. UE is still very useful tool for diagnosing PTMC with HT.

Poster 525 Autoimmunity Wednesday & Thursday Poster Clinical 9:00 AM PREVALENCE OF HASHIMOTO THYROIDITIS IN TYPE 1 DIABETES ADULTS M.M. Oliveira, P. Tavares, S. Monteiro, P. Rodrigues, A. Sousa, E. Lemos, I. Duarte, B. Sobral, A. Tavora, C. Guerra, G. Rocha Endocrinology, Centro Hospitalar Vila Nova de Gaia, Porto, Portugal The prevalence of autoimmune diseases is high in type 1 diabetes mellitus (DM1) patients. Autoimmune thyroid disease, especially Hashimoto thyroiditis (HT) is the most prevalent. The diagnosis depends of the presence of serum peroxidase antibodies (TPOAb) and inflammatory structural changes identified by a variety of sonographic criteria. The aim of this study was to evaluate the presence of TPOAb, thyroid dysfunction (TD) and some parameters in thyroid sonography like volume, echogenicity, sonographic texture, nodules and vascularity, in DM1 patients, and to assess a possible correlation between glycemic control (HbA1c), TPOAb positivity and structural changes. The study included 150 DM1 patients, 76 male (50,7%) with an average age of 34 years (18–61) who have had DM1 for 14,14 years (1–43), with a BMI 24,58 Kg/m2 (17,3-39). TPOAb, TSH, HbA1c were determined and a thyroid sonography was performed in a unique scanner by the same operator. In 6 patients it was not possible to obtain TPOAb, those were excluded from further analysis. TPOAb was positive in 33 (22,9%) patients. Prevalence of TPOAb was significantly higher in women (31% vs 15,1%; p = 0,029) but was not related to patient age, BMI, HbA1c and longstanding DM1. Hypoechogenicity, heterogeneity, abnormal volume, pseudonodular and micronodular hypoechoic infiltration were associated significantly with TPOAb positivity (p < 0,05). There were no significant correlations between the other sonographic variables (vascularity and the presence of nodules). Hypothyroidism was significantly more prevalent in patients with positive TPOAb (39,4% vs 14,5% p = 0,003). Negative TPOAb patients with hypothyroidism did not have any sonographic changes. After excluding patients with TD, a significant difference in TSH levels between TPOAb positive and negative group was not found. Higher TPOAb prevalence is found in DM1 than in general population, and occur more often in women. Sonography is a noninvasive diagnostic imaging modality that provides information about the inflammatory activity and is useful for identifying patients at risk for developing TD. Screening for asymptomatic TD with TSH and TPOAb should be performed in this group.

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Poster 526 Autoimmunity Wednesday & Thursday Poster Clinical 9:00 AM HIGHER PREVALENCE OF THYROID CANCER IN PATIENTS WITH THYROID NODULES (TN) AND HASHIMOTO’S THYROIDITIS (HT) AT THE FIRST CLINICAL EVALUATION COMPARED TO TN PATIENTS WITHOUT THYROID AUTOIMMUNITY AND HT PATIENTS WITHOUT TN FOLLOWED-UP FOR 1-9 YEARS F. BOI1, C. Serafini1, N. Arisci1, C. Satta1, S. Casula1, S. Scudu1, F. Pani1, M. Lai2, S. Mariotti1 1 Department of Medical Sciences ‘‘M. Aresu’’, University di Cagliari, Endocrinology, Monserrato - Cagliari, Italy; 2Department of Citomorphology, University of Cagliari, Cagliari, Italy Several studies suggest a significant association between Hashimoto’s thyroiditis (HT) and thyroid cancer, but this relationship needs confirmation. In this study we compared the prevalence of thyroid cancer in HT associated to thyroid nodules vs HT without thyroid nodules at the first diagnosis and during the follow-up. A total of 484 patients with a diagnosis of HT at their first clinical evaluation were subdivided into two groups: 243 HT patients without thyroid nodules (HTN-) and 241 with one or more nodules (HTN + ). FT3, FT4, TSH Tg/TPO-autoantibodies and thyroid ultrasound were performed in all cases; fine needle aspiration cytology (FNAC) were performed in 155 patients with TN and 74 patients underwent surgery. This last group was compared to a group of 161 patients with TN submitted to FNAC without any evidence of associated thyroid autoimmunity (NHTN + ). HTN + patients had higher prevalence of suspicious/malignant cytology (Tir 4-5) (HTN + 44/152 = 28.9%) compared to NHTN + patients (12/161 = 7.4%, p < 0.0001). In the group submitted to thyroidectomy, malignant histology was found in 48/74 (64.9%) HTN + and in 16/37 (43.3%) NHTN + patients (p < 0.05). The histotype distribution was 44 papillary (PTC), 2 follicular (FTC), 2 medullary (MTC) thyroid carcinomas in HTN + and 13 PTC, 2 FTC, 1 MTC in NHTN + patients, PTC being the only tumor significantly associated to HT. Interestingly, the prevalence of multicentric PTC was significantly higher (14.4%) in HTN + than in NHTN + (5.6%) patients (p = 0.0085). Finally, in the HTN- group, a minority (22/130 = 17%) of patients with available follow-up (1-9 years) developed one or more TN, but only 3 of them required FNAC which resulted benign (Tir-2) in all cases. None of these patients was submitted to thyroidectomy. This study confirms a higher prevalence of PTC in patients with HT associated to TN at the first clinical evaluation, compared to patients without thyroid autoimmunity. Conversely, no evidence of increased prevalence of thyroid malignancy was found in patients with HT without associated nodules at the first clinical evaluation during the first years of follow-up. This study might provide a clue to understand the association between HT and thyroid cancer.

Poster 527 Autoimmunity Wednesday & Thursday Poster Clinical 9:00 AM A STUDY OF SERUM IGG4 LEVELS IN CLINICAL METAMORPHOSIS OF AUTOIMMUNE THYROID DISEASE IN THAI PATIENTS Y. Thewjitcharoen1, S. Krittiyawong1, S. Porramatikul1, E. Wanothayaroj1, N. Lekpittaya1, J. Jeamjiraprasert2, S. Nakasatien1, T. Himathongkam1 1 Diabetes and Thyroid Center, Theptarin Hospital, Bangkok, Thailand; 2Division of Laboratory, Theptarin Hospital, Bangkok, Thailand

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WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015

Poster 528 Autoimmunity Wednesday & Thursday Poster Translational 9:00 AM SERUM LEVELS OF IL-17 AND IL-23 IN HASHIMOTO’S THYROIDITIS J. Guerenova1, I. Manolova2, S. Stanilova3 1 Department of Endocrinology, Medical Faculty, Trakia University, Stara Zagora, Bulgaria; 2Department of Health Care, Medical Faculty, Trakia University, Stara Zagora, Bulgaria; 3Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora, Bulgaria

A continuum between Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) exists within the spectrum of autoimmune thyroid disease (AITD). Measurement of serum IgG4 had been suggested to distinguish subtypes of AITD which had different clinical course from typical cases. Fluctuating AITD patients offer valuable opportunities for studying the predictive value of elevated serum IgG4 which might lead to innovative treatment in this special subset of AITD patients. A cross-sectional study was performed in 20 AITD patients who evolved from hyperthyroid Graves’ disease to spontaneous hypothyroidism or vice versa in Theptarin hospital, Bangkok, Thailand compared with 40 patients with hyperthyroid Graves’ disease, 40 patients with subclinical or overt hypothyroid Hashimoto’s thyroiditis, and 40 healthy subjects. Serum levels of total IgG and IgG4 were measured and the proportion of elevated serum IgG4 levels (defined by serum IgG4 levels ‡ 135mg/dL) was compared with control patients. A series of 20 Thai patients with clinical evolution of AITD was analyzed with a median follow-up at 92 months (range 3–380 months). There were 18 cases of evolved GD to HT and 2 cases of evolved HT to GD. In the patients of hyperthyroid GD who transformed into HT (16 women and 2 men, age 45.8 – 9.6 years), the median interval duration after discontinuation of anti-thyroid drugs was 8 years (range 0.5–22 years). Elevated serum IgG4 were found in 45.0% of fluctuating AITD patients, 40.0% of control GD patients, and 27.5% of control HT patients which were not statistically significant ( p = 0.331). None of the factors including age, sex, duration of AITD, smoking status, the presence of opthalmopathy, and thyroid auto-antibodies associated with elevated serum IgG4 levels. Interestingly, healthy control subjects revealed a wide variation of serum IgG4 level (range 2-431 mg/dL) and elevated serum IgG4 were found in 55.0% of healthy subjects. From our perspective, elevated serum IgG4 levels seem to reflect non-specific findings rather than separate forms of autoimmune thyroid disease. At present, clinical utility of serum IgG4 measurements in AITD is inconclusive and require further investigation.

Overproduction of proinflammatory cytokines plays a significant role in the maintenance of chronical inflammation and endothelial dysfunction of autoimmune Hashimoto’s thyroiditis (HT). Recent research has demonstrated a prominent role of newly discovered T helper (Th) 17 subset and its main cytokine interleukin (IL) - 17 in the induction of autoimmune disorders. Further work has shown that the signaling induced by IL-23 on Th17 cells is crucial to obtain a pathogenic and sustained phenotype. To provide the involvement of IL-23/IL-17 axis in pathologic processes and to clarify the role of IL-23 and IL-17 in different stages of disease activity we investigated fifty-nine patients with autoimmune thyroiditis: 24 patients with euthyroid HT (Group I), 9 patients with hypothyroid HT (Group II), and 26 subjects treated with Levothyroxine (Group III). Twenty-four healthy subjects were included as controls. Concentrations of IL-23 and IL-17 in the serum samples of patients and controls were evaluated by ELISA kits. Serum level of IL-23 was significantly higher in all HT patients (44.50 – 4.16 pg/ml) as well as in sub-groups of patients - in group I (34.43 – 4.61) group II (44.96 – 14.06) and group III (53.63 – 6.63) in comparison with controls (12.44 – 3.06, p < 0.05). Serum concentrations of IL-17 were not statistically different in group of Hashimoto’s thyroiditis patients (2.89 – 0.63 pg/ml) compared to controls (4.55 – 1.14), but in hypothyroid HT patients were measured significantly lower levels (1.40 – 0.51, p = 0.018). Our results suggest the involvement of IL-23/IL-17 axis in the development of HT and his severity. Moreover, upregulated secretion of IL-23 could be a biomarker for progression and monitoring of Hashimoto’s thyroiditis.

Poster 529 Disorders of Thyroid Function Wednesday & Thursday Poster Basic 9:00 AM EFFECT OF ALPHA LIPOIC ACID ON DELAYED DAMAGE IN IRRADIATED RAT THYROID MODEL J. Jung1, J. Han2, J. Jung1, S. Kim1, S. Woo3, B. Jeong4, J. Kim5, J. Hahm1, K. Kang4 1 Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea (the Republic of); 2Internal Medicine, Samsung Changwon Hospital, Changwon, Korea (the Republic of); 3 Otolaryngology, Gyeongsang National University School of Medicine, Jinju, Korea (the Republic of); 4Radiation Oncology, Gyeongsang National University School of Medicine, Jinju, Korea (the Republic of); 5Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, Korea (the Republic of) Exposure of the thyroid to radiation is often unavoidable, although the thyroid gland is a non-target organ during radiotherapy of head and neck cancers. Radiotherapy-induced thyroid disorders include hypothyroidism, thyroiditis, Graves’ disease, adenoma, and carcinoma. In our previous study, a-lipoic acid (ALA) attenuates radiationinduced acute injury in rat thyroid. The present study aims to

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 demonstrate more delayed protective effect of a-lipoic acid (ALA) on radiation-induced thyroid injury in long term period. Rats were assigned to four groups: controls (CTL), irradiated (RT), given ALA before irradiation (ALA + RT), and received ALA only (ALA, 100 mg/kg, i.p.). ALA was administered at 24 h and 30 minutes prior to irradiation. The neck area including the thyroid gland was evenly irradiated with 2 Gy per minute (total dose of 18 Gy) using a photon 6-MV linear accelerator. Rats were sacrificed on week 4 and 8 after irradiation. We evaluated activity index including follicular size, colloid density and cell height by H&E and PAS stain. We are also assessed the tissue fibrosis and expression of TGF-b1 and collagen. To investigate effect of ALA on radiation-induced oxidative stress, immunohistochemical staining for 8-OHdG and MDA and PCR for NOX subunit mRNA level were performed. And also, GSH level was measured. All of these were induced in RT group compared to other groups and ALA pretreatment ameliorates these expression, mRNA level, and GSH level induced by radiation. Therefore, this data provide that ALA pretreatment was effective not only acute injury but also delayed damage in irradiated rat thyroid model and ALA could be therapeutic drug for treatment of patients with thyroid injury during radiotherapy in head and neck.

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ges in io-PTH levels during thyroid surgery will most accurately predict patients who will require postoperative supplementation.

Poster 531

Disorders of Thyroid Function Wednesday & Thursday Poster Basic 9:00 AM INTRAOPERATIVE PTH LEVELS ARE PREDICTIVE OF POST-OPERATIVE HYPOCALCEMIA C.L. Pomeranz1, Z. Al-Qurayshi1, H. Mohamed1,2, R. Aslam1, P. Friedlander1, E. Kandil1 1 Surgery, Tulane University School of Medicine, New Orleans, LA; 2 General Surgery, State University of New York, Albany, NY

Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM A NOVEL PAX8 GENE MUTATION (S54C) IN A FAMILY WITH CONGENITAL HYPOTHYROIDISM AND HIGH PROPORTION OF AFFECTED INDIVIDUAL P. Srichomkwun1, L.D. Vries3, O. Admoni4, S. Refetoff1,2 1 Medicine, University of Chicago, Chicago, IL; 2Pediatrics, University of Chicago, Chicago, IL; 3Juvenile Diabetes Unit, Schneider Children’s Medical Center of Israel, Petahc Tikvah, Israel; 4 Pediatric Endocrine, Ha’Emek Medical Center, Afula, Israel

Immediate single Parathyroid hormone (PTH) levels following thyroid surgery have been used to detect patients at risk for postoperative hypoparathyroidism and hypocalcemia. We hypothesize that the drop in intraoperative PTH (io-PTH) levels during thyroid surgery can be a more specific approach at predicting patients in need of calcium supplementation. We identified 126 patients who underwent thyroidectomy or central neck dissection between January 2014 and March 2015. Pre and postoperative PTH levels immediately after surgery were collected. Low post-operative PTH and io-PTH was defined as a PTH measurement < 10 pg/mL. The percentage drop in PTH was compared. Transient hypocalcemia ( < 8.4 mg/dL) developed in 14 (11.1%) patients, however, only 5 patients (5.5%) developed hypocalcemic symptoms. Post-operative hypocalcemia was associated with a lower single post-operative PTH compared with normocalcemic patients (mean 17.83 + / - 29.74 vs 51.15 + / - 33.42). Sensitivity, specificity, and accuracy using single low post-operative PTH values were 85%, 86%, and 86% respectively. The positive predictive value (PPV) = 44% and negative predictive value (NPV) = 98%. Hypocalcemic patients also showed a larger percent drop (mean - 65.19% + / - 48.37 vs 10.42% + / - 38.09) in io-PTH during thyroid surgery. The optimal cutoff percent drop value based on ROC analysis was shown to be - 85.14% with a sensitivity, specificity, and accuracy of 71%, 96%, and 94% respectively. The PPV = 71% and NPV = 96%. A single postoperative PTH level immediately at the end of surgery is a sensitive and specific predictor of post-thyroidectomy hypocalcemia. However, percent drop is more specific at predicting hypocalcemia after thyroid surgery. Evaluation of chan-

Congenital hypothyroidism (CH) is a common congenital endocrine disorder with an incidence of 1:3000 to 4000 worldwide. Paired box transcription factor 8 (PAX8) is a thyroid transcription factor that plays an important role in thyroid organogenesis and development. To date more than 20 different PAX8 gene mutations causing thyroid dysgenesis have been reported. We report a novel mutation in PAX8 gene in a large family with variable phenotypic presentation. Four generations of a Hungarian Ashkenazi family were affected. In the two generations studied all 4 siblings and 8 of 10 offsprings were affected. Five were diagnosed at birth (TSH 21– 442 mU/L) and 7 were diagnosed at 2–30 years of age (TSH 6– 18 mU/L). One affected individual had thyroid hemiagenesis on ultrasound and 6 had neurological and cognitive abnormalities, including, Parkinsonism, psychomotor developmental disorder and attention deficit disorder. Direct sequencing of the PAX8 gene, revealed a novel single nucleotide substitution (c.162 A > T) resulting in the replacement of serine-54 with cysteine (S54C), which segregated with elevated serum TSH levels.These findings confirm the important role of PAX8 in the development of the thyroid gland.. The mutation is located in a highly conserved area of the gene, which encodes the DNA-binding domain of PAX8. Other mutations of the same amino acid (S54G and S54R) have been also shown to exhibit functional impairment (decreased DNA binding and impart decreased transcriptional activity of the thyroperoxidase and thyroglobulin promoter). We report a novel mutation of the PAX8 gene causing autosomal dominant CH with variable expressivity. The unusual features are high proportion of affected individuals (12 of 14) and neurocognitive abnormalities (6 of 14).

Poster 530

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WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015

Poster 532 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM ANTI-CTLA4-INDUCED GRAVES DISEASE (GD): A RARE CAUSE OF HYPERTHYROIDISM (HYPERT) IN PATIENTS (PTS) WITH METASTATIC MELANOMA (MM) M. Cabanillas1, S.G. Waguespack1, M. Pitteloud1, A. Roman-Gonzalez2,1, A. Jessop3, E. Santos3, M. Davies4, R. Dadu1 1 Department of Endocrine Neoplasia and HD, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 2Department of Endocrinology, Hospital Universitario San Vicente Fundacion Universidad de Antioquia, Medellin, Colombia; 3Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; 4Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX Anti-CTLA4 drugs (ipilimumab [ipi], tremelimumab [treme]) can cause autoimmune disease of endocrine organs, including the thyroid. We describe 3 mM pts with anti-CTLA4-induced GD/GD-like disease. Pt 1: 59 y/o F with hyperT after 3 doses of ipi. TSI was high (fig 1A). Pertechnetate thyroid scan (Tc-99) showed increased uptake in the thyroid, consistent with (c/w) GD (fig 1B). Pt started B-blocker and methimazole (MMI). Due to neutropenia, MMI was discontinued (d/c). She had a remarkable tumor response, thus 4th ipi was not given. FT4 and TSI levels dropped to near normal (nml) limits (fig 1A) 12 wks after her last ipi and she is asymptomatic from mild GD. Pt 2: 59 y/o F with hyperT after a 4th ipi dose. Tg Ab and TPO were + but normal TSI. Tc99P showed diffuse uptake. She was also diagnosed with concurrent hypophysitis. Pt was treated with replacement steroids and MMI which controlled her hyperT. TSI 2 mos after 5th ipi dose was high. Eventually she was treated with MMI and thyroid replacement. Pt 3: 51 y/o M developed proptosis c/w GD ophthalmopathy (OP) after 7 doses of treme. He was treated successfully with high dose steroids. She had mild hyperT noted biochemically, but remained asymptomatic. TSI was nml with + TPO. Thyroid uptake/scan (I-123) showed 4.8% uptake (nml 10–40%). Imaging was not characteristic of thyroiditis or GD, however he had had a large iodine load 6 wks prior. He was observed without treatment (tx). 4 mos later, repeat TSI was elevated and TSH/FT4 normalized. Treme was d/c’d, as the pt had a remarkable tumor response.

We describe 3 cases of anti-CTLA-induced GD/GD-like disease. Pt 1 was unable to take MMI and observed off anti-thyroid tx, possibly going into spontaneous remission (SR) from GD after d/c of ipi. Pt 2’s case was complicated by hypophysitis but was never challenged off MMI. Pt 3 had a confusing picture with an equivocal scan, possibly from previous iodine load or a mixed picture of thyroiditis and GD and thyroid levels normalized off treme and without tx of hyperT. GD/GD-like disease should be considered in patients who develop hyperT during anti-CTLA4 therapy. The cases presented suggest that SR from GD/GD-like disease is possible following cessation of antiCTLA4 drugs.

Poster 533 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM TO TREAT OR NOT TREAT AS MYXEDEMA COMA. USING THE DIAGNOSTIC SCORING SYSTEM FOR TWO INTERESTING CASES, WAS IT REALLY HELPFUL? A.A. Achira, D. Abushanab, H. Elbadawi, W. Taha Endocrinology and Metabolism, Wayne State University, Detroit, MI Myxedema coma (MC) has a very high mortality rate if left untreated, so a new diagnostic scoring system was implemented to facilitate its early recognition and treatment. Case 1: A 77-year-old woman with history of hypothyroidism after total thyroidectomy was admitted with altered mental status (AMS) and found to have pneumonia, hypoxia, hypothermia, hypotension, and bradycardia. Laboratory results showed a TSH level of 108 and free T4 less than 0.1. Case 2: A 69-year-old woman with post-ablative hypothyroidism presented with hip pain after a fall and was found to have hip dislocation and rhabdomyolysis. She underwent surgical hip reduction and developed acute shortness of breath. An echocardiogram showed large pericardial effusion and pericardiocentesis was performed. The patient was off levothyroxine for 6 months due to noncompliance. Laboratory results showed a TSH level of 40.2, free T4 less than 0.1, and hyponatremia. The diagnosis of MC is primarily clinical, with no clear-cut criteria that might distinguish either hypothyroidism alone or coma of other etiologies from true MC. In view of the high morbidity and mortality of MC, the development and application of criteria for its identification could allow earlier diagnosis and treatment. A score of 60 in the proposed scoring system is potentially diagnostic for MC, whereas scores between 25 and 59 could classify patients at risk for MC, and a score less than 25 is unlikely to indicate MC. MC was diagnosed in case 1 based on a score of 80, and the patient was begun on IV levothyroxine and hydrocortisone. Although case 2 had many precipitating events, including the fall and two surgical procedures, the score was only 55; therefore, the patient was only treated with oral levothyroxine. Both patients improved and had no complications. These two cases reinforce the utility of the diagnostic scoring system as a tool to aid in the early recognition and more effective treatment of patients with MC, or even impending MC. However, it should be considered in the clinical context of the patient.

Poster 534 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM SHOULD THYROIDECTOMY BE PREFERRED OVER RAI FOR TREATMENT OF THYROTOXIC PERIODIC PARALYSIS N. Gupta, A. Patel, W. Goldner UNMC, Omaha, NE

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015

Thyrotoxic periodic paralysis (TPP) is an uncommon but severe manifestation of hyperthyroidism. Definitive treatment of hyperthyroidism is necessary to prevent recurrence. We present four such cases treated at our institution and discuss pros and cons of therapy for hyperthyroidism. All four patients were males and none of them were of Asian ethnicity, presenting with complaint of muscle weakness in setting of low potassium, elevated free T4 and free T3 and suppressed thyroid stimulating hormone (TSH).Etiology of hyperthryoidism was found to be Grave’s disease in all four patients. In addition to potassium and supportive treatment for TPP, they were all treated with methimazole and propranolol until they reached a euthyroid state. Once euthyroid, 3/4 patients were treated with total thyroidectomy and 1/4 patient was treated with radioactive iodine treatment (RAI ). Those treated with total thyroidectomy did not have further paralytic episodes. One patient who received RAI therapy experienced two additional paralytic episodes following RAI therapy while he was still hyperthyroid. Now that he is no longer hyperthyroid, his TPP has not recurred. All four patients are currently doing well on levothyroxine replacement. Currently, there is lack of optimal definitive treatment for thyrotoxic periodic paralysis. In our experience, initial treatment with anti-thyroid medications followed by total thyroidectomy resulted in less recurrent paralytic episodes as compared with RAI therapy which was associated with recurrent TPP until euthyroid state achieved.

Poster 535 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM ROLE OF PLASMAPHERESIS IN THYROTOXICOSIS COMPLICATED BY METHIMAZOLE-INDUCED AGRANULOCYTOSIS P. Hanseree, D. Elson Endocrinology, University of Wisconsin Hospital and Clinics, Madison, WI Uncontrolled hyperthyroidism can be critical and life threatening. In some situations treatment options are limited. Plasmapheresis may be considered as a stabilizing measure, providing a window to treat definitively with thyroidectomy in patients who cannot tolerate medical therapy. We report the experience of a patient with a favorable response to plasmapheresis. A 53-year-old female with a history of Graves’ disease diagnosed in September 2014, admitted with atrial fibrillation with rapid ventricular response. She underwent CT angiogram to rule out pulmonary embolism. She was treated with methi-

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mazole as a bridge to definitive therapy with radioactive iodine. The patient postponed RAI treatment and developed agranulocytosis in December, admitted with pneumonia, sepsis, and acute kidney injury, requiring ventilatory and pressor support, and dialysis. Absolute neutrophil count was 240/uL. She was euthyroid on admission and Methimazole was discontinued. She clinically improved with antibiotic treatment, but developed recurrent thyrotoxicosis and had uncontrolled atrial fibrillation treated with amiodarone. Thyroid function tests revealed TSH 0.02 (0.36–4.2 uIU/mL), free T4 2.7 (0.7–1.45 ng/ dL), and free T3 5.4 (2.2–4.0 pg/mL). Patient underwent plasmapheresis in preparation for total thyroidectomy. Atrial fibrillation converted to normal sinus rhythm during first plasmapheresis session. Free T4 and free T3 trended down and normalized on day 4. The surgery was delayed due to soft tissue infection of the neck. Patient had second plasmapheresis on day 6 and had thyroidectomy on the following day. Patient has done well after the surgery and is maintained on levothyroxine replacement. Agranulocytosis is a rare complication of thionamide therapy and requires interruption of treatment. Plasmapheresis is an alternative treatment for hyperthyroidism, achieving rapid decline in plasma thyroid hormone levels. Plasmapheresis should be considered as an option to stabilized patients with severe thyrotoxicosis with life threatening complications, allowing for definitive interventions.

Poster 536 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM A RARE THYROID HORMONE RECEPTOR BETA (THRb) GENE MUTATION IN A 14-YEAR-OLD GIRL WITH GRAVES’ DISEASE: A CASE REPORT G. Chen, S. Xu, H. Sun, H. Di, C. Liu Endocrine and Diabetes Center, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, China Resistance to thyroid hormone is a rare syndrome, where although the level of thyroid hormone is elevated, the level of thyroid stimulating hormone is not suppressed. Early diagnosis is difficult particularly when complicated with Graves’ disease. The patient in our case report is, to the best of our knowledge, is rarely met in China. A 14-year-old girl was diagnosed with Graves’ disease in 2010 and was given methimazole 10mg tid. The level of thyrotropin was gradually increased, while free thyroxine was still outside the normal range. Her father was also presented thyroid dysfunction as thyroid hormone resistance. Blood sample of the girl and her father were collected and deoxyribonucleic acid was isolated for molecular genetic testing. The results revealed a mutation in the gene for thyroid hormone receptor beta. Missense mutation in exon 10 of the gene for the first 95 bases was found that the C was mutated to T, codon ACU was changed to AUU with the result of encoding amino acid by threonine to isoleucine, and the rest genes had no change. According to the clinical and biochemical features and her family history, the clinical diagnosis was confirmed as ‘‘thyroid hormone resistance syndrome complicated by hyperthyroidism due to Graves’ disease’’, the treatment of methimazole 10mg qd will be conntinued and the girl is followed up in our clinic. We report the presence of a rare mutation in the thyroid hormone receptor beta gene in patient with Graves’ disease.

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Poster 537 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM HOW RITONAVIR MAY INFLUENCE THYROID FREE THYROXINE LEVELS REVIEW ON MEDICATIONS THAT INTERFERE WITH THE PROPER INTERPRETATION OF THYROID FUNCTION TEST RESULTS F. Chebbi1, C. Jublanc1, A. Khalife2 1 Pitie´-Salpeˆtrie`re hospital, Paris, France; 2Hammoud Hospital, Hammoud, Lebanon Subclinical abnormal thyroid patterns are common in the HIVinfected patient HIV individual on HAART: Subclinical hypothyroidism, Isolated low FT4 and Euthyroid sick syndrome There are many Iso-forms of P450 cytochromes. Each family metabolizes preferentially certain substrates which, moreover, can be inducers or inhibitors of CYP. Antiproteases, in particular ritonavir, is an inhibitor of cytochrome P450 3A and CYP2D6 (to a lesser extent) and slow down the biotransformations of various drugs which accumulate in the body. It also appears to induce CYP3A as well as other enzymes, including glucuronyl transferase, CYP1A2, and possibly CYP2C9. Serum TSH, FT4, FT3 were measured by electrochemiluminescence immunoassays on the Roche Modular Analytics E170 (Roche Diagnostics) In the Synacthen test, plasma cortisol levels were measured at time 0 as well as at time 60 minutes following an intramuscular injection of 0.25 mg Synacthen 1st patient (45 years) hospitalized for monitoring a micro-prolactinoma operated in 2011. HIV seropositivity, first discovered in 2009, is treated by ATRIPLA (EFAVIRENZ, EMTRICITABINE and TENOFOVIR). Hormonal tests were in the normal range, only FT4 in lower part of the range 2nd patient (61 years) hospitalized for an adrenal incidentaloma HIV seropositivity was discovered in 2009, during the assessment of a lymph node tuberculosis and treated by PREZISTA and NORVIR. Her FT4 was also in lower part of the range. Our patients have repeatedly low FT4 (10.6 and 11.4 pmol/l) with normal TSH (1.62 and 1.70 mUI/l) and normal FT3. The morning serum cortisol and adrenocorticotropic hormone (ACTH) levels were repeatedly low. Baseline cortisol level was very low 19.3 nmol/l at start with cortisol levels of 673 nmol/l after 60 min. In a physiological situation, we would aspect a rise of the cortisol level at least above 500 nmol. Isolated low FT4 levels (TSH normal, FT4 levels low, Absent clinical features) is common among HIV-infected individuals (prevalence 1.3%–6.8%), especially associated with use of didanosine, stavudine and ritonavir. Its clinical significance is unclear and no treatment indicated. The suggested mechanism is increased hepatic induction of glucuronyl transferase enzyme. UDP-glucuronosyltransferase (UDP-GT) inducers have been shown to lower plasma levels of thyroxine (T4) by increasing its glucuronidation and elimination by the liver. The interpretation of abnormal thyroid function test results may be complicated by the concomitant presence of medications and nonthyroidal illnesses. It is important that clinicians recognize the effects of drugs on laboratory interpretation, especially for HIV who are on several medications including anti-retrovirals.

Poster 538 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM THYROID STORM COUPLED WITH SEVERE POSTPARTUM CARDIOMYOPATHY: SUCCESSFUL MANAGEMENT & INSIGHT INTO PATHOGENESIS M. Glodowski1, C. Vaz2 1 Internal Medicine, Temple University Hospital, Philadelphia, PA; 2 Endocrinology, Temple University Hospital, Philadelphia, PA

We describe the management of postpartum thyroid storm with cardiomyopathy. 25 y/o F with Graves’ disease presented to ED with palpitations and chest pain at 3 weeks postpartum after pregnancy complicated by severe hyperthyroidism due to medication nonadherence. She delivered a 2 lb infant at 29 weeks.TSI 241( < 140). Medications: labetolol, metoprolol, and methimazole. She had BP 153/74 mmhg, sinus tachycardia 127 bmp. She was given metoprolol 50 mg po, then 5 mg IV · 2. BP dropped to 60/30 and she arrested (PEA). She had return of circulation after one round of CPR and epinephrine. Labs showed TSH 0.04 mIU/ml [0.29–5.10], FT4 5.7ng/dl [0.6–1.6] FT3 1,320 pg/dl [n 250–390]. Wartofsky score was 50. CXR showed pulmonary edema. Echo showed LVEF 30%. Swan-Ganz catheter revealed CI of 1.84 with PCWP of 22. She was treated with PTU 200 mg q6h, hydrocortisone 100 mg IV q8h, lugol’s iodine 10 drops q8h and esmolol drip for rate control, which was discontinued on the same day due to hypotension and decreased CI. She was treated with milrinone, diuresis, and afterload reduction. Over the next week hemodynamics improved. She was restarted on beta blocker and transitioned back to methimazole. On discharge, TSH 0.02 mIU/ml, FT4 0.5 ng/dl, FT3 210 pg/dl. The association between hyperthyroidism and high output heart failure is well known, but low output heart failure is rarely seen. The net effect of T3 mediated decreased SVR, increased stroke volume, and increased contractility is high output heart failure(1, 2), which itself may lead to low output heart failure. Low output heart failure may also result from the tachycardia associated with hyperthyroidism(3). Our patient had elements of both postpartum cardiomyopathy and tachycardia induced cardiomyopathy, compounded by the onset of thyroid storm. While most studies report exacerbation or relapse of Graves’ occurs between 2–8 months postpartum, our patient presented at just 3 weeks (4, 5). Postpartum patients of Graves’ disease should be monitored for thyroid storm which can exacerbate postpartum cardiomyopathy. Beta blockers should be used judiciously in thyrotoxicosis associated with low output heart failure to avoid worsening of cardiogenic shock.

Poster 539 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM ACUTE PSYCHOSIS ASSOCIATED WITH GRAVES’ DISEASE S.M. Cuadra Mongalo1, A. Rizvi1, A.J. Munoz2, S. Sirinvaravong1 1 Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of South Carolina School of Medicine, Columbia, South Carolina, Columbia, SC; 2Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, William Jennings Bryan Dorn Veterans Affairs Medical Center, Columbia, SC The typical presentations of Graves’ disease include mild psychiatric manifestations such as anxiety and emotional lability. Extreme behavioral and personality changes such as psychosis, agitation and depression are less common. We present a case of Graves’ disease in a young woman debuting as acute psychosis. A 24-year-old woman presented to the ED due to auditory hallucinations with intrusive thoughts commanding her to hurt herself and her newborn. Her physical exam revealed tachycardia and subtle tremor. Akathisia and tachylalia were evident. The thyroid gland was not enlarged and there were no bruits. The patient denied personal or family history of thyroid or psychiatric diseases. She was admitted to the psychiatric ward under the diagnosis of ‘‘postpartum psychosis.’’ TSH was undetectable with elevated free T4 of > 8.0 ng/dl and free

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 T3 of > 30.0 pg/ml. RAI uptake and scan showed diffuse increased radiotracer uptake. Thyroid ultrasonography revealed a homogeneous parenchyma with hyperemia. She was diagnosed with Graves’ disease and treated with methimazole. As her thyroid function tests improved over the course of the hospital stay, her psychotic features progressively subsided. The patient was subsequently readmitted twice with similar symptoms despite improved thyroid function tests. She was considered psychosis NOS - bipolar disorder with psychotic features. It appeared that thyrotoxicosis may have been a major precipitant for the initial acute psychotic episode. Thyrotoxicosis has been described both as a cause of organic psychosis as well as a precipitant of underlying affective psychosis. More severe psychiatric features have been described in patients with Graves’ disease and toxic goiter. These may aggravate an underlying tendency to major psychiatric diseases in some patients. The mechanism of cognitive and behavioral dysfunction in hyperthyroidism is unknown. Symptoms often remit with successful therapy of the hyperthyroid state. However, acute changes in thyroid levels can precipitate psychoses. Residual mental illness may persist as seen in this case. Patients with abrupt or unusual onset and manifestations of psychotic symptoms should be screened for underlying or concomitant thyrotoxicosis.

Poster 540 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM A RARE CASE OF PROPYLTHIOURACIL INDUCED SENSORINEURAL HEARING LOSS H. Anaedo, S. Clark Endocrinology, Albany medical center, Albany, NY Propylthiouracil (PTU) induced sensorineural hearing loss and its association with ANCA- small vessel vasculitis has been rarely described. We report a 56 yo F who has known Graves’ disease initially on methimazole, but was discontinued due to severe rash and switched to PTU.Unfortunately 1 week after starting PTU she noticed acute hearing loss in her left ear, which started with tinnitus and then muffling in that ear with progression to her right ear. She was seen by audiologist, as well as ENT who confirmed sensorineural hearing loss on the left ear. She was tried on low dose prednisone without much improvement in her symptoms, MRI brain negative for intracranial lesion or possible etiology for her hearing loss. Her PTU was discontinued and she was planned for thyroidectomy for treatment of her Graves disease. Her symptoms improved on discontinuation of PTU and after thyroidectomy. PTU has been linked to MPO-ANCA-associated small-vessel vasculitis but very rarely to sensorineural hearing loss. Suggested mechanism includes dysfunction of outer hair cells of the organ of Corti from Inner ear blood flow impairment from ANCA- smallvessel vasculitis. This mechanism was proposed in the three case reports so far in the literature and they described associated athralgia and fever.Our patient had classic athralgia,weakness and headache with the hearing loss which improved on stopping the PTU.MRI brain was obtained to rule out possible causes including menigioma,acoustic neuroma and multiple sclerosis.She did not have any history of ear trauma or presbycusis. Given that symptoms started shortly after starting PTU and improved after stopping it, we were confident that it was the cause of the sensorineural hearing loss.The exact etiology of the sensoriloss is not clear but the MPOANCA small vasculitis is a plausible explaination and should be considered in all patients with simillar symptoms. PTU can cause sensorineural hearing loss and this awareness should trigger a MPO-ANCA testing and discontinuation of the

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medication with trial of high dose steroid.This is the first case reported in our population to the best of our knowledge.More case reports and studies are needed to collaborate our finding.

Poster 541 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM HYPERTHYROIDISM FOLLOWED BY WORSENING PRIMARY HYPOTHYROIDISM IN A PATIENT TREATED WITH IPILIMUMAB AND PEMBROLIZUMAB Z. Batacchi, L. Alarcon-Casas Wright Division of Endocrinology, Metabolism and Nutrition, University of Washington, Seattle, WA Ipilimumab and Pembrolizumab are immunostimulatory agents used to treat metastatic melanoma. Ipilimumab is a monoclonal antibody which binds to the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4 ) and Pembrolizumab is a monoclonal antibody which inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on T-cells. Thyroid dysfunction may ensue as immune-related adverse effects of these medications. 55 year old man with a history of metastatic scalp melanoma, type 2 diabetes mellitus and primary hypothyroidism diagnosed 6 years ago with positive thyroid peroxidase antibodies. He had been stable on the same dose of levothyroxine 75mcg daily since diagnosis. Ipilimumab was commenced for treatment of melanoma. Prior to the first dose, TSH was 4.597 (0.400–5.00microIU/mL) and total T4 was 8.0 (4.8– 10.8mcg/dL). Three of four planned doses of Ipilimumab were given before he developed headache and fatigue. Investigations revealed hypophysitis (central adrenal insufficiency, central hypogonadism) and hyperthyroidism. Brain magnetic resonance imaging revealed an enlarged pituitary gland compared to prior exams. TSH was low on 2 occasions with elevated total T4 and Free T4 on two occasions. Ipilimumab was discontinued and within 3 weeks, his thyroid function tests improved: TSH 0.554 (0.400–5.00microIU/mL) and total T4 of 10.7 (0.400–5.00microIU/mL). He continued levothyroxine 75mcg daily. Four months later Pembrolizumab was initiated. He has received 6 doses in the last 4 months. His TSH has reproducibly and progressively increased, most recently 20.353 (0.400–5.00microIU/mL), despite increasing the dose of levothyroxine. The case describes a patient with baseline primary hypothyroidism who developed opposing effects in thyroid function after consecutive use of the immune check-point inhibitors Ipilimumab and Pembrolizumab. Individually, the immune-related adverse effects of these drugs upon the thyroid are uncommon and, to the best of our knowledge, have not been reported as sequential effects in one patient. This underscores the importance of close monitoring of thyroid function during treatment with these agents.

Poster 542 Autoimmunity Wednesday & Thursday Poster Clinical 9:00 AM SINGLE CENTRE EXPERIENCE OF CONSECUTIVE THYROTOXIC PERIODIC PARALYSIS (TPP) CASE SERIES N. Jauhar, S. Dissanayake, R. Srinivasa, V. Sonawane, B. Varadarajan Endocrine, Khoo Teck Puat Hospital, Singapore, Singapore TPP is an unusual manifestation of thyrotoxicosis with increased predilection to men of Chinese and south-east asian descent. We present a case series of consecutive TPP in our centre to evaluate demographics, pattern of presentation, etiology and

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response to treatment. We looked at 11 cases with a discharge diagnosis of TPP over a 2 year period. Demographics: Age 37 – 9 years (mean – SD), 91% males, 64% Chinese, 27% Malays and 9% Fillipino origin. For 91% thyrotoxicosis and paralysis were simultaneously diagnosed. 27% recalled previous episodes of self-limiting weakness. Presentation: 36% had a known precipitant (exercise and carbohydrate rich meal in 18% each). The majority (82%) had their weakness onset in late evening or early morning (55% between midnight and 6 am and 27% between 6pm and midnight). The weakness was painful in 27%, 73% had solely lower limb weakness and 27% had weakness of all 4 limbs. The mean leg muscle power was 2.1/5 (range 1–4) and arm 3.7/5 (range 1 - 5). Proximal weakness was more marked than distal in all patients. 91% had depressed reflexes. Potassium: Mean level at presentation 2 – 0.6mmol/l ( < 1.5–3.2). Thyroid biochemistry: Mean T4 61 – 33pmol/l (1.9– > 100), TSH 0.006 – 0.001mIU/l (< 0.005–0.009). Aetiology of hyperthyroidism from a composite of biochemistry and radiology: 82% Graves’, 9% nodular goiter and 1 patient with exogenous T3 supplement. Treatment: 91% were treated with intra-venous replacement of potassium (range 20– 70 mmol). 64% were also given oral replacement. Time to normalization of potassium was 11 hours (range 5–23 hours). There was complete neurological recovery in all patients. 91% were discharged on oral anti-thyroid drugs. 45% either completed or are in the process of receiving their definitive treatment (1 surgery, 3 radioiodine and 1 came-off exogenous T3). Our case series highlights several classical features of TPP, reminds that this complication can occur with any etiology of hyperthyroidism and reinforces the need for increased physician awareness to suspect in appropriate settings and to consider definitive treatment to minimize risk of relapse.

Poster 543 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM PROBABLE ACUTE PYOGENIC THYROIDITIS CAUSING HYPERTHYROIDISM N. Jauhar, B. Varadarajan Endocrine, Khoo Teck Puat Hospital, Singapore, Singapore Acute infectious thyroiditis is a rare disorder and many such patients are euthyroid with less than one third presenting with hyperthyroidism. We present an elderly gentleman with an acute hyperthyroidism secondary to thyroid abscess. The patient presented with a five day history of neck pain and swelling associated with fever, dysphagia and dysphonia. On examination he had a diffusely enlarged and tender goiter. His palms were sweaty, there was a fine tremor and he had palmar erythema. There were no signs of Graves’ opthalmopathy or pretibial myxedema. Investigations revealed: neutrophilic leukocytosis, elevated ESR 113mm/H, hyperthyroid biochemistry fT4 71.6pmol/L, TSH 0.0059mIU/L and negative thyroid auto-antibodies. Computed tomography scan of the neck revealed a left thyroid lobe abscess measuring 3.2 · 3 · 4 cm with rim enhancement and a high attenuation central fluid component. There was also retropharyngeal fluid suggestive of extension of the abscess. Attempted bedside aspiration of the abscess was unsuccessful. He was started on empirical intravenous antibiotics, oral steroids and b-blockers with good clinical response. Hence a conservative plan to observe his abscess response clinically and radiologically was made. A subsequent Tc uptake scan done 2 weeks after initial presentation showed enlarged left lobe of the thyroid with diffusely reduced uptake. On ultra-sound there were multiple nodules of varying size and echogenicity in both lobes and

isthmus. The previously noticed abscess had consolidated itself to a dominant nodule in the left lobe measuring 32 · 34 mm with microcalcifications and internal vascularity. A FNAC of this nodule is being undertaken to evaluate the nature of this nodule. The dose of the steroids was gradually tapered and the patient remains well with the most recent thyroid function spontaneously resolved to euthyroidism. In summary, this patient presented with acute self-limiting hyperthyroidism with the underlying etiology of a thyroid abscess complicating a suspicious dominant nodule on the left lobe.

Poster 544 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM CASE OF THE VANISHING THYROID NODULE L. Kang, M. Charitou Endocrinology, Diabetes, and Metabolism, Stony Brook University Hospital, Stony Brook, NY Subacute thyroiditis is diagnosed clinically. Ultrasonography may help in the diagnosis of thyroiditis. The thyroid may appear normal or enlarged and is usually diffusely or focally hypoechogenic. A 40-year-old woman was referred to our endocrinology clinic for evaluation of a thyroid nodule and a low TSH. She complained of left neck discomfort, palpitations, weight loss, and sweats. She was taking propranolol after right carotid artery dissection a few years ago, and her primary care physician increased the dose due to tachycardia. On physical examination, the left thyroid lobe was slightly increased in size and tender to palpation. The patient appeared anxious but did not have tremors or tachycardia. Laboratory results showed TSH 0.4 mIU/L (0.45–4.5), Free Thyroxine 1.4 ng/dL (0.82–1.77), and Thyroid Peroxidase Antibody 10.2 IU/mL ( < 35). A thyroid ultrasound revealed a 3.5 cm hypoechoic nodule located in the left middle lobe with internal vascularity. She then underwent a thyroid uptake and scan which showed 0% uptake. She was subsequently diagnosed as having subacute thyroiditis and was treated with ibuprofen. One month later during a follow up visit, she complained of right neck pain and had resolution of left neck discomfort. At that visit, thyroid ultrasound performed showed resolution of the previously seen left thyroid nodule. The right lobe measured larger compared to its size on the previous ultrasound performed. Treatment was initiated with a corticosteroid taper due to persistent neck pain. Repeat thyroid function tests performed 6 weeks later showed a TSH of 21 mIU/L. At that time, her previously endorsed right neck pain completely resolved and corticosteroids were discontinued. Two subsequent TSH measurements performed 4 and 12 weeks later were 6.6 mIU/L and 4.4 mIU/L

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 respectively. Patient was clinically euthyroid both times and all her neck pain had resolved. This case illustrates the potential for thyroiditis to present as a suspicious nodule. After treatment and resolution of symptoms, the nodule may disappear on ultrasound. When thyroiditis is suspected and a nodule is found on ultrasound, it is prudent to avoid fine needle aspiration as the nodule will most likely resolve.

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as visual field defects and headache as well as endocrine complications such as hypopituitarism. TSHoma is a rare condition, which can present insidiously and must be considered in patients with evidence of central hyperthyroidism even if an adenoma is not immediately evident on imaging.

Poster 546 Poster 545 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM TSHOMA: AN ATYPICAL PRESENTATION S. Shetty, J. Figueroa Flores, I. Hartman, S. Ali Endocrinology, UT Southwestern Medical Center, Dallas, TX First described in 1960, Thyroid stimulating hormone (TSH)secreting pituitary tumor or TSHoma is a very rare condition with an incidence of one case per million. It has been estimated that less than 2% of all pituitary tumors are TSHomas. The characteristic presentation is a pituitary macroadenoma causing central hyperthyroidism and goiter. We report our experience with an atypical TSHoma presenting with features of hyperthyroidism and disabling sensory neuropathy of the lower extremities. A 58-year-old Caucasian female was referred to our clinic with abnormal thyroid function tests and a 1-year history of poor appetite, weight loss, diarrhea and palpitations. She also complained of severe sensory neuropathy in both her lower extremities. Physical examination was significant only for a non-tender goiter without palpable nodularity. Free T3 and free T4 were both elevated at 5.8 pg/ml and 2.3 ng/dL respectively in the setting of an elevated TSH of 7.14 mIU/ L. Thyroid antibody testing was found to be negative. An initial MRI of the brain failed to visualize any pituitary abnormality, however a repeat pituitary protocol MRI done at our facility revealed a 3 mm mass of the pituitary gland suggestive of a microadenoma (Fig) TSHomas are typically large and invasive tumors. Signs and symptoms of the expanding tumor mass are therefore often the presenting features and symptoms of hyperthyroidism can be mild. About 60% of these tumors co secrete GH and/or prolactin. Failure to recognize the presence of a TSHoma may result in dramatic consequences such as thyroid ablation, which may cause an increase in pituitary tumor volume. Conversely, early diagnosis and treatment with surgical excision may prevent neurological complications such

Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM RADIOIODINE ABLATION FOR AMIODARONE-INDUCED THYROTOXICOSIS ALLOWS RE-INTRODUCTION OF THE DRUG A. Thirumalai, S. Trikudanathan Medicine/Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA In the U.S., 3–5% of patients treated with amiodarone develop amiodarone-induced thyrotoxicosis (AIT) between 4 months and 3 years after initiation of treatment. Management includes corticosteroids and/or thionamides, often with cessation of amiodarone. This poses a problem when amiodarone is required to control lifethreatening arrhythmia. A 36 year old man with non-ischemic cardiomyopathy was treated with amiodarone for ventricular arrhythmias for 15 months. A month after stopping amiodarone, he developed symptoms and biochemical evidence of hyperthyroidism. Evaluation was unrevealing for type of AIT. The patient was treated with methimazole and prednisone for a year with normalization of thyroid function. However in that interval he developed atrial fibrillation, worsening heart failure and recurrent ventricular arrhythmias. Restarting amiodarone was considered but worsening hyperthyroidism was a serious concern. A year after stopping amiodarone, radioactive iodine uptake was 24%, so radioiodine ablation (RAI) was performed and amiodarone was restarted after 1 week. After an initial worsened hyperthyroid phase, he became hypothyroid and was started on levothyroxine and remained stable on amiodarone. Reintroduction of amiodarone for worsening arrhythmias is always challenging in patients with a prior history of AIT. However, if the hyperthyroidism is definitively cured then amiodarone could be safely resumed. The added advantage of permanently curing the hyperthyroidism is avoiding the side effects of long-term thionamide and/or corticosteroid therapy. This can only be done either by thyroidectomy or by RAI. The former is usually difficult in these highrisk patients and the latter is usually not successful since amiodarone blocks iodine uptake for a long time. This case illustrates that RAI can be successfully utilized in the presence of adequate radioiodine uptake. In this patient amiodarone was successfully reintroduced and both arrhythmias and thyroid function have remained stable even at 2 years follow-up. Radioiodine ablation effectively treats AIT and also allows reintroduction of amiodarone.

Poster 547 Disorders of Thyroid Function Wednesday & Thursday Poster 9:00 AM PAINLESS THYROIDITIS: SUBCLINICAL HYPERTHYROIDISM FOLLOWED BY HYPOTHYROIDISM A. Kotwal, A. Shaikh Department of Medicine, University of Massachusetts Medical School, Worcester, MA

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Painless thyroiditis could be subacute lymphocytic throiditis or Hashimoto’s autoimmune throiditis. Lymphocytic thyroiditis usually presents as a thyrotoxic phase sometimes followed by a hypothyroid phase that resolves in a short duration. Hashimoto’s thyroiditis usually presents with hypothyroidism, however, some patients report a preceding thyrotoxic phase. A 59 year old Caucasian lady without any history of endocrine or autoimmune disorders, presented to the clinic with complaints of insomnia and hot flashes. She did not report any weight changes, skin changes or abnormal bowel movements. Thyroid gland was firm, smooth, non-tender and not enlarged. The rest of the physical examination was within normal limits. Laboratory workup revealed a low TSH of 0.04 uIU/mL (reference 0.28–3.89) with a normal free T4 of 1.01 ng/dL (reference 0.58–1.64); T3 was not tested. On follow up 1 month later, there was no change in her examination but she was found to have an elevated TSH of 26.88 uIU/mL, low free T4 of 0.48 ng/dL and low total T4 of 4.4 mcg/dL (reference 4.5-12.0). Levothyroxine 75 mcg daily was initiated, anti-TPO test was ordered and the patient advised to follow up in 4 weeks. This case demonstrates possible painless thyroiditis which initially presented as subclinical hyperthyroidism and within 4 weeks progressed to hypothyroidism. If this is painless lymphocytic thyroiditis then it will likely resolve, however Hashimoto’s thyroiditis would persist. Anti-TPO antibody could be positive in both conditions. In the thyrotoxic phase, I-123 uptake scan reveals decreased uptake, however, it is not useful in the hypothyroid phase. It would have been useful to perform I-123 uptake scan at the initial visit of this patient. Hypothyroidism due to painless subacute lymphocytic thyroiditis usually resolves in 6–8 weeks, whereas that due to Hashimoto’s autoimmune thyroiditis usually persists for life. Levothyroxine supplementation is recommended if the TSH is > 10 uIU/mL even in the absence of symptoms. Follow up is necessary to monitor for resolution of the hypothyroid phase.

Poster 548 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM THYROID FUNCTIONAL DISEASE AND MORTALITY IN END-STAGE RENAL DISEASE PATIENTS RECEIVING PERITONEAL DIALYSIS C. Rhee1, V. Ravel1, E. Streja1, R. Mehrotra4, S. Kim1, J. Wang1, S. Brunelli2, G.A. Brent3, K. Kalantar-Zadeh1 1 Nephrology, University of California Irvine, Huntington Beach, CA; 2DaVita Clinical Research, Minneapolis, MN; 3UCLA, Los Angeles, CA; 4University of Washington, Seattle, WA End-stage renal disease patients receiving peritoneal dialysis (PD) have a higher burden of thyroid functional disease. This may be influenced by peritoneal effluent protein losses as well as iodine-induced thyroid disease from povidone-iodine agents. In the general population, thyroid functional disease may be associated with higher risk of cardiovascular (CV) disease and death. PD patients have an exceedingly high background CV mortality, but the impact of thyroid disease, defined by thyrotropin (TSH), upon death risk remains unknown. We examined the association of thyroid functional status with allcause mortality in a 5-year cohort (1/2007–12/2011) of PD patients from a large national dialysis organization with ‡ 1 TSH measurement. Patients were classified as: hyperthyroid, euthyroid, or hypothyroid (TSH < 0.5, 0.5-10.0, > 10.0mIU/L, respectively). Given the controversy regarding optimal TSH targets in the general population and uncertainty regarding the normal reference range in PD patients, we also examined finer gradations of TSH: < 0.1, 0.1– < 0.5, 0.5– < 3.0, 3.0– < 5.0, 5.0– < 10.0, ‡ 10.0mIU/L. Associations between time-dependent thyroid functional status with mortality were deter-

mined using time-dependent Cox models with 2 levels of adjustment (unadjusted and adjusted for case-mix covariates: age, sex, race/ ethnicity, diabetes). Among 1484 patients, 7% and 18% had hypo- and hyperthyroidism, respectively. Hypo- and hyperthyroidism were each associated with higher mortality risk in unadjusted case-mix analyses (ref: euthyroidism): (Figure, Upper Panel). When examined in finer categories, there was a graded association between higher TSH and mortality risk (ref: TSH 0.5– < 3.0mIU/L); a similar pattern was observed for lower TSH and mortality (Figure, Lower Panel). In subgroup analyses, stronger associations for both hypo- and hyperthyroidism with mortality were observed in those who were younger ( < 65 years) and female. Hypo- and hyperthyroidism were each associated with higher mortality in PD patients, independent of case-mix covariates. Further studies are needed to determine if CV mechanisms underlie these associations, and if thyroid-modulating therapies ameliorate mortality risk in this population.

Poster 549 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM CARBIMAZOLE INCREASES SERUM TRIIODOTHYRONINE, AND IMPROVES QUALITY OF LIFE AND DEPRESSION IN PATIENTS WITH PRIMARY HYPOTHYROIDISM K.N. Elfayoumy1, A. El Essawy1,4, U.B. Elgazzar2, M. abolabbas3, M.Z. Elmansy1

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 1

Internal Medicine, Faculty of Medicine, Al-Azhar University, New Damietta, Egypt; 2Biochemistry, Faculty of Medicine, Al-Azhar University, New Damietta, Egypt; 3Psychiatry, Faculty of Medicine, Al-Azhar University, New Damietta, Egypt; 4Service de Nephrology, Hospital Nord, CHU de Saint-Etienne, Saint-Etienne, France

Many hypothyroid patients are not tolerating and not satisfied with levothyroxine (LT4), complaining of depression and many symptoms like: palpitation, anxiety, and insomnia. Older studies used large doses of both carbimazole and LT4 for Hashimoto’s thyroiditis (HT), as Graves’ disease and HT were considered as very closely related syndromes produced by thyroid autoimmunity. Also, both drugs are widely used together to treat Graves’. The aim of this study was to estimate thyroid profile, quality of life (QOL), and depression before and after adding small doses of carbimazole to reduced doses of LT4 in patients with 1ary hypothyroidism who can’t tolerate LT4. 19 female patients diagnosed with 1ary hypothyroidism on a stable dose of LT4 for at least 6 months, but didn’t tolerate it, were included. They were divided into two groups; group 1 included 10 patients with HT and 2 patients with non specified 1ary hypothyroidism, and group 2 included 7 patients with subtotal thyroidectomy for Graves’. All patients received carbimazole (10 mg/day) beside LT4 (25 lg thrice/week) for 10 weeks. At the start and end of the study we assessed QOL and depression, and blood samples were taken for thyroid profile and TPO Ab. In spite of non significant changes in TSH and FT4, there was significant[in FT3 (p < 0.001) in addition to significant improvement in depression and QOL in the whole study population (p = 0.017 and

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p < 0.001 respectively). There was non significant improvement in TSH in group 1 (p = 0.053). Surprisingly in group 2, in spite of significant[in TSH (p = 0.007) and non significantYin FT4 (as we reduced LT4 dose), there was non significant[in FT3 with significant improvement in QOL (p < 0.001). Positive TPO Abs didn’t convert. Whether carbimazole helps in improvement of the pathology of a hypothyroid gland or in peripheral deiodination of T4 to T3 (where the serum and tissue levels of the latter may be responsible for improvement of symptoms) is in need of investigation. Adding carbimazole to LT4 improves FT3, QOL, and depression in 1ary hypothyroid female patients. Further studies are needed to determine the proper dose of this regimen in different cases.

Poster 550 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM REDUCING UNNECESSARY FREE THYROID HORMONE TESTING AT AN ACADEMIC AMBULATORY HOSPITAL: A QUALITY IMPROVEMENT (QI) INITIATIVE J. Gilmour, A. Weisman, S. Orlov, J. Vecchiarelli, A. Goldberg, R. Goldberg, G. Mukerji Endocrinology, women’s college hospital, Toronto, ON, Canada Free thyroxine (fT4) and free triiodothyronine (fT3) are often ordered when not clinically warranted, leading to unnecessary healthcare expenditures. Preventing laboratory overuse by reducing unnecessary fT4 and fT3 testing is one strategy in resource stewardship [1]. We implemented a QI initiative aimed at reducing the number of ft4/ft3 processed at Women’s College Hospital, an academic ambulatory care hospital in Toronto, Canada by 50%. The Model for Improvement framework for continuous QI was employed. A baseline audit was conducted between Oct 2013 and Sept 2014. QI tools were implemented to create sequential change ideas: 1) Education of physicians regarding appropriate clinical indications for ordering fT4/fT3 began December 17, 2014 and 2) a ‘‘reflex’’ laboratory, forced-function system began March 9, 2015, in which fT4 was only performed if the TSH was not in the reference range and fT4/fT3 were only performed if clinical justification was provided. Differences in weekly median TSH, fT3 and fT4 were evaluated using a Kruskal-Wallis test. Data was analyzed for special cause variation with statistical process control (SPC) charts. The median number of fT4 and fT3 processed per week were significantly reduced from 94 and 37.5 respectively at baseline, to 72.5 and 32 post-education, and 61 and 10 post ‘‘reflex’’ (p < 0.0001, p = 0.0002, respectively). Comparing pre-intervention to the ‘‘reflex’’ period, there was 35% reduction in fT4 and 73% reduction in fT3. TSH was stable over the time interval, with only 5% variation. SPC charts demonstrated special cause variation following implementation of the ‘‘reflex’’ system for both fT4 and fT3.

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Inappropriate testing of free thyroid indices occurs frequently and implementation of ‘‘reflex’’ fT4 strategy after education was feasible and effective in reducing free hormone testing by 54%. Ongoing data collection will allow for assessment of sustainability and future improvement interventions will be considered. 1. Choosing Wisely Canada: Canadian Society of Endocrinology and Metabolism, Five Things Physicians and Patients Should Question. Choosing Wisely, Initiative of the Canadian Medical Association 2013 [cited 2014 November 10]. Statistical Process Control Chart: Number of fT4 Tests Processed Per Week.

Poster 551 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM RAPID RESTORATION OF BONE MASS FOLLOWING SURGICAL MANAGEMENT OF HYPERTHYROIDISM WITH TOTAL THYROIDECTOMY- A PROSPECTIVE CASE CONTROL STUDY IN SOUTHERN INDIA P. Karunakaran General surgery, Government Mohankumaramangalam Medical College, Salem, India, Salem, India Hyperthyroidism is a well established cause of high bone turnover osteopenia and osteoporosis. Bone mineral density (BMD) is known to improve following treatment of hyperthyroidism. However, the rate and extent of bone re-mineralization following treatment of hyperthyroidism at cortical vs. trabecular sites is unclear. Few studies have examined the effect of surgical management of hyperthyroidism with Total thyroidectomy on the restoration of bone mass. Therefore, we prospectively evaluated BMD, bone mineral content (BMC) and bone areal size at spine, hip and forearm before and after total thyroidectomy. Forty patients (19M/21F; age: 36.4 – 9.8y) with overt hyperthyroidism and 31 euthyroid subjects (8M/23F; age: 33.9 – 9y) who were surgical candidates were included in the test and control group respectively. Bone indices were measured by Dual energy X-ray absorptiometry initially at the time of diagnosis and six months after total thyroidectomy in both groups. Serum calcium, alkaline phosphatase and 25-OH-VitaminD3 were assessed serially. Baseline BMD of hyperthyroid subjects at spine, hip and forearm were lower than euthyroid controls (p0.001) with concomitant elevation of alkaline phosphatase (mean + / - SD: 143.18 + / - 72 vs. 71.9 + / - 23.1 IU/L control, p < 0.001). 25OHD level was 24.27 + / 10.61 and 26.12 + / - 14.63ng/ml in case and controls respectively. Among hyperthyroid cases, Post-treatment BMD expressed as BMC in g/sq.cm were 0.9717 + / - 0.1215 (vs. pretreatment 0.9096 + / - 0.141, p0.001) at spine, 0.8741 + / - 0.1167 (vs. pretreatment 0.7985 + / 0.1247, p0.001) at hip and 0.67 + / - 0.091 vs. pretreatment 0.6426 + / - 0.1134, p0.191) at forearm. The percent change in the BMD was 8.27%(p0.001), 7.58%(p0.001) and 2.95%(p0.191) at spine, hip and forearm respectively. Surgical management with total thyroidectomy improved the bone loss associated with hyperthyroidism as early as 6 months at hip and spine despite concomitant Vitamin D deficiency. Delayed recovery of bone indices at forearm, a cortical bone requires further long-term evaluation.

Poster 552 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM CHOICE OF ANTITHYROID DRUGS AND THE OUTCOME OF PATIENTS WITH THYROID STORM L. Vydro2, S. Joglekar2, S. Sheh2, H. Yau1, S. Naing1 1 Division of Endocrinology, UCSF-Fresno, Fresno, CA; 2 Department of Internal Medicine, UCSF-Fresno, Fresno, CA

Thyroid storm (TS) is a rare but life-threatening manifestation of thyrotoxicosis. Primary treatment is with an antithyroid drug: propylthiouracil (PTU) or methimazole (MTZ). Since the 1940s, PTU has been preferred for TS due to the evidence that T3 levels are normalized more rapidly. More recently, MTZ has been favored by some due to concerns over PTU-related hepatotoxicity. This study was performed to compare the effects of PTU and MTZ on clinical and biochemical outcomes in patients with TS. A retrospective cohort study was conducted on all adult, nonpregnant patients with TS admitted to a single academic hospital from 11/2004 to 10/2014. Patients were identified by ICD9 codes and the diagnosis was verified with Burch-Wartofsky (BW) score of ‡ 45. Clinical and biochemical parameters were compared at time of admission and on day 3 of treatment. 34 total cases of TS were identified, 14 treated with PTU and 20 with MTZ. There were no significant differences in age, gender, ethnicity, BMI and BW scores between 2 groups. Daily median dose during first 3 days were 600mg for PTU and 60mg for MTZ. Mortality rate (0% in PTU vs 5% in MTZ groups; p = 1.0), ICU length of stay (LOS) (4 vs 5 days; p = 0.75) and total hospital LOS (4 vs 4.5 days; p = 0.54) were similar. There were no statistically or clinically significant differences in temperature (36.8 vs 36.7C), HR (94 vs 94/min), RR (18 vs 18/min), SBP (118 vs 117 mmHg), DBP (66 vs 68mmHg), ALT (26 vs 29.5; NR 10–40 U/L), AST (34 vs 38.5; NR 8–40 U/L), Alk Phos (113 vs 118; NR 25–100 U/L), Hb (11.4 vs 11.8; NR 14.0–18.0 g/dL), WBC (6.1 vs 7.5; NR 4.0–11.0x103/uL), or PLT (178 vs 154.50; NR 140.0–440.0 ·103/uL) on day 3 of treatment. No adverse reactions requiring discontinuation of treatment occurred in both groups. There were no significant differences in clinical and biochemical outcomes between the two treatment groups. Both drugs appeared to be safe and efficacious in the acute management of thyroid storm. To our knowledge, this is the first study comparing the effects of PTU versus MTZ on the outcomes of patients with thyroid storm.

Poster 553 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM SCREENING FOR THYROID DYSFUNCTION IN PREGNANCY - REVIEW AND UPDATE TO LABORATORY UTILIZATION PRACTICES AT ONE MAJOR ACADEMIC MEDICAL CENTER J. Colby, L. Lee, B. Adams, A. Woodworth Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN Thyroid, Endocrine, and OB-GYN societies’ guidelines recommend thyroid dysfunction screening in high-risk women via TSH, evaluated with trimester-specific reference intervals (RI), and abnormal results reflexed to Free Thyroxine (FT4) measurements. The aim of this study was to review current ordering practices and facilitate compliance with recommendations for thyroid screening in normal pregnancies. Trimester-specific RIs for TSH and FT4 were verified on the Abbott Architect i2000 with normal pregnant patients. Patients < 18 years, a personal or family history of thyroid disease, detectable thyroid autoantibodies, and/or twin pregnancies were excluded. Records from normal pregnant patients presenting to Vanderbilt Clinics for new OB evaluations were reviewed. Patients < 18 years, a history of thyroid disease, and/or twin pregnancies were excluded. Among 1773 included pregnancies, 1100 had TSH measurements. TSH and FT4 were simultaneously ordered in 560 patients. Using trimester-specific RIs, 16 and 70 abnormally low and high TSH results, respectively, were identified. FT4 was ordered with or after

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 abnormal TSH results in 61 patients. Further, 33 high TSH results were considered normal by non-pregnant RIs; of these, only 7 had a FT4 order. Unnecessary follow up testing was performed in 70 of 87 patients with normal TSH results that appeared abnormal by nonpregnant RIs. Our review revealed 3 practices that were contrary to guidelines which resulted in misinterpretation and inappropriate utilization of thyroid function tests: (1) indiscriminate screening for thyroid dysfunction, (2) screening with both TSH and FT4 orders, and (3) use of non-pregnant reference intervals to evaluate TSH results. Investigation revealed a commonly used prenatal lab order set that included both TSH and FT4. Further, trimester-specific RIs for TSH and FT4 were not displayed with results. Implementation of trimester-specific RIs and removal of FT4 from standard OB order sets may reduce mis-ordering and misinterpretation of thyroid function tests in pregnancy. Guideline-driven testing algorithms and/or patient-specific interpretive reporting may assist in adherence to recommended testing for thyroid dysfunction in pregnancy.

Poster 554 Autoimmunity Wednesday & Thursday Poster Clinical 9:00 AM HASHIMOTO’S THYROIDITIS AND VITAMIN D INSUFFICIENCY: RELATIONSHIP WITH ANTI-THYROPEROXIDASE ANTIBODIES AND INTERLEUKIN-4 I.M. Botelho1, A.M. Neto1, M.A. Tambascia1, C.A. da Silva3, S.M. Alegre2, D.E. Wittmann1 1 Endocrinology Division, University of Campinas, Campinas, Brazil; 2Clinical Medicine Division, University of Campinas, Campinas, Brazil; 3Institute of Biology, University of Campinas, Campinas, Brazil Hashimoto’s Thyroiditis (HT) is characterized by the presence of autoantibodies against thyroid tissue. T and B-lymphocytes mediate tissue destruction with the involvement of cytokines groups (Th-1, Th-2, Th-17). Some studies have shown a relationship between vitamin D (Vit D) insufficiency and the presence of autoimmune diseases such as HT. Our aims were to study the association of vitamin D insufficiency in HT and serum interleukins, thyroid function tests and anti-thyroid autoantibodies antithyroperoxidase (TPOAb), anti-thyroglobulin (TGAb), anti- thyrotropin receptor (TRAb). Blood samples were collected from 54 patients with HT and 54 healthy individuals, all aged 18 to 75 years. We measured serum interleukins (TNF-alfa, IFN-gama, IL-2, IL-4, IL-5, IL-17), 25OHVitD, TSH, free T4, calcium, phosphorus, PTH, TPOAb, TGAb and TRAb. Thyroid volume was estimated by ultrasound. Patients and control subjects were matched by sex and age. The significance level for statistical analysis was 5%. Vitamin D insufficiency was present in 21 (38.9%) controls and 37 (68.5%) patients (p = 0.002) IL - 2 was higher in controls compared to patients (median 0.42 vs. 0.18 pg/ml; p = 0.017). Serum TNF-alpha (median 11.9 versus 15.4 pg/ml; p = 0.004) and IL-5 (median 0.83vs. 1.0 pg/ml; p = 0.032) were higher in the HT group. There was no significant difference in the concentrations of other interleukins between the two groups. There was an inverse correlation of Vit D with IL-4 (r = - 0.23; p = 0.018) and TPOAb (r = - 0.196; p = 0.042) in the group as a whole. Patients with HT had a significantly higher frequency of vitamin D insufficiency than controls. IL- 5 and TNF-alpha levels were higher in the HT group, in agreement with recent studies, which have not demonstrated a relation to other cytokines. Lower levels of vitamin D were associated with higher concentrations of TPOAb, indicating some relationship with thyroid lymphocytic infiltration and increased

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autoimmune inflammatory activity. The inverse correlation between IL-4, an interleukin from Th2 group, and vitamin D, in accordance with literature data, suggests immune response is exacerbated in cases of low vitamin D levels.

Poster 555 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM PULMONARY HYPERTENSION IN GRAVES’ DISEASE: WORSE CARDIAC AND PULMONARY FUNCTIONS IN HYPERTHYROID PATIENTS. I.M. Botelho1, D. Camargo2, A.M. Neto1, M. Corso3, M.C. Vaz1, R. Castro1, B. Nakano1, M.A. Tambascia1, D.E. Wittmann1 1 Endocrinology Division, University of Campinas, Campinas, Brazil; 2Cardiology Division, University of Campinas, Campinas, Brazil; 3Pulmonary Diseases Service, University of Campinas, Campinas, Brazil Graves’ disease is an autoimmune thyroid disorder characterized by glandular hyperfunction and secretion of thyroid hormones. Pulmonary hypertension (PH) is a condition defined by pressure increase in the pulmonary capillary. Studies show an association between GD and PH but the pathophysiology is not completely known. Our aims were to evaluate and compare heart and lung functions in euthyroid (group E) and hyperthyroid (group H) patients with GD. 47 patients with GD were included, aged 22 to 74 years old 87.2 % of female, 25 in hyperthyroidism and 22 euthyroid for at least 6 months. Blood samples were collected for serum TSH, free T4 and free T3 measurement. The same cardiologist performed echocardiography in the period of thyroid function tests assessment. Spirometry and 6 minutes walking test were also preformed. PH was verified in 48% hyperthyroid patients and 33% euthyroid patients (p = 0.31). There were no differences in relation to age (p = 0.091) or the following parameters of echocardiography: pulmonary hypertension (p = 0.31), pericardial effusion (p = 0.28), diastolic dysfunction (p = 0.79), hyperdynamic state (p = 0.48), right ventricular diameter (p = 0.23), systolic pulmonary artery pressure (p = 0.10), pulmonary capillary pressure (p = 0.11), cardiac output (p = 0.88) and ejection fraction (p = 0.49) were also similar. Mean pulmonary artery pressure was higher in group H (median 19 vs. 8 mmHg; p = 0.04). There were no differences in walking test parameters between both groups. In spirometry, we observed lower first second forced expiratory volume (FEV1) in group H (median 85.5 vs. 95; p = 0.03). There were no differences for other spirometry parameters. The frequency of PH in GD was similar in hyperthyroid and euthyroid patients. However, the significant frequency in both groups (48% and 33.3%) suggests not only influence of increased thyroid hormones, but also of the autoimmune process. Additionally, we verified worse pulmonary function (decreased FEV1) and an increased mean pulmonary artery pressure in hyperthyroid GD patients.

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Poster 556 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM DOES LOW SERUM TSH WITHIN THE NORMAL RANGE HAVE NEGATIVE IMPACT ON QUALITY OF LIFE OF HEALTHY ELDERLY PEOPLE? D.S. Chachamovitz1,2, P.D. Viga´rio3,4, A.V. Moerbeck2, M.G. Soffientini2, C.W. Rosemberg2, E.G. Luna2, M. Vaisman1, P.D. Teixeira1 1 Endocrinology, UFRJ, Nitero´i, Brazil; 2Internal Medicine, Esta´cio de Sa´ University, Rio de Janeiro, Brazil; 3Physical Education and Sports School, UFRJ, Rio de Janeiro, Brazil; 4Postgraduate Program of Rehabilitation Sciences, Augusto Motta University Center (UNISUAM), Rio de Janeiro, Brazil To evaluate quality of life in healthy elderly people with different thyroidstimulating hormone (TSH) levels within the normal range, and the impact of methimazole treatment to increase serum TSH level to the upper half of the normal range in those with initial TSH levels < 1.0lIU/mL. Initially, a cross-sectional study with healthy elderly people aged ‡ 65 years was conducted. Thereafter, those with TSH levels 0). Out of 451 patients (77.02 – 7.9 years, 54% females), TFT were obtained in 195 at day 8. Baseline tertiles of TSH levels were not associated with mortality risk (p > 0.05). Nonetheless, per each 1.0 mU/ L increase in D TSH, mortality risk was significantly reduced (HR:0.84, CI 0.74-0.95, p = 0.005) in a model adjusted for sex, age and ACE-27. In addition, each 1.0 lg/dl increase in total T4 at day 8 was also independently associated with lower mortality risk (HR: 0.66, CI 0.52– 0.85, p = 0.001). Changes in DT3 were not significantly associated with mortality risk. Patients with a baseline TSH value above the normal range ( > 5 mU/L) and at higher tertiles of baseline TSH values were less likely to present a day 8-increase in TSH levels (OR 0.191, CI 0.058–0.628, p = 0.006) and (OR = 0.64, CI 0.44–0.92, p = 0.018) respectively after adjustment for confounders (age, sex, previous history of thyroid dysfunction, ACE-27 and baseline T4 and T3 tertiles). Patients with higher baseline TSH values showed limited ability to increase their TSH levels at day 8, a variation of TFT that was significantly associated with a better prognosis. Our results confront the generalized knowledge that high TSH levels in critically-ill patients should be always attributed to the recovery phase of NTI.

Poster 558 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM THE INTERRELATION BETWEEN HYPOTHYROIDISM AND GLAUCOMA. A CRITICAL REVIEW AND META-ANALYSIS M. Thvilum, F. Brandt, T.H. Brix, L. Hegedu¨s Department of Endocrinology and Metabolism, Odense University Hospital, Odense C, Denmark

Poster 557 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM HIGHER TSH VALUES AT BASELINE IN ELDERLY IN-PATIENTS ARE RELATED TO WORSE OUTCOME N. Sforza1, J. Rosenfarb1, R. Rujelman1, M. Macias1, S. Frid1, C. Frigerio1, M.P. Fosatti1, M.C. Faingold1, T. Meron˜o2, G. Brenta1

The literature reports conflicting results on the association between hypothyroidism and glaucoma. We sought to clarify this by conducting a critical review and meta-analyses. Based on an electronic PubMed search, using the Medical Subject Heading terms hypothyroidism, myxoedema and glaucoma or intra ocular pressure, case-control studies, cohort studies and cross sectional studies were identified and reviewed. Using meta-analysis, the relative risk (RR) of co-existence of glaucoma and hypothyroidism was calculated. 12 studies fulfilled the inclusion criteria and could be categorized into two groups based on the exposure. The group with glaucoma (5679 patients) as exposure and hypothyroidism as outcome comprised eight studies. Among these, we found a non-significantly increased risk of hypothyroidism associated with glaucoma (RR 1.65; 95% confidence interval [CI]: 0.97–2.82). Based on 4 studies (165,980 patients) with hypothyroidism as exposure and glaucoma as

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 outcome, we found the risk of glaucoma to be significantly increased (RR 1.39; 95% CI: 1.08-1.78). Based on these meta-analyses, there seems to be an association between hypothyroidism and glaucoma. However, larger scale studies with better phenotype classifications, longer follow-up time and taking co-morbidity and other biases into consideration are needed to address a potential causal relationship.

Poster 559 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM THYROID DYSFUNCTION IN ERDHEIM-CHESTER DISEASE D.T. O’Keeffe1, S. Maraka1, M.V. Shah2, R.S. Go2, M.S. Mundi1, B.L. Clarke1 1 Endocrinology, Mayo Clinic, Rochester, MN; 2Hematology, Mayo Clinic, Rochester, MN Erdheim-Chester Disease (ECD) is a rare, infiltrative, non-Langerhans histiocytosis that can affect any organ system including endocrine. Our objective was to describe thyroid dysfunction in patients with ECD. We retrospectively reviewed the medical records of patients evaluated at Mayo Clinic, from January 1990 to June 2014. A tissue biopsy confirming the diagnosis at pathology review was necessary for inclusion in the study. In all cases, the diagnosis of ECD was confirmed using clinical criteria in conjunction with histopathologic findings. Clinical, laboratory, and imaging data were collected. Fifty-five patients with confirmed ECD were included in our study. The median age at diagnosis was 55 years (range, 30–80), while the median time of onset of symptoms prior to diagnosis was 24 months (range, 1–275). There was a male predilection with a male to female ratio of 1.5:1. Hypothyroidism was identified in 19 out of 45 (42%) patients, while in the remaining 10 patients, there was either no TSH checked or thyroid dysfunction was not documented. No cases of hyperthyroidism were identified. Fifteen patients out of the 45 patients (33%) had primary hypothyroidism and 4/45 (9%) had secondary hypothyroidism. Thirteen out of the 45 patients had thyroid antibodies checked; 4/13 (30%) were positive (2 thyroid peroxidase; 2 thyroid microsomal). Three out of the 45 (7%) patients had a neck ultrasound which showed thyroid nodules without other abnormalities. This is the largest case-series of patients with ECD. It typically affects the skeletal system, though non-osseous involvement has also been reported. Apart from bone infiltration, endocrine system involvement has been described, primarily affecting the pituitary gland. To date thyroid infiltration in ECD has been an uncommon finding and limited data exists on thyroid function in these patients. Our results demonstrate a significant prevalence of hypothyroidism (42%) in patients with ECD compared to the general population (4%). In addition, the low rate of positive thyroid antibodies suggests either a central cause or perhaps infiltration of the gland as the cause of hypothyroidism. We suggest that all patients with ECD should be screened for thyroid dysfunction.

Poster 560 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM LONG-TERM PROGNOSIS OF THE PATIENTS WITH GRAVES’ HYPERTHYROIDISM INITIALLY TREATED WITH POTASSIUM IODIDE K. Okamura Dept of Medicine and Clinical Science, Kyushu University, Fukuoka City, Japan

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Since potassium iodide (KI) therapy was shown to be effective for the treatment of the patients with Graves’ hyperthyroidism who showed side-effects to thionamide antithyroid drugs, we tried KI treatment for untreated Graves’ hyperthyroidism from the beginning. In this study, we will report on the long-term prognosis. Between 1991 and 2000, 164 patients with untreated Graves’ hyperthyroidism were treated with 100mg KI from the beginning and followed for more than five years (5–21 years). Serum free T4 level declined in most of the patients and 60 patients (36.6%) were successfully treated by KI alone (KI-sensitive or A group) and 104 patients (63.4%) required combination therapy with KI and thionamaide drug (Partially KI-sensitive or B group). [Result] In A group, a) remission was observed in 38.3% after 1312 (259–3826) days (median, range), b) well controlled with a small maintenance dose of KI, with or without synthesized l-T4, after disappearance of TSH Receptor Antibody (TRAb) in 25.0%, c) became hypothyroid in 13.3% and d) 23.3% were considered to be still active with positive TRAb (15.0% were treated by ablative therapy). In B group, a) remission was observed in 31.7% after 1820 (937–5528) days, b) well controlled with a small maintenance dose of KI or thionamide in 12.5%, c) became hypothyroid in 1.0% and d) 50.0% were considered to be active or intractable (34.6% were treated by ablative therapy). [Discussion] It was shown that long-term prognosis was better in the KI sensitive Graves’ patients (A group) and 76.7% of the patients were wellcontrolled without taking thionamide drugs. On the other hand, partially sensitive patients (B group) required longer duration of treatment or ablative therapy, although remission was also observed in about a third of the patients if treated for more than 5 years. KI therapy may be useful for the initial treatment of the patients with KI-sensitive untreated Graves’ hyperthyroidism without severe complications.

Poster 561 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM CLINICAL EVALUATION OF THE IMMULITE 2000 TSI ASSAY* C. Conarpe2, D. Kiaei1, N. Birmingham1, J. Lei1, V. Chuma-Bitcon3 1 R&D, Siemens Healthcare, Tarrytown, NY; 2Clinical Affairs, Siemens Healthcare, Tarrytown, NY; 3Global Marketing, Siemens Healthcare, Tarrytown, NY Thyroid stimulating immunoglobulins (TSI) are a hallmark of Graves’ disease (GD). The IMMULITE 2000 TSI assay is an innovative automated immunoassay for the quantitative detection of TSI in serum and plasma. The time to first result is 65 minutes. This study compares the diagnostic accuracy of IMMULITE 2000 TSI assay to Roche’s Anti-TSHR assay and THYRETAIN TSI Reporter Bioassay. Literature supports the use of TSI in algorithms for faster time to diagnosis and for the reduction of overall direct costs of GD diagnosis. The clinical utility of a TSI assay includes a determination of the autoimmune etiology of thyrotoxicosis, monitoring Graves’ patient therapy, prediction of remission or relapse, confirmation of Graves’ ophthalmopathy, and prediction of hyperthyroidism in neonates. Serum samples from 735 individuals were analyzed by all three methods. The sample population included patients diagnosed with GD, toxic multinodular goiter, nontoxic goiter, sub-acute thyroiditis, thyroid cancer, Hashimoto’s thyroiditis, Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, Crohn’s disease, Sjo¨gren’s syndrome, Celiac disease, Addison’s disease, as well as apparently healthy individuals. All patients diagnosed with GD had a clinical

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assessment and all associated laboratory tests were documented at the time of enrollment. To calculate the clinical sensitivity and specificity, 0.55 IU/L, 1.75 IU/L, and 140% SRR were used as the cutoff values for the IMMULITE 2000 TSI, Anti-TSHR, and THYRETAIN BioAssay, respectively. The clinical sensitivity (95% confidence interval) of IMMULITE TSI was 96.8% (92.0%–99.1%), Anti-TSHR was 96.8% (92.0%–99.1%), and THYRETAIN 91.2% (84.8%–95.5%) The clinical specificity of the IMMULITE TSI was 98.6% (96.9%– 99.5%), Anti-TSHR 97.3% (95.3%–98.7%) and THYRETAIN 99.3% (97.9%–99.9%). The IMMULITE 2000 TSI assay is a sensitive quantitative immunoassay for the specific detection of TSI in the routine diagnosis and assessment of GD patients. * Under FDA review. Not available for sale.

Poster 562 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM OPTIMIZATION OF RESOURCES TO RULE OUT PRIMARY HYPOTHYROIDISM IN A PUBLIC HOSPITAL L.M. Bergoglio1, M.S. Lussana1, G.A. Mahler1, S.E. Leiva1, L. Mun˜oz2 1 Clinical Hospital. National University of Co´rdoba, Co´rdoba, Argentina; 2Children Hospital, Co´rdoba, Argentina Different first line strategies (1) have been proposed to diagnose primary hypothyroidism. Objective: to evaluate the additional contribution of free thyroxine (FT4), total thyroxine (T4T) and Free T4 Index (FT4I) to Thyrotropin (TSH) only, and to propose an alternative pair [TSH + thyroid antiperoxidase antibodies (TPOAb)] to the usually requested (TSH + FT4). Results of 97 untreated non-pregnant patients, who attended the Laboratory for evaluation of their thyroid function were analyzed; TSH, TPOAb, FT4, and T4T (by Immulite, Siemens); and FT4I (by Elecsys Roche). Statistics: Descriptive, Spearman’s correlation coefficient, and Fisher’s test. Euthyroidism: Normal (N) TSH 69/97 (71.1%); N TSH/N TT4 69/ 97 (71.1%); N TSH/N FT4I 69/97 (71.1%); r: TT4 - FT4I: 0, 9424 (p < 0.0001); N TSH/N FT4 58/97 (59.8%); r: T4L - IT4L: 0, 7206 (p < 0.0001). Hypothyroidism: High TSH 28/97 (28.9%); Subclinical: N TT4 25/28 (89.3%) *; Subclinical N FT4 20/28 (71.4%) *; * Fisher test: p < 0.05. Clinical: Low TT4 3/28 (10.7%) **; Clinical: Low FT4 8/28 (28.6%) **; ** Fisher test: p < 0.05; Thyroiditis: + TPOAb/N TSH 11/97 (11.3%); + TPOAb /H TSH 13/97 (13.4%). Discussion: 71.1% of the Euthyroid patients could have been characterized only with N TSH, no one had low T4T or IT4L, but some of them had paradoxically low FT4. There was an excellent correlation between TT4 and FT4I, although moderate between FT4 and FT4I. The high percentage of Clinical hypothyroidism -when characterized with FT4- would seem overrated by the suboptimal performance of FT4 by some immunomethods. The prevalence of TPOAb coincided with the literature. The advantage of knowing from the beginning the autoimmune etiology of hypothyroidism, and the lack of additional information provided by FT4 in the first approach when TSH is Normal, suggest TSH + TPOAb as a good pair to confirm Euthyroidism, instead of the commonly requested TSH + FT4. On the contrary, when TSH is High, for defining Clinical or Subclinical condition, or when non-primary pathology is suspected, it is suggested TT4 or FT4I preferably to FT4 as second line tests. (1) Brenta, G. et al. Arq. Bras Endocrinol Metab. 57:265-91, 2013.

Poster 563 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM HEALTH-RELATED QUALITY OF LIFE IS IMPAIRED IN UNTREATED AUTOIMMUNE HYPOTHYROIDISM AND IMPROVES AFTER SIX MONTHS OF LEVOTHYROXINE SUBSTITUTION. K.H. Winther1, P. Cramon2, T. Watt2, J.B. Bjorner3, O. Ekholm5, ˚ .K. Rasmussen2, U. Feldt-Rasmussen2, M. Groenvold4, A 1 1 L. Hegedu¨s , S.J. Bonnema 1 Endocrinology, Odense University Hospital, Odense, Denmark; 2 Endocrinology, Rigshospitalet, Copenhagen, Denmark; 3Optum Insight Inc., Eden Prairie, MN; 4Public Health, Copenhagen University, Copenhagen, Denmark; 5Public Health, University of Southern Denmark, Copenhagen, Denmark Hypothyroidism is often detected, and subsequently treated, due to health-related quality of life (HRQL) considerations. However, disease specific HRQL impairments and changes following thyroid hormone substitution have not previously been assessed with a validated disease specific instrument. Eighty-one patients with autoimmune hypothyroidism answered disease-specific (ThyPRO) and generic (SF-36) HRQL questionnaires before and 6 months after initiation of levothyroxine substitution. ThyPRO consists of 85 items that assess physical, mental, and social domains of functioning and well-being in patients with benign thyroid disorders. The items are summarized in 13 scales. SF-36 consists of 36 items summarized in 8 scales. Normative ThyPRO (n = 739) and SF-36 (n = 6,638) data were collected from representative general population samples. Score differences between patients and the general population and associations between thyroid stimulating hormone (TSH) and HRQL were assessed with multivariate linear regression analyses adjusted for age, gender, comorbidity and educational status. Changes following treatment were analyzed with the paired t-test. All analyses were adjusted for multiple testing (Hochberg method). Prior to treatment, patients’ ThyPRO scores were impaired, compared to the general population, on all 9 comparable scales ( p-values < 0.0001). The same was observed for 7 of 8 SF-36 scales. ThyPRO scores improved significantly, on 8 of 13 scales during 6 months’ levothyroxine substitution. ThyPRO deficits compared to the general population remained only on 1 of 9 comparable scales (i.e. the hypothyroid symptoms scale, p-value < 0.0001). SF-36 scores improved significantly on 4 of 8 scales. The greatest HRQL baseline deficit and response to treatment was found in the tiredness (ThyPRO) and vitality (SF-36) scales. No significant associations between TSH and HRQL were found. For untreated autoimmune hypothyroidism, both disease-specific (ThyPRO) and generic (SF-36) HRQL are impaired, but improve significantly after 6 months of levothyroxine substitution. In this population, ThyPRO nearly normalized, while some SF-36 deficits persisted at 6 months.

Poster 564 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM TRANSIENT CENTRAL HYPOTHYROIDISM IN NEONATES BORN TO MOTHERS WITH GRAVES DISEASE G. Alcaraz, A.M. Va´zquez, M. Abalovich, M.C. Calabrese, M. Stivel, M. Frydman, S. Gutie´rrez Endocrinology Division, Durand Hospital, Buenos Aires, Argentina Central hypothyroidism (CH) in newborns of mothers with uncontrolled Graves’ disease (GD) is an under recognized and potentially

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severe complication that may have a similar prevalence of neonatal thyrotoxicosis. Although transient, it usually requires prolonged treatment to minimize the risk of neurological damage. Objective: Communicate the occurrence of central hypothyroidism in neonates (NN) of mothers with inadequately treated GD during pregnancy, analyzing clinical and biochemical maternal features. Maternal determinations: FT4, TSH by chemiluminescence; and TRAb by RR (RV < 15 %). Cord blood determinations: T4 (RV: 8–14 mcg/dl); FT4 (RV: 1.2–2 ng/dl) and TSH (3.2–15 IU/l) and TRAb. CH diagnosis: neonatal T4 40 and LDL < 150 mg/dl), without coronary risk factors or ED causing drugs. Serum ET1 as a marker of ED was measured by ELISA and CRP as an inflammation marker was measured by immunoturbidimetric method. ET1 and CRP were repeated when euthyroidism on LT4 treatment was achieved. Statistical Analysis: Mann-Whitney, Wicoxon and t Test, when appropriate. Patients (n = 44) and Controls (n = 19): Age (mean – SD) 34.9 – 9.9 and 33.9 – 6.5 years old (p NS); Body Mass Index (BMI) 24.1 – 3.4 and 22.7 – 2 (p NS), respectively. Twenty four SH patients were reevaluated after 8.9 – 3.9 months of LT4 treatment. We observed no significant differences in lipid values between SH and controls. ET1 and CRP levels were significantly higher in patients with SH than in the control group (see Table). ET1 decreased significantly with treatment, but persisted significantly elevated compared to controls. CRP did not change with LT4 therapy. The results support that subclinical hypothyroidism per se, regardless of other risk factors such as dyslipidemia, can cause endothelial dysfunction and inflammation. These disorders could at least partially improve on LT4 treatment. It could be speculated that a longer euthyrodism period should be necessary to normalize ET1 levels.

Poster 566 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM DEVELOPMENT OF A SHORT VERSION OF THE THYROID-RELATED PATIENTREPORTED OUTCOME THYPRO T. Watt1, J.B. Bjorner2, M. Groenvold2, P. Cramon1, K.H. Winther3, ˚ .K. Rasmussen1, J.E. Ware4, L. Hegedu¨s3, S.J. Bonnema3, A U. Feldt-Rasmussen1 1 Medical Endocrinology, Copenhagen University Hosptal Rigshospitalet, Copenhagen, Denmark; 2Health Service Research, University of Copenhagen, Copenhagen, Denmark; 3Medical Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark; 4University of Massachusetts, Warwick, MA Thyroid diseases affect quality of life. ThyPRO is an international comprehensive well-validated patient-reported outcome, measuring thyroid-related quality of life. The current version is rather long, 85 items. The purpose of the present study was to develop an abbreviated version of ThyPRO, with conserved good measurement properties. A cross-sectional (N = 907) and a longitudinal sample (N = 435) of thyroid patients were analyzed. A graded item response theory (IRT) model was fitted to the cross-sectional data. Short- form scales with three items were aimed for, by selecting items with best fit according to the IRT model, avoiding cross-culturally non-invariant items. Seven scales measuring mental and social well- being and function as

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well as one overall quality-of-life (QoL)-impact item were analyzed in a bi- factor model, to develop a supplementary composite score. Short-form scales were linked to original scales with IRT-based summed-score-linking. Agreement between the short and long form was estimated by agreement plots, intra-class correlations, and mean score levels. Responsiveness was compared by relative validity indices, clinical validity by ability to detect clinically relevant differences, and test-retest reliability by intra-class correlation. One four-item scale was not abbreviated and one two-item scale was omitted from the short-form. For the 11 scales undergoing abbreviation, ten with three and one with four items were developed. A bi-factor model with good overall fit was fitted to the composite score, including the single QoL-item. Responsiveness and clinical validity of the short-form scales were preserved as were test-retest reliability (0.75 to 0.89). Short- vs. long-form intra-class correlations were high, 0.89 to 0.98, and the mean scale levels were similar. A 39-item version of the ThyPRO, with good measurement properties, was developed and is recommended for clinical use.

Poster 567 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM THYROIDECTOMY FOR GRAVES’ DISEASE: ONE SURGEON’S EXPERIENCE S. de Leo2,1, P. Srimatkandada3, E. Pearce3, D. McAneny4, L. Braverman3 1 Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; 2Endocrine Unit, Fondazione IRCCS Ca’ Granda, Milan, Italy; 3Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center, Boston, MA; 4Department of Surgery, Boston Medical Center, Boston, MA Definitive treatment of Graves’ disease includes anti-thyroid medications, radioactive iodine (RAI) ablation, and thyroidectomy. In the United States, RAI ablation is the most common therapy for Graves’ disease. However, an operation is favored in patients who have symptomatic goiters or moderate to severe eye disease, and when patients express a preference for surgery. We analyzed a cohort of patients with Graves’ disease, operated on by a single high-volume surgeon at Boston Medical Center, to carefully evaluate rates of complications during and after thyroidectomy. A retrospective chart review was completed of 168 consecutive patients (81% women, average age 40 years) who underwent thyroidectomy, all via cervical approach, for Graves’ disease between 2004 and 2014. Gland size ranged from 10.8 g to 386 g, mean 66 g. Five patients (3%) had been treated with radioactive iodine ablation prior to surgery. Eighty-three patients (49%) had eye disease. Complications occurred in five patients (3%): one patient developed permanent hypoparathyroidism, two patients (1.1%) had a hematoma requiring neck re-exploration (one with an occult Factor XI deficiency, and the other with a 218 g goiter), one patient experienced an exacerbation of hypertension during surgery and required the institution of antihypertensive medication, and one patient developed a right lower lobe pulmonary collapse that required bronchoscopy and overnight mechanical ventilation. No patients had permanent recurrent laryngeal nerve paralysis. Moreover, final pathology revealed 11 patients (6.5%) with an incidental papillary thyroid carcinoma. In conclusion, surgery is a safe alternative therapy for Graves’ disease when performed by an experienced thyroid surgeon. Furthermore, no patients had recurrent or persistent hyperthyroidism, in contrast to those historically treated with 131-I or anti-thyroid medications.

Poster 568 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM PATIENTS WITH CENTRAL HYPOTHYROIDISM ARE LESS SUFFICIENTLY TREATED WITH L-THYROXINE THAN PATIENTS WITH HYPOTHYROIDISM AFTER RADIOIODINE OR AFTER THYROIDECTOMY E. Pirnat3,1, G. Setnikar2, B. Samec2, S. Gaberscek3,2, T. Kocjan2,4, K. Zaletel3 1 University Medical Centre, Ljubljana, Slovenia; 2Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; 3Department of Nuclear Medicine, University Medical Centre, Ljubljana, Slovenia; 4 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centr, Ljubljana, Slovenia Unlike in patients with hypothyroidism after radioiodine (HRI) or after thyroidectomy (HTh), in those having central hypothyroidism (CH) treatment with L-thyroxine (L-T4) cannot rely on thyrotropin (TSH) levels. Therefore, treatment of CH still represents a risk of under- or overtreatment. Our aim was to establish the adequacy of LT4 treatment in our CH patients. In this retrospective study we included consecutive patients treated with L-T4 because of CH and compared them with patients adequately treated for HRI or HTh. Patients with HRI and HTh had TSH level within the reference range (0.35–5.5 mU/L). Cumulative weekly dose of L-T4, levels of free thyroxine (fT4), and free triiodothyronine (fT3) were evaluated. The fT4/fT3 ratio was calculated. We included 40 patients with CH, 110 patients with HRI and 42 patients with HTh. According to ANOVA analysis, patients with CH, HRI and HTh did not differ with respect to age (median (range), 64 (26–86), 50 (18–85), and 64 (25–87) years, respectively, p = 0.103). The weekly dose of L-T4 was similar in all three groups (median (range), 700 (350–1252), 700 (175–1400), and 700 (175–1275) mcg, respectively, p = 0.393). Levels of fT4 were significantly lower in CH than in HRI and HTh (median (range), 15.6 (12.7–21.8), 18.3 (12.2– 28.8), and 18.7 (13.8–25.5) pmol/L, respectively, p < 0.001 for both). Levels of fT3 were similar in CH, HRI and HTh (median (range), 4.5 (2.7–6.0), 4.3 (3.2–6.2), and 4.3 (2.9–5.5) pmol/L, respectively, p = 0.139 and p = 0.572, respectively). Accordingly, lower fT4/fT3 ratio was observed in CH than in HRI and HTh (median (range), 3.7 (2.5–5.2), 4.1 (1.2–7.6), and 4.4 (2.5–6.1), respectively, p = 0.003 and p = 0.001, respectively). In spite of similar weekly dose of L-T4, patients with CH have lower fT4 levels and lower fT4/fT3 ratio as compared to patients adequately treated for HRI or HTh. The difference is probably caused by the inability to rely on TSH levels in CH patients. Considering our reference values and these results, the fT4 level above 18.0 pmol/L, and the fT4/fT3 ratio above 4.0 would guarantee an adequate treatment in majority of patients with CH.

Poster 569 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM THERAPEUTIC OPTIONS FOR GRAVE’S DISEASE AND TOXIC NODULAR DISEASE: EXPERIENCE OF AN ENDOCRINOLOGY DEPARTMENT J. Silva, C. Ivo, M. Marcelino, H. Simoes, L. Lopes, D. Passos, J. Castro Portuguese Armed Forces University Hospital, Lisboa, Portugal The thyroid pathology is an area of special interest in our department. Hyperthyroidism represents 3.4% of the 8144 patients followed. The

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 aim of this study is to characterize the therapeutic approach in patients with Grave’s disease (GD) and toxic nodular disease (TND). Retrospective study of 217 patients diagnosed with GD and TND, evaluated according parameters of therapeutic option, efficacy, relapse rate and associated complications at 6 months and 1 year. Variables were analyzed by methods of descriptive statistics: frequency and contingency tables for categorical variables and mean, s.d., minimum and maximum for continuous variables. From 217 patients, 138 were included in the study (91 GD and 47 TND). In TND 68% were female, aged 59.5G13.2 years. GD 75% were female, aged 42.69G15 years. In both diseases the decision for surgical treatment was chosen, respectively, in 48.9 and 2.8% of the medical cases. Treatment with radioactive iodine in 40.4 and 19.7% and anti-thyroid drugs (ATD) in 10.6 and 77.5% of cases. All patients that underwent surgical treatment remain euthyroid at the end of 1 month, with no recurrence after 12 months. Average dose of iodine in TND was 9.5 mCi, with 89.4% achieving euthyroidism at 6 months, with 20% of recurrences at 12 months and 15.7% became hypothyroidism. Average dose of iodine in GD was 11.5 mCi, achieving 71.4% euthyroidism in 6 months, 11.8% recurrences at 12 months and 16.7% became hypothyroidism. With ATD became Euthyroidism, 80% (for GD) and 81.5% (for DNT) with 25% recurrences 25% in GD and 45.7% in DNT at 12 months. The treatment of choice was the surgical approach to TND and ATS for the GD, with recurrences rates similar to those of the literature !1% with surgery, 50% ATD and 20% with iodine.

Poster 570 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM RADIATION FROM RADIOIODINE THERAPY DOES NOT INDUCE THICKENING OF THE CAROTID INTIMA MEDIA J. la Cour1, U. Andersen1, C.H. Sorensen4, B. Nygaard2, L. Jensen3 1 Department of Clinical Physiology, Nuclear Medicine and PET, Righospitalet, Glostrup, Denmark; 2Section of Endocrinology, Department of Medicine, Herlev Gentofte University Hospital, Herlev, Denmark; 3Department of Clinical Physiology and Nuclear Medicine, Herlev Gentofte University Hospital, Herlev, Denmark; 4 Department of ENT, Head & Neck Surgery and Audiology, Rigshospitalet Gentofte, Gentofte, Denmark Atherosclerosis evolves or accelerates after external radiation exposure of arteries both early and late. Radioiodine therapy of benign thyroid disease exposes the carotid arteries to approximately 4-50 Gy pr. GBq thereby increasing the risk of atherosclerotic events. Increased risk of cerebrovascular events is seen after radioiodine therapy. We aimed to study whether atherosclerosis develops early and/or late after radioiodine therapy of benign thyroid disease. We examined patients treated for benign thyroid disorders (from nontoxic goitre to hyperthyroidism). Signs on early damage from radioiodine were studied in 39 radioiodine treated patients, followed for a year (examined before and after 1, 3, 6 and 12 months). Late damage was studied in a cross-sectional case-control design with radioiodine treated patients as cases (n = 193) and patients treated with surgery as controls (n = 95). All patients were examined with ultrasound by the same operator measuring our main outcome carotid intima media thickness (CIMT) and plaque status (plaque status only in late damage). Data were analysed with repeated measurements for longitudinal data, and with multivariate regression for cross-sectional data. Results were adjusted for age, sex, cholesterol, smoking status, known atherosclerotic disease and BMI We found no changes in CIMT or plaque after radioiodine treatment either early (p = 0.58) or late (p > 0.2 for CIMT, p = 0.76 for plaque, median follow up since radioiodine of 9.8 years); Further-

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more, thyroid status did not influence these atherosclerosis markers (p > 0.05 for both). We were not able to detect any early or late changes in CIMT or plaque after radiation from radioiodine, pointing towards a very low effect of radiation from radioiodine therapy on atherosclerosis development.

Poster 571 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM SUB-CLINICAL HYPOTHYROIDISM WITH IODINE DEFICIENCY IN NEW JERSEY L.B. Munshi1, S. Kargutkar2 1 Internal Medicine, Monmouth Medical Center, Eatontown, NJ; 2 Endocrinology, Monmouth Medical Center, Long Branch, NJ Iodine deficiency is a common cause of hypothyroidism in the developing countries. It is not believed to be present in the developed countries such as United States. The Iodine levels are not routinely checked on lab work in the patients with hypothyroidism. We are presenting a case series of patients with subclinical hypothyroidism and low Iodine levels. 49-Year-Old Caucasian female, 47-Year-Old Caucasian female, 57-Year-Old Caucasian male and 64-Year-Old Caucasian female presented with symptoms of hypothyroidism. The labs showed elevated TSH and normal T3 & T4. The thyroid antibodies were negative and Iodine level was low in these cases. Upon appropriate Iodine replacement their clinical symptoms resolved and TSH returned to normal range. It is believed that industrialized countries like US and Europe do not have iodine deficiency. But the increase in use of weight loss foods, vegetarian/vegan foods has increased the susceptibility for Iodine deficiency. Also there are many patients in Nursing homes or Rehabs who are on very limited diet. The use of salt restricted diet can also be a factor. All these factors can cause iodine deficiency presenting with elevated TSH and symptoms of hypothyroidism. Typically TG (Thyroglobulin) and TPO antibodies are negative. Although the recommendations by ATA is not to treat subclinical hypothyroidism until the TSH is greater than 10, on appropriate replacement of the Iodine these patients improved clinically and their TSH returned to normal. In patients with subclinical hypothyroidism and negative thyroid antibodies, iodine level should be checked and replaced if low. ATA & the Endocrine Society advise U.S women to be on supplement with 150 mcg of Iodine per day beginning preconception.

Poster 572 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM POSSIBLE FACTORS AFFECTING THE THERAPEUTIC OUTCOME OF RADIOIODINE THERAPY IN PATIENTS WITH AFTN H. Zhang, N. Jiang Sun Yat-Sen University,, Guangzhou, China To evaluate pretreatment factors affecting the results of radioactive iodine (RAI) treatment on patients with hyperthyroidism caused by autonomous function thyroid nodule (AFTN). We retrospectively analyzed AFTN patients with RAI between 2008 and 2013. 113 patients (26 male, 87 female) with AFTN were entered in the study and followed up until 12 months after therapy. Qualification of these patients were based on clinical features, high levels of serum FT3 and FT4, low levels of serum TSH and

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characteristic appearance on thyroid scans and ultrasound. Some of the patients were treated with anti-thyroid drugs before 131I therapy (28 patients). All patients received RAI based on nodule size, age and clinical findings. The activity dose was calculated by the use of Marinelli’s formula. The absorbed dose was 300Gy. Patients clinical status and thyroid hormone levels were evaluated 3, 6, 9 and 12 months after treatment. Successful treatment was defined as the absent of hyperthyroidism, and disappear of hot nodules after RAI therapy 12 months. Patients with suppressed or normal TSH who were taking anti-thyroid drugs were classified as failures. When analyzing possible factors affecting post-therapeutic outcome, the incidence of therapy success rate was not significantly associated with age, sex, BMI, nodule size and HT severity (P > 0.05), additionally analysis showed lower probability of treatment success in patients with anti-thyroid drugs (P < 0.01). 131I therapy is a simple, safe, effective and economical treatment of AFTN diseases. In AFTN patients, anti-thyroid medication tended to reduce the therapeutic efficacy. Those patients might need higher doses.

Poster 573 Disorders of Thyroid Function Wednesday & Thursday Poster Translational 9:00 AM LDL FROM THE PATIENTS WITH SUBCLINICAL HYPOTHYROIDISM SHOW INCREASED LIPID PEROXIDATION AND OXIDATIVE STRESS C. Xu1, L. Gao2, J. ZHAO1 1 Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China; 2 Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China Population-based studies have demonstrated that subclinical hypothyroidism (SCH) is an independent risk factor for atherosclerosis (OR = 1.9). Although some studies have demonstrated that serum cholesterol levels are elevated in patients with SCH, others have not shown any effect of SCH on these lipid measurements. Therefore, the association between SCH and atherosclerosis cannot be entirely explained by dyslipidemia accompanied with SCH. Lipid peroxidation also plays an important role in the development of atherosclerosis. We aimed to evaluate the oxidation stress in SCH patients. Hydroxy-octadecadienoic acids (HODEs), hydroxyl-eicosatetraenoic acids (HETEs) and gp91phox are considered the most reliable oxidative biomarkers. The concentrations of HODEs and HETEs both in LDL and in plasma were examined in euthyroid, mild SCH, and significant SCH subjects. The concentration of gp91phox was assayed in SCH patients with normal or high LDL-C levels, and healthy controls. We analyzed the association among these biomarkers, extent of atherosclerosis, and SCH. The concentrations of HODEs and HETEs increased obviously in significant SCH patients compared to euthyroid subjects, while there was no difference between mild SCH and euthyroid group. Both 9HODE (r = 0.376, p = 0.041) and 13-HODE (r = 0.447, p = 0.013) in LDL were linearly and positively correlated with TSH. Additionally, oxidative stress was also confirmed by the increased concentration of serum gp91phox in SCH patients with high LDL-C levels. Gp91phox is positively correlated with LDL-C (r = 0.57, P < 0.05) and TSH (r = 0.61, P < 0.05) in SCH patients with high LDL-C levels. Notably, after adjustment for LDL-C levels, gp91phox is still positively correlated with TSH(r = 0.57, P < 0.05). Our findings showed that lipid peroxidation was markedly enhanced in SCH patients, which might be associated with high level of oxidative stress. Our study suggested that qualitative as well as

quantitative changes in serum lipids resulting from SCH may add to atherosclerosis risk. Therefore, we suggest monitoring of oxidant status and lipid levels besides TSH levels in SCH patients.

Poster 574 Iodine Uptake & Metabolism Wednesday & Thursday Poster Basic 9:00 AM TSH-INDUCED THYROID PEROXIDASE EXPRESSION IS INHIBITED BY NITRIC OXIDE INVOLVING THE FORKHEAD FACTOR FOXE1 M. Montesinos, J.P. Nicola, M. Nazar, V. Peyret, A.M. Lucero, C.G. Pellizas, A.M. Masini-Repiso Centro de Investigaciones en Bioquı´mica Clı´nica e Inmunologı´a Consejo Nacional de Investigaciones Cientı´ficas y Te´cnicas (CIBICI-CONICET). Departamento de Bioquı´mica Clı´nica, Facultad de Ciencias Quı´micas, Universidad Nacional de Co´rdoba, Co´rdoba, Argentina Thyroid peroxidase (TPO) is essential for thyroid hormone synthesis mediating the covalent incorporation of iodine into tyrosine residues of thyroglobulin (I- organification) and the coupling of iodotyrosyl residues to form thyroid hormones. Thyrotropin (TSH) is the main hormonal regulator of TPO gene expression. The thyroid transcription factor FoxE1 is crucial for TSH-induced TPO expression. Previous studies have indicated that nitric oxide (NO) represses TSH-induced Itransport and organification in thyroid cells. Moreover, NO donors inhibit TSH-stimulated TPO mRNA expression in the rat thyroid cell line FRTL-5. Here, we aimed to further explore the molecular mechanism underlying the inhibitory effects of NO on TPO expression. FRTL-5 cells were incubated with the NO donors sodium nitroprusside and S-nitrosoglutathione. TPO and FoxE1 expression was evaluated through western blot, RT/qPCR, and gene reporter

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 assays. FoxE1 binding to TPO promoter was evaluated by gel shift assays and chromatin immunoprecipitation assays. Both NO donors decreased TSH-induced TPO mRNA and protein expression. NO-reduced TPO expression resulted from transcriptional repression of the TPO gene in response to activation of cyclic guanosine monophosphate/soluble guanylate cyclase (cGMP/cGK) pathway. Deletion and mutagenesis analysis of the TPO promoter revealed the FoxE1 binding site Z as mediator of the NO-induced repression of TPO promoter activity. Coincidently, NO donors decreased the TSH-stimulated FoxE1 binding to the TPO promoter. Further characterization of the role of NO on FoxE1 expression revealed that NO donors reduced the TSH-stimulated FoxE1 level by inhibiting FoxE1 gene expression. Interestingly, FoxE1 overexpression prevented the NO donorsinhibited TPO gene expression in response to TSH. We demonstrated that the NO modulation of TPO transcriptional expression involves NO-triggered inhibition of FoxE1 expression which leads to a reduced transactivation of the TSH-stimulated TPO promoter. These results strongly reinforce the regulatory role of NO on thyroid cell function, an observation of potential pathophysiological relevance in human thyroid pathologies associated with chronic NO production.

Poster 575 Iodine Uptake & Metabolism Wednesday & Thursday Poster Basic 9:00 AM CHANGING THE SUBSTRATE SPECTRUM OF MCT10 BY STRUCTURE GUIDED AMINO ACID EXCHANGES D. Braun1, J. Johannes2, U. Schweizer1 1 Institut fu¨r Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms Universita¨t Bonn, Bonn, Germany; 2Institut fu¨r Experimentelle Endokrinologie, Charite´-Universita¨tsmedizin Berlin, Berlin, Germany Several transport proteins mediate the transport of thyroid hormones across plasma membranes. The most specific thyroid hormone transporter is monocarboxylate transporter 8 (MCT8) which facilitates the uptake and efflux of T3, T4, rT3, and 3,3’-T2. MCT8 shares 49% amino acid identity with monocarboxylate transporter 10 (MCT10). Both transporters belong to the major facilitator superfamily of 12 transmembrane-spanning proteins. When comparing the potential transport channels of MCT8 and MCT10 by homology modeling, we identified a set of only twelve amino acids differing between these two proteins. Although sharing such a high homology, MCT8 and MCT10 differ in their substrate spectrum. MCT10 is able to facilitate the transport of T3 but not T4. Furthermore, MCT10 is known as a transporter for aromatic amino acids, which are not transported by MCT8. Amino acid exchanges were introduced into human MCT10 by site directed mutagenesis and stably transfected into MDCK1 (Madin-Darby canine kidney) cells. Radioactive uptake experiments were performed to measure the ability of the mutated protein to facilitate the transport of T3, T4, and tryptophan. Here we report how we mutated eight selected amino acids in MCT10 to the corresponding amino acids found in MCT8 with the aim to change the substrate specificity of MCT10 to a MCT8-like pattern. The resulting MCT10MCT8 chimera showed an increase of T4 uptake to a level found in MCT8wt and a loss of tryptophan transport. Subsequently, we reduced the number of amino acid exchanges and identified S121, Y184 and T207 as residues important for T4 uptake. The amino acid Y184 turned out to be an essential residue for the transport of aromatic amino acids since mutation of Y184 to the corresponding amino acid found in MCT8 (MCT10Y184F) alone abolished the uptake of tryptophan.

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By changing three out of 515 amino acids in MCT10 to the corresponding amino acids found in MCT8, we changed the substrate specificity of the transporter and ‘‘taught’’ MCT10 to facilitate the uptake of T4, which is normally not a substrate of the protein.

Poster 576 Iodine Uptake & Metabolism Wednesday & Thursday Poster 9:00 AM EFFECT OF IODINE SUPPLEMENTATION ON PREGNANT RATS WITH MILD TO MODERATE IODINE DEFICIENCY W. Teng, Z. Shan, X. Sun Endocrine department, Endocrine Institue, China Medical University, Shenyang, China Iodine is essential for thyroid hormone metabolism in mothers and fetuses. Severe iodine deficiency during pregnancy results in neurodevelopmental disorders in children and affects their health. Compared with severe iodine deficiency, the consequences of mild to moderate iodine deficiency (MMID) are uncertain. One hundred 4-week-old female Wistar rats were randomly divided into normal (normal iodine intake, N) and MMID (low iodine intake, L) groups. The rats were fed for the next 3 months, and further divided into 2 subgroups after pregnancy: NP (normal iodine pregnancy) and NP + (normal iodine pregnancy with supplement), and LP (low iodine pregnancy) and LP + (low iodine pregnancy with supplement). All the rats were fed with the low-iodine diet and administered drinking water containing different concentrations of potassium iodide. The concentration of iodine was determined by inductively coupled plasma mass spectrometry. Urinary iodine was increased in early pregnancy and decreased as pregnancy progressed. The concentration of iodine in maternal and offspring thyroid, placenta, and amniotic fluid of the LP group decreased during pregnancy, whereas that of NP rats maintained stability. The concentration of iodine in maternal and offspring thyroid and amniotic fluid of the LP + group increased compared with LP group. Normal rats can meet their iodine needs during pregnancy, and iodine supplementation has no effect on iodine metabolism during pregnancy. In MMID rats, there is insufficient iodine storage for pregnancy, and iodine supplementation can slow the decline in iodine storage during pregnancy. Iodine supplementation during pregnancy was beneficial for MMID rats, while the time and dose of iodine supplementation requires further research. When iodine supplement to normal rats, it also needs to pay attention to consequences of iodine excess during pregnancy.

Poster 577 Iodine Uptake & Metabolism Wednesday & Thursday Poster 9:00 AM ENDEMIC GOITER IN A VEGAN TODDLER IN THE US O. Yeliosof2, L.A. Silverman1 1 Pediatric Endocrinology, Goryeb Children’s Hospital, Morristown, NJ; 2Goreyb Children’s Hospital, Morristown, NJ Endemic goiter, i.e. iodine deficiency, is the most common cause of acquired hypothyroidism in the world. Iodine is essential for normal growth and development. Iodine deficiency is uncommon in the Western world due to salt iodination programs. The incidence of iodine deficiency may be rising due to the popularity of restrictive diets. Methods/Case Presentation: A 23-month-old boy on a vegan diet was diagnosed with hypothyroidism during an evaluation of macrocephaly. He had normal newborn thyroid screening. He was

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breastfed until 16 months of age by a vegan mother on prenatal vitamins. After weaning, the child ate vegan homemade foods, no fish or cow’s milk and no iodinated salt. The child was not taking vegetables that contained thiocynate or cyanoglucosides nor vitamins. His physical exam noted normal growth, macrocephaly and an open anterior fontanel. He had a minimally palpable thyroid. Thyroid ultrasound revealed mild enlargement. Anti-thyroid antibodies were negative. Laboratory evaluation noted in table: Mother’s urinary iodine was noted to be 100 mcg/liter, reflecting her iodine sufficiency. The child started 25 mcg of L-T4 and added iodized salt to the diet at the initial visit. A children’s multivitamin containing 100 mcg iodine was added when the iodine deficiency was confirmed. The thyroid function normalized. US dietary iodine sources vary widely. Iodinated salt, seafood and dairy provide iodine; these sources are not present in a strict vegan diet. As most infants are breast fed or drink formula, iodine content in their diets should be adequate; > 90 mcg iodine per day is the current recommendation. Upon transition to cow’s milk, the iodine content of 88 mcg/8 oz continues to provide RDA. As non-dairy milk does not contain iodine, this source of iodine is not present in a toddler who follows a vegan diet. Conclusions: Iodine insufficiency has been recognized in women of childbearing age following vegan diets, thus prompting recommendations for supplementation during pregnancy and lactation. This case highlights the risk for iodine deficiency in children transitioned to vegan diets after discontinuation of breast/formula feeding and the need for continuing iodine supplementation.

Poster 578 Iodine Uptake & Metabolism Wednesday & Thursday Poster Clinical 9:00 AM BARIATRIC SURGERY REDUCES URINARY IODINE LEVELS- A PROSPECTIVE 10-YEAR-REPORT FROM THE SWEDISH OBESITY SUBJECT (SOS) STUDY S. Manousou2,4, L. Carlsson2, R. Eggertsen2,3, L. Hulthe´n2, K. Landin-Wilhelmsen1,2, P. Jacobson1,2, L. Sjo¨stro¨m2, P. Svensson2, H. Filipsson Nystro¨m1,2 1 Deparmtent of Endocrinology, Sahlgrenska University Hospital, Go¨teborg, Sweden; 2Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Go¨teborg, Sweden; 3Mo¨lnlycke Health Care Center, Mo¨lnlycke, Sweden; 4Department of Medicine, Skaraborgs Hospital, Sko¨vde, Sweden Iodine is essential for the thyroid metabolism. Iodine deficiency may be a risk of bariatric surgery (BS). The hypothesis was that patients undergoing gastric by-pass surgery (GBP) suffer from iodine mal-

absorption, whereas vertical banded gastroplasty patients (VBG) with an intact gastro-intestinal tract do not. Both groups may have reduced dietary iodine intake compared to obese non-surgery patients (OB). From the Swedish Obesity Subject (SOS) study, a non-randomized prospective study of obese patients 1987–2000, 188 GBP patients were retrieved and matched to 188 VBG and 188 OB patients. 24hurinary iodine excretion (24-UIE), thyrotropin (TSH) and information on intake of iodine containing products were collected at baseline and after 2 and/or 10 years. These groups were compared to matched non-obese population based controls (non-OB) (n = 188) (the WHO MONICA project). After 10 years, BMI had decreased in GBP and VBG from mean 43.7 and 43.3 to 33.2 and 36.2 kg/m2, respectively. BMI was stable in OB 42.0 to 41.8 kg/m2 and non-OB 25.2 to 27.0 kg/m2. Median 24UIE was similar at baseline in GBP, VGP and OB (214, 201 and 203 lg) and did not differ after 2 years. After 10 years, 24-UIE in GBP, VBG and non-OB was similar (160, 149 and 142 lg) and was lower than in OB controls 189 lg, p < 0.01 (BS vs OB) and p < 0.0001 (OB vs non-OB). At baseline, median TSH was higher in SOS patients, 1.48 mIU/L, than in non-OB, 0.98 mIU/L, p < 0.01. After 10 years, TSH increased in the non-OB to 2.20 mIU/L and did not differ from GBP and OB groups, whereas VBG had lower TSH 1.50 mIU/L than the non-OB, p < 0.0001. In the SOS cohort, the milk consumption decreased during 10 years while the fish consumption increased in the BS treated patients. Obese subjects had higher 24-UIE than non-obese controls. Patients undergoing bariatric surgery decreased in 24-UIE to levels within a normal iodine intake, explained by a reduction in dietary iodine intake rather than iodine malabsorption from gastric by-pass. There was no effect of surgery on thyroid hormone levels except from the well-known obesity effects. The groups will be further analyzed for use of iodine containing supplements that may mask iodine deficiency in a sub-population.

Poster 579 Iodine Uptake & Metabolism Wednesday & Thursday Poster Clinical 9:00 AM SERUM THYROGLOBULIN AS A BIOMARKER OF IODINE DEFICIENCY IN AN ADULT POPULATION A. Krejbjerg1,2, L. Bjergved3, I. Bu¨low Pedersen1,2, A. Carle´1, N. Knudsen4, H. Perrild4, L. Ovesen5, L.B. Rasmussen6, P. Laurberg1,2 1 Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 2Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 3Research Centre for Prevention and Health, The Capital Region of Denmark, Glostrup, Denmark; 4Depertment of Endocrinology, Bispebjerg University Hospital, Copenhagen, Denmark; 5Department of Gastroenterology, Slagelse Hospital, Slagelse, Denmark; 6Department of Nutrition, National Food Institute, Technical University of Denmark, Søborg, Denmark Serum thyroglobulin (Tg) is recommended by WHO as an effect indicator when monitoring the iodine status of a population and a median dried blood spot Tg of 13lg/l has been proposed as a cut-off value for children. We studied which factors determine the serum Tg level in an adult population and how this may affect Tg as a biomarker of iodine deficiency (ID). Two identical cross-sectional studies were performed before (C1a: 1997–98, n = 4649) and after (C2: 2004-05, n = 3570) the Danish mandatory iodine fortification (IF) of salt (13 ppm) in 2000. Additionally, an 11-year follow-up study of C1a was performed after IF (C1b: 2008-10, n = 2465). All studies took place in the same two regions with mild (Copenhagen) and moderate (Aalborg) ID before

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iodine and creatinine in urine and thyroglobulin in serum. Participants with TGAb below 100 u/L and at least three samples were included in the analysis. Participants enrolled were 48 men and 49 women; 33 Caucasians and 39 Inuit in town, 25 Inuit in settlement; 50 present smokers, 15 past smokers and 30 never smokers. A total of 81 were included in the analysis. Overall variation was higher for UIC compared to TG (Coefficient of Variation (CV): 83.6% vs 73.5%) with also a marked difference in the median individual variation (CV of UIC vs TG: 46.1% vs 15.1%). The number of samples needed for a 95% precision with 95% conficence interval was 80 for TG and 440 for UIC. Variation was much lower for TG compared to UIC. Consequently, the number of samples needed for similar reliability of estimates was more than 5 times higher for UIC compared to TG.

Poster 581

IF, determined by urinary iodine concentrations (UIC) of spot urine samples. After IF, the C2 study found Aalborg to have mild ID and Copenhagen to have sufficient iodine intake. In C1b, UIC had decreased again classifying both regions as mildly ID. Serum Tg was measured by immunoradiometric method (Thermo Fisher Scientific). In a multivariate linear regression model, multiple factors were related to Tg (Figure 1). Some were directly related to iodine intake (C1a before IF vs. C1b after IF, UIC level and region) and some were likely mediators of iodine intake effects on Tg (thyroid nodularity, thyroid size and autonomy with low TSH). Others were caused by assay interference (Tg-Ab positivity) or worsening of ID (childbirths and smoking). Despite the clinical indicators of ID before IF, none of the studies had a median Tg > 13 lg/l (C1a: median Tg = 10.4 lg/l, Copenhagen = 9.3 lg/l, Aalborg = 12.0 lg/l; C2: Tg = 9.1 lg/l, Copenhagen = 9.0 lg/l, Aalborg = 9.3 lg/l; C1b: Tg = 8.9 lg/l, Copenhagen = 8.9 lg/l, Aalborg = 8.8 lg/l). Multiple factors were associated with Tg in an adult population, some, not all, were effect modifiers of ID. This should be taken into consideration when using Tg as a marker of ID in an adult population. Moreover, the Tg results may depend on assay and we suggest to include a reference population with sufficient iodine intake when Tg is used to evaluate ID.

Poster 580 Iodine Uptake & Metabolism Wednesday & Thursday Poster 9:00 AM PRECISION OF IODINE NUTRITION LEVEL DESCRIPTION BY USE OF THYROGLOBULIN IN SERUM S. Andersen1,2, P. Laurberg1,3 1 Arctic Health Centre, Dept. of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark; 2Geriatric & Internal Medicine, Aalborg University Hospital, Aalborg, Denmark; 3Endocrinology, Aalborg University Hospital, Aalborg, Denmark Iodine nutrition status may be assessed by measuring iodine concentration in urine (UIC) or thyroglobulin (TG) in serum. The precision of estimates and the number of participants needed has been settled for iodine in urine but not yet for thyroglobulin. We surveyed subjects living in North Greenland four times over a year. Participants were enrolled with a balanced representation of Caucasians and Inuit in town, Inuit in town and settlement, men and women, and age groups 30-39 and 40-49 years. Diet, supplement use and life style factors were assessed by questionnaires. Food intake were computed from food frequency questionnaires. We measured

Iodine Uptake & Metabolism Wednesday & Thursday Poster Clinical 9:00 AM URINARY IODINE EXCRETION IN CHILDREN AND ADOLESCENTS IN FUKUSHIMA AFTER THE NUCLEAR ACCIDENT: THE FUKUSHIMA HEALTH MANAGEMENT SURVEY H. Shimura1,3, S. Suzuki2,3, T. Fukushima2,3, S. Midorikawa3, T. Matsuzuka4, Y. Ito1, T. Ohhira3, M. Abe3, A. Ohtsuru3, S. Yamashita3, S. Suzuki2 1 Department of Laboratory Medicine, Fukushima Medical University, Fukushima-shi, Japan; 2Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima-shi, Japan; 3 Radiation Medical Science Center for the Fukushima Health Management Survey, Fukushima Medical University, Fukushima-shi, Japan; 4Department of Otolaryngology, Fukushima Medical University, Fukushima-shi, Japan Previous reports showed urinary iodine concentration in Japanese children was higher than those in other countries. After the occurrence of nuclear accident in March 2011, the iodide intake has not been studied in children and adolescents in Fukushima prefecture. The aim of this study was to assess the urinary iodine concentration (UIC) in children and adolescents in order to originally contribute to a re-evaluation of radioactive iodine uptake at the time of the nuclear accident in Fukushima. This study was a cross-sectional study between October 2011 and March 2015. 2093 children and adolescents 2 to 22 years old who participated the secondary examination of Thyroid Ultrasound Examination program and were examined UIC were subjected to this study. The median age of subjects was17 years (interquartile range, 14–19 years). UIC was determined by the ammonium persulfate digestion on microplate (APDM) method. The median UIC was 168 lg/L, which is relatively low in comparison with previous reports studying other areas in Japan. While no significant difference between male and female UIC was observed, UIC relative to creatinine excretion (UI/Cr) in female was significantly higher than that in male. The highest UIC was observed in subjects aged 8 years, and was declined in parallel with age. Evaluation of UIC by the place of residence at the time of examination showed that there were no significant differences in UIC between three regions in Fukushima Prefecture and the outside of Fukushima. Determination of iodine status by WHO criteria showed that 25.2% and 28.1% of subjects might be in iodine deficiency and excess, respectively. The present study uncovered the iodine status of children and adolescents after the nuclear accident. Even though a spot UIC was influenced by daily food contents, the fact that about half of subjects were in iodine deficiency or excess suggests that further monitoring

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of iodide status might be beneficial for not only for re-evaluation of iodine thyroid blocking strategy at the time of the nuclear accident but also for long-term health management of Fukushima residents.

Poster 582 Iodine Uptake & Metabolism Wednesday & Thursday Poster Clinical 9:00 AM RELATIONSHIP BETWEEN AGE AND RADIOACTIVE IODINE UPTAKE OF RECURRENT LESION OF DIFFERENTIATED THYROID CARCINOMA T. Kikumori1, S. Iwano2 1 Breast and Endocrine Surgery, Nagoya University Hospital, Nagoya, Japan; 2Radiology, Nagoya University Hospital, Nagoya, Japan Targeted systemic therapies have been recently introduced in management of recurrent Differentiated Thyroid Carcinoma (DTC). However, indications of these agents are currently limited to Radioactive Iodine (RAI) refractory DTC. Refractoriness to RAI can be demonstrated by RAI non-avidity of recurrent lesions. Demonstration of refractoriness could be a barrier in terms of time and medical resources. Age has been considered as a prognostic factor of recurrent DTC and has been suggested to be related to iodine nonavidity. The present study was performed to evaluate the influence of age on RAI uptake of recurrent lesions of DTC. Two hundred and sixty-five patients who underwent first RAI Whole Body Scan (WBS) for recurrent DTC at our hospital between 2004 and 2014 were retrospectively studied, which included 200 patients of Papillary Thyroid Carcinoma (12 patients of Follicular variant (FVPTC)), and 65 patients of Follicular Thyroid Carcinoma (FTC). All but one case were RAI-naı¨ve as ablation has not prevailed until recently in Japan. RAI uptake was determined by visual uptake in the metastatic site at diagnostic or post-therapeutic RAIWBS. RAI uptake in lung metastases was demonstrated in 19 out of 146 cases of classic Papillary Thyroid Carcinoma (cPTC), 4 out of 5 cases of FVPTC, and 15 out of 33 cases of FTC. In patients of cPTC with lung metastases, the mean age of patients with RAI non-avidity (60.7 – 11.1y) was significantly higher than those with RAI avidity (42.1 – 16.6y) ( p < 0.001). RAI avidity had significant inverse cor-

relation with age ( p = 0.023). In lymph node metastases of cPTC, comparable results were obtained. In contrast, in lung and bone metastases of FTC, age of patients had no correlation with RAI avidity. RAI avidity of metastatic lesions of cPTC in elderly patients, especially in those older than 60 years was seldom demonstrated. Strategy of skipping RAI treatment could be taken into account considering age and histological type.

Poster 583 Iodine Uptake & Metabolism Wednesday & Thursday Poster Clinical 9:00 AM INFLUENCE OF EXCESSIVE IODINE INTAKE ON THE THYROID FUNCTION AND SPECTRUM OF THYROID ABNORMALITIES IN POPULATION OF TURINSK, SVERDLOVSK REGION, OF RUSSIA A. Kiyaev1, N. Platonova2, F. Abdulhabirova2, E. Troshina2, G. Gerasimov3 1 Ural Medical Universety, Yekaterinburg, Russian Federation; 2 Endocrinology Research Centre, Moscow, Russian Federation; 3 Iodine Global Network, Moscow, Russian Federation Previous surveys showed chronic iodine excess - median urinary iodine concentration (UIC) over 500 mcg/l - supposedly due to water contamination in population of Turinsk, a town in Sverdlovsk Region of Russia. Aim: conduct an assessment of the effects of chronic iodine excess on thyroid function and spectrum of thyroid abnormalities in schoolchildren and adults. Assessment was conducted in 100 schoolchildren and 100 adults residing in Turinsk and 97 schoolchildren and 100 adults in the control site (city of Pervouralsk) with optimal UIC. Assessment included thyroid ultrasonogrpahy, urinary iodine and dry spot TSH in schoolchildren and TSH and TPO-ab in adults. Iodine was also measured in random water samples from 10 households in Turinsk. Median UIC in schoolchildren in Turinsk (719 mcg/l) was significantly higher (129 mcg/l) than in Pervouralsk resulting in higher prevalence of thyroid enlargement and TSH level. In adults TSH level as well as prevalence of subclinical hypothyroidism and autoimmune thyroiditis were higher in residents of Turinsk compared to control group from Pervouralsk. Iodine excess alters thyroid function in schoolchildren and adults increasing prevalence of thyroid enlargement in children and autoimmune thyroidis in adults.

Poster 584 Iodine Uptake & Metabolism Wednesday & Thursday Poster 9:00 AM NUTRITIONAL SURVEY FOR THE INDIRECT ASSESSMENT OF IODINE INTAKE BY PEDESTRIANS ˜O INTERVIEWED IN A CENTRAL SQUARE OF RIBEIRA ˜ O PAULO, BRAZIL PRETO, SA M.D. Alves Clı´nica me´dica, Universidade de Ribeira˜o Preto, Ribeira˜o Preto, Brazil INTRODUCTION- Iodine is an essential micronutrient for the human organisms for the synthesis of thyroid hormones. The WHO recommends a daily iodine intake of 150 lg for normal adults. In Brazil, the main source of iodine is industrialized salt for domestic consumption, with a recommended intake of less than 5 g/day, although Brazilians consume on average 12 g/day. In 2013, The National Agency of Sanitary Surveillance (ANVISA) determined an iodine concentration of 15 to 45 mg/kg salt in an attempt to reduce

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 excessive iodine intake. We performed a nutritional survey for an indirect assessment of iodine intake by pedestrians interviewed in a central square of Ribeira˜o Preto. MATERIAL, METHODS - A total of 1634 volunteers were assessed (932 women, 57.03%, and 702 men, 42.97%) ranging in age from 18 to 95 years (women) and from 18 to 101 years (men). RESULTS- About 14.93% of women and 12.93% of men were 18 to 30 years old; 15.97% and 12.93% were 30 to 40 years old; 17.02% and 20.93% were 40 to 50 years old; 18.93% and 17.32% were 50 to 60 years old; 19.62% and 19.02 were 60 to 70 years old, and 13.53% and 17.79% were older than 70 years, respectively. No interviewee stated that he/she did not use non-iodinated salt for food preparation; 0.86% of the women and 3.90% of the men stated that they did not add salt to their food; 50.30% and 31.70% used little salt; 35.58% and 54.14% used a moderate quantity; 10.41% and 11.70% used a lot of salt, and 2.85% and 2.43% had the habit of carrying a salt shaker to the dining table. We detected 12 women (43–80 years) and 7 men (31–71 years) with goiter. During blood pressure determination, 10 hypertensive women and 20 hypertensive men reported that they ingested a lot of salt. CONCLUSION- Although iodine concentration has been reduced in industrialized salt, salt consumption continues to be high in Brazil, indicating the need for an educational campaign on the part of the government for a reduction of its intake, thus preventing thyroid dysfunction and arterial hypertension. Acknowledge to Endocrinology League (2014, 2015) of UNAERP and to UNAERP for support.

Poster 585 Thyroid & Development Wednesday & Thursday Poster Basic 9:00 AM THE EFFECT OF VARYING DEGREES OF FETAL/NEONATAL THYROID HORMONE INSUFFICIENCY ON ANGIOGENESIS-ASSOCIATED GENE EXPRESSION AND BLOOD VESSEL DENSITY IN THE DEVELOPING RAT BRAIN G.W. Anderson2, T. Bastian3, T. Nguyen1, K. Thibert1 1 Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota, Duluth, MN; 2Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota, Duluth, MN; 3Department of Pediatrics, University of Minnesota, Minneapolis, MN Adequate thyroid hormone (TH) is necessary for normal mammalian brain development. Brain development is energetically demanding and requires delivery of oxygen, nutrients, hormones, and signaling molecules via the brain vascular network. Angiogenic signaling and blood vessel density were previously shown to be reduced in the early postnatal severely TH-deficient brain. Our objective was to compare neonatal brain angiogenic signaling and blood vessel density following mild, moderate, and severe fetal/neonatal TH deficiency. Three separate experiments were performed where pregnant rats were given 1, 3, or 10 ppm propylthiouracil from early gestation through mid-lactation. mRNA expression of vasculogenesis-associated genes was assessed in postnatal day 10 (P10), P12, or P15 brains. Neonatal brain mRNA levels of Vwf, Flk1, Cxcl12, and Hif1alpha were not significantly altered following developmental TH deficiency. Fetal/neonatal PTU treatment significantly reduced neonatal brain Glut1, Ang2, and Vegfa mRNA levels in age-, brain region-, and dose-dependent fashions, suggesting decreased blood vessel growth in the developing TH-deficient brain. To test the possible effects of altered angiogenic gene expression more directly, neonatal brain blood vessel branch point density was assessed using GLUT1 immunohistochemistry. No significant changes in branch point density were observed at any PTU dose in either the hippocampus or cortex.

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Expression of some angiogenesis genes is altered by PTU treatment in some brain regions during development. However, these altered expression patterns are not associated with changes in vascular density. Further work is needed to explore the possible functional implications of PTU-dependent altered angiogenic gene expression during brain development.

Poster 586 Thyroid & Development Wednesday & Thursday Poster Basic 9:00 AM EFFECTS OF MATERNAL THYROID PEROXIDASE ANTIBODY ON BRAIN DEVELOPMENT OF OFFSPRING IN MOUSE MODELS X. Wang, Y. Zhou, Z. Shan, W. Teng Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, China Maternal thyroid peroxidase antibody (TPOAb) positive is a very common endocrine disorder in pregnancy. However, the effect of maternal positive TPOAb on brain development of offspring remains unclear. Our study established TPOAb positive model in C57bl/ 6mice and explored whether maternal TPOAb positive affected brain development of offspring. Female C57bl/6 mice immunized with recombinant adenoviruses which insert the mouse TPO cDNA. We measured free thyroxin (FT4) and serum TPOAb titer in mater mice to confirm the presence of positive TPOAb. In offspring mice, total thyroxine (TT4) in brain homogenate and TPOAb titer in serum were measured. Offspring in postnatal day 40(PND40) test Morris water maze to measure spatial learning, tail suspension test and forced swimming test to measure depression-like behavior. MBP, RC3, THRa, BDNF mRNA were measured as well. Maternal serum TPOAb titers increased through pregnancy compared to controls, thyroid hormone levels were normal.The test (T) group offspring had higher serum TPOAb titers than the control (C) group in PND10, p = 0.00.T group had lower brain homogenate TT4 level than C group in PND0, p = 0.018. In Morris water maze, T group had longer escape latency time and had less times of each mouse crossed the platform area compared with C group. In tail suspension test and forced swimming test, the total immobility time measured among T group was significantly higher compared to control group. Offspring in T group had lower mRNA level in MBP, RC3 and THRa, and BDNF mRNA become lower in PND10 and PND40. Maternal TPOAb positive could increase TPOAb level and affect thyroid function in offspring mice; meanwhile it impaired offspring spatial learning and led some depression-like behavior. Some thyroid hormone related gene mRNAs were also lower in brain tissue of offspring from maternal TPOAb positive mice.

Poster 587 Thyroid & Development Wednesday & Thursday Poster Basic 9:00 AM DESIGN AND INITIAL IMPLEMENTATION OF A NATIONWIDE CAPACITY BUILDING PROGRAM FOR EDUCATING PRIMARY CARE PHYSICIANS OF INDIA IN THYROID MANAGEMENT T. Soni1, S. Bhalla1, D. Monga1, A. Gaurang1, A. Unnikrishnan2, S. Deshpande2, R. Srivastava1, D. Prabhakaran1 1 Public Health Foundation of India, Delhi, NCR, India; 2Chellaram Diabetes Institute, Pune, India

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Thyroid disorders are common, in India, with 42 million suffering from thyroid diseases. A recent study has shown that one in ten adult Indians have hypothyroidism. Given the high burden and its morbidity, there is an urgent need to strengthen the skills of primary care physicians to recognize and manage these diseases early. To address this challenge, a comprehensive training initiative ‘Certificate Course in Management of Thyroid Disorders (CCMTD)’ was conceptualized to cover 13 states, 2 Union Territories and 22 cities of India. To our knowledge, a program on thyroid education of this magnitude has not been carried out to date. The program is a partnership model between Public Health Foundation of India (PHFI), Delhi and Chellaram Diabetes Institute (CDI) Pune. The objective is to empower the Primary Care Physicians (PCPs) via a curriculum that was developed initially at CDI and reviewed by 15 national experts in the field of Endocrinology. This was further refined and vetted by a pool of 25 specialists in the field who delivered the course content to the PCPs. The course comprises of didactic lectures, case studies, learning activities and instructional videos. We established a robust monitoring mechanism of onsite random visits by a team of observers who were drawn from a national pool of public health experts. It was expected that 500 physicians would enroll for the first cycle and that 2000 physicians would eventually be trained over three cycles. The actual enrolment in the first cycle was 750. Over 47% of participants were postgraduates specialized in Internal Medicine, Pediatrics and so on. Around 22% were affiliated to the state and central government services. High enrolment rate reveals a felt need of the physician community from India in education on thyroid disease management. This course is an example of a private-public partnership model to empower primary care physicians.

Poster 588 Thyroid & Development Wednesday & Thursday Poster 9:00 AM A NOVEL MUTATION IN THYROID PEROXIDASE GENE CAUSING CONGENITAL GOITROUS HYPOTHYROIDISM IN A GERMAN-THAI PATIENT C. Sriphrapradang1, Y. Thewjitcharoen2, S. Chanprasertyothin3, S. Nakasatien2, T. Himathongkam2, O. Trachoo1 1 Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 2Diabetes and Thyroid Center, Theptarin Hospital, Bangkok, Thailand; 3Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Thyroid dyshormonogenesis is responsible for 10–15% of cases with congenital hypothyroidism and usually inherited. We report a 26year-old German-Thai male with congenital hypothyroidism caused by a compound heterozygous mutation in the thyroid peroxidase (TPO) gene. The patient presented with delayed bone growth and muscular hypotonia. He was diagnosed as congenital goitrous hypothyroidism at the age of 4 months. He has been treated with levothyroxine replacement therapy and failed to withdraw levothyroxine. The growth and development were normal except moderately impairment of fine motor and coordination. He lived in Germany but later in his life, he and the family moved to Thailand. His goiter size was increased due to poor compliance. Ultrasonography of the thyroid gland showed suspicious pattern of malignancy. He later received near-total thyroidectomy. Pathology was multinodular goiter without malignancy. Genetic analyses by the direct sequencing entire exons and flanking regions of TPO gene were performed in the index case and family members. We found a compound heterozygote of novel TPO

mutation of c.1727C > T in exon 10 resulting in amino acid substitution (p.Ala576Val) and c.2268_2269insT in exon 13 causing a frameshift mutation which introduced a stop codon after the insertion site. The latter had been reported in Chinese subjects. However, there is no previous report of c.1727C > T mutation in the literature. We found the allele contained a novel exon 10 mutation inherited from German mother and an exon 13 mutation from Thai father. Relying on two bioinformatic softwares, this variant is likely causing protein damaging. This novel mutation has not been found in 50 normal individuals. A novel TPO mutation has been identified. The present report emphasizes the importance of regularly follow-up and patient’s compliance to received adequate levothyroxine replacement to avoid prolonged stimulation of thyroid tissue by TSH.

Poster 589 Thyroid & Development Wednesday & Thursday Poster 9:00 AM AN UNUSUAL CASE OF ACUTE SUPPURATIVE THYROIDITIS IN A CHILD E. Okawa1, C. Astley1, K.R. Whittemore3, L. Laffel2,1, S. Huang1 1 Endocrinology, Boston Childrens Hospital, Boston, MA; 2 Pediatrics, Joslin Diabetes Center, Boston, MA; 3 Otolaryngology, Boston Childrens Hospital, Boston, MA Acute suppurative thyroiditis is rare, accounting for 0.1%-0.7% of thyroid disease, and is often secondary to a predisposing congenital anomaly. Most patients are euthyroid on presentation. Here we report an unusual case of acute suppurative thyroiditis with concurrent severe thyrotoxicosis and the rapid evolution of a large abscess documented on serial imaging. A 3 year old previously healthy boy presented with days of fever, neck pain, and anterior neck swelling. Physical exam was notable for tachycardia, a diffusely enlarged, firm, tender thyroid gland, and a resting tremor. A neck ultrasound revealed a heterogeneous hyperemic thyroid gland. Laboratory studies showed evidence of significant inflammation and severe thyrotoxicosis without evidence of autoimmunity (see table). The patient was admitted and started on atenolol and intravenous ampicillin-sulbactam. At 48 hours he was afebrile, but his neck exam became asymmetric. A computed tomography scan showed a left thyroid abscess with air adjacent to a left fourth brachial cleft sinus tract, as well as a small right thyroid phlegmon. Incision, abscess drainage and direct laryngoscopy/bronchoscopy by Otolaryngology were uncomplicated. Intraoperative cultures grew Streptococcus intermedius; this was successfully treated with oral amoxicillinclavulanate. Atenolol was continued until thyroid hormone levels normalized. Three weeks after drainage, repeat thyroid function

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 studies were notable for a rising TSH (peak 47.94 mcunit/mL) and hypothyroxinemia (nadir 4.7 mcg/dL). He was started on levothyroxine 50 mcg/day (3.2 mcg/kg/day); this was tapered to 25 mcg after 2 months. Follow-up magnetic resonance imaging uncovered a residual fourth branchial cleft sinus tract for which he will undergo surgical excision by Otolaryngology. This case illustrates the rapid development of a thyroid abscess in a child with a predisposing congenital anomaly and the rare manifestation of severe thyrotoxicosis that resolved with primary treatment of the infection. In young children who present with fever and thyrotoxicosis, an index of suspicion for suppurative thyroiditis and abscess formation should be maintained even when initial imaging is negative for focal abnormalities.

Poster 590 Thyroid & Development Wednesday & Thursday Poster Clinical 9:00 AM DO OFFSPRING OF WOMEN WITH THYROID DISEASE IN PREGNANCY SHOW EMOTION DYSREGULATION AT ADOLESCENCE? J.F. Rovet 1 Neuroscience and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada; 2Pediatrics & Psychology, University of Toronto, Toronto, ON, Canada Recent evidence links maternal thyroid disease in pregnancy to infant regulatory problems, autism risk, childhood psychopathology, and, adulthood psychiatric disorders, which may reflect altered fetal brain programming from early thyroid hormone (TH) loss. Since emotion dysregulation (ED) in adolescence is a known risk factor of later psychiatric illnesses, which are also sexually dimorphic, we asked if male and female adolescents born to women treated for hyperthyroidism or hypothyroidism during pregnancy have increased rates of ED. A further goal was to examine for changes in brain morphology in brain regions supporting emotion regulation (ER). We studied 10 youth aged 10–12 years born to hyperthyroid women (HYPER; 5M,5F), 23 to hypothyroid women (HYPO; 11 M,12F), and 23 to normothyroid women (NORM; 15M,9F), all from the same birth cohort. They underwent psychological testing and an MRI scan. Parents completed three questionnaires: BRIEF assessing ED via two scales and CBCL and Conners for behavior problems. FreeSurfer Image Analysis Suite served to extract brain

A. Percent of males and females in each group with emotion dysregulation; B. Conners’ Emotional Lability subscale scores in SD units; C. Regions differing in size from NORM group

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volumes from MRI scans for ER (amygdala, A; orbitofrontal cortex, OFC; cingulate; insula) and non-ER regions. Groups were stratified by emotion dysregulation presence (ED + ) or absence (ED-). Figure 1 shows HYPER males had the highest rates of ED + (80%), followed by HYPO males (40%), whereas NORM males and all females showed low rates. HYPER males also had the highest incidence of externalizing and affective disorders. HYPER and HYPO males were both seen to be more emotional labile than other while HYPER males and HYPER females scored highest on hyperactivity. MRI findings showed in HYPER, ED + had larger volumes than ED- in all ER regions while in HYPO, ED + showed intermediate increases in A and OFC. In contrast, all ED + showed smaller volumes in non-ER regions than ED-. Males born to women with thyroid disease in pregnancy have increased ED risk, whereas females are unaffected. Associations between ED risk and increased brain volumes in structures belonging to the regulatory network may reflect an effect of lack of TH on apoptosis. These findings suggest that the fetal brain programming of ER regions is vulnerable to gestational TH loss.

Poster 591 Disorders of Thyroid Function Wednesday & Thursday Poster Translational 9:00 AM FUNCTIONAL CHARACTERIZATION OF THYROIDPEROXIDASE GENE MUTATIONS INVOLVED IN CONGENITAL HYPOTHYROIDISM AND FETAL GOITER M.M. Silva2, T.M. Rodrigues3, M.M. Freitas1, A.P. Oliveira1, G. Medeiros4, I. Rubio1 1 Departmento of Biological Sciences, Federal University of Sa˜o Paulo - UNIFESP, Sa˜o Paulo, Brazil; 2Department of Morphology and Genetics, Federal University of Sa˜o Paulo, UNIFESP, Sa˜o Paulo, Brazil; 3School of Medicine of the Federal University of Minas Gerais, Belo Horizonte, Brazil; 4Thyroid Unit, Cellular and Molecular Endocrine Laboratory, LIM-25, Faculdade de Medicina da Universidade de Sa˜o Paulo (FMUSP), Sa˜o Paulo, Brazil Congenital hypothyroidism (CH) is the most common cause of preventable mental retardation. Thyroid peroxidase (TPO) mutations are frequent genetic defects associated with CH and iodide organification defect (IOD). Fetal goiter is a rare condition that indicates severe impairment of thyroid hormone synthesis in intrauterine life and may cause fetal and neonatal morbidities or mortality. Thyroglobulin and TPO gene mutation have been detected in few cases of fetal goiter. This study aimed to functionally characterize mutations identified in CH patients with IOD or fetal goiter. The known mutations p.Gln660Glu, p.Gly319Glu and the new mutations p.Cys296Alafs*21 and p.Ala911fsX49 were introduced in pCDNA containing wild type TPO cDNA (wtTPO) by site direct mutagenesis. The p.Cys296Alafs*21 (c.DelT886) introduces a new stop codon at 316 residue and the p.Ala911fsX49 (c.2733_2742 dupGGGCCGCAGC) may introduce 49 new aminoacids. Hela cells were transfected with the mutatedTPO and wtTPO vectors and stable clones were selected with geneticin (600lg/ml). The peroxidase activity of TPO was measured by fluorescence using the Amplex RED kit (Invitrogen). Reduced peroxidase activity (reduction of 45 - 72%) was observed in cells expressing all mutantTPO as compared to that expressing wtTPO (p < 0.05). The p.Cys296Alafs*21, identified in heterozygosis in fetal goiter patients, leaded to the lowest TPO activity (17.46 – 2.09%) when compared to wtTPO. This patients also harbored the p.Arg665Trp mutation also which promotes the reduction of the TPO activity and improper membrane localization. The activity of cells expressing the other TPO mutants associated to partial IOD were: p.Ala911fsX49: 38.61 – 0.78%; p.Gly319Glu:

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44.09 – 0.97% and p.Gln660Glu: 53.28 – 2.51%. Immunofluorescence and western blot analysis are being performed to determine cellular localization and the size of the mutant proteins. This study demonstrated that the mutations significantly reduced the peroxidase activity of TPO, which may promote the impairment of thyroid hormone synthesis and consequently CH. The genotype/ phenotype correlation in CH due to TPO mutations remains to be confirmed.

Poster 592 Thyroid & Development Wednesday & Thursday Poster Clinical 9:00 AM HISTOPATHOLOGY AND SPECIFIC THYROID GENE EXPRESSION IN A SERIE OF HUMAN ECTOPIC THYROID TISSUE: FETAL ARCHITECTURE IN THYROID ECTOPIA R.Y. Camargo7, C.T. Kanamura2, C.U. Friguglietti3, S. Iorcanski4, C.R. Nogueira8, A.J. Tincani5, A. Bezerra6, G. Medeiros7, I. Rubio1 1 Biological Sciences, Federal University of Sa˜o Paulo - UNIFESP, Sa˜o Paulo, Brazil; 2Adolfo Lutz Institute, Sa˜o Paulo Public Health Service, Sa˜o Paulo, Brazil; 3Head and Neck Surgery of Santa Catarina Hospital, Sa˜o Paulo, Brazil; 4Servicio de Endocrinologı´a, Hospital de Pediatrı´a Dr Juan Garrahan, Buenos Aires, Argentina; 5 Departamento de Cirurgia na Disciplina de Cirurgia de Cabec¸a e Pescoc¸o, Faculdade de Cieˆncias Me´dicas da UNICAMP, Campinas, Brazil; 6Universidade de Fortaleza - Unifor, Fortaleza, Brazil; 7 Thyroid Unit, Cellular and Molecular Endocrine Laboratory, LIM-25, Faculdade de Medicina da Universidade de Sa˜o Paulo (FMUSP), Sa˜o Paulo, Brazil; 8Department of Internal Medicine, Botucatu School of Medicine UNESP, Botucatu, Brazil Ectopic thyroid is the most common cause of congenital hypothyroidism and results from a migration defect of the developing gland. Ectopia has also been detected in asymptomatic subject, causing dysphonia, dysphagia or coexisting with normal located thyroid. Thus, the fact that some patients with ectopic thyroid remain euthyroid, at least for a period of life, has yet to be elucidated. The aim of this study was to investigate the histopathological features and functional characteristics of a serie of human ectopic thyroid tissues, through the expression of specific thyroid genes. Six ectopic thyroids tissues were histologically examined, and the expression of Na/I Symporter, TSH receptor, thyroid transcription factor-1 and PAX 8 was assessed by immunohistochemistry. One ectopic sample from an adult hypothyroid patient was located at oropharynx and showed a fetal architecture, with groups or cords of oval thyrocytes and primitive follicles. A lingual thyroid sample from a one-month girl exhibited a normal thyroid pattern. Her hormonal thyroid status was not investigated before surgery. Three lingual thyroid and one ectopia located at hyoid bone showed colloid goiter pattern. One of these patients was euthyroid and the others were on hypothyroidism before surgery. All ectopic thyroid tissues expressed the specific thyroid genes with similar localization to that observed in a developing or in normal thyroid, albeit focal follicles areas or thyrocytes within follicles did not express several of these genes. This is the first time that the arrest of the thyroid structural development is observed in an ectopic thyroid. Interestingly, this tissue was able to express specific thyroid genes but not to respond to TSH stimuli. This study also confirms that normal location is not a requirement for the thyroid terminal differentiation and thyroid hormone production. Thus thyroid structural and functional differentiations are independent of thyroid migration. However, in some ectopic patients the amount of thyroid hormone synthesis is limited, not enough to support the body growth.

Poster 593 Thyroid & Development Wednesday & Thursday Poster 9:00 AM THE NONRECURRENT LARYNGEAL NERVE: AN ANATOMIC VARIATION WORTH TO KNOW ABOUT IN THYROID AND PARATHYROID SURGERY M. Anwar2, M. Alshehri2, A. Kadi2, J. Bamford1, E. Kandil2 1 Neurosurgery, Tulane University School of Medicine, New Orleans, LA; 2Surgery, Tulane University School of Medicine, New Orleans, LA Intraoperative nerve monitoring (IONM) has been debated over as a tool to identify laryngeal and vagus nerves during thyroid surgeries. Non-recurrent laryngeal nerve (NRLN) is an anatomic variation of the predominant recurrent laryngeal nerve. Laryngeal nerve injury is one of the most common complication of these surgeries. Successful identification and preservation of this variant will help the surgeons to avoid substantial complications. Our objective was to examine the efficacy of IONM for successful identification of the NRLN. We retrospectively analyzed the database of all the patients who underwent thyroid surgeries by a single surgeon from January 2012 to May 2015. Patients’ demographic data and operative reports including the IONM reports were reviewed. Average stimulation thresholds with resulting amplitudes and latencies of NRLN, right RLN, left RLN, and right vagus nerve were compared. Preoperative and postoperative laryngoscopy were done in all patients. We identified 10 right sided NRLN (1.9%). Early in the operative exposure the average latency was found to be significantly shorter for stimulating the right vagus nerve with NRLN, compared to stimulation of vagus nerve with RLN (1.09ms – 0.292 vs. 3.43ms – 1.036; P < 0.001). No significant difference was found between the initial amplitudes of NRLN and right vagus nerve (880.4 lV – 529 vs. 817.10 lV – 467.32; P = 0.68). All NRLN patients exhibited normal functioning of vocal cords on postoperative laryngoscopy. Nonrecurrent laryngeal nerve is recognized in 1.9% of cases. Intraoperative nerve monitoring along with comprehensive knowledge of surgical anatomy helps the surgeon to swiftly recognize this uncommon anatomical variation. Decreased latency of the vagus nerve raised our surgeon’s suspicion for the presence of a NRLN, which allowed the cautious preservation of the nerve, thus resulting in excellent postoperative outcomes for our patients. Herein, we present an electrophysiologic algorithm that can be an adjunct in early prediction of the presence of NRLN to avoid NRLN injuries.

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Poster 594 Thyroid & Development Wednesday & Thursday Poster Clinical 9:00 AM RECURRENT LARYNGEAL NERVE MANAGEMENT IN THYROID SURGERY: CONSEQUENCES OF ROUTINE VISUALIZATION, APPLICATION OF INTERMITTED, STANDARDIZED AND CONTINUOUS NERVE MONITORING G. Dionigi1, H. Kim2, C. Wu3, S. Rausei1, L. Boni1, F. Chiang3, M.L. Tanda4, E. Piantanida4, V. Pappalardo1, D. Inversini1 1 University of Insubria (Varese-Como),, 1st Division of General Surgery, Research Center for Endocrine Surgery, Department of Surgical Sciences and Human Morphology., Varese, Italy; 22. KUMC Thyroid Center Korea University, Anam Hospital, 2. Department of Surgery, Division of Breast and Endocrine Surgery, Minimally Invasive Surgery and Robotic Surgery Center, Seoul, Korea (the Republic of); 33. Kaohsiung Medical University Hospital, Kaohsiung Medical Universit, Department of Otolaryngology,, Kaohsiung City, Taiwan; 44. University of Insubria (Varese-Como), 4. Department of Endocrinoly, Varese, Italy Objective: To compare the consequences of routine visualization (RV), application of intermitted (I-IONM), standardized (S-IONM) and continuous nerve monitoring (C-IONM) for recurrent laryngeal nerve (RLN) management in thyroid surgery. RV includes 698 RLNs managed solely with visual identification. In a second study period 777 RLNs were handled by the application of I-IONM. 3rd period 768 RLNs monitoring was performed according to standards i.e. VN stimulation before (V1) and after thyroidectomy (V2). C-IONM via VN stimulation included n.626 RLNs. A standardized intraoperative management scheme for those RLN that experienced C-IONM EMG changes (decrease amplitude and increate latency combined) was routinely applied. The following issues were analyzed and compared per each period study: RLN identification rate, RLN branching detection, assessment of NRLN, intraoperative recognizable nerve damage, stage thyroidectomy rate, transient or definitive RLN lesions, bilateral nerve palsy, RLNP recovery time. Identification and preservation of RLN was achieved in 96% (2,699/ 2,806) RLN. Significance for nerve identification rate was achieved (p = 0.03) when statistical analysis was applied between RV vs. SIONM and C-IONM. Extralaryngeal RLN bifurcation was identified in 21%, 44%, 43%, 46% of RLN dissected respectively per period (p = 0.005). The incidence of paralysis in identified and unidentified RLN was 3,8% (107/2,806) and 82% (52/63) respectively. Rates of temporary/permanent RLNP were 16,7/1,7%, 5/1,1%, 4,5/1%, 3,1/0% per period study respectively (p = 0.07). Recognizable intraoperatively nerve damage was respectively 15%, 45%, 100%, 100% for period study (p = 0.03). Recovery of injured nerves was significantly faster in C-IONM group. S-IONM and C-IONM cumulate 40 stage procedures. The application of a standardized technique, the adherence to guidelines, the introduction of C-IONM allowed to (1) increase the RLN identification rate; (2) reduce the severity of injuries of RLN in terms of (a) reset bilateral RLNP, (b) faster recovery time, (c) lower definitive RLNP; (3) gather detection of RLN branching and NRLN; (4) recognize intraoperatively nerve stress; (5) cumulate stage procedures.

Poster 595 Thyroid & Development Wednesday & Thursday Poster Basic 9:00 AM EFFECTS OF M-TOR SIGNALING PATHWAY ON BRAIN DEVELOPMENT OF OFFSPRING IN MATERNAL SUBCLINICAL HYPOTHYROIDISM Y. Zhang, Z. Shan, W. Teng Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory

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of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, China Thyroid hormone is indispensable for fetal brain development, and maternal thyroid hormone deficiency is thought to result in severe and irreversible brain impairments in learn and memory. Maternal subclinical hypothyroidism is a very common endocrine disorder in pregnancy. Our group had shown maternal subclinical hypothyroidism had negative impact on neurodevelopment. Our study established maternal subclinical hypothyroidism (SCH) model in Wistar rat and explored whether mTOR signaling pathway affected brain development of offspring. In the present study, we performed thyroidectomy and injected LT4 daily in Wistar rats to induce maternal subclinical hypothyroidism. We measured total thyroxin (TT4) and thyrotropin (TSH) in mother rats to confirm the presence of subclinical hypothyroidism. Offspring in postnatal rats day 40(PND40) test, Morris water maze were measured. m-TOR signaling pathway were also measured in offspring of hippocampus. In Morris water maze, SCH and CH groups had longer latency time and less times of each rat crossed the platform area compare with CON group. Consistent with behavioral results, Western blotting showed decreased activation of important downstream modulators of m-TOR signaling pathway: phosphor-serine/threonine protein kinase AKT (P-AKT), phosphor-PDK1 (P-PDK1), phosphormTOR (P-mTOR), as well as phosphor-4E-BP1(P-4E-BP1) compared with CON group at postnatal day3(PDN3) in hippocampus. Maternal subclinical hypothyroidism could impair offspring spatial learn and memory. And decreased activation of the m-TOR signaling pathway in pups was maybe related to impairments of cognitive function.

Poster 596 Thyroid & Development Wednesday & Thursday Poster Clinical 9:00 AM INCREASE IN SERUM TSH WITHIN REFERENCE RANGE CAN AFFECT BLOOD PRESSURE: A 5-YEAR FOLLOW-UP STUDY Z. Shan, F.W. Jiang, W. Teng Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, China There is controversy on the relationship between serum TSH and blood pressure. This prospective study was to investigate whether serum TSH within reference range had impacts on future blood pressure. 623 participants with normal TSH (0.3-4.8mIU/l) from a stratified sample survey in 2007 were followed-up after 5 years. Finally, 531 participants (306 women) without previous thyroid diseases were included in this prospective study. Participants were divided into subgroups according to TSH levels of 1.0-1.9mIU/l. We analyzed the associations of serum TSH within reference range and blood pressure. Excluding participants using antihypertensives, results of multiple linear regression showed that changes in serum TSH levels during follow-up had positive correlation with the changes in SBP after adjusting the age, gender, smoking status, BMI, HOMA-IR at baseline ( B = 2.227, P < 0.05 ). Participants with TSH 1.0–1.9mIU/l at baseline were divided into three groups according to the changes of TSH levels at follow-up (0.3–0.99, 1.0–1.9 and 1.91–4.8 mIU/l). Increases in SBP and DBP during follow-up were significantly higher in group with increased TSH compared with the group with stabled TSH (SBP 7.7 – 2.4 VS. 0.6 – 1.6, P < 0.05; DBP 5.8 – 1.5 VS. 1.2 – 1.2, P < 0.05). However, levels of blood pressure were declined

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in group with decreased TSH without significance compared with the group with stabled TSH. There were co-variations between serum TSH levels and blood pressure during follow-up. A 1mIU/l increase in TSH within reference range was associated with about 2 mmHg increase in SBP. As TSH increased to high-normal range, DBP also increased accordingly during 5-year follow-up.

Poster 597 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM SOCIAL DISADVANTAGES OF PATIENTS WITH HASHIMOTO’S THYROIDITIS (HT) IN JAPAN S. Iwama-Carlson1, N. Momotani1, Y. Inoue2, M. Morino2 1 Tokyo Health Service Association, Tokyo, Japan; 2International Catholic Seibo Hospital, Tokyo, Japan For over 40 years, HT has been misrepresented as an intractable disease within segments of government, healthcare and life insurance companies and the general population of Japan - although HT does not meet these criteria. The primary reason for this misinformation is that HT was inappropriately included with a number of known intractable diseases for study by the Japan Ministry of Health and Welfare (1973– 1975). Consequently, many prefectures initiated direct financial support program to the patients with HT by misinterpreting it as an intractable disease. The aim of this study is to investigate cases wherein the misrepresentation of HT as an intractable disease has become socially disadvantageous to patients with HT. Our patients diagnosed with HT were surveyed regarding their general awareness of HT plus experiences in obtaining private health or life insurance coverage; 16 life insurance companies were next surveyed as to acquiring coverage when HT is present; We also surveyed prefectures regarding their financial support programs for constituents with HT. Respondents were 190 of 210 consecutively seen patients: 73 patients thought HT was a serious or intractable disease; 59 patients were aware HT doesn’t encumber daily life as long as thyroid hormone levels are within normal ranges; 4 female patients thought their fetus would be deformed and suffer from disabilities; 20 patients had been denied insurances; 4 patients with HT could obtain insurance. From the 16 Life Insurance Companies surveyed: 1 - ‘‘deny’’; 9 ‘‘accept with restrictions’’, 2 - ‘‘accept’’ and 4 - ‘‘no response’’; The company denying insurance indicated ‘‘HT has no cure’’. Four out of 47 prefectures currently offer people with HT direct financial support programs similar to other intractable diseases - no one surveyed knew about the purposes behind the financial support programs. HT remains misunderstood by a segment of healthcare and life insurance companies and certain prefectures; Additionally, many patients with HT do not have an accurate understanding about HT. If there are similar circumstances in other countries, perhaps the International Thyroid Congress should disseminate correct information about HT on a global basis.

Poster 598 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM C1ORF24 REPRESSES AUTOPHAGY IN THYROID CARCINOMA CELL LINE B.H. Nozima1, G.J. Pereira2, S.S. Smaili2, G. Carvalheira1, J.M. Cerutti1 1 Morphology and Genetics, Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil; 2Pharmacology, Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil

To address the problem of incomplete diagnosis of thyroid nodules, we previously performed gene expression profiling of follicular thyroid adenoma and follicular thyroid carcinoma. Further validation analysis identified C1orf24 as a thyroid carcinoma marker. C1orf24 (aliases Niban and FAM129A) was first described as oncogene expressed in renal tumors from animal models of sporadic and hereditary renal tumors. Although little is known about the role of C1orf24 in cancer, it was suggested that C1orf24 might link and coordinate mTOR and ER stress. As ER stress upregulates autophagy and mTOR integrates the main signaling pathway that control autophagy, we investigated whether C1orf24 impairs autophagic flux in thyroid carcinomas. siRNA-mediated knockdown of C1orf24 was performed in papillary thyroid carcinoma cell line TPC1. We next assessed the effects of C1orf24 silencing on autophagy. To trigger autophagy, TPC1 cells were subjected to nutrient starvation. To monitor autophagic activation, we initially investigated the autophagic flux (LC3-II turnover and p62) by Western blot in the presence or absence of lysosomal degradation inhibitor NH4Cl. We next detected the autophagosome and autolysosome formation by fluorescence microscopy (mCherryGFP-LC3B vector). At first, both GFP and mCherry are detected in autophagosomes (yellow puncta). When autophagosomes fuse with lysosomes, GFP is degraded, which results in LC3 emitting only red fluorescence (red puncta). C1orf24 knockdown activates autophagy by increasing LC3-II turnover and p62 degradation regardless of starvation. C1orf24 knockdown in TPC1 cell line expressing mCherry-GFP-LC3B induced a switch from yellow to red fluorescence, indicating a functional autophagic process. We investigated whether C1orf24 modulates ULK1 phosphorylation during autophagic process. C1orf24 knockdown in TPC1 cell line reduced ULK1 phosphorylation at S758, which in turns activates ULK1 and initiate autophagic process. Taken together, these results suggest that C1orf24 represses autophagy in TPC1 cell line. Whether C1orf24 can represent a valuable target for the therapy of thyroid cancers remains speculative.

Poster 599 Thyroid Cancer Wednesday & Thursday Poster Basic 9:00 AM CHRONIC SRC INHIBITION PROMOTES A MORE AGGRESSIVE TUMOR PHENOTYPE. B.E. Kessler1, K.E. Wuensch1, L.A. Pike1, S.B. Sams2, J. Kim3, A. Tan3, R. Schweppe1 1 Division of Endocrinology, Diabetes, and Metabolism, University of Colorado, Aurora, CO; 2Department of Pathology, University of Colorado, Aurora, CO; 3Division of Medical Oncology, University of Colorado, Aurora, CO There are currently no effective therapies for patients with advanced thyroid cancer, especially those with distant metastases. We have shown that Src is a novel, clinically relevant target in thyroid cancer however; resistance mechanisms to single-agent targeted therapies inevitably arise. To more effectively target Src and combat mechanisms of resistance, we generated thyroid cancer cell lines (BRAFand RAS- mutant) to be resistant to the FDA approved Src inhibitor, dasatinib, in vitro. The effect of Src inhibitor resistance was assessed in vivo via orthotopic and flank injections of control or dasatinib-resistant (DasRes) thyroid cancer cell lines. Final tumor volumes were calculated upon dissection. Invasion scores and proliferation were evaluated by H&E and Ki67 staining, respectively. Collagen deposition/density was assessed by second harmonic generation imaging.

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 We show a significant increase in final tumor volume of the BRAF-mutant DasRes cells (BCPAP) compared to their Control counterparts (4-fold increase, p = 0.05) although no changes in invasion or proliferation were observed. In the RAS-mutant (Cal62) DasRes tumors, a significant increase in final tumor volume (3-fold greater, p = 0.0002) and proliferation ( p = 0.005) was detected. Interestingly, collagen density was significantly decreased in both BRAF- and RAS-mutant DasRes tumors compared to the Control tumors, as quantified by second harmonic generation imaging (BCPAP (BRAF): p = 0.005; Cal62 (RAS): p = 0.05). Consistently, RNA-sequencing of DasRes cell lines demonstrated a decrease in transcripts of collagen I (2.37-fold), as well as the extracellular matrix (ECM) protein fibronectin (1.6-fold), compared to the control cells. Taken together, these data show that acquired resistance to Src inhibition promotes a more aggressive phenotype in vivo, and increased proliferation and alterations in the tumor ECM are likely important. Other models of inhibitor resistance have also demonstrated changes in ECM structure and composition as a potential tumor reprogramming response to targeted therapies. Ongoing studies are addressing the potential mechanisms involved in these responses in order to more effectively target these pathways in the clinic.

Poster 600 Thyroid Cancer Wednesday & Thursday Poster Basic 9:00 AM CHARACTERIZATION OF TIMP-2, MT1-MMP AND CD147 PROTEINS USING AN IN VITRO THYROID TUMOR-STROMA INTERACTION MODEL A.B. Della Vedova, L. Fozzatti, A.M. Masini-Repiso, C.G. Pellizas, A.C. Donadio Bioquı´mica Clı´nica, CIBICI-CONICET, Co´rdoba, Argentina Solid tumors are not simply clones of cancer cells. Instead, they are composed of multiple cells types and extracellular matrix. Interactions between tumor cells and the stroma influences disease initiation and progression. In thyroid cancer, there is little or no information on epithelial-stromal interaction. In preliminary studies, we found that thyroid tumor cell-fibroblasts (Fb) interaction promotes the secretion and activation of metalloproteinases ( MMPs) and tumor cell migration. The aim of our work was to analyze the modulation of proteins related with MMPs expression and activation: TIMP-2, MT1-MMP and CD147 in thyroid cell-Fb co-culture. As an in vitro tumor-stroma cell interaction model, non-tumor cells (N-ThyOri), thyroid papillary carcinoma cells (TPC-1) and thyroid anaplastic cells (8505c) were co-cultured with normal Fb. TIMP-2 and MT1-MMP mRNA were studied by qRT-PCR. The expression and glycosylation of CD147 were assessed by immunoprecipitation, western blot and flow cytometry. We observed changes in the proportion of the expression levels of TIMP-2 related to MT1-MMP in Fb-N-ThyOri co-cultures, but no diferences in TIMP2 and MT1-MMP expression were detected in Fb8505c co-cultures. The analysis of Fb CD147 expression did not show any significant differences after its co-culture with TPC-1, 8505c and N-ThyOri cells. In addition, no changes in CD147 glycosylation profile was detected. Fb-thyroid tumor cell interaction modulates differentially the expression of proteins such as TIMP-2 and MT1-MMP which would be consistent with the observed changes in the profile of secreted and activated MMPs. These observations suggest the involvement of tumor cell - stroma interactions in thyroid carcinogenesis.

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Poster 601 Thyroid Cancer Wednesday & Thursday Poster Basic 9:00 AM PVALB, ANALYSIS OF THE EFFECT OF ECTOPIC EXPRESSION IN CARCINOMA LINES OF THYROID T.B. Mendes1, B.H. Nozima1, A. Budu2, R.B. de Souza1, M.H. Catroxo3, M.L. Dutra4, J.M. Cerutti1 1 Department of Morphology and Genetics, Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil; 2Department of Biophysics, Federal University of Sa˜o Pualo, Sa˜o Paulo, Brazil; 3Laboratory of Electron Microscopy, Center for Research and Development of Animal Health, Biological Institute, Sa˜o Paulo, Brazil; 4Department of biosciences, Federal University of Sa˜o paulo, Santos, Brazil We have previously identified PVALB (parvalbumin) as a new Hu¨rthle Cell Adenoma (HCA) marker, as shows positive tumor cell staining for HCAs but was negative in a wide range of thyroid carcinomas, mainly Hurtle cell carcinomas. However the role of PVALB in the pathogenesis or progression of Hurtle cell tumors is not definitively know. To characterize PVALB function in thyroid cancer, we here explored the biological effects of ectopic expression of PVALB in thyroid carcinoma cell lines cDNA plasmid encoding PVALB was transfected into two thyroid follicular thyroid carcinoma cell lines (FTC133 and WRO). We evaluated the effect of ectopic expression of PVALB in multiple cellular and molecular approaches such proliferation assay, cell cycle progression and apoptosis analysis by flow cytometry,and Transmission Electron Microscopy (TEM). We found that ectopic expression of PVALB inhibited cell proliferation while induced cell cycle arrest and apoptosis in thyroid cancer cells. Compared to control, TEM shows that PVALB promoted increased mitochondrial density in these cells. Interestingly, the cytoplasmic accumulation of abundant mitochondria that frequently display abnormal morphology is a pathognomonic of Hu¨rthle tumors. Our results together suggest that PVALB may act as a tumor suppressor gene. Its aberrant expression in Hu¨rthle tumors may represent an important mechanism associated with the genesis and/or progression of Hu¨rthe tumors.

Poster 602 Thyroid Cancer Wednesday & Thursday Poster Basic 9:00 AM INDUCTION OF OSTEOCLASTOGENESIS FROM HUMAN MONOCYTES USING POORLY DIFFERENTIATED THYROID CANCER CELL Y. Takahashi1, H. Doi2, K. Fujimori1, N. Nakashima1, K. Sato3, N. Ohuchi1 1 Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Kami Hospital, Kami, Japan; 3Tosendo Hospital, Wakuya, Toda, Japan Bone is the second most frequent site of metastasis resulting from thyroid cancer. Activation osteoclasts with subsequent bone resorption is required to establish thyroid cancer bone metastasis. Receptor activator of nuclear factor kappa beta ligand (RANKL), key mediators of osteoclast differentiation and function, play a pivotal role in bone destruction induced by metastatic bone tumors, whereas previous reports with breast or prostate cancer cell lines suggested that tumor derived interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemotactic protein 1 (MCP-1) mediate osteoclast formation from osteoclasts precursors by RANKL-independent pathway. We cultured DH-14-3 cell that was established from a patient with poorly differentiated thyroid cancer in whom multiple bone metastases alone (Tohoku J Exp Med. 2013;230:75). Levels of IL-6, IL-8, MCP-1

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and RANKL in the culture supernatant were measured using ELISA. Osteoclastogenesis by conditioned media of DH-14-3 cells was assayed by counting the number of tartrate-resistant acid phosphatase-positive cells after culturing human peripheral blood monocytes with macrophage-colony stimulating factor. In addition, the resorption activity of osteoclasts was measured by using bone resorption assay. The mean level of IL-6, IL-8, MCP-1, and RANKL in the supernatant of DH-14-3 culture was 4310, 10700, 567, 46 pg/mL, respectively. The monocytes with conditioned media had approximately 4fold higher osteoclast formation (P = 0.002) and 5-fold higher bone resorption (P = 0.025) compared to the control culture. Both osteoclast counts and bone resorption areas were significantly decreased by adding anti-IL-6 antibody to DH-14-3 culture supernatant (P = 0.01), whereas co-incubation with anti-IL-8 antibody, anti-MCP-1 antibody and anti-RANKL antibody failed to inhibit osteoclast differentiation and bone resorption. Thus, only anti-IL-6 antibody inhibited differentiation and induction of osteoclasts from monocytes with conditioned media of DH-14-3 cells. In summary, these results indicate that IL-6 in the DH-14-3 culture supernatant induces osteoclastogenesis. IL-6 may be a key mediator in treatment for thyroid cancer bone metastasis.

Poster 603 Thyroid Cancer Wednesday & Thursday Poster Basic 9:00 AM IN VITRO X-RAY IRRADIATION INDUCES REARRANGEMENTS NOT ONLY OF RET, BUT ALSO OF ALK IN HUMAN THYROID EPITHELIAL CELLS K. Hamatani, K. Koyama, S. Yano, M. Taga, Y. Kusunoki Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan Molecular studies of papillary thyroid cancer (PTC) in atomic-bomb survivors have indicated frequent occurrence of RET/PTC rearrangements in PTC cases exposed to relatively high radiation doses. It has also been found that the echinoderm, microtubule-associated, protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene occurs more frequently in: 1) PTC cases exposed to ‡ 5 mGy; 2) those with no RET, NTRK1, BRAF or RAS gene alterations; and 3) those showing solid/trabecular architectures in the cancerous regions. Based on these findings, we hypothesized that the EML4-ALK fusion gene in PTC is a consequence of radiation exposure and plays an important role in PTC development. To clarify whether radiation exposure induces EML4-ALK fusion in human thyroid epithelial cells, we conducted in vitro X-ray irradiation experiments using immortalized human thyroid epithelial cells and investigated the occurrence of EML4-ALK fusion in the irradiated cells. Immortalized human thyroid epithelial cells (Nthy-ori 3) irradiated with single doses of 0, 0.2, 1 or 5 Gy were split into 6-well plates at a density of 1.8 · 104 cells per well, and then cultured for an additional 8-10 days. Using total RNA extracted from each well, cDNA was synthesized with gene-specific primers in a 20 ll reaction volume and subjected to PCR amplification in a 50 ll reaction volume. Preliminary X-ray irradiation experiments with 5 Gy indicate induction not only of RET rearrangements (RET/PTC1 and RET/ PTC3) but also of ALK rearrangements (EML4-ALK variant 1 and variant 2) in immortalized human thyroid epithelial cells. Full-scale X-ray irradiation experiments with single doses of 0, 0.2, 1 or 5 Gy indicated that EML4-ALK fusion events increased with increased dose. Ionizing irradiation can induce not only RET/PTC rearrangements but also EML4-ALK fusion in immortalized human thyroid epithelial

cells. This suggests that EML4-ALK fusion gene found in PTC among atomic-bomb survivors might be a result of radiation exposure.

Poster 604 Thyroid Cancer Wednesday & Thursday Poster Basic 9:00 AM THE EXPRESSION OF E-CADHERIN IN PAPILLARY THYROID CANCER AND THE RELATIONSHIP WITH THE HASHIMOTO’S THYROIDITIS E. KIM1, S. Park1, J. Choi2, S. Choi1, I. Nam-Goong1, Y. Kim1 1 Internal Medicine, Ulsan University Hospital, University of Ulsan, Ulsan, Korea (the Republic of); 2Biomedical Research Center, Ulsan University Hospital, Ulsan, Korea (the Republic of) Human papillary thyroid carcinoma (PTC) is often associated with Hashimoto’s thyroiditis (HT), and their coexistence improves the prognosis of PTC. E-cadherin is a calcium-dependent intercellular adhesion molecule and is specifically involved in epithelial cell-to-cell adhesion. In cancer, E-cadherin expression is often down-regulated during carcinoma progression and metastatic spread of aggressive tumors. In this study, we investigated the expression of E-cadherin in PTC patients and the relationship with HT in PTC. The expression of E-cadherin mRNA and protein in thyroid tissues of the normal, and the PTC patients with HT or without was determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. The expression of E-cadherin in different types of thyroid cancer was investigated in papillary thyroid cancer (TPC) cells (TPC1, SNU373, and SUN 790), anaplastic thyroid cancer (ATC) cells (8505C, and CAL62), and follicular thyroid cancer (FTC) cells (FTC133) by Western blot. Cell migration was measured in TPC1 and FTC133 cells after transfect with E-cadherin by wound healing assay. We also measured the mRNA expression of N-cadherin and ICAM-1 in thyroid tissues by RT-PCR and real time PCR, respectively. The expression of TGF-b1 in thyroid tissues and the plasma levels were also assayed by RT-PCR, Western blot, and ELISA. The expression of E-cadherin mRNA and protein was significantly increased in PTC patients compared with PTC patients with HT. Among thyroid cancer cells, the expression of E-cadherin was only observed in FTC cells, and the overexpression of E-cadherin inhibited cancer cell migration. Meanwhile, the expression of TGFb1 mRNA and protein was increased in PTC patients with HT compared with PTC patients, and also, the plasma levels were significantly increased in PTC patients with HT. The mRNA expression of N-cadherin and ICAM-1 was significantly decreased in PTC patients with HT compared with PTC group. Our results indicate that the expression of E-cadherin was higher in PTC patients with HT than in PTC alone. This suggests that the presence of PTC with HT may attenuate the tumor aggressiveness with metastatic spread through the up-regulation of E-cadherin.

Poster 605 Thyroid Cancer Wednesday & Thursday Poster Basic 9:00 AM GENE EXPRESSION PROFILES OF PAPILLARY THYROID MICROCARCINOMA W. Kim1,2, J. Lee1, G. Son3, J. Bae4 1 surgery, Korea University College of Medicine Guro Hospital, Seoul, Korea (the Republic of); 2Surgery, Ajou University Hospital, Suwon, Korea (the Republic of); 3Surgery, Korea University College of Medicine Ansan Hospital, Ansan, Korea (the Republic of); 4 Surgery, Korea University College of Medicine Hospital, Seoul, Korea (the Republic of)

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To help improve diagnosis, prognosis, and treatment of papillary thyroid microcarcinoma, we performed gene expression profiling and compared to pair normal thyroid tissues. We performed microarray analysis with 6 papillary thyroid microcarcinoma and 6 pair normal thyroid tissues. Differentially expressed genes were selected using paired t test, linear models for microarray data, and significance analysis of microarrays. Real-time quantitative reverse transcription-polymerase chain reaction was used to validate the genes. We identified 91 differentially expressed genes (84 upregulated and 7 downregulated ; MET, TIMP1, QPCT, PROS1, LRP4, SDC4, CITED1, DPP4, LRRK2, and RUNX2) in the gene expression profile. We identified the gene expression profile of papillary thyroid microcarcinoma.

Poster 606 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM FMTC-ASSOCIATED PTC LINKED WITH RET (C618S) MUTATION A.L. Manosalva-Corte´s1, H.Y. Estupin˜an-Velasquez1, H. Gutierrez3, M. Garcia Ardila1, J.S. Insuasty-Enrı´quez2, C.I. Vargas-Castellanos1, A.A. Herrera-Hernandez3, H.J. Arteaga1 1 Biomedical Basic Sciences, Universidad Industrial de Santander, Bucaramanga, Colombia; 2Internal Medicine, Universidad Industrial de Santander, Bucaramanga, Colombia; 3Surgery, Universidad Industrial de Santander, Bucaramanga, Colombia

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Germ-line mutations in the RET proto-oncogene are the cause of MEN2-associated medullary thyroid carcinoma (MTC), while the somatic RET/PTC1 rearrangements are the predominant genetic alteration in papillary thyroid carcinomas (PTCs). PTC occurring in association with MTC is a rare entity. Although the reported cases of this association are increasing the related molecular alterations remain unknown. Germ-line RET proto-oncogene mutations seem to be the potential trigger in the simultaneous development of these two histological types of malignancies. Different RET germ-line mutations involving a cysteine residue in the extracellular cysteine-rich domain of the RET receptor have been reported. Thus, MEN2A and FMTC are mainly associated with RET codon 634 mutations, while RET(C618S) has been reported in MEN2A, FMTC and HSCR phenotypes. In this report we present a kindred of 31 members carrying a germline RET(C618S) mutation with one member, studied until now, affected by both PTC and MTC. The patient, a female 42 years old at diagnosis time, has been assisted and surgically treated in our University Hospital. At the treatment initiation she has multiple metastatic tumors and after 10 years of diagnosis she has not evidence of other endocrine tumors. Four additional family members are reported to suffer from thyroid tumors. Health status and mutation carrier condition of the other family members are currently under investigation. To our knowledge this is the first report showing the relationship between the RET(C618S) mutation and PTC in association with MTC in more than one member of a family affected by FMTC. RET K603Q, M918T, V804L and recently C634S mutation have been reported in families with MEN2 affected by both MTC and PTC. Studies about the potential transforming activity of RET(C634S), RET(K603Q), RET(C634R) and RET(M918T) using PC Cl 3 cells have shown that these RET mutants have mitogenic activity, but significantly lower as compared with RET/PTC1 chimera. Our findings suggest that the RET(C618S) mutation may also be linked with FMTC -associated PTC cases. This observation warrants further molecular and cellular studies regarding the transforming activity of RET(C618S) mutation in cellular models.

Poster 607 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM AGGRESSIVE PAPILLARY THYROID CANCER ASSOCIATED WITH CONNEXIN26 MUTATION A. Skolnick, M. Brito Endocrinology, North Shore-LIJ, Great Neck, NY Connexin26 (Cx26) is a gap junction protein that is considered to be a tumor suppressor. Cx26 mutations are the most common cause of autosomal recessive deafness. In addition, Cx26 plays an important role in lymphatic invasion, lymph node and distant metastasis in solid tumors including the thyroid. We present a case of a carrier of Cx26 mutation who presented with an aggressive form of papillary thyroid carcinoma (PTC). A 37 year old male presented with an upper respiratory infection. Chest x-ray demonstrated adenopathy with CT scan confirming chest and neck lymphadenopathy and a thyroid nodule. Fine needle aspiration of the nodule and cervical lymph node were consistent with PTC. He underwent total thyroidectomy with lymph node dissection. Pathology revealed well differentiated, multifocal PTC, 1.3 cm with extrathyroidal extension, and 13/17 positive lymph nodes (largest 6.0 cm). He was treated with 150 mCi of radioactive iodine. On posttreatment scan, increased uptake was identified in the thyroid bed and in the right lower lateral neck. He and his wife are both carriers for Cx26 mutation and their son has congenital deafness. Therefore, a thyroid ultrasound was performed on his wife revealing a 1.7 cm left

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thyroid nodule. FNA cytology revealed atypia of undetermined significance. A repeat FNA is scheduled with gene expression classifier. Aggressive forms of well differentiated thyroid cancer are uncommon. Tumor genetics are continuing to influence our evaluation and management of thyroid carcinoma. Cx26 may influence tumor size and/or lymph node metastasis in thyroid cancer. The aggressive nature of PTC in our patient and possible thyroid carcinoma in his spouse warrant further investigation into the link between Cx26 and thyroid carcinoma. Screening their child may be indicated especially if the mother has thyroid cancer. The Cx26 mutation is a common cause of congenital deafness, and may be associated with carcinogenesis. Cx26 may be an additional genetic marker to use when assessing risk for thyroid carcinoma. Immunohistochemical staining of Cx26 protein on pathology can further support the link between Cx26 and thyroid cancer.

Poster 608 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM IS THE CRIBRIFORM MORULAR VARIANT OF PAPILLARY THYROID CANCER AN INDICATION FOR COLONOSCOPY AND GENETIC TESTING? S.A. Milan1, B. Newbrough2, R. Rosario2, G. Coleman1, H. Reinhart1 1 Surgery, Texas Tech University Health Sciences Center, El Paso, TX; 2William Beaumont Army Medical Center, El Paso, TX The cribriform morular variant of papillary thyroid cancer (CMVPTC) is a rare variant that is associated with familial adenomatous polyposis (FAP). Here we discuss the importance of recognition of the association and recommendations for management, including consideration for colonoscopy and genetic testing. A 28 year old female, without remarkable medical history other than a palpable thyroid nodule that was identified on a routine exam had a preoperative FNA showing papillary thyroid carcinoma subsequently underwent uncomplicated total thyroidectomy. The pathology report demonstrated CMV-PTC with positive immunohistochemical stain for beta catenin (Image 1). The patient was referred postoperatively for screening colonoscopy, which was negative. Up to one-third of newly diagnosed cases of FAP are in patients without a family history. Thyroid cancer in patients with FAP is typically diagnosed earlier than colon cancer. Recognition of the association

High power view (400X) beta catenin showing nuclear and cytoplasmic staining.

of CMV-PTC with FAP presents an opportunity for early diagnosis of this colon cancer syndrome. Review of the literature revealed a significant proportion of occult FAP (17–66%) was identified due to recognition of thyroid pathology. However, while CMV-PTC is associated with FAP, sporadic CMV-PTC has also been described. Reports of patients with CMV-PTC and non-FAP associated colon polyps also exist and further complicate the issue of whether genetic testing, colonoscopy, or both, is indicated when this entity is clinically recognized. Clinical recognition of the association between CMV-PTC and FAP is essential as FAP confers a 100% lifetime risk of colorectal carcinoma if untreated. CMV-PTC is often diagnosed significantly earlier than colon cancer in patients with FAP and represents an opportunity for early treatment. Additionally, given the reports of non-FAP colon polyps in patients with CMV-PTC, colonoscopy is recommend when the diagnosis of CMV-PTC is rendered with consideration for genetic testing. Clinicians should not rely on family history or genetic testing alone to rule concomitant colonic polyposis when CMV-PTC is recognized. Further studies are needed to determine the true prevalence of FAP associated CMV-PTC.

Poster 609 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM RARE CO- PRESENTATION OF PAPILLARY AND FOLLICULAR THYROID CANCER WITH MULTIPLE MALIGNANCIES LINKED WITH 3 MUTATIONS IN CANCER RELATED GENE VARIANTS OF UNKNOWN SIGNIFICANCE: A CASE REPORT H. Amer, A. Aggarwal, J. Cabral, V. Mohan, P. DeSantis, T. Jose, S. Williams, C.V. Villabona Cleveland Clinic Florida, Weston, FL Genetic alteration is the driving force for tumor genesis. Variants of Unknown Significance (VUS) are missense and splice mutations that have no clear biological relevance. These mutations constitute about 30% of all variants. We present a case with papillary and follicular thyroid cancer along with multiple organ neoplasms which might be linked with VUS. 67 year old female presented with thyroid nodules which had increased uptake on PET scan. She had a past history of Pheochromocytoma, invasive ductal carcinoma of the right Breast, Acoustic Neuroma, Endometriosis, Colonic adenoma, pancreatic and renal cysts for which she underwent unilateral adrenalectomy, hysterectomy, and breast lumpectomy. Family history was positive for pancreatic cancer, Glioblastoma and Prostate cancer. Fine Needle Aspiration of multiple thyroid nodules was consistent with papillary and follicular neoplasm which was followed by total thyroidectomy and Radio-Active Iodine (RAI) therapy. Due to the presence of multiple cancers, genetic testing was recommended which showed VUS on the following genes: MSH2, CHEK2 and TMEM127. Our patient is hetrozygous for the p.L279V (c.835C > G) VUS in the MSH2 gene, c.592 + 4A > G VUS in the CHEK2 gene and the p.T89R (c.266C > G) VUS in the TMEM127 gene. Mutations in MSH2 gene are linked to an increased incidence for Hereditary Non Polyposis Colon Cancer (HNPCC), prostate and endometrial cancer. Mutations in CHEK2 gene are linked to an increased risk for NonBRCA breast cancer and a 2-fold risk of papillary thyroid cancer. Mutations in the TMEM127 gene are linked to an increased incidence for pheochromocytoma. We report rare Co- Presentation of Papillary and Follicular Thyroid Cancer with Multiple Malignancies likely to be linked with three VUS on gene MSH2, CHEK2 and TMEM127. The Patient being the index case, consideration for genetic testing or/and

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 surveillance might be appropriate for other family members. DNA banking is also recommended as a reference for future generations.

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Thyroid Cancer Wednesday & Thursday Poster 9:00 AM INTRACARDIAC METASTASIS FROM PAPILLARY THYROID CARCINOMA M.D. Cox, A. Hinson, B.M. Wilkerson, B.C. Stack, D.L. Bodenner Otolaryngology - Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, AR

Thyroid Cancer Wednesday & Thursday Poster 9:00 AM ‘‘AGGRESSIVE’’ FOLLICULAR VARIANT OF THYROID PAPILLAR CARCINOMA WITH HEMATOGENOUS METASTASIS- OR MAYBE A HYBRID? O. Bosˇkovic´1, A. Filipovic´2, S. Medenica1 1 Department of Endocrinology, Clinical Center of Montenegro, Podgorica, Montenegro, Bar, Montenegro; 2Endocrine Surgery Clinic, Clinical Center of Montenegro, Faculty of Medicine University of Montenegro, Podgorica, Montenegro, Podgorica, Montenegro

Cardiac metastasis from epithelial thyroid cancer is rare. Less than 60 cases have been reported in the last 135 years1. An 84-year old African American woman with metastatic papillary thyroid cancer and bilateral lung metastases was treated with a total thyroidectomy and level VI lymph node dissection, followed by radioactive iodine ablation and external beam radiation. Computerized tomographic imaging studies showed multiple pulmonary nodules and a pancreatic head lesion consistent with metastases. In 2014, patient was observed to have a 2.7 cm right atrial mass detected on a screening echocardiogram performed for entry into a clinical trial of a vascular endothelial growth factor/tyrosine kinase inhibitor. The patient was a poor candidate for surgery and had already been treated with 542.1 mCI if I-131. The patient died twelve weeks later while under inpatient hospice care. Hematogenous dissemination and local intravascular extension is more commonly observed in follicular thyroid cancer2. In contrast, papillary thyroid cancer tends to invade locally and disseminates by lymphatic vessels of the neck and upper mediastinum2. The more common sites for cardiac metastases are the pericardium, epicardium, and the right side of the heart1, as in our patient. Cardiac tumors tend to cause symptoms reflective of the site of cardiac involvement rather than their histopathologic origin. The prognosis of metastatic cardiac disease arising from primary thyroid malignancy appears to be poor, and a review of the literature (N = 54) reported a survival of 12.5 weeks. We present a rare case of metastatic cardiac disease arising from a primary thyroid malignancy. Heart metastasis, while rare and often asymptomatic, is a serious complication that is associated with a poor prognosis.

Papillar thyroid carcinoma (PTC) is the most common type of thyroid cancer, 70% to 80% of all thyroid cancers. The follicular variant of papillary thyroid carcinoma (FVPTC) is believed to behave in a clinical manner similar to PTC and to follow a similar indolent course. A 65-year old female was admitted to the hospital for the operative treatment due to exulcerated lymphogenic metastasis on the right side of the neck and local recidive on the anterior side of the thrachea, and with pulmonal and liver metastasis. Five years ago, total thyreoidectomy was done due to multicentric PTC, size 30x7 mm, follicular variant, staging pT4aNxMx. She received two adjuvant radioactive iodine (RAI treatment, dose 5.55 GBq. Suppressive levothyroxine treatment was started. Three years later, the extirpation of supraclavicular lymph nodes right side size 33 mm was done, lymphogenic metastasis in the neck subregion V was verified by pathohistology (PH), followed by the third RAI treatment. Diagnostic posttreatment whole body scintigram vizualized discrete zone of focal intensive accumulation od radioiodine in jugulum. No outpatient control was done in the next two years, when she was admitted to the hospital due to aforementioned operative treatment. Laboratory finding showed adequate thyrotropin suppression and low Tg level, but high anti Tg Ab level; CA 19-9 186.1 elevated (normal range 0–37 U/ml). PH findings revealed metastatic papillar thyroid carcinoma with cutaneous and lymphogenic metastasis. Multislice Computed Tomography of the chest showed lung and liver metastatic deposites. Five cycles of neck brachytherapy were done. FVPTC, wherein follicular patterned tumors with nuclear features of PTC, whether invasive or not, behaves like usual PTC, with

Right atrial involvement by cardiac metastasis from papillary thyroid carcinoma can be seen in this coronal CT image

Exulcerated lymphogenic metastasis of the follicular variant of papillary thyroid carcinoma on the right side of the neck and local recidive on the anterior side of the thrachea

Poster 610

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multiple tumor foci in the gland, lymphatic invasion and nodal metastases, and rare hematogenous spread. Although a majority of these tumors will behave in an indolent fashion, some can metastasize to distant sites, as presented in this case. The presented case is an ‘‘aggressive’’ FVPTC with hematogenous metastasis or maybe a hybrid between follicular carcinoma and PTC.

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Poster 612

Poster 614 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM NUCLEAR ACCIDENT CESIO 137 IN BRAZIL : A TERROR IN THE PAST, AN UNCERTAINTY AT PRESENT. A CASE REPORT OF THYROID CANCER IN PATIENTS EXPOSED TO RADIATION 28 YEARS AGO F.D. Amorim Filho Head and Neck Surgery, Instituto da Tireoide & Laringe, Goiania, Brazil The accident nuclear occurred in Brazil in 1987 it was the world’s largest occurred.It is estimated that over 6000 people were affected by irradiation, over 600 people were infected directly, 60 people already died from complications arising from exposure to radioactive material. This case report it is a patient,female,which was identified by ultrasound of the neck node in the thyroid. The patient was exposed to radioactive Cesium, her husband was one of the victims who died due to the nuclear accident. The patient underwent total thyroidectomy and was confirmed carcinoma. Some risk factors are involved in the emergence of the cancer, the Cesium 137 is a radioactive element and is a potentially cancer forming. The people who came in contact with Cesium-137 in Brazil accident received doses elevated and after 28 years one pacient has developed the second primary tumor. The nuclear accident in Brazil was great severity for the people who were involved. After 28 years a second primary tumor was diagnosed in the thyroid of a patient who survived next accident. For the survivors left the certainty of a terrible past and the uncertainty of a future without disease.

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Poster 615 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM SERIES FDG PET/CTS PREDICT DEDIFFERENTIATION OF RECURRENT PAPILLARY THYROID CARCINOMA L. Xie1, D. Wu1,2 1 Nuclear Medicine Department, William Beaumont Hospital, Royal Oak, MI; 2William Beaumont Hospital, Royal Oak, MI Dedifferentiation of thyroid cancers to anaplastic thyroid cancers (ATC) represents a severe development of the malignancy, as patients with ATC often have a very poor prognosis despite appropriate treatment. There is no imaging modality that would predict dedifferentiation of thyroid cancers. The patient was a 60-year-old female with completion thyroidectomy on 11/18/2008. Pathology revealed multifocal papillary thyroid carcinomas (PTC) involving both lobes, with the largest tumor of approximately 2 cm with extrathyroid extension only in the left lobe. There was no aggressive histology and no evidence of nodular metastasis. Postsurgical I-131 scan showed three small foci of uptake confined to the right thyroid bed, suspicious for remnants or metastasis, for which she was treated with 160 mCi of I-131 on 1/22/ 2009. One year later, I-131 scan under Thyrogen stimulation was negative, but stimulated thyroglobulin (Tg) was elevated to 120. First FDG PET/CT was performed on 9/21/2010, which revealed a single focus of uptake in the left thyroid bed with max SUV 8.8. The patient chose no treatment. On 4/13/2012, PET/CT demonstrated a mildly enlarged lesion with max SUV 13.1, but non-stimulated Tg was decreased to 4.1. Left neck dissection was done, followed by radiation. Pathology revealed recurrent PTC without evidence dedifferentiation. On 4/4/2013, PET/CT showed improvement with mild FDG activity in the left thyroid bed, with max SUV only 2.6, and non-stimulated Tg was non-detectable. However, PET/CT on 2/13/ 2014 showed a markedly enlarged left neck mass with max SUV of 25.7 (nearly ten times higher than the prior max SUV). In contrast, non-stimulated Tg was mildly elevated to 6.1. FNA revealed dedifferentiation of recurrent thyroid cancer to ATC. She passed away four months later despite chemotherapy.

N/A Data from this case suggest that marked interval increased metabolic activity on series FDG PET/CTs could predict dedifferentiation of recurrent PTC to ATC.

Poster 616 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM FALSE POSITIVE THYROGLOBULIN DUE TO HETEROPHILE ANTIBODIES C. Liu1, T.W. Kurtz2

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Medicine, University of California, San Francisco, San Francisco, CA; 2Pathology and Laboratory Medicine, University of California, San Francisco, San Francisco, CA Heterophile antibodies (HAB) may interfere in immunometric assays (IMA). While it is known that HAB can affect TSH testing, interference in thyroglobulin (Tg) measurement may be less well known. We describe a patient with a history of papillary thyroid cancer (PTC) with false positive Tg levels due to HAB to bring awareness of this phenomenon to avoid unnecessary therapy and investigation. 39 yo man diagnosed with PTC on a screening neck ultrasound (US) underwent total thyroidectomy in September 2012. Pathology revealed a well differentiated right 8 mm PTC, T1NX. Tg by Beckman Coulter IMA was 29 ng/mL before surgery, and 9.4 and 7.9 ng/ mL 6 months after surgery, without Tg antibodies. Because of elevated Tg, he underwent recombinant human thyrotropin (rhTSH) stimulated I123 scanning, followed by treatment with 75mCi of I131 in May 2013. Both pre-therapy I123 and post-therapy I131scans showed thyroid bed and a right supraclavicular uptake, the latter suspicious for a supraclavicular node metastasis. Tg was 8.2 ng/mL on the day of treatment. Post-therapy, Tg remained positive, varying from 5.5 to 8.1 ng/mL. PET-CT did not show apparent disease. In July 2014, rhTSH stimulated I123 scan showed resolution of previous neck uptake but stimulated Tg was 5.5 ng/mL. He was monitored without additional therapy. Recent Tg was 10.1 ng/mL without apparent disease on neck US. HAB interference in the Tg IMA was suspected and confirmed by HAB blocking studies and by the finding of undetectable Tg in a radioimmunoassay (RIA) with functional sensitivity of 0.5 ng/mL. Presence of HAB can lead to false Tg results, mostly elevated, as seen in this patient. Clues to HAB interference include failure of appropriate Tg stimulation with rhTSH or hypothyroidism and persistent Tg elevation in spite of resolution of iodine avid tissues in the appropriate clinical setting. Many tests rely on IMA, including Tg. Clinicians should be aware of HAB interference leading to false positive results which can lead to anxiety, unnecessary therapy and investigation. Testing the same sample in a different Tg assay, either RIA or a different IMA, and use of HAB blocking agents in the Tg IMA, may be useful in confirming assay interference by HAB.

Poster 617 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM CASE REPORT: LATE METASTASIS OF SMALL CELL LUNG CANCER (SCLC) TO THE THYROID T. Tomemori, T. Mitsuhashi, K. Hiruma, H. Sugisaki, Y. Yanagi, T. Kurokawa Head and Neck Oncology/Otorhinolaryngology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome hospital, Tokyo, Japan

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Metastatic thyroid cancer is rare, but the number of cases seems to have increased in recent years. Investigation of over 200 cases of thyroid cancer at our faculty revealed 4 metastatic cases including 1 of lung cancer metastasis. Through the detailed report of lung cancer metastasis, we aim to assess our treatment regimens and results for such rare metastatic cases. Investigation of 219 cases of thyroid cancer treatment, which were performed at our faculty in recent 19 years (1996–2014), revealed 4 metastatic cases. These cases were: 2 from kidney, 1 each from skin and lung. We report a detailed clinical history of lung cancer metastasis to the thyroid and evaluated our managements retrospectively. [Case] The patient was a 59-year-old man, who was diagnosed and treated as SCLC. He was treated with standard procedure and recovered completely. After 4 years follow-up, growing thyroid tumor revealed as the metastatic SCLC by fine needle aspiration (FNA) cytology. Further examination have shown no other metastatic site so that total thyroidectomy after 3 courses of induction chemotherapy (CDDP + CPT-11) was performed and 6 courses of adjuvant chemotherapy (AMR; Amrubicin Hydrochloride) was executed subsequently. After 2.5-year follow-up since last AMR, this patient is still alive with no recurrence. SCLC is prognostic poor lung cancer, but limited disease (LD) type shows relatively good survival rate as 30% of 3-year survival rate. We experienced the very rare case that late metastasis only to the thyroid once SCLC have cured completely. Furthermore combined modality therapy of total thyroidectomy and 2 types of chemotherapy provided complete remission (CR) again. We assume that achievement of secondary CR was caused by modification of chemotherapy regimen by detailed pathology of thyroid metastasis. Positron emission tomography (PET) and tumor marker pro-GRP were useful for diagnosis in this case. The management of metastatic thyroid cancer remains controversial. Although long-term prospective studies are still required, flexible combined modality therapies are important for such rare cases, based on our experiences.

Poster 618 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM NEED FOR A COMPLETE DIAGNOSTIC WORK-UP FOR THE DETECTION OF METASTASIS OF MEDULLARY THYROID CARCINOMA P.P. LIMONE1, F. Garino1, M. Deandrea1, P. Razzore1, G. Lacidogna1, A. Filice2, V. Arena3, A. Balbo Mussetto1, R.E. Pellerito1 1 A.O. Ordine Mauriziano di Torino, Torino, Italy; 2Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; 3IRMET Torino, Turin, Italy The detection of bone and liver metastasis of medullary thyroid cancer, and the consequent therapeutic decision, is often difficult. A 55 y old woman with a history of total thyroidectomy + lateral and central neck dissection (December 2013) for a medullary thyroid cancer (pT3mpNb pM1 - St. IVb), and subsequent excision of a single liver metastasis ( January 2014), was referred to our Department in march 2015 for very high calcitonin levels (24.850 pg/ml). A neck US scan showed no residual thyroid tissue but two small metastatic lymphnodes (4 and 7 mm), at IV and VI left cervical compartments. A thorax CT was negative; an abdominal MR showed multiple small liver images, suggestive of metastasis (3 to 7 mm); however, the apparent tumor bulk did not account for the calcitonin levels. Further investigations were then planned. A 18-FDG-PET was negative. A 18F-DOPA-PET confirmed the neck lympnode

metastasis, and a disomogeneous liver uptake, with a single area of greater uptake at IV segment, though non specific of cancer metastasis. A 68-Ga-Dotatate-PET-CT, while confirming lymphnode metastasis, disclosed areas of uptake in juxtajugular and paratracheal sites and multiple areas of uptake in spine, left humerus, right scapula, left femur and right ischium (SUV 5 vs 0.9 of the surrounding bone); furthermore, a diffuse liver uptake with focal areas of uptake (SUV 13 vs 10 of the whole liver) was seen, although not attributable for a certainty to secondary lesions. A treatment with Lu-DOTATOC was ruled-out, because of the low probability of effectiveness. A course of vandetanib was then started. This case confirms that metastasis of medullary thyroid cancer are often difficult to be detected, and that in some patients multiple imaging studies should be performed to obtain a correct assessment of the extension of the disease and to plan an adequate therapeutic approach.

Poster 619 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM THYROID SWELLING WITH FLUSHING AND DIARRHOEA : A CASE REPORT S. Mahamad1,2, N. Kitan3, S. Basro1, Z. Hussein2, A. B2 1 Endocrine/ Otolarygology, MEEI, Boston, MA; 2Endocrine Surgery, Hospital Putrajaya, Putrajaya, Malaysia; 3Endocrine Surgery, Hospital Putrajaya, Putrajaya, Malaysia Diarrhea and flushing has been detected in 28–39% of Medullary Thyroid Cancer(MTC) patients.We presented a case of a misdiagnosed MTC. A 41 year old man had failed left hemithyroidectomy for a follicular neoplasm.He had tachycardia and hypotension during induction which was thought attributed to an anaphylactic reaction to morphine. The patient had a history of euthyroid leftthyroid swelling for 6 months.Thyroid examination showed a large leftthyroid gland without cervical lymphadenopathy.CT scan revealed an enlarged left thyroid gland with necrotic left cervical and supraclavicular nodes.His thyroid function tests and iPTH level were normal. The patient reported a six month history of chronic diarrhea, associated with facial and chest flushing that ended spontaneously after defecation.There was no family history of thyroid carcinoma or pheochromocytoma. His left thyroid nodule was rebiopsied and reported as MTC.His calcitonin level and serum carcinoembryonic antigen(CEA) were elevated.His 24hour urine for methanephrines,catecholamines,vanillymandelic acid,histamine and 5-hydroxyindoleacetic(5-HIAA)were normal.CT findings of the adrenal glands were normal and without evidence of metastasis.His was diagnosed with sporadic MTC. The patient was given intravenous octreotide perioperatively.A total thyroidectomy and neck dissection was completed without recurrence of prior symptoms.The pathological examination revealed MTC with metastases to bilateral cervical and superior mediastinal nodes.His calcitonin and CEA levels normalized.He was discharge four days after surgery with thyroxine replacement,calcium and alpha calcidol supplement. MTC arises in parafollicular C cell which secreted neuropeptide substance that can give rise to carcinoid syndrome.High calcitonin in this patient was probably the cause of flushing and diarrhoea.A study showed that high calcitonin will act on calcitonin receptor(CTR) on intestine and increase the secretions.Octreotide,is a long acting somatostatin analoque that act as inhibitor of the intestinal secretion.

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peroxidase antibodies with normal thyroid function. TU showed two hypoechoic nodules, of 27mm in the right lobe and 17mm in the left one.FNA was performed and was negative for atypical cells. A month later she was admitted for dyspnea, dysphagia and stridor. A CT scan revealed a cervicothoracic goiter with compression of the trachea. Thyroidectomy + lymphadenectomy + tracheostomy were performed. Histopathology revealed a diffuse large B-cell lymphoma of the thyroid with infiltration of the lymph nodes and two papillary microcarcinomas, one classic and the other one follicular type. She received 6 courses of R-CHOP that resulted in complete remission. Conclusion: PTL is a rare cause of TM. It should be suspected in patients with rapidly enlarging goiter and history of HT. To our knowledge, it’s the first case reported with coexistence of multifocal papillary microcarcinomas and diffuse large B-cell lymphoma of the thyroid.

Poster 621

Post Total thyroidectomy and lymph node dissection specimen. This case illustrates a hormonal effect of MTC that can cause nuisance in operating room if its not detected early. We also present a successful treatment with octreotide and surgery.

Poster 620 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM COEXISTENCE OF PRIMARY THYROID LYMPHOMA AND MULTIFOCAL PAPILLARY MICROCARCINOMAS N. Rella1,3, M.L. Garcı´a1, G. Szuman2, M. Scioscia2 1 Endocrinology, Sanatorio Dr Julio Mendez, Buenos Aires, Argentina; 2endocrinology, Sanatorio Dr Julio Mendez, Buenos Aires, Argentina; 3endocrinology, Hospital Britanico, Buenos Aires, Argentina Thyroid cancer is the most common endocrine malignancy, accounting for approximately 1% of all malignancies; however, primary thyroid lymphoma (PTL) is a very rare entity, and accounts for only 5% of all thyroid malignancies (TM), with an annual estimated incidence of 2 cases per million. Women are more commonly affected, and typically, it presents in the seventh decade of life. Patients with Hashimoto’s thyroiditis (HT) are at greater risk for developing PTL. The most common presentation of PTL is a rapidly enlarging goiter, with associated compressive symptoms. Cervical lymphadenopathy is present in the majority of cases and classic B-type symptoms occur less commonly. Most patients are euthyroid at presentation. Thyroid ultrasound (TU) and fine needle aspiration (FNA) cytology, using flow cytometry and immunohistochemistry, remain the main modalities used to confirm the presence of lymphoma, but sometimes a surgical intervention may still be required, not only for definitive diagnosis but also to preserve the airway. Treatment and prognosis of PTL depend upon the histology and stage at diagnosis. Simultaneous occurrence of both papillary carcinoma and PTL is very rare. A 70 year old woman was referred with recent diagnosis of thyroid nodules. Laboratory tests revealed elevated antithyroid

Thyroid Cancer Wednesday & Thursday Poster 9:00 AM PAPILLARY THYROID CARCINOMA ARISING IN A THYROGLOSSAL DUCT CYST: A CASE REPORT G. Kim1, T. Jennings2, J. Joseph1 1 Medicine/Endocrinology and Metabolism, Albany Medical College, Albany, NY; 2Pathology, Albany Medical College, Albany, NY A thyroglossal duct cyst (TDC) is the most common congenital anomaly of the thyroid, accounting for 75% of midline neck masses diagnosed during childhood. It rarely persists into adulthood (7%). Carcinoma arising in TDC is a rare condition. The diagnosis is usually made postoperatively after the excision of the cyst. We report an unusual case of a 55-year-old male who presented with a 3 year history of midline neck mass consistent with TDC. CT neck revealed a midline bilobed peripherally enhancing nodule anterior to the hyoid bone measuring 1.5 · 0.7 cm with coarse calcification. He underwent excision of the cyst and pathology showed 1.2 · 0.8 · 0.7 cm papillary thyroid carcinoma. Ultrasound of the thyroid revealed subcentimeter bilateral thyroid nodules. Subsequently, patient opted for total thyroidectomy with central neck dissection. Pathology was benign with negative lymph nodes. TDC carcinomas are extremely rare with the reported incidence of 1–2%. Papillary carcinomas comprise approximately 85% followed by mixed papillary/follicular pattern comprising 7%, and less than 5% are of squamous cell type. Although the origin of TDC carcinoma is controversial, most convincing theory is that papillary thyroid carcinoma arise de novo from the thyroid tissue within the cyst wall rather than metastatic spread from an occult primary in the thyroid gland. The diagnosis of TDC carcinoma is usually incidental; however, our patient had calcifications on imaging in the TDC suspicious for TDC carcinoma. The Sistrunk operation is often considered adequate, but the management dilemma exists regarding the need for total thyroidectomy as thyroid gland involvement is reported in up to 33% of the cases. The overall prognosis of TDC carcinoma is excellent. Malignant transformation of the TDC, though rare, should be included in the differential diagnosis of a neck mass. The diagnosis is rarely made preoperatively. Histopathological evaluation is generally required for rendering the diagnosis. The need for total thyroidectomy in patients with TDC carcinoma remains controversial. Therefore, risk stratification to identify patients who may need more aggressive therapy should be an important step in the management of TDC carcinoma.

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WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015

Poster 622 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM RARE CASE REPORT ON ANTERIOR MIDLINE NECK MASSES IN ADULTS RESULTING IN THYROGLOSSAL DUCT CYST CARCINOMA M. Hache-Marliere1, S.J. Batista1, A. Gonzalez-Pantaleon2 1 Endocrine Surgery, CEDIMAT, Santo Domingo, Dominican Republic; 2Endocrinology, CEDIMAT, Santo Domingo, Dominican Republic Thyroglossal duct cyst (TGDC) carcinoma is a rare endocrine tumor in adults. Nearly 300 cases have been reported. Due to its embryological origin from the thyroid gland, there is still controversy as to whether it is a primary carcinoma or secondary metastatic cancer from thyroid gland proper. The appropriate treatment path has not been defined and if it warrants complementary thyroidectomy or sparing. We report on two young adults presenting with an insidious course of large midline neck masses ( > 5cm). Patient A is a 35-year-old male with a 3 year history of a mass in the anterior region of the neck, with no sign of discomfort besides the visible mass; on physical exam thyroid gland was normal with no enlarged cervical lymph nodes. He underwent Sistrunk procedure without preoperative fine needle aspiration biopsy (FNA); postoperative histology was consistent with metastatic papillary thyroid carcinoma. Total thyroidectomy was performed, histology yielded Hashimoto’s thyroiditis. Patient B is a 25-year-old male with a 1-year history of an anterior neck mass, also with no signs of discomfort other than a visible mass. The thyroid glands were normal and no palpable cervical lymph nodes on physical examination. Thyroid function tests were normal. Preoperative FNA biopsy was compatible with thyroglossal duct cyst. He underwent removal of the cyst (not Sistrunk procedure) and had recurrence of the enlarging anterior neck mass. Subsequently, underwent Sistrunk surgical procedure by ENT team, histology report was consistent with papillary thyroid carcinoma. A total thyroidectomy was performed and histological postoperative report was negative for cancer. Considering patients’ young age and clinical presentation, radioactive iodine (I-131) therapy was performed along with thyroid hormone suppressive therapy. Management for TGDC carcinoma is based on case reports. New treatment algorithms are based on small case reports. Removal of the thyroid gland allows for long-term monitoring of thyroglobulin

levels and the use of I131 scintigraphy and I131 ablation therapy. We suggest the creation of a network of investigators to understand the true prevalence, risk factors and treatment outcomes of TGDC.

Poster 623 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM RARE CASE OF THYROID LYMPHOMA A. Somasundaram1, L. Bischoff2, M. Shirodkar1 1 Endocrinology, Thomas Jefferson University Hospital, Philadelphia, PA; 2Endocrinology, Diabetes, and Metabolism, Vanderbilt University Medical Center, Nashville, TN Primary thyroid lymphoma is a rare cause of thyroid malignancy with an estimated annual incidence of 2 per 1 million1. We describe a diffuse large B cell lymphoma of the thyroid presenting as a rapidly enlarging goiter and lymphadenopathy. An 85-year-old Caucasian female presented with an enlarging neck mass and difficulty breathing for two months. There was no history of thyroid disease or risk factors for thyroid malignancy. Review of symptoms was positive for fatigue and hoarseness. Physical exam revealed bilateral large, firm, masses of the neck. Her TSH was 8.25 (0.4–4.5 mIU/L) thyroid peroxidase antibodies were negative. Levothyroxine 25 mcg daily was initiated. Thyroid ultrasound confirmed enlargement of both lobes (Left 8.6 · 2.9 · 3.9 cm and right 7 · 4.4 · 4 · 4 cm) multiple nodules of mixed attenuation, favoring Hashimoto’s thyroiditis. FNA of the left nodular area was predominantly lymphoid cells, atypical lymphocytes, and Hurthle cells with atypia. CT of the neck showed thyroid enlargement, without tracheal compression, scattered cervical lymph nodes, a left 1.2 · 1 cm level IIA lymph node with medial displacement of the left vocal cord. A repeat FNA with flow cytometry was suspicious for lambda monoclonal B cell population. Serum immuno electrophoresis was normal. She underwent a left lobectomy for progressive compressive symptoms. The frozen section was positive for lymphoma and final pathology confirmed diffuse large B cell lymphoma of thyroid. Staging PET CT revealed involvement of thyroid, bone marrow and lymph nodes. Chemotherapy with Rituximab, Cyclophosphamide, Vincristine and prednisone was initiated. Primary thyroid lymphoma should be suspected in an enlarging goiter with compressive symptoms. Accurate diagnosis is essential to provide the correct treatment. A rapidly enlarging goiter with compressive symptoms is a unique presentation of primary thyroid lymphoma.

Poster 624 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM DISPARITIES IN THE TREATMENT AND SURVIVAL IN MEDULLARY THYROID CANCER, SEER 1998–2011 A. Roche1, S.A. Fedewa2, A.Y. Chen1 1 Otolaryngology - Head and Neck Surgery, Emory University School of Medicine, Atlanta, GA; 2Epidemiology, Emory University School of Public Health, Atlanta, GA

CT scan. Large Anterior Midline Mass

Medullary thyroid cancer is a relatively rare neoplasm of the thyroid but accounts for 14% of thyroid cancer related deaths. Female sex, young age at presentation, and stage at presentation have been found to predict survival. Factors related to socioeconomic status, race and ethnicity have been less well described. Data for patients with medullary thyroid cancer from 1998 to 2011 in the Surveillance, Epidemiology, and End Results Program (SEER) registry were examined. Differences in receipt of thyroidectomy and lymph node examination by race/ethnicity were examined using

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015

RA

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Poster 626

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logistic regression models. Overall (OS) and Disease-Specific (DS) survival were examined by race/ethnicity using Kaplan Meier survival curves. 1647 patients were included in the analytic cohort (72.37% white, 8.44% black, 13.48% Hispanic, and 5.70% Other). 93% of patients received surgical treatment for MTC. There were no differences in receipt of thyroidectomy by race/ethnicity, however, black patients (OR = 0.61, CI 0.39%–0.93%) were less likely to undergo lymph node examination compared to Non-Hispanic white and male patients. Black and Hispanic patients had lower overall (HR = 2.40, 95%CI; HR = 1.81, 95%CI, respectively) and disease-specific survival (HR = 2.85, 95%CI; HR = 1.24, 95%CI, respectively) when compared to Non-Hispanic White patients in adjusted analyses. Our study is the first population-based cohort of patients with medullary thyroid cancer to observe that Black race was associated with thyroidectomy alone, without receipt of lymph node examination as well as overall survival, and disease specific survival. Racial disparities exist in the type of treatment as well as outcomes in patients with medullary thyroid cancer.

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Differentiated thyroid carcinoma (DTC) in children and adolescents is an uncommon occurrence and the most adequate treatment approach and surveillance strategy for this group of patients is a matter of debate. Here, we aimed to describe the clinical presentation and outcomes of children and adolescents with DTC followed at our institution. DTC patients 18 years-old or younger at diagnosis were selected from a cohort of 880 DTC patients attending the Thyroid Clinic of a university-based hospital. Baseline clinical and oncological characteristics, interventions, disease status and outcomes are described. A group of 30 children and adolescents with DTC were included. The mean age at diagnosis was 14.6 – 3.3yrs, and 25 (83.3%) were female. Twenty-nine (96.7%) patients had papillary thyroid carcinoma histology, with a median tumor size of 2.2 cm (P25–75 1.7– 3.5), cervical metastasis occurred in 19 (63.3%) and distant lung metastasis in 4 (13.3%). Twenty-six (86.7%) patients were in stage I and 4 (13.3%) in stage II (TNM staging). All patients underwent total thyroidectomy and twenty-seven (90.0%) received radioactive iodine therapy, with a median dose of 100 mCi (P25–75 100–150). After a median follow-up of 5.0yrs (P25–75 3.0-9.8), 15 (62.5%) were disease free, 5 (20.8%) had persistent biochemical and 4 (16.7%) structural disease. Interestingly, the post-operative stimulated thyroglobulin (sTg) cut-off point of 12 ng/ml had a sensitivity of 100% to predict disease free status on long term follow-up (area under the receiver operation characteristic curve 0.98, P < 0.001). No deaths were registered. A trend towards a less aggressive DTC clinical presentation and more favorable outcome in children and adolescents was observed, probably reflecting earlier diagnosis over the last decades. Postoperative sTg seems to be a promising tool for risk stratification to guide therapeutic follow up strategies.

W

Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM DIFFERENTIATED THYROID CANCER IN CHILDHOOD AND ADOLESCENCE: A REFERRAL CENTER EXPERIENCE J. Dora, R.S. Scheffel, A.L. Maia Endocrine Division, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil

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Poster 625

Poster 627 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM MATCHING MUTATIONS IN MULTIFOCAL PAPILLARY THYROID CANCER ARE ASSOCIATED WITH HIGHER RISK OF CENTRAL COMPARTMENT NODAL METASTASIS W. Li, S. Carty, K. McCoy, M.T. Stang, Y. Nikiforov, L. Yip University of Pittsburgh, Pittsburgh, PA Multifocal papillary thyroid carcinoma (MPTC) occurs in *50% of thyroid cancer patients. Up to 60% of cases may arise as synchronous primary tumors with distinct molecular alterations, but MPTC may also represent intraglandular spread in which case separate tumor foci would have the same driver mutation. Our study aim was to examine whether the presence of the same or different mutations was associated with histologic variability and short-term recurrence. We reviewed records of 191 patients who had initial thyroidectomy for MPTC with molecular testing of ‡ 2 foci for BRAF, NRAS,

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HRAS, KRAS mutations, and RET/PTC1, RET/PTC3 and PAX/ PPARG rearrangements. Clinicopathological features and histologic recurrence were examined. Identical ‘‘matching’’ mutations (SAME) were identified in 78 patients (41%) and differing mutations (DIFF) were detected in MPTC of 113 patients (59%). The study cohorts were similar in mean age at diagnosis (p = .2), rate of BRAF V600E positivity (p = .4), and proportion of patients received central compartment node dissection (CND, p = .8). Histologic MPTC features were similar between the 2 groups including frequency of bilobar disease (p = .3) and presence of lateral lymph node metastasis (LNM, p = .8). Compared to DIFF patients, SAME patients had a higher rate of central LNM (53% v. 31%, OR = 2.6, P = 0.009) and a higher percentage of positive central compartment lymph nodes (mean 36% v. 16%, p = .01). In subset analysis of 127 patients who had at least 1 BRAF V600E positive PTC, SAME patients still had a higher rate of CLNM than DIFF patients (65% v. 36%, OR 3.4, p = .005). At mean follow-up of 23 (0.2-85) months, reoperation for recurrence occurred in 5% of patients and the rate did not differ by cohort (p = .5). 40% of multifocal PTC foci have matching mutations, and those patients have a 2.5X higher risk of central compartment LNM. The findings suggest that multifocality may be due to intraglandular spread more often than is currently appreciated and may manifest a more aggressive disease pattern. When identical molecular alterations are detected preoperatively in ‡ 2 tumor foci, CND should be strongly considered at the initial operation.

Poster 628 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM ATA RISK STRATIFICATION BETTER PREDICTS THE MORTALITY RATE THAN AGE-BASED TNM STAGING IN DTC PATIENTS C. Bal, S. Ballal, M.P. Yadav Nuclear medicine, All India Institute of Medical Sciences, New Delhi, India AJCC/UICC staging is recommended in all differentiated thyroid cancer (DTC) patients that is based on age and TNM status that predicts disease mortality. ATA guidelines emphasize on risk stratification along with TNM staging for predicting long-term outcome. The present study aimed to compare the impact of risk stratification verus TNM stage, particularly the effect of age in the survival outcome in DTC patients. The retrospective study involves adult DTC patients treated between Jan 1971 to Dec 2013, with minimum follow-up of 12 months. The medical records of 4442 patients were reviewed. The patient who had aggressive histology, shorter duration of follow-up or inadequate data was excluded. Finally, 4035(M:1187(29.4%) and F:2848(70.6%); PCT:85.4% and FCT:14.6%) patients fulfilled the inclusion/exclusion criteria. We grouped these patients as per the age at the time of diagnosis into Gr1(21–44y), n = 2562 (63.5%), Gr2(45– 59y), n = 903(22.4%) and Gr3(60–84y), n = 569(14.1%). Each group further sub-stratified as low-risk, intermediate-risk and high-risk based-on ATA risk status. Events were defined as documented recurrence or disease progression or death due to DTC. The mean follow-up duration was 72 – 40.0 months (range: 12534). In Gr1, 2384 (93%) were in Stage I and 177 (7%) in stage II. In Gr2, 138 (15.2%), 158 (17.4%), 101 (11%), 273 (30.2%), 39 (4.3%), 194 (21.4%) were Stage I, II, III, IVA, IVB and IVC, respectively. Similarly, in Gr3 46 (8%), 89 (5.6%), 31 (5.4%), 193 (33.9%), 49 (8.6%), 162 (28.4%) were Stage I, II, III, IVA, IVB and IVC, respectively. On the basis of risk stratification Gr1 had 1066 (41.6%), 1280 (50.6%), 216(8.4%), Gr had 293(32.4%), 376 (41.6%), 234

(25.9%) and Gr3 had 122 (21.4%), 230(40.4%) and 217(38.2%) as low-risk, intermediate-risk and high-risk, respectively. Total event rates in Gr1, Gr2 and Gr3 were 3.4%, 9.9% and 16.7%, respectively and p values were p < 0.000 (Gr1 vs Gr2) and p-0.000 (Gr2 vs Gr3). Table1 depicts overall event rates and mortality in the three groups and between risk categories. Irrespective of the age, high-risk category has higher event rates and poorer survival outcomes. ATA risk stratification better predicts the mortality rate than age-based TNM staging.

Poster 629 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM CHARACTERISTICS OF PATIENTS ON LENVATINIB WITH TREATMENT-EMERGENT HYPERTENSION IN THE SELECT TRIAL J. Choi, S. Abouzaid, X. Li, P. Rietschel Eisai Inc., Woodcliff Lake, NJ Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer based on the phase 3 SELECT trial. Any-grade treatment-emergent hypertension (TE-HTN), as per Common Terminology Criteria for Adverse Events v4.0, occurred in 73% of patients who received lenvatinib. Grade 3 TE-HTN occurred in 44% of patients; only 1 grade 4 TE-HTN event was reported. To assess potential predictors of TE-HTN, we compared characteristics of lenvatinib-treated patients with and without TE-HTN. Patients received lenvatinib or placebo (24 mg/d; 28-d cycle). Descriptive statistics were used to compare demographic and clinical characteristics between patients with and without TE-HTN. Logistic regression was used to assess baseline characteristics (age, gender, weight, region, Eastern Cooperative Oncology Group [ECOG] status, prior vascular endothelial growth factor (VEGF)-targeted therapy, baseline comorbidities, and number of metastatic sites) as predictors of TE-HTN. Unadjusted progression-free survival (PFS) was also examined. Of the lenvatinib-treated patients (n = 261) who experienced TEHTN (n = 190), a higher proportion were women (57% vs 38%, P = 0.005), had hepatic impairment (13% vs 4%, P = 0.047), and had a lower number of metastatic sites at baseline (P = 0.032) compared with patients without TE-HTN. These differences remained after adjusting for baseline characteristics. The likelihood of developing TE-HTN was lower for men (odds ratio [OR] 0.43; 95% confidence interval [CI] 0.23-0.78; P = 0.006) and for patients without baseline hepatic impairment (OR 0.28; 95% CI 0.08-0.99; P = 0.047). The likelihood of TE-HTN was higher for patients with £ 1 metastatic site (OR 3.31; 95%CI 1.44–7.60; P = 0.005). Unadjusted results showed that lenvatinib-treated patients with TE-HTN had higher median PFS (18.8 vs 12.9 months, P = 0.009) compared with those without TE-HTN. Female gender, baseline hepatic impairment, and a lower number of metastatic sites may be associated with a higher likelihood of developing TE-HTN in patients treated with lenvatinib. In SELECT,

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patients who developed TE-HTN with lenvatinib treatment had a higher PFS than those who did not experience TE-HTN.

Poster 630 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM RELATION BETWEEN INCREASES IN 18FDG-PET SUV AND SIZE OF LESIONS IN THYROID CARCINOMA I. Singh1, A. Bikas1, C.A. Garcia2, L. Wartofsky1, S. Desale3, K. Burman1 1 Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, MedStar Washington Hospital Center, Washington, DC; 2Division of Nuclear Medicine, MedStar Washington Hospital Center, Washington, DC; 3Biostatistics and Bioinformatics, Medstar Health Research Institute, Hyattville, MD 18

FDG- PET/CT scans have utility in oncology for the diagnosis, staging, and surveillance of various malignancies. This imaging modality is primarily used in high-risk thyroid cancer patients with elevated serum thyroglobulin (Tg) levels and negative radioiodine imaging. Increases in SUV values of given lesions on serial subsequent scans require interpretation as to disease progression and prognostic significance. This pilot study investigated the correlation between an increase in SUV with the change in size of individual lesions in patients with thyroid cancer. A retrospective chart review of patients with histologically confirmed thyroid cancer, monitored with serial 18FDG- PET/CT scans from 2008 to 2013, was performed. Of 101 patients screened, 47 cases had at least one lesion that showed an increase in SUV on follow-up and were selected for analysis. A mixed effects model was used after normalization of data. A positive correlation was found between SUV and tumor area. For every increase of 1 unit of SUV, an increase of 0.62 sq mm in area (p < 0.0001) can be expected for the first scan; 0.06 (p = 0.22), 0.12 (p = 0.046), 0.19 (p = 0.02) and 0.33 (p = 0.003) for the second, third, fourth and fifth scans, respectively. There was also a significant correlation between percentage change in SUV with area. Analysis on cube root transformed data was significant in 4 of 5 groups: scan 1-2 (p = 0.0001), scan 2–3 (p = 0.0005), scan 3–4 (p = 0.008), scan 4–5 (p = 0.66), overall (p < 0.0001). After exclusion of outliers, for 1% change in SUV, the expected percentage change in area on subsequent scans was found to be 0.34% (p = 0.0006), 0.26% (p = 0.005), 0.4% (p = 0.0740) and 0.41% (p = 0.27) for the second, third, fourth and fifth scan respectively. The association was similarly significant in cases with > 25% increase in SUV. Secondary analysis showed a significant association between SUV and Tg (p = 0.035) but not between SUV and TSH (p = 0.85). A significant positive correlation was noted between lesion area and SUV. An increase in lesional SUV in subsequent scans may portend tumor growth and could prompt consideration for earlier or more aggressive intervention.

Papillary thyroid cancers (PTC) usually show good prognosis, however some of them are aggressive and might show bulky tracheal bleeding and/or occlusion of airway, which might lead to fatal status. Therefore, proper and novel criteria (Tori’s criteria) for reconstruction of the tracheal defect after resection in the operation of PTC was examined in terms of site and area of invasion, and moreover, our original deltopectorial (DP) flap reconstruction was estimated if the method could be standardized as reconstruction. Patients and methods: For the past 15 years, 212 cases were operated diagnosed as PTC invasive to trachea. M1 in 26 cases. Those are divided into 5 groups in terms of operative procedures. (A)shaving; 170 cases, (B)wedge resection; 8, (C)window resection with DP flap reconstruction; 21, (D) cylindrical resection with direct suture; 8, (E) total laryngectomy; 5. We developed the new procedure i.e. DP flap reconstruction. When the site of invasion is at the level of the cricoid cartilage, flap is pulled through the tunnel underneath skin and raised to cover the defect of trachea and tracheostomy was made just above the sternal notch, on the other hand, if the site of invasion is rather low, skin is cut and divided longitudinally to put the DP flap on the ‘‘skin-crevasse’’. By such device, postoperative management of airway control is achieved safely. All cases were examined histopathologically besides the perioperative complications, and outcome of each case was retrospectively searched. Result: As to perioperative complications, minor leakage was found in one case in group (D). No mortality in all for 15 years. Two cases in (A) and one in (D) showed recurrence. DP flap reconstructon in terms of long time prognosis is reported for the first time. It was free from complications, reached good prognosis and thought to be excellent in terms of patients’ QOL. Conclusion:Shaving might be applied to most of the cases, and if invasion reached mucosa, our original method, i.e. window resection with DP flap reconstruction could be sure and safe method which would be standardized as reconstructive procedure for advanced PTC, in that respiratory risk is very low and postoperative QOL of patients is excellent.

Poster 631

Poster 632

Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM DELTOPECTORIAL FLAP RECONSTRUCTION WITH PREOPERATIVELY TRANSPLANTED AURICULAR CARTILAGE AS SAFE AND SURE METHOD FOR PAPILLARY THYROID CANCER INVADING THE TRACHEA M. Tori2,1, K. Yoshidome3, T. Shimo2,3, K. Anno3, T. Takahashi4 1 Surgery, Osaka Police Hospital, Osaka, Japan; 2Endocrine surgery, Osaka Police Hospital, Osaka, Japan; 3Breast Surgery, Osaka Police Hospital, Osaka, Japan; 4Cardiovascular surgery, Osaka Police Hospital, Osaka, Japan

Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM SERUM TG IS FREQUENTLY UNDETECTABLE BY MASS SPECTROMETRY (TG-MS) IN TGAB-POSITIVE DIFFERENTIATED THYROID CANCER (DTC) PATIENTS WITH STRUCTURAL DISEASE. I. Petrovic1, S. Fatemi3, J. LoPresti1, S.K. Grebe4, A. AlgecirasSchimnich4, B.C. Netzel4, C. Spencer2 1 Medicine, University Southern California, Pasadena, CA; 2Medicine, University of Southern California, Los Angeles, CA; 3Endocrinology, Kaiser Permanente, Panorama City, CA; 4Laboratory

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Medicine and Pathology, Mayo Medical Laboratories, Rochester, MN Serum Thyroglobulin (Tg) measured by immunometric assays (Tg2GIMA, functional sensitivity £ 0.10 ng/mL) is primarily used to detect persistent/recurrent DTC when TgAb is absent, but when present TgAb interferes with Tg2GIMA causing falsely low/undetectable values that might mask disease. Currently, when TgAb is detected, laboratories reflex Tg testing to a TgAb-resistant methodology [Tg-MS or radioimmunoassay (Tg-RIA)] with the goal of improving clinical sensitivity to detect disease in the presence of TgAb. The goal of this study was to determine agreement between serum Tg measurements made by three Tg-MS (Mayo, Quest and ARUP) methods, a Tg2GIMA (Beckman) and a Tg-RIA (USC) in TgAb-positive (n = 20) and TgAbnegative (n = 27) cohorts of DTC patients with structural disease. 60 Sera from 47 patients (42 with local and 5 with distant metastatic disease), drawn within 6 months of disease detected by biopsy and/or anatomic imaging, were retrieved from frozen archive and aliquoted for Tg measurement by the Mayo, Quest and ARUP MS, Tg2GIMA (Beckman) and RIA (USC) methods. Specimens had concordant TgAb status (positive/negative) established by three different methods. Patients WITHOUT TgAb: Tg was detected in 28/29 by 2GIMA (median 5.5, < 0.10–185 ng/mL), 23/29 by Mayo-MS (median 9.4, < 0.5-170 ng/mL), 22/29 by Quest-MS (median 14.6, < 0.4– 170 ng/mL), 22/29 by ARUP-MS (median 8.2, < 0.5-170 ng/mL) and 27/29 by Tg-RIA (median 11.1, < 0.5-190 ng/mL). There were significant discordances among Tg-MS values (meanCV = 23 – 16(sd), range 8-77%). Patients WITH TgAb: Tg was undetectable in 22/ 31(71%) by 2GIMA, 24/31(77%) by Mayo-MS, 12/19(63%) by Quest-MS, 23/26(88%) by ARUP-MS and 4/31(13%) by RIA. Current Tg MS methods frequently report undetectable serum Tg for TgAb-positive DTC patients with structural disease whereas TgRIA is often detectable, although interference causing false-positive Tg-RIA cannot be excluded. Whether these undetectable Tg-MS values reflect tumor Tg polymorphisms, low Tg secretion by some tumors, suboptimal Tg-MS sensitivity or TgAb-enhanced Tg metabolic clearance, needs further study.

Poster 633 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM OUTCOME OF BONE METASTASES IN 52 PATIENTS WITH DIFFERENTIATED THYROID CANCER I. Califano, C. Cabezon, S. Deutsch, A. Lowenstein, F. Pitoia Departamento de Tiroides de SAEM, Buenos Aires, Argentina Bone metastases (BM) from differentiated thyroid cancer (DTC) are associated with poor survival rates. Due to the low frequency of this entity, we performed a multicentric retrospective study aiming to evaluate the presentation, outcome and cause of death in this group of patients We reviewed file records from 10 databases. BM were diagnosed by: i) biopsy and/or ii) radioiodine (RAI) bone uptake + elevated thyroglobulin (Tg) levels and/or c) bone uptake of 18-FDG in the PET-CT scan + elevated Tg levels. Clinical-pathological features of the BM were analyzed. Causes of death were classified as due to BM when they could be attributed to a direct complication from BM. Statistic analysis: SPSS Windows 19.0. 52 patients were included (44% male, mean 54 years). 81% older than 45 years while 58% had papillary histology.BM were synchronous with DTC diagnosis in 46%. BM were symptomatic in 65% of the cases. Multiple BM were present in 65% of patients, while simultaneous metastatic disease was found in 69%. Calcemia was normal in all cases; 98% of patients received treatments for the BM: RAI, bisphosphonates, surgery, external beam radiotherapy, and/or

other therapies.Mean follow up after diagnosis of BM was 34 months. Status on last evaluation was: DTC-related death 56%, alive with persistent disease 36%, death from other causes 4%, no evidence of disease 4%. When DTC-related causes of death (n = 29) were analyzed, 34.4% of patients died of direct complications of BM or their treatments; Hu¨rthle cell carcinoma and painful BM were associated with death related to BM (p < 0,05) BM were mainly found in patients over 45 years old, with similar gender distribution. Multiple treatment modalities were used underscoring the importance of a multidisciplinary approach. Although BM were associated with incurable disease, mortality was mainly related to the spread of DTC to other sites.

Poster 634 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM SHORT AND LONG-TERM OUTCOMES AFTER ROBOTIC VERSUS CONVENTIONAL OPEN TOTAL THYROIDECTOMY IN PATIENTS WITH PAPILLARY THYROID CANCER: A CASE-MATCHED RETROSPECTIVE STUDY S. Lee, M. Kim, J. Choi, T. KIM, E. Ban, C. Lee, J. lee, S. Kang, J. jeong, K. Nam, W. Chung Yonsei Universtiy Hostpital, Seoul, Korea (the Republic of) There is substantial controversy over the role of robot in thyroid surgery, and whether robotic total thyroidectomy (R-TT) can be justified as a standard treatment for thyroid cancer patients needs to be clarified. To assess the short- and long-term operative outcomes and oncologic outcomes of R-TT, it was compared to conventional open TT (O-TT) after propensity score matching of the cohorts. We conducted a retrospective review of patients undergoing TT with CCND for papillary thyroid cancer (PTC) by a single surgeon. A total of 833 patients had 5 or more years of follow-up and 94 (11.3%) were lost to follow-up at our institution. Of these patients, 245 (33.2%) patients were performed R-TT and 494 (66.8%) patients were performed O-TT. The mean follow up duration was 74 (range 61-91) months. Propensity score matching was used to match this group with 206 patients who underwent R-TT. We analyzed the patient and tumor characteristics, postoperative morbidity, and oncologic outcomes. The two groups were similar in patient characteristics. The operation time was significantly longer in the R-TT group than in the O-TT group (p < 0.001). R-TT was associated with an equivalent complication rate including hypocalcemia, recurrent laryngeal nerve palsy, bleeding, chyle leakage, wound infection and seroma. In terms of short and longterm oncologic outcomes, there were no significant differences in the number of retrieved central lymph nodes (p = 0.101) and serum thyroglobulin concentration (p = 0.249). In addition, disease-free survival were similar between both groups (98.1% vs 96.5%, p = 0.813 ). This represents the first report of the 5-years’ surgical outcomes of R-TT for thyroid cancer, demonstrating the short and long-term oncologic quality after R-TT group is as effective as those in O-TT group.

Poster 635 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM NEGATIVE EXPRESSION OF CPSF2 PREDICTS A POORER CLINICAL OUTCOME IN PATIENTS WITH PAPILLARY THYROID CARCINOMA M. Kim1, T. Kim1, T. Sung2, W. Kim1, Y. Park3, D. Song3, S. Park1, H. Kwon1, Y. Choi1, E. jang1, M. Jeon1, Y. Shong1, S. Hong2, W. Kim1

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Internal Medicine, Asan Medical Center, Seoul, Korea (the Republic of); 2Surgery, Asan Medical Center, Seoul, Korea (the Republic of); 3Pathology, Asan Medical Center, Seoul, Korea (the Republic of) The BRAFV600E mutation is a promising prognostic biomarker for patients with papillary thyroid carcinoma (PTC), but the incidence variation of that differs widely depending on geographic regions. A recent study reported that loss of cleavage and polyadenylation specificity factor subunit 2 (CPSF2) gene was associated with increased cellular invasion, cancer stem cells, and aggressiveness of PTC. This study aimed to evaluate CPSF2 protein expression as a prognostic marker for PTC, especially in regions with high prevalence of the BRAFV600E mutation. This study included 159 patients with classical PTC who underwent a total thyroidectomy and received ablative doses of 131I. The expression of CPSF2 protein was evaluated by immunohistochemistry and graded semi-quantitatively. The presence of the BRAFV600E mutation was evaluated by direct sequencing. Negative protein expression of CPSF2 was observed in 34 (21.3%) of the 159 PTCs. The BRAFV600E mutation was significantly associated with CPSF2 positivity ( p = 0.03). In multivariate analysis, negative CPSF2 expression was significantly associated with cervical lymph node metastasis (OR 2.56, p = 0.28), and distant metastasis (OR 3.48, p = 0.02). After adjusting for age, gender, tumor size, extrathyroidal invasion, lymphovascular invasion, and the BRAFV600E mutation, the CPSF2-negative group was significantly associated with lower recurrence-free survival compared to the CPSF2-positive group (Hazard Ratio 2.14, p = 0.03). Negative protein expression of CPSF2 is independently associated with a poor clinical outcome in PTC. CPSF2 could be a useful prognostic marker for PTC in regions with a high prevalence of the BRAFV600E mutation.

Poster 636 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM 5 YEARS FOLLOW UP OF THYROGLOBULIN (TG), THYROGLOBULIN ANTIBODIES (TGAB) AND NECK ULTRASOUND (US) IN PATIENTS WITH PAPILLARY THYROID MICROCARCINOMA (MPTC) TREATED WITH TOTAL THYROIDECTOMY BUT NOT ABLATED WITH 131I A. Matrone3, A. Faranda3, E. Molinaro3, L. Agate3, D. Viola3, L. Valerio3, C. Giani3, L. Torregrossa1, P. Piaggi2, P. Vitti3, R. Elisei3 1 Department of Surgical Pathology, Medical, Molecular and Critical Area, Unit of pathological anatomy, Pisa, Italy; 2Phoenix Epidemiology and clinical research branch national institute of diabetes and digestive and kidney disease, National Institutes of Health, Phoenix, Arizona, Phoenix, AZ; 3Dipartimento di Medicina Clinica e Sperimentale - Unit of Endocrinology, University of Pisa, Pisa, Italy Serum Thyroglobulin (Tg) and Thyroglobulin Antibodies (TgAb) assays are considered as the cornerstone for the post-operative management of patients with differentiated thyroid cancer (DTC) after the initial treatment. Less is known about the significance of this parameters in pts who do not perform radioiodine ablation (RRA) as in case of mPTC We retrospectively evaluated epidemiological, clinical and pathological data of 170 consecutive patients with mPTC, surgically treated at our Department from 2006 to 2012. The inclusion criteria were the unifocality of the tumor and at least three or more determinations of serum Tg, TgAb and US in our department. The exclusion criteria were pts who performed RRA or during the follow up and a lower number of serum Tg, TgAb and US determination. The

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aim of our study was to clarify the significance of the Tg and TgAb trends during the follow up. We divided our pts in group A (120 pts) (TgAb < 20 mU/L) and in group B (50 pts) (TgAb > 20 mU/L) and we analyzed the Tg and TgAb course during the follow up (mean 5.1 yrs, median 5 yrs). In Group A, 78/120 (65%) had an undetectable Tg ( < 0.5 ng/ml) at the first control, 22/120 (18%) had a Tg between 0,5-1 ng/ml and 20/120 (17%) had Tg > 1 ng/ml; at the end of follow up only in 16/120 (13%) Tg values were > 1 ng/ml, but in all pts (120/120) neck US was negative for lymphnode metastases, at the beginning and at the end of follow up. In group B, only in 3/50 (6%) there was an increase in TgAb more than 20%, in 42/50 (84%) pts, there was a decrease more than 20%, and 5 (10%) pts have stable titers of TgAb; in this subgroup of pts neck US was negative (50/50). The 5 years follow up of mPTC not treated with RRA shows a very good outcome and the absence of recurrence until now. The course of Tg and TgAb in this subgroup of pts seems to give limited informations with respect to neck US, maybe related to the good prognosis of this tumor.

Poster 637 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM TEMPORAL TRENDS IN POST-SURGICAL SERIAL THYROGLOBULIN (BOTH STIMULATED AND UNSTIMULATED HIGH SENSITIVITY) AMONG PAPILLARY THYROID CARCINOMA PATIENTS NOT RECEIVING RADIOACTIVE IODINE ABLATION L. Kashat, S. Orlov, D. Orlov, F. Salari, P.G. Walfish Mount Sinai Hospital / University of Toronto, Toronto, ON, Canada With the availability of high sensitivity serum thyroglobulin (hsTg) assays and an increasing number of papillary thyroid carcinoma (PTC) patients not receiving radioactive iodine (RAI), the clinical significance of post-surgical Tg testing remains unclear. We aimed to determine the temporal trends in serial Tg among PTC patients not receiving RAI using TSH-stimulation (Stim-Tg) and unstimulated hsTg (u-hsTg). We prospectively analyzed serial Stim-Tg measurements after total thyroidectomy – therapeutic central neck dissection among 123 consecutive low/intermediate-risk PTC patients who did not receive RAI, of whom 104 also had serial u-hsTg measurements available. Patients were followed for a median of 6.5 years, with Stim-Tg commencing 3 months after surgery and u-hsTg commencing 1.8 years after surgery, as the assay became available. TSH stimulation was performed by either recombinant human TSH (rhTSH), 9-day T3 withdrawal or 22-day T4 withdrawal. To account for within-patient correlations of repeated Tg measurements, temporal trends in Stim-Tg and u-hsTg were assessed using General Estimating Equations. Stim-Tg models were adjusted for method of TSH stimulation, whereas u-hsTg models were adjusted for concurrent TSH level. A total of 337 Stim-Tg (2.7/patient) and 602 u-hsTg (5.8/patient) measurements were analyzed. Stim-Tg was assessed using rhTSH, T4 withdrawal and T3 withdrawal in 202(60%), 41(12%), and 94(28%) measurements, respectively. When adjusted for method of TSH stimulation, serial Stim-Tg measurements did not significantly change over time (all p = NS). The estimated change in Stim-Tg per year for rhTSH, T4 withdrawal and T3 withdrawal was 0.01lg/L, - 0.08lg/L and 0.04lg/L, respectively. Serial u-hsTg measurements did not significantly change over time after adjusting for concurrent TSH level (p = NS). The estimated change in u-hsTg per year was - 0.003lg/L. Of note, the mean Stim-Tg and u-hsTg measured was 1.2lg/L and 0.3lg/L, respectively. No patients had evidence of structural recurrence during the duration of follow-up.

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Among low/intermediate-risk PTC patients not treated with RAI, serial post-surgical Stim-Tg and u-hsTg measurements do not change significantly over > 6 years of follow-up.

Poster 638 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM A MULTI-COHORT PHASE II TRIAL OF VB-111 IN ADVANCED RADIOACTIVE IODINE-REFRACTORY DIFFERENTIATED THYROID CANCER S. Jasim1, M.E. Menefee2, R.C. Smallridge3, J. Burton5, C. Bieber2, Y. Cohen4, D. Harats4, K.C. Bible5 1 Divisions of Endocrinology, Mayo Clinic, Rochester, MN; 2Medical Oncology, Mayo Clinic, Jacksonville, FL; 3Divisions of Endocrinology, Mayo Clinic, Jacksonville, FL; 4VBL Therapeutics, Or Yehuda, Israel; 5Medical Oncology, Mayo Clinic, Rochester, MN VB-111 is a non-replicating engineered AD-5 adenovirus with prepro-endothelin promoter triggering apoptosis of tumor vasculature by expressing a FAS-chimera transgene in response to tumor necrosis factor stimulation. Having demonstrated in vivo preclinical activity of VB-111 in differentiated thyroid cancer (DTC) models, we evaluated VB-111 in patients with advanced radioactive iodine refractory (RAIR) DTC This open label industry-sponsored dose-escalating study assessed safety and efficacy of VB-111 in progressive, metastatic, RAIR DTC. VB-111 was administered as a single intravenous infusion at 3 · 1012 (first cohort), or at 1 · 1013 viral particles (VPs) every 2 months (second cohort). Twenty nine patients with metastatic RAIR DTC with disease progression within the 6 months prior to enrollment were treated (14 papillary, 10 Hu¨rthle cell, 5 follicular). Median age was 63 (range: 34–78). Seventeen (58%) previously received radiotherapy, 11 (38%) tyrosine kinase inhibitors and 8 (27%) cytotoxics. Thirteen patients received a single dose of 3 · 1012 VPs (cohort 1); 17 received up to 12 doses at 1 · 1013 VPs every two months (cohort 2). Most patients (69%) developed self-limited flu-like symptoms beginning about 6 hours after infusion lasting < 2 days. There were 15 AEs at CTCAE grade ‡ 3, 6 considered at lease possibly related to VB-111: fever and/or chills (n = 3),diarrhea (1), pulmonary hemorrhage (1) and congestive heart failure (1). Three patients (10%) experienced transiently increased activated partial thromboplastin time in association with induction of antiphospholipid antibodies (as has been previously described with Ad5 vector), one of whom with a history of hemoptysis and lung metastasis experienced a temporally-associated self-limited symptomatic pulmonary hemorrhage. Several patients attained lesional responses. Six patients (35%) in cohort 2 met the primary endpoint of 6-month progression-free survival, compared to three patients (23%) in cohort 1 VB-111 was well tolerated in most RAIR DTC patients, with early evidence of dose-dependent disease stabilization. A randomized controlled trial is required to further assess the efficacy of VB-111 in patients with RAIR DTC.

Poster 639 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM EARLY PROGNOSTIC FACTORS AT THE TIME OF FIRST RADIOACTIVE IODINE THERAPY PREDICT SURVIVAL OF PATIENTS WITH BONE METASTASES FROM DIFFERENTIATED THYROID CARCINOMA Y. Choi, W. Kim, H. Kwon, M. Jeon, T. Kim, Y. Shong, W. Kim Asan Medical Center, Seoul, Korea (the Republic of)

Bone is the second most common site of distant metastases for differentiated thyroid cancer (DTC) after the lungs. Patients with bone metastases was associated with poor clinical outcomes, however their clinical course was heterogeneous due to recurrent skeletal complications. This study aims to evaluate early prognostic factors associated with survival in patients with bone metastases from DTC. This retrospective study included 93 patients with bone metastases from DTC in a single center. We evaluated prognostic factors associated with over-all survival (OS) according to the time of initial radioactive iodine therapy (RAIT). Median age of 93 patients (Male = 30 and F = 63) was 55.4 years and 55 patients (59%) had papillary thyroid cancer. Forty five patients (59%) were dead during median 7.6 years follow-up. Patients who diagnosed bone metastasis before initial RAIT (n = 32) had significantly poor OS (HR 1.86, 95% CI 1.02 - 3.39, p = 0.04). There was no significant difference in OS according to the RAI-avidity after initial RAIT in all study subjects ( p = 0.18). However, RAI-avid bone metastases had better OS in patients who confirmed bone metastases before initial RAIT (HR 0.27, 95% CI 0.10 - 0.76, p = 0.01). In patients who detected bone metastasis after initial RAIT, older age ( > 45 years), elevated serum thyroglobulin level ( > 250 ng/ml), and presence of skeletal related events (SRE) were significantly associated with poor OS. RAI avidity was not significant prognostic factor in these patients. Bone metastases detected before initial RAIT was important prognostic factor for patients with bone metastasis from DTC. RAI avidity after initial RAIT was good prognostic indicator only in patients who detected bone metastases before initial RAIT.

Poster 640 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM DIET AND THE RISK OF THYROID CANCER: RESULTS FROM A LARGE, PROSPECTIVE COHORT M. Singer1, M. Diaz-Insua2, S. Chang1 1 Otolaryngology - Head & Neck Surgery, Henry Ford Health System, West Bloomfield, MI; 2Urology, Henry Ford Health System, Detroit, MI Certain factors, such as a history of radiation exposure or a family history, are associated with an increased risk of developing thyroid carcinoma. The possible role of dietary habits in this disease is less well understood. In an effort to better assess this relationship data from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was analyzed. We evaluated the association between dietary patterns and the consumption of micronutrients, vitamins, isoflavones, iodine-rich and soy-rich foods with thyroid cancer risk in participants in the PLCO trial. The PLCO study is a randomized, controlled trial designed to determine whether certain screening exams reduce mortality from prostate, lung, colorectal and ovarian cancer. Participants provide extensive data on lifestyle, including on dietary patterns. Development of thyroid cancer during the course of the trial was also recorded. Data was collected between November 1993 and December 2009. Data from 61,223 participants (30,812 men and 30,411 women) age 50 years or older was analyzed. Among this cohort, 90 cases of thyroid cancer (30 men, 60 women) were diagnosed. Adherence or nonadherence to the USDA Food Guide, DASH Eating Plan or a Mediterranean diet was not associated with an altered risk of developing thyroid cancer. Of specific dietary components, only the consumption levels of the isoflavone formononetin, mostly derived from legumes, differed between cases and control, with less consumption (.014 mg/day vs. .011 mg/ day) associated with the development of thyroid cancer (p = 0.004). While some trends were present no significant associations were identified with dietary patterns or the consumption of specific foods,

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nutrients, or vitamins and the development of thyroid cancer in this large, prospective database. Based on this study, there is no clear evidence to implicate dietary habits as a possible risk factor for thyroid cancer.

Poster 641 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM STUDY ON SURGERY ADAPTATION OF ASYMPTOMATIC SMALL PAPILLARY THYROID CANCER - CONSIDERATION FROM EPIDEMIOLOGICAL POINT OF VIEW K. Takebe Takebe Breast & Thyroid Care Clinic, Takamatsu, Japan Surgical cases of papillary thyroid cancer have increased in many countries recently. The main factor is that the ultrasound examination device is widely spread. Improved image quality is also a factor. We studied the operation adaptation of asymptomatic small thyroid cancer detected by ultrasound examination or other modalities. From 1990 to 1995, we presented the results of our ultrasound screening for thyroid cancer in Kagawa Prefecture, Japan (1 million people). The subjects were 11,189 women with no neck symptoms. They were examined using a surface ultrasonic apparatus. After detecting abnormalities, fine needle aspiration cytology was carried out. If the patient were diagnosed with cancer, a lobectomy was performed with a side neck lymph node dissection. 140 cases of thyroid cancer were detected in this screening. The histological type of all detected cancer was papillary carcinoma. The detection rate of tumors with diameters of 3mm or more was 3.6%; 10mm or more was 0.88%; 15mm in the tumor diameter was 0.27%. Lymph node metastasis was observed 33% in tumors sized 3*9mm, 56% in tumors sized 10*14mm, and 94% in tumors sized 15mm or more. If we enforce the thyroid cancer screening by ultrasound examination, the detection rate of thyroid cancer of 3mm is 3.6%, the detection rate of 10mm or more is 0.88%. In these cases, surgery in unnecessary and clearly overtreatment. We inferred that small papillary thyroid cancer is passed without problems accompanied by lymph node metastasis. The detection rate for tumors sized 15mm or more is 0.27%. A significantly reduced rate of 0.88 % for detected tumors of more than 10mm was observed. Currently surgery is recommended for tumors sized 10mm or more, but we propose that surgery start at 15mm. The annual number of deaths from thyroid cancer in Kagawa Prefecture over the past ten years is approximately five. Therefore, even by starting at the 15mm tumor-size range, there is still a possibility of unnecessary surgery and overtreatment. The detection of thyroid cancer through aggressive use of ultrasound is not recommended. Surgical indications of subclinical thyroid cancer should be determined with restraint. Asymptomatic small papillary carcinoma should be regarded as innocent.

Poster 642 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM COMPARISON OF TRANSAXILLARY APPROACH, RETROAURICULAR APPROACH, AND CONVENTIONAL OPEN HEMITHYROIDECTOMY: A PROSPECTIVE STUDY AT SINGLE INSTITUTION D. Lee, K. Lee, W. Han, K. Oh, J. Cho, S. Baek, S. Kwon, J. Woo, K. Jung Department of Otorhinolaryngology-Head and Neck Surgery, Korea University, College of Medicine, Seoul, Korea (the Republic of) The aims of this study were to evaluate and compare the surgical outcomes and postoperative subjective functional parameters of

transaxillary (TA) and retroauricular (RA) approach thyroidectomy with conventional hemithyroidectomy. From May 2011 through December 2013, 153 patients who underwent hemithyroidectomy were prospectively categorised in to three groups according to the surgical approach (TA, RA, and conventional groups). All patients underwent prospective acoustic and functional evaluations using a comprehensive battery of functional assessments preoperatively and 1 week, 1 month, 3 months, 6 months, and 12 months postoperatively. Age at diagnosis was significantly lower in TA (n = 50) and RA groups (n = 42) than in the conventional group (n = 61) (P < 0$001). The frequency of vocal cord paralysis, inadvertently excised parathyroid, and hematoma did not differ among the groups (P = 0$447, 0$519, and 0$069, respectively). Three months postoperatively, maximal vocal pitch was significantly higher in the RA group than in the conventional and TA groups (P = 0$021). Although overall pain score was not different, dysphagia handicap index of the RA group 1 month postoperatively was significantly higher (P < 0$001) than in other groups. Chest paresthesia was significantly more severe in the TA group, especially at 3 months postoperatively (P = 0$035). The cosmetic satisfaction score in RA and TA groups than conventional group (P = 0$001 and 0$035, respectively) 3 and 6 months postoperatively. Both TA and RA hemithyroidectomy were followed by excellent surgical outcomes, especially for cosmesis. Delayed recovery of swallowing in RA and chest paresthesia in TA may be their weaknesses.

Poster 643 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM THE PREDICTIVE VALUE OF SALIVARY SCINTIGRAPHY FOR XEROSTOMIA FOLLOWING I-131 ABLATION IN THYROID CANCER PATIENTS J. Oh, E. Choi, I. Yoo, J. Ryu, Y. Chung

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Nuclear medicine, Incheon St.Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea (the Republic of) To investigate of the predictive value of pre-ablation salivary scintigraphy for xerostomia after I-131 ablation in thyroid cancer patients. Thirty consecutive post-thyroidectomy patients (male:female = 8:22, mean age 52.1 yrs) for thyroid cancer were included in this prospective study and underwent salivary scintigraphy between Aug 2015 and June 2015 before I-131 ablation. Six months after I-131 ablation, the symptoms of xerostomia were evaluated with questionnaires. The preablation salivary scans were correlated with clinical outcome of postablation xerostomia. Sixteen patients (53.3%) showed abnormal scintigraphic finding and 14 (46.7%) had normal scan. The patterns of abnormal findings were decreased excretion function (n = 12) and impaired uptake and excretory function (n = 4). Of 30 patients, 16 patients (53.3 %) presented xerostomia after I-131 ablation. The mean duration between ablation and onset of symptoms was 3.8 months. Of 16 patients, 12 patients had abnormal scan (12/16 = 75%) and 4 (4/16 = 25%) had normal scan. Patients with abnormal scan finding had significantly higher frequency of post-ablation xerostomia in comparison with those with normal scan (p = 0.026, RR = 2.63, 95% CI: 1.09–6.3). Pre-ablation salivary scan may provide predictive information for post-ablation xerostomia.

Poster 644 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM PREFERENCE ANALYSIS FOR THE DIAGNOSIS AND MANAGEMENT OF THYROID MICROCARCINOMA IN GENERAL POPULATION USING AN ONLINE QUESTIONNAIRE IN KOREA J. Park2, J. Yoo1 1 Department of Information and Communication Engineering, Chungbuk National University, Cheongju, Korea (the Republic of); 2 Department of surgery, college of medicine, College of Medicine, Chungbuk national University, Cheongju, Korea (the Republic of) The incidence of papillary thyroid microcarcinoma (PTMC) has been rapidly increased during past 15 years in Korea. All patients who were diagnosed as PTMCs have undergone thyroidectomies with a few exceptions. As many reports have recently shown an excellent long-term prognosis of PTMC, an optimal timing for diagnosis and management of PTMC has become the subjects for much controversy in Korea. Patients’ right to know their disease status and decide treatments is getting more important. That is why Korean thyroid association and Korean association of endocrine surgeons are revising guidelines. The aim of present study is to analyze people’s preference in Korea for the diagnosis and management of thyroid microcarcinoma using an online questionnaire. The questionnaire consists of 3 questions about preference for the diagnosis and management of PTMC and additional 3 questions about respondents’ personal information. An online survey has conducted from March 3rd to June 3rd in 2015. A total 2,308 persons (1246 males, 1053 females) answered questionnaire. Number of respondents is 8 in 2nd, 1487 in 3rd, 321 in 4th, 255 in 5th, 197 in 6th, and 34 in 7th decade, respectively. If there is a thyroid nodule measuring less than 1 cm in diameter and suspicious for PTMC, 95.7% of respondents want to know a cytologic diagnosis for it. If a thyroid nodule turns out to be a PTMC, 59.5% of respondents want to remove it immediately. For the surgical management of PTMC, 53.0% of respondents are worried more about recurrences than complications which may follow wider surgical extents. In subgroup analyses, respondents who are younger than 40 year-old more often want to remove PTMC immediately than others:

66.7% vs 32.7% (p < 0.05). Respondents who underwent thyroid surgery for cancer (n = 91) are worried more about recurrences than others: 69.2% vs 52.4% (p < 0.05). In conclusion, most of respondents in present study want to diagnose suspicious thyroid nodules immediately. However, there are opposing opinions about the optimal timing for surgical treatment and surgical extents. In the revised guidelines for PTMC in Korea, a patient’s right to know their disease status and decide treatments should be emphasized all the more.

Poster 645 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM PROPOSAL OF A NEW STAGING SYSTEM AND TREATMENT ALGORITHM FOR ANAPLASTIC THYROID CANCER BY INDUCTION WEEKLY PACLITAXEL T. Uruno, Y. Ogimi, F. Saito, C. Masaki, J. Akaishi, C. Tomoda, K. Matsuzu, A. Suzuki, K. Ohkuwa, H. Shibuya, W. Kitagawa, M. Nagahama, K. Sugino, K. Ito Department of Surgery, Ito Hospital, Tokyo, Japan Anaplastic thyroid cancer (ATC) has the worst prognosis of any cancer. Cause-specific survival rates (CSS) differ significantly by UICC stage, with 6-month CSSs of 60% for stage IVA, 45% for IVB, and 19% for IVC in Japan. While ATC often arises from dedifferentiation of differentiated thyroid cancer (DTC), even patients with ATC with coexisting distant metastases from DTC are classified as stage IVC. Because distant metastases from DTC are usually slow-glowing and do not affect the clinical course or outcome of patients with ATC, separating these patients from IVC seems reasonable. The present study proposes a new staging system, and introduces our treatment algorithm and outcomes using induction weekly paclitaxel (PTX, 80 mg/m2). Between 1993 and 2014, a total of 142 patients were classified based on our ATC staging system and evaluated for treatment outcomes. Our ATC staging system makes reference to the extent of ATC lesions alone, regardless of DTC metastasis (Table). With cases since 2009, we have used weekly paclitaxel as the initial treatment for all patients, regardless of ATC staging. After 4-8 administrations of PTX, surgery was considered for patients with stage A or B disease. After surgery, additional PTX (total, 12-16 administrations) followed by neck radiation (Rx, 40–60 Gy) was performed. The 6-month and 1-, 2- and 5-year CSS rates were 100%, 68.6%, 51.4%, and 25.7% for ATC stage A, 62.1%, 36.0%, 22.5%, and 15.0% for B0, 35.2%, 24.0%, 8.0%, and 8.0% for B1, and 11.5%, 1.9%, 0%, and 0% for C, respectively. In stage A (n = 7), all patients underwent curative surgery. PTX significantly prolonged CSS (p = 0.049). In stage B (B0 + B1, n = 79), Rx significantly prolonged CSS (odds ratio (OR), 0.25; 95% confidence interval (CI), 0.14-0.44; p < 0.001), while curative surgery (p = 0.22) and PTX (p = 0.069) did not. However, induction PTX resulted in a high rate of curative surgery (16/19 cases, 84.2%), which would also have contributed to longer CSS. In stage C (n = 56), both PTX (OR, 0.43; 95%CI, 0.20–

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0.85; p = 0.014) and Rx (OR, 0.45; 95%CI, 0.24–0.84; p = 0.012) correlated significantly with longer CSS. Our ATC staging system is useful to predict the CSS of patients with ATC. PTX improves CSS in patients with ATC.

Poster 646 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM ROUTINE SERUM CALCITONIN MEASUREMENT IN THYROID NODULAR DISEASE IN A SERIES OF 724 PATIENTS S.T. Bostico1, M. Storani1,2, F. Subies2, M. Musich1 1 Endocrinology, CMLibertador, Martinez, Argentina; 2Endocrinology, Hospital Central San Isidro, San Isidro, Argentina Medullary thyroid carcinoma (MTC) accounts for 4 to 10% of malignant thyroid tumors. Sporadic MTC occurs in 75% and 25% is inherited. The survival rate is 40 to 75% at 10 yr. Early diagnosis and radical surgical treatment are crucial to improve the prognosis of the disease. Serum Calcitonin (CT) is the most specific and sensitive marker of MTC with better accuracy than cytology, but its routine measure is still under discussion because of its cost-benefit and the hypercalcitoninemia, not MTC. Objective: Early diagnosis of MTC by routine measurement of serum CT in thyroid nodular disease. Serum CT was measured in 724 patients with thyroid nodular disease: 632 women (mean 55yr) and 92 men (mean 57yr). Thyroid ultrasound, measurement of TSH, Ft4, TT4, thyroid antibodies and CT by immunochemiluminescense were performed. Fine needle aspiration (FNA) was done in palpable nodules, greater than 10 mm or with sonographic suspicious features. In patients with elevated basal CT, measurement Calcitonin in washout of FNA (WO-CT) was done. Surgery was recommended when citology was malignant, suspicious of malignancy and for clinical criteria. Hypercalcitoninemia was considered with two dosages with values > 12 ng/ ml in women and > 18ng/ ml in men. When positive, genetic study of the RET proto-oncogene was requested. In two patients hypercalcitoninemia was detected. In both, the WO-CT was > 36ng/ml and MTC was confirmed by histology (Stage I and III). The genetic study was positive in one patient (Exon 14Val804Met- Familial MTC). In the other patient polymorphisms (Exon 13 and exon 15, L769L and S904S, heterozygous) was detected. In both cases Calcitonin has remained normal since surgery. The results of this study confirm that screening thyroid nodules with serum CT measurement allowed the diagnosis of MTC at least in one patient, at stage I. The prevalence of MTC was of 0.3%. WOCT was very useful to confirm the diagnosis. RET positive finding in a patient with MTC permitted us to evaluate his family. The presurgical diagnosis allowed us to determine the surgical technique, which is a crucial decision for improving the prognosis of the disease.

General Hospital, Boston, MA; 4Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; 5Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH; 6Kolling Institute of Medical Research, University of Sydney, St. Leonards, NSW, Australia; 7Eisai Inc., Woodcliff Lake, NJ; 8Division of Endocrinology and Metabolism, Harbor-UCLA Medical Center, Torrance, CA; 9Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX Lenvatinib (LEN) is approved for radioiodine-refractory differentiated thyroid cancer based on the phase 3 SELECT trial. Nearly all patients (pts) had an adverse event (AEs, LEN vs placebo, respectively: any-grade, 100% vs 90%; grade 3, 72% vs 22%; grade 4, 12% vs 8%). We have previously reported an analysis of hypertension, management, and correlations with efficacy. Here we examine the 5 other most common LEN-emergent AEs in SELECT. Pts received LEN (24 mg/d; 28-d cycle) or placebo. AEs were reported per Common Terminology Criteria for Adverse Events v4.0. Univariate analyses were performed for progression-free survival (PFS) and overall survival (OS); variables with P < 0.2 were included in a multivariate analysis with baseline characteristics (Eastern Cooperative Oncology Group [ECOG] status, prior VEGF-targeted therapy, weight, age, region, and histology). Among the most common LEN-emergent AEs (Table), there were no grade 4 events. Generally, AEs, while significant, occurred early in the course of treatment and were resolved (Table). Active management of these AEs (if any) was primarily with dose modifications. Treatment discontinuation due to AEs also occurred in 2 (1%) pts with proteinuria and 4 (2%) pts with fatigue. Multivariate analyses showed no significant associations between these 5 AEs and PFS. In a multivariate analysis, ECOG status (P = 0.001), histology (favoring follicular vs papillary, P = 0.002), and any-grade diarrhea (P = 0.023) were found to be significantly associated with OS (median OS for LEN-treated pts with diarrhea: not reached; without: 17.1 months). In SELECT, LEN-emergent AEs typically occurred early during the course of treatment, and were primarily managed with dose modifications. A significant association between OS and diarrhea was found.

Poster 647 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM INCIDENCE AND TIMING OF COMMON ADVERSE EVENTS IN LENVATINIB-TREATED PATIENTS WITH RADIOIODINE-REFRACTORY THYROID CANCER FROM THE SELECT TRIAL R. Haddad1, M. Schlumberger2, L. Wirth3, E. Sherman4, M.H. Shah5, B. Robinson6, C. Ductus7, A. Teng7, A. Gianoukakis8, S.I. SHERMAN9 1 Head and Neck Oncology Program, Harvard Medical School, Dana Farber Cancer Institute, Boston, MA; 2Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and University Paris-Sud, Paris, France; 3Department of Medicine, Massachusetts

Poster 648 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM CAN PREOPERATIVE THYROGLOBULIN ANTIBODY LEVELS PREDICT DISEASE PROGRESSION IN DIFFERENTIATED THYROID CANCER? K. Jo, M. Kim, J. Ha, D. Lim Division of Endocrinology & Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea (the Republic of) The relation between differentiated thyroid cancer (DTC) and Hashimoto’s thyroiditis is widely recognized, but there is a lack of

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understanding about meaning of preoperative high thyroglobulin antibody(TgAb) in thyroid cancer patients. To uncover this issue, we examined a large series of DTC patients with or without TgAb. The aims of our study are to find out any correlation between preoperative serum TgAb level and prognosis in differentiated thyroid cancer patient and further validate the significance of that relationship. This retrospective hospital-cohort study enrolled consecutive 952 DTC patients with preoperative TgAb data. All the patients had undergone total thyroidectomy from Jan. 2006 to Aug. 2011 with or without radioiodine ablation(RAI). The clinical parameters included patient demographics, primary tumor characteristics, radioiodine therapy, thyroid function test, preoperative thyroglobulin, thyroglobulin antibody levels, and cancer recurrence. The mean follow-up period were 51.0 – 13.2 months (range, 36*101months) 198 patients were preoperative TgAb positive(TgAb + , TgAb ‡ 70IU/mL). TgAb positive group had significantly higher rate of RAI (92.6% vs 84.6%, p 0.003), lymphatic invasion(34.3% vs 25.7%, p 0.010). Also TgAb positive patients more likely to have recurrence during follow-up, but not significantly different (5.1% vs 3.7% p 0.240). Relapse free survival was longer in TgAb + group, but no statistically significant. (15.3 vs 14.5 months, p 0.65). When comparing only in patients undergone RAI, there was no significant difference in recurrence rates. And there was TPO Antibody (TPOAb) data from 853 patients, presence of TPOAb did not affect the prognosis. The results suggest that preoperative TgAb-positive patients with DTC were no significant differences from negative patients. But TgAb status at diagnosis point could reflect risk of patients.

Poster 649 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM DIASTOLIC DYSFUNCTION IS COMMON IN LONG-TERM SURVIVORS OF PEDIATRIC DIFFERENTIATED THYROID CARCINOMA M.S. Klein Hesselink1, G. Bocca2, Y.M. Hummel3, A.H. Brouwers4, J.G. Burgerhof5, E.W. van Dam6, B. Havekes7, M.M. van den Heuvel-Eibrink8, E.P. Corssmit9, L.C. Kremer10, R.T. NeteaMaier11, H.J. van der Pal10,12, R. Peeters13,14, J.T. Plukker15, C.M. Ronckers10, H.M. van Santen16, P. van der Meer3, T. Links1, W.J. Tissing17 1 Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; 2Pediatric Endocrinology, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Groniningen, Netherlands; 3Cardiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; 4Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; 5Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; 6 Internal Medicine, VU University Medical Center, Amsterdam, Netherlands; 7Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, Maastricht, Netherlands; 8Pediatric Oncology, Sophia Children’s Hospital, Erasmus Medical Center, Rotterdam, Netherlands; 9Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, Netherlands; 10Pediatric Oncology, Emma Children’s Hospital, Academic Medical Center, Amsterdam, Netherlands; 11Endocrinology, Radboud University Medical Center, Nijmegen, Netherlands; 12Medical Oncology, Academic Medical Center, Amsterdam, Netherlands; 13 Endocrinology, Erasmus Medical Center, Rotterdam, Netherlands; 14 Rotterdam Thyroid Center, Erasmus Medical Center, Rotterdam, Netherlands; 15Surgical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands;

16

Pediatrics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, Netherlands; 17Pediatric Oncology, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Groningen, Netherlands Long-term exogenous subclinical hyperthyroidism has been associated with diastolic dysfunction in adult survivors of differentiated thyroid carcinoma (DTC). The presence of cardiac abnormalities in survivors of pediatric DTC has not been assessed yet. Our objective was to study the prevalence of systolic and diastolic dysfunction in survivors of pediatric DTC in relation to the level of thyroid-stimulating hormone (TSH; also known as thyrotropin) suppression during follow-up. In this multicenter study, cardiac assessments were carried out in more than 5-year survivors of pediatric DTC (age at diagnosis £ 18 years) treated in the Netherlands between 1970 and 2009. Using echocardiography, systolic (left ventricular ejection fraction, LVEF) and diastolic (early diastolic tissue velocities, e’) functions were evaluated. Diastolic dysfunction was defined as septal and/or lateral e’ less than 2 SD of the mean of age-adjusted reference data. Images were stored for central analysis. All TSH levels during follow-up were collected from medical records. Multivariate linear regression analysis was performed to explore the association between diastolic function, expressed as the mean of septal and lateral e’, and geometric mean TSH level. Sixty-six DTC survivors (86.4% women) were included. Median follow-up time was 16.7 (interquartile range 8.3–25.2) years. LVEF < 50% was found in 1 survivor, whereas diastolic dysfunction was present in 14 survivors (21.2%). At evaluation, survivors with diastolic dysfunction were older (median 37.9 vs. 28.3 years, p = 0.013), had a higher body mass index (median 26.3 vs. 23.8 kg/m2, p = 0.022) and a higher diastolic blood pressure (median 79 vs. 73 mmHg, p = 0.010) than survivors with normal diastolic function. Other risk factors did not differ between both groups. TSH level during followup was not associated with diastolic function. Diastolic dysfunction is frequently observed in asymptomatic long-term survivors of pediatric DTC. However, no association with TSH level during follow-up was found. More research is needed to reveal the clinical implications of our findings.

Poster 650 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM PEDIATRIC DIFFERENTIATED THYROID CARCINOMA IN THE NETHERLANDS: A NATIONWIDE FOLLOW-UP STUDY M.S. Klein Hesselink1, M. Nies1, G. Bocca2, A.H. Brouwers3, J.G. Burgerhof4, E.W. van Dam5, B. Havekes6, M.M. van den Heuvel-Eibrink7, E.P. Corssmit8, L.C. Kremer9, R.T. Netea-Maier10, H.J. van der Pal9,11, R. Peeters12,13, K.W. Schmid14, J.T. Plukker15, C.M. Ronckers9, H.M. van Santen16, W.J. Tissing17, T. Links1 1 Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; 2Pediatric Endocrinology, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; 3Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; 4Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; 5Internal Medicine, VU University Medical Center, Amsterdam, Netherlands; 6Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, Maastricht, Netherlands; 7Pediatric Oncology, Sophia Children’s Hospital, Erasmus Medical Center, Rotterdam, Netherlands; 8 Internal Medicine, Division of Endocrinology, Leiden University

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 Medical Center, Groningen, Netherlands; 9Pediatric Oncology, Emma Children’s Hospital, Academic Medical Center, Amsterdam, Netherlands; 10Endocrinology, Radboud University Medical Center, Nijmegen, Netherlands; 11Medical Oncology, Academic Medical Center, Amsterdam, Netherlands; 12Endocrinology, Erasmus Medical Center, Rotterdam, Netherlands; 13Rotterdam Thyroid Center, Erasmus Medical Center, Rotterdam, Netherlands; 14Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 15Surgical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; 16 Pediatrics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, Netherlands; 17Pediatric Oncology, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Groningen, Netherlands Treatment for differentiated thyroid carcinoma (DTC) in pediatric patients is mainly based on evidence from adult series due to lack of data from pediatric cohorts. Our objective was to evaluate the presentation, complications, and long-term outcome in patients with pediatric DTC in the Netherlands. In this nationwide study, presentation, treatment-related complications and outcome of patients with pediatric DTC (age at diagnosis £ 18 years) treated in the Netherlands between 1970 and 2013 were assessed from medical records. One hundred seventy patients were identified. Overall survival was 99.4% after median follow-up of 13.5 (range 0.3–44.7) years. Extensive follow-up data were available of 105 patients (83.8% women), treated in 39 hospitals. Papillary and follicular thyroid carcinomas were diagnosed in 81.0% and 19.0%, respectively. Median age at diagnosis was 15.6 (range 5.8–18.9) years. At initial diagnosis, 43.8% of the patients had histologically confirmed cervical lymph node metastases; 13.3% had distant metastases. All patients underwent total thyroidectomy, 43.8% combined with lymph node dissection as part of initial treatment. Radioiodine was administered to 97.1% of the patients, with a median cumulative activity of 5.66 (range 0.74–35.15) GBq. Postoperative transient and permanent hypoparathyroidism were observed in 15.2% and 23.8% of the patients, respectively, and recurrent laryngeal nerve injury in 12.4%. At last known follow-up, 8.6% of the patients had persistent disease and 7.6% had a recurrence. TSH (also known as thyrotropin) suppression was not associated with recurrent disease (OR 2.00, 95% CI 0.78 to 5.17, p = 0.152). Survival of pediatric DTC is excellent. Therefore, minimizing treatment-related morbidity has a major priority. However, our study shows a frequent occurrence of postoperative complications after treatment for pediatric DTC. In this cohort, a large number of centers provided care for a small number of patients. As surgical complications may be reduced by centralization of care, this seems warranted for pediatric patients with DTC. Data on late effects of treatment on bone, salivary glands and quality of life in this patient group will be presented in the near future.

Poster 651 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM STIMULATED THYROGLOBULIN (TG) MEASURED BEFORE OR AFTER RADIOIODINE THERAPY HAS A CLINICAL IMPACT ON THE MANAGEMENT OF PATIENTS WITH DIFFERENCIATED THYROID CARCINOMA M. bauriaud, S. Brillouet, L. Dierickx, D. Vallot, O. Caselles, F. Courbon, Z. Slimane Radiopharmacie, institut universitaire du cancer, Toulouse, France Stimulated thyroglobulin (Tg) with administration of recombinant human thyrotropin (rh-TSH) during ablation with iodine-131 is the

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most important tumor marker in the monitoring of patients with differentiated thyroid carcinoma (DTC). Tg should be measured the third day after the second injection of rh-TSH, but to avoid the postponed due to iodine-131, Tg is often measured the day after the second injection of rh-TSH before the ablation. There is no evidence that Tg measured three days after radioiodine therapy is a more sensitive marker than the Tg measured before the administration of iodine-131. The objective of this prospective study was to evaluate the clinical impact in the choice of one of these two Tg for the follow up of these patients. This study included 140 patients with differentiated thyroid carcinoma (DTC) who underwent thyroidectomy with apparently total tumor resection. All patients had Tg measurement before radioiodine therapy (Tg1), 3 days after the last injection of rh-TSH (Tg2) and one year after ablation (Tg3). All serum Tg were measured using the same sensitive IRMA assay standardized on the European reference standard (CRM 457). ROC curve is a function of both the sensitivity and specificity and take into account the entire range of error rates. Area under the ROC curve summary measure of the accuracy. Sensitivity and specificity were evaluated with the use of the optimal threshold value calculated to maximize the Youden’s index. This index is defined as the sum of sensitivity and specificity minus one. The cut-off obtains using the youden index were respectively 2.55 for Tg1 and 3.65 for Tg2. In the two cases, the area under the curve was estimated to 0.66. After backwared selection, only Tg1 remain significant (OR = 3, 8 95%CI = [1, 7; 8;47] p < 0.001). Tg stimulated with rh-TSH measured before radioiodine therapy seems to be the most sensitive marker to predict the recurrence of DTC in patients.

Poster 652 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM COMPARISON BETWEEN THREE SERUM CALCITONIN ASSAYS: GOOD CORRELATION AND AGREEMENT IN BOTH HEALTHY CONTROLS AND IN PATIENTS WITH MEDULLARY THYROID CARCINOMA C.P. Camacho, T. Alves, T. Kasamatsu, J.H. YANG, S.C. Lindsey, F.D. Valente, G.K. Furuzawa, R.M. Maciel, J.R. Martins, J.G. Vieira Medicine, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil The recent ATA revised guidelines for medullary thyroid carcinoma (MTC) use high and low values of serum calcitonin (sCT) as critical points to modify the management of patients. The aim of this study is to verify if three calcitonin assays have equivalence for use in daily practice. We analyzed the sCT measurements on healthy subjects, negative or positive RET mutation relatives and MTC patients. The study was approved by the internal review board, and all participants signed the informed consent. The clinical and laboratory data were used in the analysis. We compare the Elecsys Calcitonin (ROCHE, USA), Diagnostic Products Corporation (DPC) Calcitonin and an immunofluorometric assay (IFMA). The IFMA assay has a sensitivity of 1.0 pg/ml, an intra-assay coefficient of variation of 2.1–6.4% and an inter-assay coefficient of variation of 7.1–9.4%. First, the Elecsys sCT was compared with DPC sCT in a set of individuals. After that, the Elecsys was compared with IFMA. The data was log transformed before the analysis. We used Pearson’s correlation and Bland-Altman plot. A p < 0.05 was considered significant. We included 59 samples in the first group (Elecsys against DPC) and 124 in the second group (Elecsys against IFMA). The correlation found was r = 0.97 (p < 0,01) in the first group (Figure 1A) and r = 0.95 (p < 0,01) on the second group (Figure 1B). The plot analysis revealed a high level of agreement for all assays with the disagreement appearing for sCT levels above 10,000.00 pg/mL.

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All three assays available in our institution have a high level of correlation and agreement and might be used for the clinical decision based on the guidelines reference points.

Poster 653 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM USEFULNESS OF ROUTINE MEASUREMENT OF BASAL SERUM CALCITONIN IN NODULAR THYROID DISEASE FOR THE DETECTION OF MEDULLARY THYROID CARCINOMA A.C. Cavallo1, P. Brenzoni2, S. Iorcansky3, M. Lencioni4, A. San Roman4, J. Guerrieri5, D. Chazarreta2, M. Rojas2, P. Saco6, M. Negueruela1 1 Endocrinologia, Hospital Universitario Austral, Buenos Aires, Argentina; 2Laboratory of Endocrinology - HUA, Pilar, Argentina; 3 Private Practice, Buenos Aires, Argentina; 4Department of PathologyHUA, Pilar, Argentina; 5Imaging Diagnostic Department-HUA, Pilar, Argentina; 6Surgery Department, Pilar, Argentina The routine measurement of serum calcitonin (sCT) to detect unsuspected medullary thyroid carcinoma (MTC) in patients with nodular thyroid disease (NTD) is controversial. Objectives: The purpose of the present study was to retrospectively assess the prevalence of hypercalcitoninemia and MTC in a cohort of NTD patients,

as well as to compare the ability of sCT measurement with ultrasonography (US) and fine needle aspiration cytology (FNAC) to predict MTC. We also aimed at studying the correlation between the levels of sCT with autoimmune thyroid disease. sCT levels were measured on basal conditions in 1608 consecutive patients (p), referred from March 2009 to December 2014 to the Hospital Universitario Austral (HUA) Endocrinology Service due to NTD.They also underwent thyroid-stimulating hormone (TSH), total thyroxin (TT4), free thyroxin (FT4), thyroperoxidase antibodies (TPO-Ab), thyroglobulin antibodies (Tg-Ab), US and FNAC tests. Based on clinical findings, 265 p were submitted to surgery. MTC was identified in 9 cases. According to the method reference values (M: up to 18 pg/ml; F: up to 12 pg/ml), hypercalcitoninemia was found in 15 of 1608 p (0.9%), 8 of them were diagnosed MTC. One MTC p had sCT less than the immunoassay limit of quantitation. Considering the adopted 27.4 pg/ml of sCT level as a cut-off (ROC analysis: area under curve of 0.933; IC 95% 0.799-1.00), sensitivity, specificity, positive and negative predicted values of basal CT to predict MTC were 88.9%, 99.9%, 80% and 99%, respectively. Only in 4 patients a correct diagnosis was obtained by FNAC in US high-risk nodules. As an additional finding, hypercalcitoninemia was not associated with autoimmune thyroid disease (independent samples t-test, p = 0,965) The prevalence of MTC was 6 per thousand in our population. Basal sCT measurement could represent a useful tool in evaluation of NTD patients, and the cut-off of 27.4 pg/ml has high sensitivity and specificity for MTC diagnosis. Finally, we did not find any significant correlation between hypercalcitoninemia and humoral and/or tissular autoimmune disease.

Poster 654 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM FALSE POSITIVE 131I WHOLE BODY SCAN IN DIFFERENTIATED THYROID CANCER A.C. Cavallo, M. Corino, V. Ilera, A. zunino, C. Cabezon

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 Thyroid Department of the Argentine Society of Endocrinology, Buenos Aires, Argentina Radioiodine whole body scan (WBS) with 131I is performed on patients with differentiated thyroid carcinoma (DTC). False-positive scans are infrequent, but may result in wrong diagnosis and lead to unnecessary therapeutic. Objective: To describe false positive findings on WBS in DTC patients and their final etiologies. Methods: Retrospective recruitment of 22 patients (p) from 10 institutions. Clinical characteristics of the population and diagnostic procedures performed are described. Statistics are evaluated with SPSS 20 22 p, 19 (86.4%) women, years 48.5 – 17.12 SD. Histological diagnosis included 17 classic papillary thyroid cancer, 1 follicular variant, 1 classic and follicular variant, 1 tall cell and 2 follicular thyroid cancer.13 patients were TNM stage I, 4 stage II, 4 stage III and 1 stage IVb. 59% of abnormal uptakes were detected after the ablative dose, median Tg 3.1 ng/ml. 31.8% were detected after subsequent therapeutic doses, median Tg 0.8 ng/ml and 9% after diagnostic WBS, median Tg 0.55 ng/ml. Final diagnosis included 5 granulomas, 3 bronchiectasias, 3 thymus, 2 tuberculomas, 2 dental disease, 2 inflammatory articulation processes, 1 laryngocele, 1 angiolipoma, 1 osseous xanthoma, 1 lung fibroma, 1 chondroma. 15 p required additional diagnostic-image techniques, 5 p needed biopsy. 2 p underwent surgery and 7 received additional radioiodine treatment. Median follow up was 73 – 48 months. At the end of the follow up 19 patients have no evidence of disease, 2 have biochemical persistence and one persistence structural. False positive WBS uptakes were detected in 13 different anatomical localizations. 91% were found with doses greater than or equal to 100 mci, and only 9% after diagnostic doses of 5 mci. Multiple diagnostic procedures were needed in order to confirm the etiology. 45.5% of the patients underwent additional therapeutic doses or surgical procedures. Inappropriate Tg values for the presence of metastases should guide the suspicion of false positives. It is imperative to acknowledge its existence to avoid unnecessary interventions.

Poster 655 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM TALL CELL VARIANT VS. CLASSICAL FORM OF PAPILLARY THYROID CARCINOMA: FACTORS RELATED TO PERSISTENCE OF DISEASE AND SURVIVAL D.E. Zantut-Wittmann, T.G. Melo, E. Ficher, L.V. Assumpc¸a˜o Endocrinology Division, Internal Medicine Department, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil Tall cell variant (TCV) of papillary thyroid cancer (PTC) is considered more aggressive variant in comparison with classical form (ClPTC), associated to less favorable survival rates and less probability of cure. Our aim was to analyze tumor characteristics, factors related to persistence of disease and survival in patients with ClPTC and TCV in one single reference center. PTC patients followed from 1981 until 2013 in a thyroid cancer reference center were included. Age at diagnosis, gender, features of tumor pathology and cancer staging according to TNM system were registered. We verified differences between evolution of ClPTC and TCV, also identifying risk factors for persistence of disease and survival curve. From 745 PTC patients followed, 265 were ClPTC (35.6%), 70 TCV (9.4%), but only 52 of these were included. The median follow up time was 84 months. TCV patients were older at diagnosis (53.5 years-old vs. 40.1 years-old, p < 0.0001), presented bigger sized tumor nodules (3.1cm vs. 2.0cm, p < 0.0001), more frequently with

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vascular and lymphatic invasion (41.2% vs. 13.7%, p < 0.0001), extra thyroid invasion (78.4% vs.14.1%, p < 0.0001) and pT4 on TNM (44.2% vs. 4.2%, p < 0.0001), with higher rate of persistence of disease (32.7% vs. 17.7%, p = 0.013). Multivariate analysis evidenced as risk factors for persistence of disease: bigger tumor nodule size (hazard ratio,HR 1.265, CI 1.094–1.462), capsule invasion (HR 1.755, Cl 1.020–3.022), extra thyroid invasion (HR 2.442, Cl 1.453– 4.104) and cervical lymph nodes metastasis (HR 1.982, CL 1.136– 3.457). Kaplan-Meyer curves showed that five-year disease-specific survival was 83.9% (Cl 95% 0.735–0.957) and ten-year was 67.6% (Cl 95% 0.535–0.852) for TCV compared to five-year 93% (Cl 95% 0.898–0.964) and ten-year disease-specific survival 79.8% (Cl 95% 0.736–0.864) for ClPTC (HR 2.146, Cl 1.225–3.762, p = 0.0076). Patients with TCV demonstrated higher rate of persistence of disease, however, the specific histology subtype was not a risk factor in this. In contrast, histopathological features indicating more aggressive tumor, regardless of being TCV or ClPTC, were related to persistence of disease. The survival disease-specific was higher in ClPTC than TCV.

Poster 656 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM SYSTEMIC SCLEROSIS ASSOCIATED WITH AUTOIMMUNE THYROIDITIS: AN INCREASED RISK OF PAPILLARY THYROID CANCER P. Fallahi1, S. Ferrari1, G. Elia1, F. Ragusa1, D. Giuggioli2, P. Miccoli3, C. Ferri2, A. Antonelli1 1 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 2Department of Medical, Surgical, Maternal, Pediatric and Adult Sciences, University of Modena & Reggio Emilia, Modena, Italy; 3Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy An increased risk of malignancy has been shown in patients with Systemic Sclerosis (SSc) with respect to the general population. So far, no study has evaluated the risk to develop thyroid cancer (TC) in SSc patients. We evaluated the prevalence of TC in 327 unselected SSc patients compared to 2 population-based, gender- and age-matched control groups: 1) 654 subjects from an iodine deficient area; 2) 654 subjects from an iodine sufficient area. Thyroid status was assessed measuring circulating thyroid hormones and autoantibodies, thyroid ultrasonography and fine-needle aspiration citology (if necessary). In SSc patients, significantly high levels (P < 0.01) of thyroid stimulating hormone, anti-thyroglobulin and anti-thyroperoxidase antibodies, and the prevalence of hypothyroidism, have been shown. Six patients with papillary thyroid cancer (PTC) were detected among SSc patients, whereas only one case was observed both in control 1 and control 2 (P = 0.003, for both). In SSc all patients with TC had evidence of thyroid autoimmunity vs. 40% of the other SSc patients (P = 0.001). This study suggests a high prevalence of PTC in SSc patients, particularly in the presence of thyroid autoimmunity; therefore, a careful thyroid monitoring is opportune during the follow-up of these patients.

Poster 657 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM SERUM TSH LEVELS AS A PREDICTOR OF MALIGNANCY IN THYROID NODULES: RESULTS OF A PROSPECTIVE STUDY L. Golbert3,4, A.P. de Cristo4, C.S. Faccin1, H.F. Goldstein2, M.S. Graudenz2, A.L. Maia4

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1

Radiology, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil; 2Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 3Internal Medicine, Endocrinology, Universidade Federal de Ciencias da Saude de Porto Alegre, Porto Alegre, Brazil; 4Endocrinology, Thyroid Unit, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil We aimed to evaluate the role of serum TSH levels as a predictor of malignancy in patients with thyroid nodules. Patients with thyroid nodule(s) who underwent Fine Needle Aspiration Biopsy under Ultrasonography guidance (US-FNAB) between 2012 and 2014 at the Thyroid Unit, Hospital de Clı´nicas de Porto Alegre were prospectively evaluated. Patients with known thyroid cancer and/or on thyroid medication were excluded. Cytology findings were classified according to Bethesda System for Reporting Thyroid Cytopathology. Cell block specimens of FNBA were use as adjunctive diagnostic method and the results were described as cytology and cell block grouped. Anatomopathological data of surgical specimen was used as the gold standard for analysis. Four-houndred-and-three consecutive patients were evaluated. The mean of age was 56.7 – 13.95 yrs and 358 (88.8%) were females. Median TSH value was 1.50lU/mL (quartiles 0.01–0.93, 0.94–1.49, 1.50–2.28 and 2.29 above). The cytological and cell block diagnostic were categorized as nondiagnostic (I, 5.2%), benign (II, 72.7 %), indeterminate (III, 8.2%), follicular lesion (IV, 6.7%) and malignant (V/VI, 7.2%). Final histological data was available for 90 (22.3%) patients, and was benign in 64 (71.1%) and malignant in 26 (28.9%). Patients with malignancy presented higher basal TSH levels (2.24 vs. 1.60; P = 0.04). Moreover, when TSH levels were analyzed as a categorical variable, a significantly increase of risk was observed for those patients with TSH concentrations in the higher quartile, as compared with those with TSH below £ 2.28 lU/mL (OR, 4.45 95%,CI1.61-12.32, P = 0,004). Further analysis using binary logistic regression identified elevated TSH levels and presence of microcalcifications on US as the only predictor risk factors for malignancy in thyroid nodules. Higher serum TSH levels in patients with thyroid nodules are associated with increased risk of malignancy. Further studies are warrant to determine the impact of the use of TSH as an adjunctive diagnostic test of thyroid nodule stratification risk.

Poster 658 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM TENTATIVE TREATMENT OUTCOMES FOR RADIOACTIVE IODINE-REFRACTORY DIFFERENTIATED THYROID CANCER (RAI-RDTC) PATIENTS RECEIVING SORAFENIB OR LENVATINIB H. Iwasaki1, H. Nakayama2, N. Suganuma1, T. Yoshida1, H. Okamoto1, T. Yamanaka1, I. Kojima1, S. Shimizu1 1 Breast and endocrine surgery, Kanagawa Cancer Center, Yokohama, Japan; 2Surgery, Yokohama City University, Yokohama, Japan The availability of Tyrosin-kinase inhibitor (TKI) that can stabilize progressive metastatic disease has changed the standard approach to treating patients with thyroid cancer. In Japan, two TKI drugs with an approved indication for radioiodine resistant metastatic thyroid cancer are sorafenib (marketed as Nexavar) which received approval in July 2014, and lenvatinib (marketed as Lenvima), in May 2015. Seventeen patients (ten women, seven men) met indication criteria, with a median age of 66.1yr (range, 53–79 yr). Sixteen patients had papillary and one had follicular thyroid carcinoma. All patients had evidence of progressive disease (PD) before start of therapy. They were treated with single agent sorafenib or lenvatinib, and had

both baseline and at least one follow-up scan for restaging purposes. All imaging data were collected, as well as the serum thyroglobulin (Tg) levels. 12 patients with RAI-rDTC receiving sorafenib 5 patients with RAI-rDTC received lenvatinib, including two patient who failed prior sorafenib therapy because of grade 3 side effect. It is too early to evaluate the progression assessment, because these TKI drugs were approved within only one year in Japan. Nevertheless, as a tentative treatment outcomes, we report that the response in target lesions was not evaluable (NE) in 15 (88%), stable disease (SD) in two (12%), and no PD. Serum Tg levels were decreased in six out of 10 patients who were negative in TgAb. Although 88% of patients temporarily suffered with various side effects, six patients expirenced improving QOL, and three patients notified reducing pain of metastatic nodes. At this point, it is hard to say that sorafenib and lenvatinib appear to be effective in patients with widely metastatic, progressive DTC, with most patients remaining NE or SD. The most noticeable response occurred in the nodal metastases was reducing pain. By the meeing, we like to make it clear whether a patient no longer responds to first-line therapy with sorafenib in particular has the chances that a second-line lenvatinib can improve outcomes because these drugs tend to have similar mechanisms of action.

Poster 659 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM MUCOEPIDERMOID CARCINOMA OF THE THYROID - A CASE REPORT M.G. Rodrigues5, L. Matos Lima1, G. Fonseca2, C. Eloy3,4 1 Surgery, Hospital CUFF, Porto, Portugal; 2Radiotherapy, Hospital CUFF, Porto, Portugal; 3Pathology, Hospital CUF, Porto, Portugal; 4 IPATIMUP, Porto, Portugal; 5Endocrinology, Hospital CUF, Porto, Portugal Mucoepidermoid carcinoma of the thyroid (TMEC) is a rare clinical and pathological entity with about forty documented cases in the literature. A 33 year old male presented for investigation of enlarged cervical right lymph nodes. An open biopsy performed at another institution disclosed metastasis of papillary thyroid carcinoma (PTC) in all five lymph nodes examined. He underwent total thyroidectomy with central and lateral neck lymph node dissection levels III/IV. The histology showed a 0.5 cm classic PTC on the right lobe, with lymphatic invasion, no extrathyroidal extension and metastases in thirteen out of nineteen lymph nodes. He was treated with RAI ablation and levothyroxine therapy. Six months after surgery a neck ultrasound demonstrated 2 suspicious lymph nodes with microcalcifications. FNAB confirmed PTC metastasis. He underwent a selective right level II/III plus a redo of VI/VII levels. In level II/III, a single 1.7cm metastasis was observed in one out of fifteen lymph nodes and, in level VI/VII, a single lymph node with a 1.6 cm metastasis that extended beyond the lymph node was observed. Both metastases had carcinoma morphology with squamous differentiation and very focally papillary architecture with psamomatous bodies. The carcinoma cells expressed TTF-1 and p63. Thyroglobulin expression was not detected. The diagnosis of the primary thyroid tumour was reviewed and confirmed the diagnosis of a low grade TMEC with the same immunohistochemical profile. A FDGPET scan was negative and ear, nose and throat examination excluded the possibility of a primary neoplasm in salivary glands and other localization. The patient’s post surgical plan was to include external beam irradiation and levothyroxin supression therapy. Given the rarity of this location primary TMEC is a challenging diagnosis with a broad differential of benign and malignant entities. Although TMEC have been characterized as usually indolent low

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grade tumors they can exhibit a locally aggressive behavior with regional lymph node involvement as this case illustrates.

Poster 660 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM INCIDENTAL VS NON INCIDENTAL PAPILLARY THYROID MICROCARCINOMA (PTMC) M.G. Rodrigues1,2, L. Matos Lima3, T. Pimenta3, D. Carvalho1,2, J. Medina2, M. Sobrinho Simo˜es2,4 1 Endocrinology, Centro Hospitalar Sa˜o Joa˜o, Porto, Portugal; 2Faculty of Medicine of Porto University, Porto, Portugal; 3Surgery, Centro Hospitalar Sa˜o Joa˜o, Porto, Portugal; 4IPATIMUP, Porto, Portugal The incidence of PTMC defined by WHO as papillary thyroid cancer of 10 mm or less in largest dimension has increased exponentially in the last two decades. Clinical significance has been a matter of debate and there is controversy as wether PTMC represents more than one disease entity with different outcomes. The objective of this study was to describe and compare histological and clinical characteristics, outcomes and factors associated with prognosis of incidental and non incidental PTMC. Retrospective analysis of clinical and pathological data of all patients operated on for thyroid cancer at our institution between 1996 and 2013. We defined incidental PTMC as those found in patients operated on for nodular goiter, Graves’ disease or toxic adenoma and nonincidental PTMC as those found in patients with a FNAB diagnostic or suspicious of malignancy. Statistical analysis was performed with SPSS 22.0 for MAC. During this period, 2532 patients were diagnosed and treated for thyroid cancer at our institution and among these 1045 (41,3%) had PTMC (919 females, 126 males, mean age of 54.6 – 14.2 and 52.1 – 13.9 y respectively). These included 794 patients with Incidental PTMC (I) and 236 with NonIncidental PTMC (NI). When comparing them according to gender, age at diagnosis ( < 45 or > / = 45 years), tumour diameter, coexistence of Hashimoto’s thyroiditis, mutifocality/multicentricity, vascular invasion, extrathyroidal extension and initial lymph node involvement we found significant differences in tumour size (3.7 – 2.8mm in I vs 7.3 – 2,4mm in NI), vascular invasion (2.5% in I vs 9.8% in NI), extrathyroidal extension (3.3% in I vs 17% in NI), multifocality (26,6% in I vs 37% in NI)] and lymph node metastases (0.3% in I vs 6% in NI) Overall 70% of patients underwent total thyroidectomy and RAI was administered to 15,2% (7,1% patients in I vs 36,5% in NI). Overal recurrence was 0.8% in I versus 2.9 % in NI. No mortality was observed. This series confirms that PTMC is a prevalent condition and that there are at least two distinct clinical entities of PTMC. Incidental PTMC has different clinical characteristics and a lower recurrence rate than non incidental PTMC.

Poster 661 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM SKELETAL METASTASES ONLY FROM DIFFERENTIATED THYROID CANCER HAS BETTER SURVIVAL OUTCOME THAN MULTIORGAN METASTASES S. Ballal, M.P. Yadav, C. Bal Nuclear medicine, All India Institute of Medical Sciences, New Delhi, India The presence of skeletal metastasis from differentiated thyroid cancer (DTC), as per ATA risk stratification, is associated with worst prognosis. The present study aimed to critically evaluate the con-

Kaplan-Meier Analysis shows Event-Free Survival Curves between Gr1 (n = 67) and Gr2 (n = 308) tribution of skeletal metastases only to those who have skeletal metastases plus other organ metastases at the time of presentation. A total of 456 patients were treated from Jan 1977 to Dec 2013 for distant metastases from DTC. Patients with less than 12 months follow-up, aggressive histological variants were excluded from the study and finally only 379 {FCT:60%, PCT:40%; M: 116 (30.6%), F: 259 (68.4%) age range :21–82 years} patients fulfilled the inclusion/ exclusion criteria. Total thyroidectomy was done in 202/379 (53.2%) patients and the remaining 177/379 (46.8%) patients had inadequate surgery. Radioiodine therapy ranging from 100-200 mCi at an interval every 6–12 months were administered until the complete disappearance of disease or administration of maximum cumulative dose of 1800 mCi. The patients were divided in to two groups: Gr1, 67/379 (17.6%) had skeletal metastases only and Gr2 308/379 (82.4%) had neck/lungs/other metastases along with skeletal metastases. Event was defined as documented recurrence or disease progression or death due to DTC. Univariate analysis using Chi square or Fisher’s exact tests and Kaplan-Meier analysis for event-free survival and overall survival were used. Log-rank tests were used for calculating p values. In Gr1, 10 (15%) were stage II and 57 (85%) in stage IVC. In Gr2, 67 (21.7%) were in stage II and 242 (78.3%) in IVC. Interestingly, 12/67 (18%) from Gr1 and 33/308 (82%) patients from Gr2 achieved complete remission. Patients with stage II disease between Gr1 and Gr2 the mortality rate was 0% and 26.4% (p = 0.000). None of other parameters shows statistical significance. The mean follow up duration was 112.8 – 45 months. On Kaplan-Meier analysis, the median event-free survival of Gr1 was 168 months Vs 96 months in Gr2 (p = 0.01) (see Image1). Similarly the median overall survival of Gr1 was 168 months Vs 108 months in Gr2 (p = 0.03). Patients with skeletal metastases only from DTC are observed to have better outcome compared to multiple organ metastases.

Poster 662 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM REGIONAL RECURRENCE IN PATIENTS WITH FOLLICULAR OR Hu¨RTHLE CELL NEOPLASIA H. Besic, N. Besic, A. Vogrin Institute of Oncology, Ljubljana, Slovenia Preoperative neck ultrasound (US) for central and lateral neck compartments is recommended for all patients undergoing

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thyroidectomy for malignant or suspicious for malignancy cytologic or molecular findings. Our aim was to find out how frequent is regional recurrence in patients with follicular or Hu¨rthle cell neoplasia and if preoperative neck US should be performed also in patients with follicular or Hu¨rthle cell neoplasia. Altogether 737 patients were surgically treated because of follicular (N = 428) or Hu¨rthle cell (N = 309) neoplasia from 1995 to 2014 at our cancer comprehensive center. Altogether 207 patients (163 females, 44 males; mean age 52 years, range 12–84 years) had thyroid carcinoma in a dominant nodule. Data about recurrence in regional lymph nodes were collected. Mean size of carcinoma was 3.46 cm. Microcarcinoma in a dominant nodule was diagnosed in only 8.2% of patients. Follicular variant of papillary thyroid carcinoma, Hu¨rthle cell carcinoma, follicular carcinoma, classical type of papillary carcinoma and other types of papillary carcinoma were diagnosed in 90 cases, 50, 39, 21 and 7 cases, respectively. Carcinoma was diagnosed in follicular and Hu¨rthle cell neoplasm in 143/428 and 64/309 cases, respectively. Regional recurrence occurred in 12/207 patients (6%) during median follow-up of 55 months (range 6–180 months). Regional recurrence was diagnosed in 1/90 patients with follicular variant of papillary thyroid carcinoma, 8/50 cases of Hu¨rthle cell carcinoma, 2/39 cases of follicular carcinoma and 1/21 patients with classical type of papillary carcinoma. Among patients with carcinoma a recurrence was diagnosed in follicular and Hu¨rthle cell neoplasms in 2% and 14%, respectively (p = 0.002). Recurrence in regional lymph nodes was diagnosed in 3/428 (0.7%) of all patients with follicular neoplasm and 9/309 (3%) of all patients with Hu¨rthle cell neoplasm. Regional recurrence is extremely rare in patients with follicular neoplasm, while patients with Hu¨rthle cell neoplasm have regional recurrence in 3%.

Poster 663 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM LOCOREGIONAL DISEASE CONTROL AFTER EXTERNAL BEAM RADIOTHERAPY IN 63 PATIENTS WITH PT4 TUMOR STAGE OF DIFFERENTIATED THYROID CARCINOMA - A SINGLE INSTITUTION EXPERIENCE N. Besic, G. Vivod, M. Domjan, M. Dremelj Institute of Oncology, Ljubljana, Slovenia Locoregional recurrence is common in patients with locally advanced differentiated thyroid carcinoma (DTC). Our aim was to find out the rate of locoregional control of disease after external beam radiotherapy (EBRT) of the neck and mediastinum in patients with DTC and pT4 tumor. Altogether 63 patients (33 males, 30 females, median age 60 years) with DTC had EBRT of the neck and mediastinum as part of multimodal treatment of pT4 tumor (35 cases pT4a, 28 cases pT4b) from year 1973 to 2010. Data on clinical factors, histopathology, recurrence, disease-free and disease-specific survival were collected. Median tumor size was 6 cm (range 2–30 cm). Of 63 patients, 21 had distant and 27 regional metastases. A total or near-total thyroidectomy, lobectomy, subtotal thyroidectomy and lymph node dissection was performed in 62%, 22%, 3% and 24% of cases, respectively. 13% of patients were not treated with surgery. All patients had EBRT and 34 had chemotherapy. Radioiodine (RAI) ablation of thyroid remnant and RAI therapy was done in 82% and 51% of cases, respectively. Follicular, papillary and Hu¨rthle cell carcinoma was diagnosed in 27, 25 and 11 cases, respectively. Median survival of follicular, papillary and Hu¨rthle cell carcinoma

was 62, 240 and 131 months, respectively. The follow-up period was 6 to 253 (median 75) months. Recurrence was diagnosed in 24 of 38 patients without persistent disease: locoregional and distant in 15 and 9 cases, respectively. The 5-year and 10-year disease-free survival was 59% and 41%, respectively. Locoregional control of disease after five and ten years was present in 67% and 45%, respectively. By the end of the study, 22 patients were still alive (10 had no evidence of disease, 12 were alive with disease), 3 were lost to follow-up, 30 patients died of thyroid carcinoma (26 of distant metastases, 1 of locoregional disease and 3 of locoregional disease and distant metastases), while 8 died of causes unrelated to primary disease. Majority of patients with DTC and pT4 tumors who were treated with EBRT of the neck and mediastinum region as part of multimodal treatment have long-lasting locoregional control of disease.

Poster 664 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM OUR EXPERIENCE IN SERUM CALCITONIN BEFORE THYROID SURGERY A. Reyes1, A. zunino1, V. Garcı´a Roel1, V. Ilera1, F. Viale1, A. Dios1, G. Olstein2, A. Colobraro3, A. Lowenstein1, M. Silva Croome1, A. Gauna1 1 Endocrinologı´a, Hospital Ramos Mejia, Caba, Argentina; 2Cirugı´a, Hospital Ramos Mejı´a, Caba, Argentina; 3Anatomı´a Patolo´gica, Hospital Ramos Mejı´a, Caba, Argentina Medullary thyroid carcinoma (MTC) is an infrequent disorder, comprising less than 4% of all thyroid cancers. About 0.3% of cases are diagnosed postoperatively (occult MTC). Fine needle aspiration biopsy has low sensitivity for diagnosis. There is still no consensus regarding routine measurement of serum calcitonin (CT) in the initial evaluation of thyroid nodules. Objectives: 1) To asses CT in all patients undergoing thyroidectomy; 2) To correlate these results with anatomopathologic findings; 3) To determine the utility of CT for the detection of occult MTC. Methods: 154 consecutive patients undergoing thyroidectomy; 14 were excluded, leaving 139 for final analysis. Indications for surgery were as follows: nodular thyroid disease Bethesda categories IV, V and VI, large goiter with compressive symptoms, nodular goiter associated with primary hyperparathyroidism. Exclusion criteria: preoperatively diagnosed MTC, family history of MTC. Factors known to cause elevation of CT such as drugs, hyperparathyroidism or chronic autoimmune thyroiditis were considered. Serum CT was measured by inmunochemiluminiescent Inmulite 2000 (analitic sensibility 2 pg/ml). Reference values: men: ND-8.4 pg/ml, women: ND-5 pg/ml. Statistics analysis: SPSS program. Fischer exact test. Results: All CT were in the normal range. 116/139 patients (83.4%) presented undetectable CT levels < 2 pg/ml. In 16.5% (23/ 139) of the cases, CT was detectable, with a maximum level of 8.5 pg/ml. Ninety percent of women (113/126) and 23% of men (3/ 13) presented CT levels under 2 p/ml (p < 0.0001). No cases of occult MTC were found. Anatomopathologic findings included 54 cases of chronic autoimmune thyroiditis/lymphocytic infiltrates (as primary or associated diagnosis), 6 of which had detectable CT levels; and 6 parathyroid adenomas, 2 with detectable CT levels. Conclusions: 1) In 139 patients submitted to thyroid surgery, no cases of occult MTC or false positive results of CT levels were found. 2) Gender male was associated with higher CT levels, as described in the literature. 3) 83.5% of the patients had undetectable CT values. 4) In chronic autoimmune thyroiditis or parathyroid adenoma, low or undetectable levels of CT were also observed.

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Poster 665 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM PERI-OPERATIVE PRACTICES IN THYROID SURGERY: AN INTERNATIONAL SURVEY A. Maniakas2, A. Christopoulos2, E. Bissada2, L. Guertin2, M. Olivier2, J. Malaise1, A. Boucher3, G. Rondeau3, T. Ayad2 1 Endocrine & Transplant surgery, Centre Hospitalier de l’Universite´ de Montre´al - CHUM, Montreal, QC, Canada; 2OtolaryngologyHead & Neck Surgery, Centre Hospitalier de l’Universite´ de Montre´al - CHUM, Montreal, QC, Canada; 3Endocrinology, Centre Hospitalier de l’Universite´ de Montre´al - CHUM, Montreal, QC, Canada Thyroid surgery for thyroid disease is one of the most commonly performed surgical procedures in the world. Peri-operative practices can however vary from one specialty, institution or country to the next. Our objectives were thus to evaluate the pre, intra and postoperative practices of thyroid surgeons focusing primarily on: 1) preoperative imaging, 2) minimally invasive procedures, 3) the use of sentinel lymph node biopsies, and 4) postoperative hospitalisation duration, amongst others. A cross-sectional survey analysis was performed by sending a short online survey to six medical associations between September and December 2014: the Quebec Association of Surgery, Quebec Association of Otolaryngology-Head & Neck Surgery, Canadian Society of Otolaryngology-Head & Neck Surgery, European Head & Neck Society, Asian Society of Head & Neck Oncology, and the International Association of Endocrine Surgery. There was a strong overall response rate of 25% (655 respondents) from 49 different countries, which increased to 30% when looking solely at Canadian respondents. The overall completion rate was of 94%. Fifty nine percent of respondents said they work in academic institutions and 58% were Otolaryngology-Head & Neck Surgeons, while the remaining were General or Endocrine Surgeons. Fifty percent of European respondents, regardless of their specialty, reported that they perform cervical ultrasounds themselves preoperatively. Minimally invasive procedures are rarely performed and respondents from Asia are the ones who perform them most commonly (15% of Asian respondents). Sentinel lymph node biopsy is performed by only 3% of respondents. Day-surgery for thyroid surgery is an attractive avenue for health care systems as it can significantly decrease costs associated to the procedure. Canadian otolaryngologists are the ones who most frequently perform daysurgery for thyroid surgery (34%). Peri-operative practices in thyroid surgery can vary significantly depending on the surgeon’s specialty and/or geographic location. This epidemiologic study is the first global survey of its kind and clearly demonstrates this variability, while allowing the thyroid surgeon to compare his practice to the current international trends.

Poster 666 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM EXTERNAL RADIATION DOSE COULD BE REDUCED BY THE USE OF RECOMBINANT HUMAN TSH IN DIFFERENTIATED THYROID CANCER PATIENTS WITH HIGH DOSE OF I-131 ABLATION THERAPY S. Kwon1, J. Kim2, S. Jeon1, J. Min1, H. Song2, H. Bom1 1 Chonnam National University Hwasun Hospital, Hwasun, Korea (the Republic of); 2Chonnam National University Hospital, Gwangju, Korea (the Republic of)

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We investigated whether the use of recombinant human TSH (rhTSH) could reduce external radiation dose after high dose of I-131 ablation therapy (IAT) in patients with differentiated thyroid cancer. We enrolled 602 patients who underwent total or subtotal thyroidectomy and 1st IAT with 3.70 GBq (100 mCi) or 6.66 GBq (180 mCi). The dose rate (lSv/hr) was measured at 1 meter from the surface of the patient before release. The dose rate was measured 48 hours (422 patients) or 72 hours (180 patients) after the administration of I-131, respectively. Patients were classified into two groups: thyroid hormone withdrawal (group 1) and the use of rhTSH (group 2). We compared the mean value of dose rate between two groups for each time interval or each IAT dose. In patients with 3.70 GBq of IAT (170 patients), the dose rate of group 2 was significantly lower than that of group 1, irrespective of time interval (48 hours: 8.04 – 5.39 lSv/hr vs. 12.22 – 6.28 lSv/hr, P < 0.001; 72 hours: 2.51 – 2.06 lSv/hr vs. 4.04 – 2.62 lSv/hr, P = 0.018). In patients with 6.66 GBq of IAT (432 patients), the dose rate of group 2 was also significantly lower than that of group 1, irrespective of time interval (48 hours: 12.54 – 7.29 lSv/hr vs. 17.66 – 8.89 lSv/hr, P < 0.001; 72 hours: 3.84 – 3.25 lSv/hr vs. 7.54 – 5.14 lSv/hr, P < 0.001). The external radiation dose was significantly reduced in patients with the use of rhTSH. Although all patients showed the dose rate below release criteria (70 lSv/hr), this study could have a potential for the optimization of radiation safety control for patients, caregivers and the general public.

Poster 667 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM INCIDENCE OF THYROID CANCER IN POST-TRANSPLANT PATIENTS IN KOREA; AN INSTITUTIONAL REVIEW H. Kwon1, J. Yi1, H. Yu1, R. Song1, Y. Chai2, S. Kim1, J. Choi3, K. Lee1 1 Surgery, Seoul National University Hospital, Seoul, Korea (the Republic of); 2Surgery, Seoul National University Boramae Hospital, Seoul, Korea (the Republic of); 3Surgery, Seoul National University Bundang Hospital, Seongnam, Korea (the Republic of) The incidence of thyroid cancer in the post-transplant recipients is 7fold higher than the general population. However, some recent studies suggest that the incidence is much smaller than the previous reports. Therefore, we conducted a retrospective cohort study to determine the incidence and the standardized incidence ratio (SIR) for thyroid cancer among the kidney and liver transplant recipients. A total of 3,036 patients received transplantation in the Seoul National University between January 1972 and August 2013. After excluding 13 patients who had undergone thyroidectomy prior to transplantation, the study was conducted on 3,021 patients (1,732

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kidney and 1,289 liver) to determine the incidence and SIR of thyroid cancer for graft recipients. Twenty three patients were diagnosed with thyroid cancer with a mean follow up period of 7.6 years. The cumulative incidences were 0.46% at 5 years, 0.63% at 15 years, and 0.73% at 25 years. The overall SIR of thyroid cancer was 2.22, and male recipients showed the 5.83-fold increased risk for thyroid cancer (Table 1). Although the SIR of female patients was 1.74, no statistically significant difference between the transplant recipients and the general population was observed. The type of the organ transplanted did not influence the SIR (p = 0.261). The increased risk of thyroid cancer in post-transplant recipients is observed only in men compared to the general population. Further study is needed to elucidate the gender difference in the post-transplant thyroid cancer incidence for an appropriate management of high-risk patients.

Poster 668 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM ULTRASOUND-GUIDED PERCUTANEOUS ETHANOL ABLATION FOR SELECTED PATIENTS WITH SMALL INTRA-THYROIDAL PRIMARY (CT1N0) PAPILLARY CANCERS: AN EFFECTIVE ALTERNATIVE TO NECK SURGERY OR OBSERVATION I. Hay1, R. Lee2, J. Morris1, M. Stan1, V. Fatourechi1, G. Thompson3, C.C. Reading2 1 Endocrinology, Mayo Clinic, Rochester, MN; 2Radiology, Mayo Clinic, Rochester, MN; 3Surgery, Mayo Clinic, Rochester, MN Small intra-thyroidal (cT1N0) papillary cancers (SIPC) now represent, globally, the commonest endocrine malignancy. Current management options range from lobectomy or near-total thyroidectomy to ‘‘active surveillance’’. An alternative approach, used successfully for eliminating neck nodal metastases ( JCEM 96: 2717, 2011), is ultrasound-guided percutaneous ethanol ablation (UPEA). Here we present our experience of treating with UPEA biopsy-proven tumor foci in 13 SIPC patients. Study patients (9F, 4M) were aged, at time of UPEA, 36–86 years (median 45 years); 5 had significant co-morbidities.Their 15 tumors (2 multicentric) varied from 4–13 mm diameter (median 8mm); tumor volumes ranged from 25–676 mm3 (median 140). UPEA technique and follow-up protocol details have been previously described (Surgery 154: 1448, 2013).The first patient had under ultrasound guidance a single injection of 0.2cc of 95% ethanol directly into his tumor focus. Subsequent patients had two injections on consecutive days; ethanol volume injected ranged from 0.45 to 1.25 cc (median 0.9 cc) 12/13 have been followed for at least 4 months and four (33%), with < 50% tumor shrinkage, had at first follow-up a 3rd injection. Neck ultrasound scans, performed at each visit, permitted recalculation of tumor volume and assessment of tumor-associated Doppler flow. 12/13 patients were followed for 0.3–4.4 years (mean 1.6 years). No episodes of painful thyroiditis, hoarseness or hypocalcemia occured after UPEA. All tumor foci have shrunk and Doppler flow eliminated. None have developed a neck nodal metastasis. Median tumor volume reduction was 76% (range 46–100%); 4/14 tumors (29%) were no longer identifiable after 0.7–2.2 years (mean 1.5 years). UPEA for SIPC (cT1N0) is well tolerated and in our institution is > $38,000 cheaper than surgery. Our results would sugest that, for SIPC patients who do not wish neck surgery and are uncomfortable with ‘‘active surveilance’’, UPEA likely represents an attractive and ‘‘minimally invasive’’ definitive management option.

Poster 669 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM CABOZANTINIB THERAPY IN MEDULLARY THYROID CARCINOMA PATIENTS OUTSIDE A CLINICAL TRIAL V. Tiedje3, L.D. Locati1, M. Kroiss2, K. Frank-Raue4, A. Garcia5, M. Kreissl6, M. Schott7, F. Orlandi8, S. Corvisieri8, D. Fu¨hrer3 1 Head and Neck Cancer Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 2University of Wu¨rzburg, Wu¨rzburg, Germany; 3University Hospital Essen, Essen, Germany; 4Endocrine Practice, Laboratory of Molecular Biology, Heidelberg, Germany; 5Hospital Universitario Marque´s de Valdecilla, Santander, Spain; 6Central Hospital of Augsburg, Augsburg, Germany; 7University Hospital Du¨sseldorf, Du¨sseldorf, Germany; 8 Studio Medico Endocrinologo, Torino, Italy Medullary thyroid carcinoma (MTC) is a rare thyroid cancer. The multi-tyrosine kinase inhibitor (TKI) cabozantinib was recently approved for treatment of progressive metastatic MTC. Treatment is challenging and must balance adverse events (AE) and tumor control. The aim is to describe the toxicity profile and efficacy of cabozantinib treatment given outside a trial throughout different countries in Europe. Retrospective analysis of MTC patients treated at 8 specialized centers in Germany, Italy and Spain was performed. Demographical patient data; type, number and efficacy of previous TKI-therapies; as cabozantinib efficacy and AE were assessed. The statistical analysis was performed with SPSS Version 21.0. Data of 15 patients with MTC (6 female) were evaluated. Median age at diagnosis was 47 years (18–62 years), a germline RET- (rearranged during transfection) mutation was known in 2 patients. The median time interval from primary diagnosis to diagnosis of metastatic disease was 2 months (range 0 to 300 months). In all patients, progression according to RECIST criteria 1.1 was diagnosed before initiation of cabozantinib therapy. Cabozantinib was given as second line TKI in 6, third line in 7 and fourth line in 2 patients. The initial cabozantinib dose range was 60 to 140 mg/d and median duration of treatment was 4,6 months (0,5–12 months). Four patients were still on treatment at the end of this study and seven patients were deceased. Grade 3 AE occurred in 6 patients. Dose reduction was necessary in 9 patients and 6 patients discontinued treatment due to AE. No grade 4 AE was reported. Best response was partial response (PR) in 4 patients. Stable disease (SD) was documented in 5 patients and progressive disease (PD) occurred in 6 patients. Median progression-free survival (PFS) was 140 days. There was no difference in PFS according to the number of previous TKI therapies. Cabozantinib resulted in objective response in more than half of MTC patients and response to therapy was independent of the number of previous TKI therapies. A significant proportion of patients discontinued treatment due to AE with likely impact on efficacy. Dose reductions were frequent and effective to manage side effects.

Poster 670 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM NUMBER-NEEDED-TO-TREAT (NNT) ANALYSIS OF THERAPIES IN RADIOIODINE-REFRACTORY DIFFERENTIATED THYROID CANCER (RR-DTC) USING INDIRECT COMPARISON G. Tremblay1, X. Li2, S. Abouzaid2,Corey Pelletier2 1 Global Health Economics and HTA, Eisai Inc., Woodcliff Lake, NJ; 2 Eisai Inc., Woodcliff Lake, NJ

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 Number-Needed-to-Treat (NNT) analyses are often used to present the comparative effectiveness of products in an intuitive format. The objective of this study was to assess the NNT for lenvatinib and sorafenib in the treatment of RR-DTC. The NNT analysis was run for each therapy against placebo at 24 months, using data from their respective trials (SELECT for lenvatinib and DECISION for sorafenib). As sorafenib progression-free survival (PFS) results at 24 months were not published, a coordinate extraction system was used to assess the PFS of sorafenib after 2 years of trial. In the absence of head-to-head trials comparing lenvatinib to sorafenib, an indirect analysis was performed to compare lenvatinib to sorafenib. NNT for PFS, overall survival (OS), and objective response rate (ORR) were assessed. A sensitivity scenario was presented where the lenvatinib SELECT trial data were corrected to match the baseline characteristics of the sorafenib DECISION trial using a matched indirect treatment comparison method. Against placebo, the NNT at 24 months for 1 patient to achieve PFS was 2.5 for lenvatinib and 10.9 for sorafenib; ORR was 1.6 for lenvatinib and 8.5 for sorafenib; and OS was 11.5 for lenvatinib and 41.7 for sorafenib. Using an indirect comparison vs sorafenib, the NNT at 24 months for 1 patient on lenvatinib to achieve PFS was 2.1, ORR was 3.9, and OS was 16.5. In the sensitivity scenario, the indirect NNT of lenvatinib or sorafenib was 21.1 for PFS and 3.4 for OS. The results suggest an advantage of lenvatinib vs sorafenib in achieving PFS, OS, and ORR in patients with RR-DTC.

Poster 672 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM RADIATION INDUCED THYROID CARCINOMA IS CLINICALLY DISTINCT FROM SPORADIC THYROID CANCER M. White1, N. Cipriani2, L. Abdulrasool1, S.P. Kaplan1, E.L. Kaplan1, P. Angelos1, R.H. Grogan1, K. Onel3 1 Department of Surgery, University of Chicago Medical Center, Chicago, IL; 2Pathology, University of Chicago, Pritzker School of Medicine, Chicago, IL; 3Pediatrics, University of Chicago, Pritzker School of Medicine, Chicago, IL Low-dose ionizing radiation ( < 20 Gy) is a well-described risk factor for thyroid carcinoma (TC). Here, we examine radiation exposure’s (RE) effect on long-term outcomes of TC when compared with sporadic TC by comparing long-term recurrence and survival by RE exposure. We hypothesize that sporadic TC is clinically distinct from TC caused by either low or high dose RE. We performed a retrospective review of patients treated for TC at our institution with a median follow up of 27 years. Patients were classified as having either sporadic, high-dose RE, or low-dose RE induced TC. Risk factors for recurrence and death were identified using Cox proportional hazards model and Kaplan-Meier curves. Risk factors measured included age at RE, dose of RE, indication for RE, and TC histology. Blinded retrospective review of histologic blocks was performed. Of 265 TC patients, 166 (63%) had no history of RE (sporadic), 93 (35%) had a history of low-dose RE, and 6 (3%) had a history of highdose RE. Gender was the only statistically significant difference between group demographics, surgical intervention, and stage (p = 0.04). When compared to sporadic TC, low-dose RE was associated with increased median overall survival, 43 years versus 38 years for sporadic (hazard ratio = 0.51, p < 0.01). High-dose RE did not show a statistically significant difference in overall median

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Kaplan-Meier Curves of Event Free Survival by radiation exposure. Event free survival is improved in the low-dose RE cohort when compared with the sporadic cohort (Hazard Ratio 0.67, p = 0.04) and was worse in the high-dose exposure cohort when compared with sporadic (Hazard Ratio 2.71, p = 0.02).

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survival, (23 years) compared to sporadic TC (hazard ratio = 2.33, p = 0.07). Event free survival was improved in the low-dose RE cohort compared with the sporadic cohort (hazard ratio = 0.67, p = 0.04) and was worse in the high-dose exposure cohort (hazard ratio = 2.71, p = 0.02). Recurrence in the low-dose RE group was equivalent to sporadic TC (hazard ratio = 0.87, p = 0.56) while rates of recurrence were higher in the high-dose RE group (hazard ratio = 2.80, p = 0.05). While RE was previously thought to cause a more aggressive variant of TC, this retrospective review demonstrates significant improvements in overall and event free survival in the low dose RE group and shorter event-free survival and time to recurrence in the high dose RE group. This suggests TC prognosis depends on the dose of radiation received.

Poster 673 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM CERVICAL LYMPH NODE THYROGLOBULIN ELEVATION FROM FINE NEEDLE ASPIRATES IS A HIGHLY SENSITIVE AND SPECIFIC MARKER OF PAPILLARY THYROID CANCER NODAL METASTASIS S. El-Kaissi Endocrinology, Cleveland Clinic Abu Dhabi, Al Maryah Island, United Arab Emirates To evaluate the utility of thyroglobulin measurement from fine needle aspirates (FNA) of cervical lymph nodes (CLN) in post-operative papillary thyroid cancer (PTC). Retrospective analysis of 41 patients (32F) with cervical lymphadenopathy post-total thyroidectomy and radioiodine ablation for PTC, who underwent CLN FNA biopsies and thyroglobulin measurement (FNA-Tg). FNA-Tg ‡ 10 mg/L was deemed elevated. The mean age of the patients was 37.3 years (range 18.4–80.6). Malignancy was detected in 16/41 patients based on an elevated FNA-Tg and/or cytological evidence of malignancy. The mean FNATg in malignant CLN was 14659 lg/L (range 5.3–81242) compared to 3.93 lg/L (range 1.00–6.42) in benign CLN. Of the 16 malignant CLN, cytology was reported as malignant in 11/16 cases, inadequate in 4/16 and benign in 1 patient. In contrast, FNA-Tg was elevated in 15/16 patients and < 10 mg/L in one patient who had strongly positive anti-thyroglobulin antibodies. Of the 6/16 cystic CLN with elevated FNA-Tg, cytology was benign in one case and inadequate in another. All 16 CLN were confirmed as malignant after surgical excision. On ultrasound, malignant CLN were more likely to be cuboidal, cystic and have abnormal vascularity on Doppler. Moreover, malignant CLN were found mostly in compartments IV and VI, whereas benign CLN were more evenly distributed. The mean short and long axes of malignant CLN were similar to those of the benign CLN. Only 1/16 patients with malignant CLN had increased uptake in the neck on a diagnostic whole body iodine scan.

An elevated CLN FNA-Tg appears to be at least as reliable as cytology in the detection of malignancy in post-surgical PTC patients, and may provide a higher diagnostic yield than cytology in cystic CLN.

Poster 674 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM THE INCIDENCE OF EXTRANODAL EXTENSION IN SIZE STRATIFIED PATHOLOGICALLY POSITIVE METASTATIC LYMPH NODES IN PATIENTS WITH THYROID CANCER M.E. Rowe1,6, E.H. Dewey1,6, I. Likhterov1, J. Hernandez-Prera5, A. Valentino5, B.M. Wenig4,3, M.L. Urken1,2 1 Otolaryngology, Mount Sinai Beth Israel, New York, NY; 2Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY; 3Pathology, Icahn School of Medicine at Mount Sinai, New York, NY; 4Pathology, Mount Sinai Beth Israel, New York, NY; 5 Pathology, Mount Sinai Hospital, New York, NY; 6THANC Foundation, New York, NY Extranodal extension (ENE) is an established prognostic indicator of a more virulent disease in thyroid cancer patients. A common presumption in the management of thyroid cancer is that small lymph node metastases do not carry suspicion of aggressive disease, and that ENE only occurs in lymph nodes that have reached a critical size. The current study aims to evaluate the incidence of ENE appearing in pathologically positive metastatic nodes based on the diameter of the node. Determining which patients are at a greater risk for an aggressive disease biology is important to aid clinicians in making decisions regarding extent of surgical and adjuvant treatment for individual patient management. Pathology was reviewed for 172 thyroid cancer patients with metastatic lymph nodes, operated on by a single surgeon from 2004 to 2015. Each of the 1126 individual positive lymph nodes from these patients was examined. Features evaluated included primary tumor histopathology, size of positive lymph nodes, size of metastatic focus in positive nodes, and number and size of lymph nodes demonstrating ENE. 173(15.4%) of the 1126 lymph nodes demonstrated ENE. Lymph nodes manifesting ENE ranged from 1.5 mm to 4.4 cm in size. ENE was evaluated in 8.9% of nodes £ 5mm in diameter,17.9% of nodes 6–10mm, 23.6% of nodes 11–15mm, 21.0% of nodes 16–20mm, and 23.5% of nodes > 20mm. Of all lymph nodes £ 10 mm in diameter, 12.7% (106 of 835 nodes) demonstrated ENE. Our results show that a significant percentage of small lymph nodes exhibit ENE, indicating that small lymph nodes should not be presumed innocent. ENE is associated with further lymph node metastasis, distant metastasis, biochemically incomplete response, and higher rates of disease-related death. To our knowledge, there are no studies that identify the incidence of ENE in pathologically positive nodes and thereby validate the presumption that small nodes are

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 not clinically significant. Further studies are important to determine the impact of nodal size with ENE on disease prognosis.

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Unlike papillary thyroid microcarcinoma, the clinical behavior of medullary thyroid carcinoma less than 1 cm in diameter (micro-MTC) is not clear because it is rarely detected. The clinical characteristics of preoperative calcitonin-negative ( < 10 pg/mL) MTC has been reported to be heterogeneous, but it was not evident in micro-MTC. Therefore, we conducted this study to evaluate the clinical feature and outcome of micro-MTC comparing to MTC > 1 cm (macro-MTC), and evaluate the clinical characteristics of calcitonin-negative micro-MTC. We reviewed the medical records of 133 patients with MTC who underwent total thyroidectomy with neck dissection in Samsung Medical Center from 1994 to 2014.Their median follow-up period was 55 (1–229) months. It was diagnosed incidentally after thyroidectomy for other reasons, during routine check-up, and during family screening for hereditary MTC. Among 133 MTC patients, 50 patients had micro-MTC. Their mean age was 48 years (15 men, 35 women). Their median tumor size was 0.7 cm, and preoperative calcitonin& CEA levels were lower than macro-MTC (median 52 vs. 854 pg/mL; 2.8 vs. 20.2 ng/mL, p < 0.001). Comparing to macro-MTC, the patients with micro-MTC had less frequent node metastasis (especially N1b), extrathyroidal invasion, and advanced stages (III/IV) (24% vs. 53%; 6% vs. 37%; 16% vs. 45%; p < 0.05). They had no distant metastasis (0% vs. 14.5%; p < 0.05). When micro-MTC patients were divided into three groups according to preoperative calcitonin levels; group 1 (1–10 pg/ mL, n = 7), group 2 (11–99 pg/mL, n = 24), and group 3 (100 pg/mL, n = 14), group 1 had smaller tumor size, less frequent node metastasis, and less frequent advanced stages (III/IV) than group 3 (median 0.5 vs. 0.8 cm; 14% vs. 57%; 14% vs. 36%, p < 0.05).). In conclusion, node metastasis, extrathyroidal invasion, and advanced stages were less common in micro-MTC than macro-MTC. Although clinical outcomes of micro-MTC seemed to be more favorable, long-term follow-up will be required. In micro-MTC, calcitonin levels were closely related to the high-risk clinicopathological factors. The results suggest that the calcitonin-negative micro-MTC maybe considered as the most favorable subset.

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Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM CLINICAL FEATURES OF MICRO-MEDULLARY THYROID CARCINOMA LESS THAN 1 CM IN DIAMETER J. Jang, Y. Cho, T. Kim, S. Kim, J. Chung Division of Endocrinology & Metabolism, Samsung Medical Center, Seongnam-si, Korea (the Republic of)

Poster 677 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM CAN A STIMULATED THYROGLOBULIN DETERMINE THE EXTENT OF TOTAL THYROIDECTOMY AND GUIDE USE OF RAI ABLATION? R. Caso Caso, J.B. Ogilvie, A. Kundel, K.N. Patel, K.S. Heller Department of Surgery, NYU Langone Medical Center, New York, NY Management of differentiated thyroid carcinoma (DTC) often entails total thyroidectomy (TT) and post-operative radioactive iodine (RAI) ablation. Total thyroidectomy eliminates multifocal disease, decreases the incidence of recurrence, and facilitates the use of RAI uptake (RAIU). This permits long-term follow-up with serum thyroglobulin (Tg). However, some clinicians believe that a true TT is not consistently achievable because postoperative RAI imaging often demonstrates residual thyroid tissue within the operative thyroid bed, thus necessitating RAI ablation. We utilized postoperative stimulated Tg (STG) and RAI imaging to determine the extent of TT in low-risk patients with DTC. We hypothesized that postoperative STG can be used as a surrogate for TT and allow for a more judicious use of postoperative RAI ablation. Postoperative STG and calculated RAIU were examined in 145 consecutive patients who underwent TT for DTC at one institution. Differences in proportions of patients were tested by means of the Pearson Chi Square test or Fisher exact test. An unpaired t test was used to compare continuous variables. P < .05 was considered statistically significant. Statistical analysis was carried out using SPSS Statistics (IBM Corp., Chicago, IL). For the entire study population, median follow-up time was 30.5 months. 972 patients underwent TT for DTC from 2007 to 2014 at NYU Langone Medical Center. 145 (15%) patients had postoperative STG (with negative anti-Tg antibodies) and RAIU recorded. 60 (41.4%) had STG < 1 ng/mL and 85 (58.6%) had STG ‡ 1 ng/mL. 50 (83.3%) patients with STG < 1 ng/mL and 40 (47.1%) patients with STG ‡ 1 ng/mL had a RAIU < 1% (P < .001). Furthermore, 38% of patients with a STG < 1 ng/mL had no measurable iodineavid thyroid tissue and/or tumor in the thyroid bed. At last follow-

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up, 56 (93.3%) patients with STG < 1 ng/mL and 66 (77.6%) patients with STG ‡ 1 ng/mL had an undetectable suppressed serum Tg (P < .001). A postoperative stimulated Tg < 1 ng/mL increases the likelihood of having a true TT with negative-remnant thyroid tissue and an undetectable suppressed serum Tg during follow-up. These findings suggest a more judicious use of postoperative RAI ablation in lowrisk DTC patients.

Poster 678 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM FACILITATING ANAPLASTIC THYROID CANCER SPECIALIZED TREATMENT (FAST): A MODEL FOR INCREASING ENROLLMENT TO ANAPLASTIC THYROID CANCER (ATC) CLINICAL TRIALS M. Cabanillas1, M.D. Williams3, B. Gunn2, S.P. Weitzman1, L. Burke4, N. Busaidy1, A. Ying1, W.N. William5, C. Lu5, S. Lai6 1 Department of Endocrine Neoplasia and HD, The University of Texas MD Anderson Cancer Center, Houston, TX; 2Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; 3Pathology, The University of Texas MD Anderson Cancer Center, Houstin, TX; 4Quality Measurement, The University of Texas MD Anderson Cancer Center, Houston, TX; 5Thoracic/ Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; 6Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX ATC is one of the rarest and deadliest cancers known to man. Exact incidence of ATC is unknown but estimated at *500-800 cases/yr in the U.S. Although several trials are available, the numbers of patients (pts) able to participate in them is very low. Thus, little progress has been made to improve treatment for ATC and no phase 2 trials, to date, have fully enrolled. Furthermore, pts are often unaware of trials or unable to participate due to rapid clinical deterioration. As a quality improvement project (QIp) performed at MD Anderson Cancer Center (MDACC), our goal was to increase the number of ATC pts evaluated at MDACC with a long term goal of increasing participation in trials. Primary QIp aim was to decrease time from referral (1st contact) to disposition (scheduling of 1st appointment) (‘‘R-D’’) to £ 5 business days in 100% of pts referred to Endocrine business center (BC) for ATC. Historical (2009–2013)

and post-QIp ( June 2014-April 2015) data were gathered via MDACC databases. Historical data revealed a median R-D for ATC pts from 2009– 2013 of 8.7 days. Analysis of reasons for delays were identified and revealed multiple causes, main ones being: 1. ATC has various synonyms which BC personnel were not aware of; and 2. physician on-call had to identify a day to see pt. We created a new process flow specifically for ATC which allowed the BC to initiate the FAST protocol. Under this protocol, pts are scheduled immediately in appointment slots (primary MD and consultants) designated only for possible ATC pts. Post-QIp data: 29 pts were referred with a diagnosis (dx) of ATC. 5 pts did not come for evaluation for various reasons. Of the 24 seen with a possible dx of ATC, 20 participated in FAST (3 entered through another BC; 1 direct referral to endocrine MD who saw pt quickly). Median R-D in these pts was 0.5 days. In addition, compared to 2012, new ATC pts increased from 15 to 30. Participation in treatment trials was 27%. Our FAST model has decreased the R-D time by 94% and resulted in a 100% increase in new ATC pts at MDACC. If our model were adopted in all major centers across the world, we believe that ATC pts could be seen more expediently to facilitate treatment and potential trial enrollment.

Poster 679 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM COMPARISON OF SURGICAL STRESS FOLLOWING ROBOTIC THYROIDECTOMY AND CONVENTIONAL OPEN THYROIDECTOMY: A PROSPECTIVE STUDY K. Kang, S. Paek, S. Park Surgery, Chung-Ang University Hospital, Seoul, Korea (the Republic of) Though thyroid surgery using da Vinci robotic system is being performed commonly for cosmetic purpose, there has never been a study to evaluate the surgical stress of robotic thyroidectomy compared with the conventional open surgery. The aim of the present study is to evaluate surgical stress by measuring several markers (such as IL-6) after surgery. The result of this study may provide an incentive for endocrine surgeons to perform robotic thyroidectomy without concerns about increased surgical stress. We performed a pilot study to evaluate the surgical stress following thyroid surgery. A total of 29 papillary thyroid cancer patients

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 from July 2014 to November 2014 were enrolled. Fifteen patients underwent robotic thyroidectomy and fourteen patients underwent conventional open surgery. One specialized endocrine surgeon performed either open or robotic thyroidectomies. Four ports technique (BABA) was used in robotic thyroidectomy and conventional thyroidectomy was performed through a 5-cm transverse cervical incision. IL-6 levels, serum WBC counts, CRP levels, the surgical plethysmographic index (SPI), and the visual analogue scale (VAS) were measured to compare surgical stress between the robotic and the open surgery group. There was no statistically significant difference between the two groups with respect to age, sex, tumor size, or pathologic stage. The rise in plasma IL-6 levels after surgery was higher after open thyroidectomy than after the robotic procedure though this difference was borderline significant. Mean SPI lever was 41.9 – 4.7 in open group compared to 39.5 – 2.2 in robotic group. (p = 0.095). VAS score was significantly changed in 2hrs and 1day after surgery (p = 0.014 and 0.029, respectively). But, there was no significant difference between the two groups in WBC and CRP response. The rise in IL-6 levels, mean SPI index and VAS score were more marked after open thyroidectomy than robotic procedure. These results demonstrated that robotic thyroidectomy can be associated with a lower systemic stress response than the open thyroidectomy. But further investigations including multicenter large scaled trial are warranted to show that robotic thyroidectomy is a real ’minimally invasive’ procedure.

Poster 680 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM RAPID POSITIVE STAIN OF PARATHYOID GLAND WITH VEIN INTRAVENOUS OF METHYLENE BLUE IN THE OPERATION OF TOTALL THYROIDECTOMY J. Fang Head and Neck Surgery Dpt, Affilliated Tongren Hospital, Capital Medical University, Beijing, China Hypoparathyroidism is a serious complication of the total thyroidectomy. We had employed the vein intranenous of methylene blue to rapid positive stain of the parathyroid glands in the operation of total thyroidectomy, to identifed the parathyriod gland and to avoid the hypoparathyroidism in the management of thyroid cancer. There were 30 patients who suffered from thyroid papillery carcinoma. Among them, there were 23 femal es and 7 males. With ages from 27 years old to 68 years old. The mean age was 43 years. The vain ivtrovinous dosage is 3 mg per kilogram with infused in the 250 ml normal saline. The methylene blue were given when the Cutaneous antisepsis were finished. And complete the infusion within 30 to 40 minutes. The pararhyroid gland were dyed light to middle blue. There were 29 patients to be identifed the dyed parathyroid glands, only one patients was not been dyed of the glands. 24 patients were identifed 4 parathyroid glands in the operation,and 5 patientds 2 glands. 9 patients experenced a temporary hypoparathyroidism within one to three weeks. There were no paminant parathyroidism 3 monthes after the operation. There no complication of the intravenous methylene blue except one patient suffered from delayed analepsia about one hour. The rapid stain of parathyroid gland with vein intravenous of methylene blue is a safe methods to identified the parathyroid gland during the totall thyroidectomy, to avoid the hypoparathyroidism in the management of thyroid cancer.

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Poster 681 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM RESULTS OF THE TREATMENT OF METASTASIS OF DIFFERENTIATED THYROID CANCER USING RH TSH (THYROGEN) P. Sykorova Department of Nuclear Medicine and Endocrinology, Charles University in Prague, Prague, Czech Republic To prevent growing metastasis during 4 weeks of a thyroid hormones withdrawal before repeated administration of therapeutic activity of i-131. A basic tool of the thyroidal cancer treatment is total thyroidectomy. If cancer is larger than 1 cm or if it is multifocal cancer, we indicate ablation of the remnant using i-131. In part of the patients, metastasis was identified on post-therapeutic scintigraphy. Those patients need further therapy. Use of rh TSH: We started to use rh TSH (Thyrogen) in the treatment of metastasis in 2005. This report covered part of the patients {treated in 2013}. There are 68 patients, 24 male ones {35.3%}, 44 female {64.7%}. Those patients were after total thyroidectomy and after ablation of the thyroid remnant using i-131 and we found metastasis using post-therapeutic scintigraphy. We planned to repeat administration of i-131 but we did not want to stop the hormone suppressive therapy. For further therapy we use rh TSH {Thyrogen}. Metastases were found in the lungs of 19 patients, in a lymph node 14, in a bone - 9, the brain - 2, both the lungs and a lymph node - 15, a lymph node and a bone - 2, the lungs and a bone 7, a lymph node and the lungs and a bone 2. Level of Thyroglobulin was 0.2-16.817 ug/l, anti TGL was found in 2 cases. The majority of patients need repeated therapy, which is usually administrated every six months. An average in this group was 5 times, one patient was treated 13 times. We use 4400-7400 Mq i-131 for metastasis. The cumulative dose was on average 23 GBq. Side effect = leucopenia after repeated therapy was observed in 5 patients {7.35%}. Our questionnaire about the comparison of both methods of therapy {withdrawal thyroxin and rh TSH} was filled in by 48 patients = 70.5%. We follow the success of the treatment. The success of the treatment is decreased level of TGL and survival. We found a decrease in the level of TGL in 13 patients = 19 %. 56 patients survived = 83%, 7 patients died {one of them by accident}, 5 became worse {repeated therapy was stopped} = 12 {17 %}. Repeated therapy using i-131 prolongs life of our patients and rh TSH helps us stop the growing of metastasis before administration and patients also feel more comfortable

Poster 682 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM THYROID MIRNA CLASSIFIER (THYRAMIR) COMPLEMENTS MUTATION DETECTION (THYGENX) NGS TESTS FOR IMPROVED MOLECULAR DIAGNOSIS OF INDETERMINATE THYROID NODULE NEEDLE ASPIRATES G. Kumar, J.W. Song-Yang, A. Timmaraju, S. Taylor, A. Mireskandari, S. Finkelstein, S. Hosono Interpace Diagnostics, New Haven, CT Introduction: The full potential of combined miRNA classifier and mutational analysis of thyroid nodules has not yet been fully characterized. Here, we document complementary aspects of performing both assays on the same sample to better diagnose and predict the clinical behavior of cytologically indeterminate thyroid nodules.

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Methods: Total Nucleic Acid (TNA), isolated from needle aspirates of thyroid nodules, were tested for over 100 alterations in the BRAF, HRAS, KRAS, NRAS, PAX8, PIK3CA, and RET genes using ThyGenX test, and for a 10 marker miRNA profiling panel ThyraMIR test designed to classify benign vs. malignant disease. The results were analyzed using surgical outcomes. Results: ThyraMIR precision studies showed minimal minimal inter- and intra- run reproducibility variance between days, runs and operators. Comparison of ThyGenX test results with respective surgical outcomes, using 64 samples, indicated the sensitivity to be 65% and specificity to be 84.1%, while the sensitivity and specificity for the combined ThyraMIR and ThyGenX tests were 80% and 85.7% respectively. Clinical ThyGenX testing of > 1000 FNAs indicated 22% of the samples had reportable DNA mutations [BRAF (33%), NRAS (33%), HRAS (17%), and KRAS (15%)] while 3.7% of the samples had RNA translocations. Of note, miRNA classifier was effective on both mutation negative and RAS mutated nodules. Conclusion: While each approach, mutation detection and miRNA classifier, showed individual limitations, the combination effectively addressed shortcomings.

Poster 683 Thyroid Cancer Wednesday & Thursday Poster Basic 9:00 AM COMBINED MUTATION DETECTION (THYGENX) AND MICRORNA CLASSIFIER (THYRAMIR) CAN BE EFFECTIVELY PERFORMED ON FIXED THYROID NODULE SPECIMENS G. Kumar, J.W. Song-Yang, A. Timmaraju, S. Taylor, A. Mireskandari, S. Finkelstein, S. Hosono Interpace Diagnostics, New Haven, CT Introduction: We describe molecular analysis of fixative treated thyroid nodule specimens such as cytology smear, cell pellet, supernatant fluid and paraffin sections. We further sought to extend it to those enriched for most altered cells using micro-dissection and interrogated cell free nucleic acid in cyto-centrifugation supernatant fluid otherwise discarded. Our approach correlates microscopic cellular features with combined mutational analysis using ThyGenX test and microRNA analysis using ThyraMIR test. Methods: Total nucleic acids were extracted from micro-dissected, archival (3–26 months) cytology and paraffin tissue slides of benign and malignant thyroid nodules. Corresponding cyto-centrifugation supernatant fluids containing cell-free nucleic acid were similarly processed for ThyGenX and ThyraMIR tests. Results: ThyraMIR and ThyGenX tests were carried out successfully from FFPE tissue sections, monolayer cyto-slides and stained smear slides. Of note, cell-free nucleic acids in cytocentrifugation supernatant fluid, discarded in cytology, was successfully analyzed for both mutational change and microRNA profiling using these tests. Microscopic slide-based molecular testing has distinct advantages over that based on fresh, separate needle aspirates. Sampling variation can be better addressed with close correlation between cellular and molecular findings. Especially noteworthy is the availability of cell free nucleic acid in supernatant fluid discarded during cytology processing reflecting the status of the thyroid nodule extracellular fluid space potentially enrich by the most proliferative cellular elements of the thyroid nodule. Conclusion: Here we show that combination testing for mutations and microRNA classifier is feasible with the potential to improve diagnosis and prediction of thyroid neoplasia and allied lesions.

Poster 684 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM RISK FACTORS FOR RADIOIODINE-INDUCED SALIVARY GLAND DYSFUNCTION IN THYROID CANCER PATIENTS B.A. Hollingsworth1, R. Nagy2, J.A. Sipos2, L. Senter- Jamieson2, S.M. Jhiang1, X. Zhang2, K. Coombes2 1 Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH; 2The Ohio State University Wexner Medical Center, Columbus, OH Sialadenitis and xerostomia are side effects of 131I therapy for some thyroid cancer patients, yet the risk factors for 131I induced salivary gland dysfunction have not been investigated. We investigated sialadenitis prevalence and xerostomia score via questionnaire among 228 thyroid cancer patients, and 143/228 patients were tested for the presence of autoantibodies SSA, SSB and RNP, which are known to associate with salivary gland dysfunction. Among 228 patients, 170 had received I-131 therapy with a mean cumulative dose of 136 mCi (range: 25–850 mCi). Patients who received I-131 had higher average xerostomia scores (p = 0.0005) and higher prevalence of sialadenitis (p < 0.0001) than patients who did not. However, the incidence of sialadenitis did not associate with higher xerostomia score. Furthermore, neither average xerostomia score nor sialadenitis prevalence increased with higher cumulative I-131 dose, even after normalization for patient bodyweight. Patients who reported family history of autoimmune disease (N = 54) had higher average xerostomia scores (p = 0.01) regardless of I-131 treatment. Patients who were diagnosed with autoimmune disease (N = 13) not only had higher average xerostomia scores regardless of I-131 treatment (p = 0.01) but also had higher incidence of sialadenitis in I-131 treated patients (p = 0.0007). The positivity of SSA, SSB, and/or RNP among 143 thyroid cancer patients did not associate with average xerostomia score or the incidence of sialadenitis. 131 I therapy increases incidence of sialadenitis and xerostomia, but increased cumulative 131I dose did not correlate with higher incidence of sialadenitis or higher xerostomia score. Patients diagnosed with autoimmune disease are at a higher risk for 131I-induced salivary gland dysfunction.

Poster 685 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM SURVIVAL IMPACT OF RADIOACTIVE IODINE ABLATION IN PATIENTS WITH FOLLICULAR THYROID CARCINOMA P. Suman1, C. Wang2, T. Moo-Young1, R.A. Prinz1, D.J. Winchester1 1 Endocrine Surgery, NorthShore University Health System, Evanston, IL; 2NorthShore University HealthSystem, Evanston, IL The impact of radioactive iodine ablation (RAI) for follicular thyroid carcinomas remains assumed but unconfirmed. We hypothesized that there is a survival improvement with the use of RAI, with the magnitude of impact dependent upon patient demographics and tumor characteristics. The National Cancer Data Base was queried from 1998 to 2006 to study patients without metastatic disease treated with near/subtotal or total thyroidectomy. Variables analyzed included tumor size, lymph node involvement, margin status, age, gender, treatment facility, race/ethnicity, comorbidity, and the use of RAI. Statistical analysis

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was performed with SAS, using Chi Square, Kaplan-Meier and Cox multivariate analysis. 11,483 patients with follicular carcinoma were diagnosed from 1998 to 2006 (mean age 52.6 years, 70% female). Positive margins were noted in 6.5%. 3.4% had pathologically involved nodes. 60.7% received RAI. RAI improved survival (82.5% vs. 76.9%, p < 0.001) at 10 years. Except for tumors less than 1 cm, a survival advantage was noted for all tumor sizes. An RAI survival advantage was noted on multivariate Cox analysis (HR 0.70 95% CI 0.62-0.78, p < 0.001) regardless of margin status, nodal status, and gender, although survival improvement was greatest for male patients, > 65 years of age, larger tumors, and positive margins. With the exception of patients with tumors less than 1 cm, there is a statistically significant survival difference for patients with follicular thyroid carcinoma who receive RAI. Delivery of RAI after thyroidectomy should be strongly considered in all patients with follicular carcinoma with the exception of those with tumors less than 1 cm.

Poster 686 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM SAFETY AND TOLERABILITY OF VANDETANIB IN JAPANESE PATIENTS (PTS) WITH MEDULLARY THYROID CANCER (MTC): A PHASE I/II OPEN-LABEL STUDY S. Takahashi1, J. Tomomatsu1, T. Okamoto2, K. Horiuchi2, A. Tsuji3, Y. Ito3, K. Uchino4, M. Komoda4, T. Todo5, K. Rito6 1 Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan; 2Tokyo Women’s Medical University Hospital, Tokyo, Japan; 3Kobe City Medical Center General Hospital, Hyogo, Japan; 4National Hospital Organization Kyushu Medical Center, Fukuoka, Japan; 5AstraZeneca KK, Osaka, Japan; 6AstraZeneca KK, Tokyo, Japan Vandetanib is an oral tyrosine kinase inhibitor that targets RET, VEGFR and EGFR. In a double-blind Phase III trial (ZETA), Western pts with locally advanced or metastatic MTC treated with vandetanib showed prolonged PFS (HR = 0.46, 95%CI 0.31-0.69, P < 0.001) and improved ORR (P < 0.001; Wells et al, 2011). We have performed a Phase I/II study to investigate the safety and tolerability of vandetanib monotherapy in Japanese MTC pts (NCT01661179). In this multicenter open-label study, Japanese pts with hereditary or sporadic, locally advanced or metastatic MTC received vandetanib tablets (300 mg qd) until objective disease progression. Primary endpoints were safety and tolerability (CTCAE v4.0). Secondary endpoints were ORR (RECIST v1.1), PFS, PK and PK/PD relationship. QTc-concentration relationships were described by an Emax model. Data were collected until 10 pts had safety follow-up ‡ 24 weeks and until all pts with measurable disease had been followed either to progression or for 56 weeks. 16 pts were enrolled; 14 (7 male, 7 female) received treatment (median exposure period: 56 weeks) and 2 were ineligible. As shown in the table, diarrhea (79%) and hypertension (64%) were commonly detected. 3 pts (21%) had QTc-related AEs which did not meet predefined criteria for QTc prolongation (2 grade 1 AEs, 1 grade 2 AE). No events led to torsades de pointes, ventricular tachycardia or sudden death; the QTc profile did not differ significantly from previous studies. One serious AE (interstitial lung disease) led to discontinuation. Of 13 pts analyzed for efficacy, 5 (39%) had partial response and 8 (62%) had stable disease ( ‡ 12 weeks). PFS at 6 and 12 months was 100% and 85%, respectively. Vandetanib PK were described by a 2-compartment model with first-order absorption and elimination.

AEs of vandetanib in this study did not differ from those in previous studies. Most AEs were manageable by standard clinical practice alone, or in combination with dose reduction or interruption; one pt discontinued because of an AE. Efficacy was similar to that previously observed. In conclusion, this study demonstrates that vandetanib monotherapy would be beneficial for Japanese MTC pts.

Poster 687 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM DIFFERENTIATED THYROID CARCINOMA PRESENTING WITH DISTANT METASTASIS AT INITIAL DIAGNOSIS : COMPARED WITH AGE GROUP (STAGE II VS STAGE IV) C. Lee, T. KIM, M. Kim, J. Choi, S. Lee, E. Ban, J. lee, S. Kang, J. jeong, K. Nam, W. Chung, C. Park surgery, Yonsei University College of Medicine, Seoul, Korea (the Republic of) Differentiated thyroid cancer(DTC) has a good prognosis and only rarely presents with distant metastasis(DM) at diagnosis. The clinical outcome of this presentation was assessed with respect to survival and factors that may determine prognosis. A retrospective review was undertaken of patients with stage M1 differentiated thyroid cancer at presentation (n = 63), reffered from 1990- 2010 at a single institution. We divied the patients with two groups (group 1 : age < 45years, group 2 ‡ 45 years). Group 1 were 23 patient and group 2 were 40 patients. All patients underwent a total thyroidectomy. Metastatic lesions were treated with high dose RI, surgical resection, external beam radiation therapy. Median duration of follow-up was 64 months (range, 2–253) Mean patient age of group 1 was 28.1 years and group was 63.1 years. Primary thyroid gland pathology were papillary carcinoma in 87.5% (group1), 69.2 (group2) and follicular carcinoma, hurthle cell carcinoma in 12.5% (group1), 30.8% (group2). Metastases were detected in the lung only (79.2% in group 1, 64.1% in group 2), bond only (16.7% in group1, 20.5% in group 2), and multiple sites (4.2% in group 1, 15.4% in group 2). At 5 and 10 years, the cancer specific survival (CSS) rates were 95.4% and 95.4% in group 1 and 49.9% and 23.1% in group 2. Overall survival(OS) rates and DSS rates were significantly different between two groups. (p = 0.001 and 0.002). In

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univariated analysis, papillary carcinoma, bilaterality, multiple metastasis and old age were significant poor prognostic factors for CSS. In the multivariate analysis, after adjusting for other factors, old age and multiple organ metastasis were the two independent poor prognostic factors for CSS. DTC patients presenting with DM in initial period appear to have relatively favorable outcomes compared with age groups. Old age and multiple organ metastases may be the most important prognoctic factors in all DM patients. However, in the young age group, persistent disease status patients were shown high ratio (over 50%). Future therapy should be directed at improving the treatment efficacy of these patients.

Poster 688 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM CLINICAL BEHAVIOR AND OUTCOME OF PAPILLARY THYROID MICROCARCINOMA ACCORDING TO THE TUMOR SIZE C. Lee1, Y. Yun2, E. Ban1, M. Kim1, T. KIM1, S. Lee1, J. Choi1, S. Kang1, J. lee1, J. jeong1, K. Nam1, H. Kim2, W. Chung1, C. Park1 1 Yonsei University Health System, Seoul, Korea (the Republic of); 2 Cardiovascular and Metabolic Diseases Etiology REsearch Center, Yonsei University College of Medicine, Seoul, Korea (the Republic of) From 2011, thyroid cancer became the most common type of cancer diagnosed in South Korea and the the papillary thyroid microcarcinoma(PTMC) is being diagnosed with increasing frequency, and its optimal management remains controversial. The treatment plan of PTMC become a big issue in South Korea. The objective of this study was to investigate the clinicopathologic features according to tumor size and to identify the risk factors for recurrence in patients

Fig 1. ROC curves for risk factors according to the tumor size of PTMC

with PTMC. And we planned to find the clinical relevance in treatment of PTMC patients. From January 1986 to December 2013, a total 6115 patients with PTMC who were treated by bilateral total thyroidectomy at a single institution were enrolled. Patients were divided eight groups based on the tumor size with 1mm interval. Clinicopathological profiles and follow-up details were investigated by retrospective chart review. Mean follow-up duration was 44 months. Of 6115 patients, 86.1% were women, average age was 48.6 years, and mean tumor size was 0.66cm. A 54.1% had extrathyroidal invasion, 42.2% had tumor multiplicity, 30.3% had bilaterality, 34.8% had central lymph node metastasis, and 9.9% had lateral lymph node metastasis. Recurrence rate was 0.9%. On a comparative analysis with tumor size group (1mm), patients with larger sized tumor had more extrathyroidal, bilaterality, nodal disease. In ROC and logistic regression analysis, the tumor size of 0.7cm was found to distinguish significant cut-off values of risk factors(extrathyroidal invasion, multiplicity, node metastasis and number of risk factors). Multivariate analysis about recurrence revealed the lymph node metastases and number of risk factors were the significant factor. PTMC is prevalent in the population. Among patients with PTMC, tumor size more than 7mm is associated with more aggressive disease. And the presence of lymph node metastases and 2 or more risk factors is strongly associated with disease-free survival. Althouth PTMC is generally associated with an excellent prognosis, clinicians should consider a different strategy for therapy and plan for followup according to tumor size and number of risk factors in PTMC patients.

Poster 689 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM ASSOCIATION OF AUTOIMMUNE ANTIBODIES WITH TUMOR AGGRESSIVENESS IN PAPILLARY THYROID CANCER S. Kim, J. Yi, H. Yu, R. Song, J. Lee, H. Kwon, Y. Chai, J. Choi, J. Jung, K. Lee Seoul National University Hospital, Seoul, Korea (the Republic of) The association between thyroid autoimmunity and papillary thyroid cancer (PTC) remains still controversial despite numerous studies. The aim of the study was to evaluate association of preoperative antithyroid globulin antibody (Tg Ab), and thyroid peroxidase antibody (TPO Ab) with high-risk clinicopathologic features in PTC patients. We prospectively enrolled 1,780 PTC patients (mean age, 46.9 – 12.0 y; 1,487 females and 293 males) who underwent surgery from February 2009 to December 2011. Each patient had blood measurement, including Free T4, T3, TSH, Tg Ab, and TPO Ab done before thyroid surgery. PTC, and Hashimoto’s thyroiditis was diagnosed by histological examination of thyroid tissue obtained after surgery. Simple and multiple analyses were performed to determine the association of thyroid autoimmunity with clinical parameters and histological findings. Elevated Tg Ab, and TPO Ab was present in 30.4% (541/1780), and 19.4% (345/1780) of PTC patients, respectively. Multiple logistic regressions showed that Tg Ab was significantly associated with younger age (continuous), female gender, and advanced tumor stage (III/IV). TPO Ab was significantly associated with absence of lymph node metastasis, and BRAF wild-type. These results suggest that elevated Tg Ab, and TPO Ab might have different role in tumor aggressiveness in PTC patients.

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Poster 690 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM EFFECT OF POSTOPERATIVE PERIOD AND THE RADIOIODINE ACCUMULATION OF THE METASTATIC LESIONS. Y. Noguchi Radiology &Nuclear Medicine, Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Japan It is well known that younger patients have a higher accumulation then elder ones, when radioiodine therapy is performed. But even in elder patients radioiodine to the metastatic lesions could be seen in some patients. T. Higashi et reported that the accumulation of radioiodine would be higher when the therapy is given before 6 month after the last operation. A retrospective survey was performed using 112 differentiated thyroid cancer (DTC) patients which have had radioiodine therapy for metastasis. In the 112 cases, 99 were papillary cancer and 13 were follicular cancer. There were 24 male and 88 female patients with the average age of 58.6. We evaluated the effect of period from the first surgery of DTC to the radioiodine therapy for metastasis, and also evaluated if the age of the patient would have any effect to the accumulation rate. In the 112 cases the average of the postoperative period was 88.2 month (1-556) and the accumulation rate of radioiodine was only 33.9%. When divided by 24 month of postoperative period, the group that had radioiodine therapy before 24 month had an accumulation rate of 51.1%, and the group which had therapy after 24 month had only 19.0%. When divided by age, the group younger than 45yrs old had an accumulation rate of 51.9% and the group older than 45 yrs old had only 28.8%. But even in the elder group, when radioiodine therapy was given before 24 month, the accumulation rate was 51.4%. From this study, it is suggested that the accumulation rate of the radioiodine therapy for metastatic DTC is not only due to age, but the postoperative period might have a large role.

Poster 691 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM A COMPARATIVE STUDY ON CLINICOPATHOLOGIC FEATURES ACCORDING TO CAPSULATION BETWEEN FOLLICULAR VARIANT OF PAPILLARY THYROID CARCINOMA AND PAPILLARY THYROID CARCINOMA S. Yang1, K. Park2, S. Jung1 1 Surgery, Kosin University college of medicine, Busan, Korea (the Republic of); 2Surgery, Hub Hu hospital, Busan, Korea (the Republic of) The follicular variant of papillary thyroid carcinoma (FVPTC) is the most common histologic subtype of papillary thyroid carcinoma (PTC). But The follicular variant of papillary thyroid carcinoma (FVPTC) is difficult to diagnose due to pathologic features. There is also debate on the optimal extent of surgery. We separated FVPTC into two groups and compared the clinical features in an attempt to apply the treatment. All 40 patients with FVPTC who were diagnosed between 1990 and 2009 were reviewed and separated into two groups, an encapsulated group and an infiltrative group, based on whether a capsule was formed or infiltration occurred. These two different subtypes of FVPTC were compared on the traits of sensitivity of diagnosis and clinicopathologic features. After review by a pathologist, 21 of 40 patients (55%) were found to have encapsulated tumors, and 18 patients (45%) had infiltrative tumors. There was no difference in age, sex, or size. Patients with encapsulated

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FVPTC had a significantly lower rate of lymph node metastasis (4.5%), multicentric tumors (18.2%), and thyroid capsular invasion (9.1%) compared with the infiltrative tumor group (50%, 50% and 50%, P < 0.05). There was no difference in FNA sensitivity between the two groups, but the sensitivity to frozen biopsy was higher in the infiltrative group. There was no recurrence in the encapsulated group, but 4 patients (22.2%) experienced recurrence in the infiltrative group. FVPTC can be separated into two subgroups by histologic features, and there are some clinicopathologic differences between the two groups. Patients who had encapsulated FVPTC had a lower rate of lymph node metastasis, multicentric tumors, and thyroid capsular invasion. They also showed a lower rate of recurrence than the infiltrative group. It is suggested that the encapsulated group can be treated with limited surgery and the infiltrative group needs aggressive treatment

Poster 692 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM PREVENTIVE EFFECT OF HUMAN ACELLULAR DERMAL MATRIX ON POST-THYROIDECTOMY SCARS AND ADHESIONS: A RANDOMIZED, DOUBLE-BLINDED, CONTROLLED TRIAL D. Kim1, J. Shin1, T. Kwon1, W. Chung2, K. Nam2, S. Kang2, C. Park2, J. Lee1 1 Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea (the Republic of); 2Department of Surgery, Yonsei University College of Medicine, Seoul, Korea (the Republic of) Acellular dermal matrix (ADM) has been used for antiadhesion formation along with wound healing in various surgical fields. The aim is to assess the efficacy of ADM implantation in the prevention of postoperative scars and adhesions after conventional, open, total thyroidectomy. Forty-four patients with papillary thyroid carcinoma undergoing thyroidectomy were randomly assigned to the study (ADM implantation) or control group (without ADM). Global photographic assessment, Vancouver scar scale (VSS), objective scar assessment, and swallowing impairment index were assessed at baseline, immediately after surgery, and at 1 and 2 months after surgery. Nineteen control and 20 study group participants completed the study. The mean VSS score of the study group was significantly lower than the controls at both 1 month (3.06 – 1.25 vs 4.41 – 1.54, respectively) and 2 months (2.76 – 1.56 vs 4.35 – 1.58, respectively) after surgery. Scar quality measures (mean melanin and erythema indexes) were significantly lower in the study group compared with controls. Study group participants had significantly lower swallowing impairment scores than controls. The mean postoperative hospitalization of both groups was not significantly different. Acellular dermal matrix-assisted implants appear to improve postthyroidectomy scar and swallowing impairments without delays in operation time.

Poster 693 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM EFFICACY AND SAFETY OF LENVATINIB BY BODY MASS INDEX IN PATIENTS WITH 131I-REFRACTORY DIFFERENTIATED THYROID CANCER FROM THE PHASE 3 SELECT STUDY M. Tahara1, L. Wirth2, M.S. Brose3, K. Newbold4, M. Schlumberger5, C. Ductus6, B. Robinson7, A. Gianoukakis8

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1

Division of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan; 2Department of Medicine, Massachusetts General Hospital, Boston, MA; 3Department of Otorhinolaryngology: Head and Neck Surgery, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; 4The Royal Marsden National Health Service Trust, London, United Kingdom; 5Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and University Paris-Sud, Villejuif, France; 6 Eisai Inc, Woodcliff Lake, NJ; 7Kolling Institute of Research, University of Sydney, Sydney, NSW, Australia; 8Division of Endocrinology and Metabolism, Harbor-UCLA Medical Center, Torrance, CA In the phase 3 SELECT study, lenvatinib, an oral multikinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRa, RET, and KIT, significantly prolonged progression-free survival (PFS) vs placebo (PBO) in patients with 131I-refractory differentiated thyroid cancer (RRDTC; hazard ratio [HR] 0.21; 99% confidence interval [CI] 0.140.31; P < 0.001). Median PFS (months) were: lenvatinib, 18.3; PBO, 3.6. In SELECT, lenvatinib was administered at a fixed dose (24mg/ d; 28-d cycle), regardless of bodyweight or body mass index (BMI). Here we analyzed efficacy and toxicities by BMI. For this subanalysis, patients were grouped by the following BMI categories: under- and normal weight (U/NW; < 25kg/m2), overweight (OW; 25-29.99 kg/m2), and obese (OB; ‡ 30 kg/m2). Of the UNW patients, 9.3% (14/151) were underweight (BMI < 18.5 kg/m2). Baseline demographics, except weight, were similar between UNW (lenvatinib = 100, PBO = 51), OW (lenvatinib = 79, PBO = 39), and OB (lenvatinib = 76, PBO = 40) patients. OB patients accounted for 48.2% of patients from North America, 26.3% of patients from Europe, and 13.6% of patients from other regions. The PFS advantage for lenvatinib observed in the overall study population was maintained in all BMI subgroups. OB patients receiving lenvatinib exhibited the greatest PFS benefit vs PBO (median PFS 16.7 months; HR 0.13; 95% CI 0.07-0.24; P < 0.0001). The objective response rate with lenvatinib was 61.0% for UNW patients, 62.0% for OW patients, and 75.0% for OB patients. The proportions of patients with grade ‡ 3 lenvatinib-related treatment-emergent adverse events (TEAEs) were similar across all BMI subgroups (UNW, 77.0%; OW, 77.2%; OB, 72.4%). Rates of drug withdrawal and dose reduction due to TEAEs were also comparable across the 3 groups. Although the incidences of grade ‡ 3 lenvatinib-related TEAEs were similar in all BMI subgroups, the incidence of fatal TEAEs was highest in patients with the lowest BMI. Lenvatinib showed efficacy and comparable toxicities across all 3 BMI subgroups in patients with RR-DTC from the phase 3 SELECT study.

Poster 694 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM ULTRASOUND FEATURES OF SPORADIC MEDULLARY THYROID CANCER. CLINICAL AND PATHOLOGIC CORRELATIONS R. Guglielmi1, A. Frasoldati2, F. Grimaldi3, I. Misischi1, M. Zini2, F. Vescini3, F. Graziano1, N. Mecca2, C. Cipri3, E. Papini1 1 Endocrinology, Regina Apostolorum Hospital, Roma, Italy; 2 Department of Endocrinology, Arcispedale S. Maria Nuova IRCCS, Reggio Emilia, Italy; 3Department of Endocrinology, Metabolism & Clinical Nutrition, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy The few studies which have retrospectively addressed the issue of sonographic (US) findings in medullary thyroid cancer (MTC) re-

ported the US appearance of MTC as inconstant and often elusive. Variable echogenicity and coarse calcifications are described as common features, and cystic changes as frequent. Thus, a large percentage of MTCs is stated to show an indeterminate and potentially misleading appearance at US examination. Aim of the study. To assess in a large series of sporadic MTCs the US findings at diagnosis, to define the risk of malignancy according to the 2014 British Thyroid Association (BTA) US Classification system, and to correlate the sonographic features with the size, pathologic stage and calcitonin levels. One hundred and seven sporadic MTCs were consecutively diagnosed at three thyroid referral centers. All patients had real-time US and color-Doppler examination, US-guided fine-needle aspiration, basal calcitonin determination and post-surgical pathologic staging. Most MTCs were solid (85%), hypoechoic (90%) and with blurred, irregular or lobulated margins (72%). Intranodular vascular signals (55%) were frequent, while macrocalcifications (8%) were an occasional finding. Mixed structure or cystic changes were observed in a minority of cases (15%). At the BTA US classification the vast majority of MTCs (91%) was categorized as class U4 (suspicious) and U5 (malignant). A not statistically significant correlation was found between the US features of the nodule and serum calcitonin levels. In most MTCs, US findings coincide with at least one of the traditional signs suspicious for malignancy. Only a minority of them (9%) show an indeterminate or, rarely, a benign appearance that could misleadingly prevent cytologic assessment.

Poster 695 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM COMPARATIVE STUDY OF BILATERAL AXILLO-BREAST APPROACH (BABA) ROBOTIC AND ENDOSCOPIC THYROIDECTOMY: AN ANALYSIS OF A LARGE MULTI-INSTITUTIONAL DATA J. Choi1, J. Jung1, J. Lee1, R. Song2, H. Yu2, H. Kwon2, S. Kim2, Y. Chai3, K. Lee2 1 Department of Surgery, Seoul National University Bundang Hospital, Seongnam-si, Korea (the Republic of); 2Department of Surgery, Seoul National University Hospital, Seoul, Korea (the Republic of); 3Department of Surgery, Seoul National University Boramae Medical Center, Seoul, Korea (the Republic of) Since Bilateral axillo-breast approach (BABA) robotic and endoscopic thyroidectomy had been introduced, numbers of operations using each method were performed in many centers. The aim of this study was to compare the large multi-institutional data of surgical outcomes of BABA robotic and endoscopic thyroidectomy and to evaluate the merits of robotic thyroidectomy. From February 2004 to March 2015, 1029 patients underwent BABA endoscopic thyroidectomy (ET), and from February 2008 to March 2015, 2003 patients underwent BABA robotic thyroidectomy (RT) in 3 large volume centers in Korea. Two groups were retrospectively compared in terms of clinicopathologic characteristics, surgical outcomes, completeness, complications, and long-term results. Both patient groups had similar demographic characteristics including age, sex, tumor size, pathologic stage, and hospital stay. RT was applied more frequently to the cancer patients after introduction of the robotic system. (ET 71.5% vs. RT 86.8%, p < 0.001) Total thyroidectomy was performed more frequently in RT group (ET 49.4% vs. RT 79.9%, p < 0.001). Regarding neck lymph node

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 dissection, the mean number of retrieved lymph node was greater in RT group (ET 3.0 – 3.63 vs. RT 5.15 – 4.78, p < 0.001), and RT group showed higher neck lymph node metastasis rate than ET group (ET 9.9% vs. RT 31.6%, p < 0.001). ET group had higher rate of transient hypocalcemia (ET 30.7% vs. RT 24.6%, p < 0.008) and vocal cord palsy (ET 15.1% vs. 10.9%, p = 0.001), however permanent hypocalcemia (ET 3.7%, vs. RT 2.1%, p = 0.062) and vocal cord palsy (ET 0.9% vs. RT 0.4%, p = 0.16) rate were not statistically significant in both groups. In long-term follow-up of cancer patients, 11 cases were recurred after ET (1.5%) and 4 cases after RT (0.2%) (p = 0.001). Both procedures could be safe and effective methods to treat thyroid diseases. However, the application of robotic system may help to overcome the limitations of the instruments and surgeon’s skills especially in patients with malignant diseases.

Poster 696 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM RADIOGUIDED OCCULT LESION LOCALIZATION IN PATIENTS WITH RECURRENT THYROID CANCER M. Tuncel1, N. Su¨slu¨2 1 Nuclear Medicine, Hacettepe University, Ankara, Turkey; 2 Head and Neck Surgery, Hacettepe University, Ankara, Turkey Most of the reoperations for persistent or recurrent thyroid cancer are related to insufficient initial surgery. The success of recurrent surgery depends on preoperative imaging and localization methods. In this study we aimed to investigate the rate of operative success in excision of recurrent lesions with radioguided occult lesion localization (ROLL)method in pts suffering from thyroid cancer. Nineteen consecutive pts (F/M:16/3 age: 43 – 13 (21–56) who were scheduled for reoperative thyroid cancer surgery were studied. All pts had biopsy confirmed recurrent thyroid cancer except one patientt with an enlarged lymph node which was later found to compatible with lymphoma. Two hours before surgery, 0.1 mL of Tc-99m (0.3 mCi)-labeled MAA was injected intralesionally under USG guidance. Surgery was carried out based on the excision of radiolabelled lesions by gamma probe and nonradiolabelled tumor foci by the guidance of USG-neck map that show relation of injected and noninjected lesions. The postoperative Tg levels and neck USG were used for the determination of surgical success. Radiolabeled and lesions drawn on neck maps were successfully resected without complications except in one patient whose lesion was partially resected due to infiltration to esophagus. In 5/19(26%) pts modified radical neck dissection was also performed in addition to the radiollabeled or lesions drawn on neck maps. Among 19 pts 29 lesions were radiolabelled (2 local recurrence and 27 metastatic lymph nodes, mediansize: 12 – 5.78 range: 5-22 mm) and a total 50 metastatic lesions were resected according to the pathology results. In one patient resected lymph nodes were compatible with lymphoma, in 2 patients although lesions were resected, increase in tumor markers were seen due to pulmonary metastases. The patient who had partial resection showed minor decrease in size of the lesion and with stable Tg levels. 15/19 (79%) pts showed > %85 decrease in stimulated Tg levels at 4 month and were in remission (stimulated Tg < 1 ng/ml and without evidence of disease on imaging) The use of preoperative USG-neck mapping with ROLL in patients with recurrent/persistent papillary thyroid cancer is an effective tool with high success rate.

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Poster 697 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM THE CRITICAL ROLE OF THYROGLOBULIN LEVELS IN THE FINE NEEDLE BIOPSY ASPIRATE OF SUSPICIOUS LYMPH NODES IN PATIENTS WITH THYROID CANCER M. Tuncel, M.C x. Tuncali Nuclear Medicine, Hacettepe University, Ankara, Turkey The detection of Tglevels from the fine needle aspirates(FNA)of suspicious lymph nodes (LN) (FNAB Tg) was found to be helpful in the appropriate diagnosis in pts with thyroid cancer (Tca). Our study aimed to reveal the role of FNABTg in the detection of LN metastases (mts) in comparison with cytology. Eighty-two pts (F/M: 60/22 age: 43 – 13 (18-81 years) with Tca were referred for LNs with suspicious USG features. 16/82(20%) pts were under TSH supression wheras in 66/82(80%) TSH was stimulated. LNs were biopsied with FNA technique under USG guidance and FNABTg levels were also determined by rinsing the biopsy syringe. Serum Tg, anti-Tg abs levels, size and USG appearance of LNs were noted. Cytological exams were classified as: 1:normal LN cells, 2: non-diagnostic, blood elements, 3:mets from Tca. FNAB Tg/ serum Tg > 1 was accepted as positive for LN mets. The pathology results, Tglevels, and follow-up were used for gold standard. One hundred and eight suspicious LNs from 82 pts with were biopsied. When the cytology class 1-2 were accepted as negative and 3 as positive for LN mets; the sens, spec, PPV, NPV and acc of cytology vs FNABTg on lesion bases were 89%, 96%, 96%, 86%, 92% vs 97%, 95%, 95%, 96%, 95% respectively. The med FNABTg levels were higher than serumTg and FNABTg of benign LNs (7007 – 11293 vs 50 – 10 and 0,35 – 0.85 ng/ml respectively p:0.006). When FNABTg/serum Tg level 1.15 was the cut-off for positive biopsy the ROC analysis revealed 97% sens and 90% spec. In 10 pts with high anti-Tg abs, there were no interference with FNABTg results. Size of lesions with class 2 cytology (15/108 (13%)) were smaller than others (7.7 – 1.8 vs 11.4 – 4.7 mm p:0.005). Among these 7/15 were malign and 8/15 were benign by FNABTg and follow-up. Two of these benign lesions were totally calcified LNs which were sequela after succesful radioiodine Tx, other 6 lesions were nonspecific small hypoechoic LNs. In 2 pts cytological results were false positive, due to malign cells from secondary primaries which were accurately excluded by low FNABTg. The combined use of cytology and FNABTg must be the standard of care for detection of LN mets in pts with Tca. FNABTg was not effected by presence of anti-Tg abs and extremely helpful for the biopsy of small LNs.

Poster 698 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM THE ROLE OF GALLIUM-68 DOTATATE PET/CT IN THE IMAGING EVALUATION OF MEDULLARY THYROID CANCER L.A. Neves1,2, G.B. Coura-Filho1, R.M. Freitas1, M.A. Pereira2, M. Tavares2, R.M. Maciel3, C. Buchpiguel1,2, A.F. Hoff1,2 1 Insituto do Cancer do Estado de Sao Paulo, Sao Paulo, Brazil; 2 Hospital das Clinicas da FMUSP, Sao Paulo, Brazil; 3 Universidade Federal de Sao Paulo, Sao Paulo, Brazil 68

Ga In medullary thyroid cancer (MTC), an elevated calcitonin level after surgical treatment indicates residual disease. Patients with

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calcitonin (CT) < 150 pg/mL usually have occult disease by standard imaging studies and the detection of disease is directly related to the CT level. Currently, localization studies include US neck, bone scan, CT chest and CT or MRI abdomen. Despite good sensitivity, detection of disease remains a challenge. A few studies have evaluated the role of Gallium-68 DOTATATE PET/CT (68Ga PET/CT) showing promising results. However there are no prospective studies correlating 68Ga PET/CT with currently recommended imaging studies. This is a study including 25 patients with MTC and elevated CT level. Imaging studies included 68Ga PET/CT, bone scan, US neck, CT neck, chest and abdomen. Patients were classified in two groups: Occult disease (elevated CT and negative imaging studies) and Metastatic disease. At present, there are 10 patients in group 1 (5 sporadic/5 hereditary; median age 55 years (37-78); M:F 2:8; median CT 136 pg/ mL (12.2–706) and 9 patients in group 2 (5 sporadic/4 hereditary; median age 45 years (33-62); M;F 6:3; median CT 7,962 pg/mL (895-50,948); median CT doubling time 20 months (1.8 - 106). In group 1, imaging studies were concordant in 7/10 patients (4 with lymph nodes (LN) detected by 68Ga PET/CT and US neck and 3 patients with all negative studies) and discordant in 3/10 patients (2 patients with LN detected only by US and 1 patient with LN only by 68 Ga PET/CT). In group 2, 2 patients had identification of all metastatic foci in both 68Ga PET/CT and other studies; in 4 patients, 68 Ga PET/CT failed to detect metastatic disease (liver in 3, lung in 2 and cervical LN in 4) and in 2 patients, 68Ga PET/CT was superior than bone scan. Comparing to standard imaging modalities, 68Ga PET/CT was superior in 1/10 patients in the occult disease group and 2/9 patients in metastatic disease group. However, it failed to detect metastatic disease in 2/10 patients in the occult group and 7/9 patients in metastatic group. Based on these results, 68Ga PET/CT does not provide optimal whole-body imaging as a single procedure in MTC.

Poster 699 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM EVALUATION OF GALECTIN-3 IN THYROID FINE NEEDLE ASPIRATION BIOPSY (FNAB) NEEDLE WASHINGS-A POSSIBLE PREOPERATIVE MARKER FOR MALIGNANCY D. Milosevic1, J. Mills1, A. Gray1, S. Miller1, M. Castro2, A. Algeciras-Schimnich1 1 Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, MN; 2Endocrinology, Mayo Clinic and Foundation, Rochester, MN Analysis of galectin-3 (Gal-3) by immunohistochemistry (IHC) has been used to distinguish benign thyroid nodules from thyroid carcinoma following cytologic or histologic examination. However, published clinical sensitivities and specificities of Gal-3 vary widely across studies likely due to variability in interpretation of staining patterns as well as differences in patient populations. Our goal was to determine if Gal-3, alone or in combination with thyroglobulin (Tg), could be measured in FNAB needle washings to differentiate malignant from benign thyroid lesions. This prospective study was approved by the Mayo Clinic Institutional Review Board. Thyroid FNAB needle washings from 26 papillary thyroid carcinoma (PTC) cases and 201 benign nodules were collected. FNAB washings were collected by rinsing each biopsy needle in 0.5 mL of saline with subsequent centrifugation to remove cellular debris. Gal-3 (BG Medicine, Waltham, MA) and Tg (Beckman Access, Brea, CA) were measured in the resulting supernatant by immunoassay.

Gal-3 concentrations were elevated in FNAB washings from PTC compared to benign nodules (median 4.9 ng/mL vs < 1.5 ng/mL, respectively; P = 0.0005). Tg was also significantly different between these groups (median 3348 ng/mL vs 612 ng/mL, respectively; P = 0.02). ROC curve analysis determined an optimal cut-off of ‡ 3.9ng/mL for Gal-3 and £ 5000ng/mL for Tg to differentiate PTC from benign thyroid nodules. Using these cut-offs, sensitivity and specificity were 62% and 91% for Gal-3 and 89% and 42% for Tg. The combination of both markers did not improve the diagnostic performance. We demonstrated that measurement of Gal-3 and Tg in FNAB washings could be used as an adjunct to cytology in the evaluation of thyroid nodules. PTC cases showed significant differences in Gal-3 and Tg concentrations compared to benign nodules. However, the sensitivities and specificities observed indicate limited clinical utility. Additional biomarkers may be necessary to fully appreciate the utility of FNAB washings in the work up of thyroid nodules.

Poster 700 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM ADDITIONAL RADIOACTIVE IODINE DIAGNOSTIC IMAGING SELDOM IDENTIFIES METASTATIC FOCI IN DIFFERENTIATED THYROID CANCER PATIENTS PREVIOUSLY DOCUMENTED TO HAVE A NEGATIVE DIAGNOSTIC SCAN AFTER TOTAL THYROIDECTOMY AND RADIOACTIVE IODINE REMNANT ABLATION A.K. Mahrous1, A.H. Alghamdi2, R.K. Grewal4, M. Sabra4, R.M. Tuttle3 1 Collage of Medicine, Imam University, Riyadh, Saudi Arabia; 2 Surgery, Prince Sultan Military Medical Center, Riyadh, Saudi Arabia; 3Memorial Sloan Kettering Cancer Center, New York City, NY; 4Memorial Sloan Kettering Cancer Center, New York City, NY Differentiated thyroid cancer is one of the common cancers that has in general a favorable prognosis yet requires life long follow up, hence a tailored follow up measures are required. Diagnostic whole body scan (WBS) can be a valuable tool for detection of RAI avid disease in properly selected patients thought to be at intermediate or high risk of recurrence. Nevertheless the frequency that a negative diagnostic scan converts to a positive RAI scan during routine follow-up is not well established. The study included 112 patients of differentiated thyroid cancer who had total thyroidectomy and RAI ablative dose followed by two diagnostic scans 6 months or more apart. The first follow up diagnostic WBS should be reported as negative for the patient to be qualified for the study. Second WBS were reviewed and RAI avid foci where identified. Patients with unstimulated Tg > 5 ng/ml or positive Tg AB interfering with Tg measurement at second scans were excluded. 5 out of 112 patients (4.46%) had their second Diagnostic WBS converted to positive after an initial negative study. Three of the positive uptakes were seen at the neck area, one was at the mediastinum and one at the lung field. Based on the clinical and laboratory/ radiological long term follow up we found that 4 out of the 5 positive cases represented either false positive uptake (two at thyroid bed and one at lung field) or had clinically insignificant uptake (one at thyroid bed). The remaining one case has the limitation of short follow up duration that prevents accurate decision about uptake significance (uptake at upper mediastinum). The practice of routine second Diagnostic WBS after initial negative one as a follow up tool to identify RAI avid clinically significant cancer residual or metastasis - unless there is strong clinical suspicion-is neither useful nor cost effective especially in the

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 presence of alternative highly sensitive disease detection tools such as sensitive thyroglobulin assays and neck ultrasonography.

Poster 701 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM PATTERNS OF RADIOACTIVE IODINE USE IN CHILDREN WITH PAPILLARY THYROID CANCER IN THE UNITED STATES: AN ANALYSIS OF 3940 PATIENTS M. Adam1, E. Ruel2, S.A. Roman1, J.A. Sosa1 1 Department of Surgery, Duke University, Durham, NC; 2 Endocrinology, Duke University, Durham, NC Controversy exists regarding use of radioactive iodine therapy (RAI) for children with papillary thyroid cancer (PTC). RAI can be associated with increased toxicities in children. Limited data exist at the population level. The aim of this study was to analyze patterns of RAI use and its potential impact on survival in children with PTC. Patients £ 18 yrs undergoing surgery for PTC were included from the NCDB (1998-2012). Patients were analyzed as low-risk (T1/T2 tumors without nodal/distant metastases or positive surgical margins) or intermediate/high-risk (T3/T4 tumors with/out nodal/distant metastases or positive surgical margins). Descriptive and survival analyses were used to characterize patterns of RAI use and survival based on risk stratification. Of 4788 children with thyroid cancer, 3940 (87%) had PTC: 1695 (43%) low-risk and 2245 (57%) intermediate/high-risk PTC. Overall, 5% were < 10, 24% 10-14, and 71% 15-18 yrs. Nodal disease was noted in 47% and distant metastases in 3%. Median follow-up was 62 mos (range 1-189 mos). Overall survival was compromised in patients with distant metastases (95.5% vs 96.4% without, p = .02). Nodal disease had no effect on survival (96.4% without vs 94.9% with, p = .2). 62% of all patients received RAI, including 48% of lowrisk and 74% of intermediate/high risk patients. Among low-risk RAI patients, 6% were < 10, 28% 10-14, 67% 15–18 yrs; 50% had T1 tumors; 31% had multifocal disease; 92% underwent total thyroidectomy; and 57% were treated at a non-academic center. RAI treatment was not associated with improved survival for low-risk PTC (98% vs 98%, p = .14), but was associated with improved survival for intermediate/high-risk PTC patients (99% vs 97% no RAI, p = .04). After adjustment, factors associated with use of RAI for lowrisk PTC were multifocal disease (OR 2.02, p < .01) and T2 vs T1 tumors (OR 2.23, p < .01). RAI is used in nearly half of pediatric patients with low-risk PTC, without significant improvement in survival in our dataset. Given the favorable overall prognosis of children with PTC, studies assessing other pertinent outcomes, such as recurrence, should be performed to better define the appropriate role for RAI in children.

Poster 702 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM EXPERIENCE OF FDG PET/CT IN DEDIFFERENTIATED THYROID CARCINOMA M. Alvarez, L. Pabon, E. Manzi, M. Renjifo Nuclear Medicine, Fundacion Clinica Valle de Lili, Cali, Colombia The application of FDG PET/CT scan is widespread for the diagnostic assessment of patients in Oncology.FDG is taken up by dedifferentiated thyroid cancer cells, which are poorly iodine avid.This metabolic study is helpful in the patient with an increased serum tumoral markers and negative radioiodine scan. The aim of this re-

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port is to describe our initial experience with PET/CT to date in patient with suspicious for dedifferentiated thyroid carcinoma. Retrospective observational study. A total of 28 FDGPET/CT scans were performed between January 2014 to June 2015.The rhTSH-stimulated PET/CTFDG (5 MBq/kg) was performed in a hybrid computer BIOGRAPH mCT128 SIEMENS, after two 0.9mg intramuscular doses of rhTSH (Thyrogen-Genzyme) administered before imaging. Measurement of serum TSH, anti-thyroglobulin antibodies(ATc) and thyroglobulin(Tg) levels was performed before FDG injection. Qualitative and semiquantitative evaluation were performed with PET/CT-FDG; this findings were correlated with demographic information, tumor histology, image studies and serum tumoral markers. 28 patients (20 women and 8 men; 56 – 11 years). Twenty-three patients had papillary carcinoma, one had micropapillary carcinoma, one had insular carcinoma and two had follicular thyroid carcinoma. All patients had previously undergone total thyroidectomy and iodine therapy (The total 131I dose was 371 + / - 240 mC (ranged 100 to 11100 mCi). PET/CT-FDG findings were positive in 20, negative in 5 and no clear in 3 cases.The Tg level was 872 + / - 3167 (ranged 0.04–16853) and the ATg level was 168 + / - 754 (ranged 0.6–4000). SUV ma´x was 7.7 + / - 10.5 g/ml (ranged 0–54.7). The 6 patients with Tg values less than 10 microg/L, 4 evidence positive PET/CT-FDG, 1 negative PET/CT-FDG and 1 no clear PET/CT-FDG. The mean SUVmax was 6 – 7.9 (range 2.2–18 g/ml). Our initial experience indicates that functional information obtained by a FDG PET/CT scan is useful in patients with well differentiated thyroid cancer, in whom dedifferentiation is suspected. This series shows that the cutoff value of 10 microg/L for the Tg, is not useful to select patient candidates for PET/CT-FDG studies to detect dedifferentiated thyroid cancer.

Poster 703 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM MENTAL EFFECTS OF RADIATION IN RESIDENTS OF FUKUSHIMA PREFECTURE WITH PROLONGED LIFE AS EVACUEES IN TOKYO M.N. Harada education, Tamagawa university, Tokyo, Japan More than four years have passed since the accident of Fukushima Daiichi Nuclear Power Stations (March 2011). Approximately 46000 evacuees are living outside of Fukushima Prefecture, and 6000 residents of Fukushima Prefecture are living in Tokyo still as evacuees. As a clinical psychologist, the author has been engaged in psychological support to evacuees from Fukushima in Tokyo. In groups that the author is mainly engaged, stress level of evacuees have been generally heightened in association with the prolonged life in Tokyo. Recently the Nuclear Emergency Response Headquarters announced the rearrangement of evacuation areas, that is, except areas where the residents have difficulties in returning for a long time, evacuation orders will be lifted before March 2017. According to the opinion survey (2015) of evacuees performed by Tokyo Metropolitan Government, 63.3% of evacuees wish to reside permanently in Tokyo, 25.2% wish to return home, and 11.5% wish to return, but not to their original place. Individual interviews* and voices of evacuees at gathering of evacuees are employed for the analysis of reasons why they do not wish to return. *interviews were supported by the The Association of Japanese Clinical Psychology Results are as follows: 1.The fear of the radiation effects about their health, especially the uncertain health effects of low-dose radiation exposure. 2.The fear of the radiation-induced thyroid cancer

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in children. 3.The fear of genetic influence of radiation. 4.Residents who may have to return before 2017 have higher fear about radiation than the others. 5.Evacuees do not want to move from the place of the current life where they have spent more than 4 years. They do not want to let the children transfer from the current school. It is very important to provide them with accurate knowledge about radiation and with opportunities for individual consultations and risk communication before they return to their homes.

Poster 704 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM THYROID SYMPTOMS EFFECT ON GENERAL LONG-TERM QUALITY OF LIFE AMONG PATIENTS WITH DIFFERENTIATED THYROID CARCINOMA A POPULATION BASED COHORT STUDY IN SWEDEN C. Hedman1, T. Dja¨rv2, P. Strang3, C.I. Lundgren1 1 Department of Molecuar Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 2Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 3Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden Although differentiated thyroid cancer (DTC) has an excellent prognosis and low incidence of recurrence, life-long follow-up as well as medication with levothyroxine might be needed. The aim of this study was to clarify how symptoms from thyroid disease and side-effects from treatment affects Health Related Quality of Life (HRQoL) many years after diagnosis, in DTC patients in Sweden. From the national all-encompassing population-based Swedish Cancer Registry, 353 patients diagnosed with DTC during 1995– 1998 were identified and invited to answer the HRQoL questionnaire SF-36 and a study specific questionnaire, 14–17 years after their diagnosis. Data were compared to a reference population as well between subgroups of patients. Of the patients with DTC, 279 (79 %) answered the questionnaires. In all, only 19 (7%) reported a recurrence. Patients reporting at least one thyroid symptom (n = 240) had significantly lower HRQoL in all eight SF-36 domains compared to patients with no thyroid symptoms (n = 39) (p < 0.002- < 0.001). Also patients with one single symptom, i.e. muscle weakness, fatigue, palpitations, bodily restlessness, sleeping disorders, sweating, flushes, lower stress resistance, dry mouth, hoarseness, dysphagia, numbness in the operation area and salivary glands problems had significantly lower HRQoL compared to those without that symptom (all p-values < 0.001).

Even if DTC comes with an excellent prognosis, patients with thyroid symptoms have lower HRQoL compared to those without symptoms. Awareness among health-care practitioners might affect to how they ask for thyroid symptoms and consider appropriate care, which in the end might improve the patient’s HRQoL.

Poster 705 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM UNUSUAL PATHOLOGY FINDINGS IN THYROID: EXPECT THE UNEXPECTED! A. Najafian, S. Kahan, M. Zeiger, M. Olson Surgery, Johns Hopkins School of Medicine, Baltimore, MD Although cytology and histopathology of thyroid lesions generally fall into common and well-defined categories, there are uncommon cases with unusual findings on FNA or final pathology. Herein, we review the prevalence and characteristics of rare categories of both thyroid FNA and histopathology at a tertiary care hospital. Institutional data from 31,510 consecutive patients from 1995– 2013 were queried. Both FNA and histology were available in 6,693 patients. To detect patients with either an unusual cytology or an unusual histopathology, we excluded patients with well-defined and more common categories of The Bethesda System for Reporting Thyroid Cytopathology and clinically common histopathologies respectively. A total of 92 cases were included: 66 (72%) had unusual FNAs (with or without an unusual histopathology) and 26 (28%) had an unusual histopathology in spite of a well-defined FNA. Half the patients (46) had both unusual FNA and unusual histopathology. Overall, 59 (89%) of unusual FNAs vs. 23 (88%) of unusual histopathologies were associated with a malignancy. In 88% of cases, FNA and histopathology were concordant (8 nodules were benign and 73 nodules were malignant on both FNA and histopathology). Unusual FNA categories included poorly differentiated carcinoma (PDC) (28%), metastasis to the thyroid (8%) (including squamous cell carcinoma (SCC), renal cell carcinoma (RCC) and melanoma), malignancy without further specification (14%), lymphoma (10%), granulomatous thyroiditis (10%), Langerhans histiocytosis (2%), necrotic debris (2%), neuroendocrine tumors (2%) and Spindle cell tumor (1%). Unusual histopathologies included PDC (15%), lymphoma (4%), metastasis to the thyroid(3%) (including RCC and SCC), cribriform-morular variant of papillary thyroid cancer (1%), hyalinizing trabecular adenoma (1%), mature teratoma (1%), palpation thyroiditis (1%) and vascular malformation(1%). Although unusual thyroid FNAs and tumors are rare, they should be considered as part of differential diagnosis, especially when cytologic findings do not fit within the Bethesda System. In terms of benign or malignant, the majority of unusual cytological findings were concordant with final pathology.

Poster 706 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM IS PROPHYLACTIC LATERAL LYMPH NODE DISSECTION SUITABLE FOR PAPILLARY THYROID MICROCARCINOMA? L. Zhang, Q. Ji Dept of Head & Neck Surg, Fudan University Cancer Center, Shanghai, China The surgical management of PTMC, especially regarding the necessity of lateral lymph node dissection, remains controversial.This study is to identify the risk factors for lateral lymph node metastasis

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 (LLNM) in papillary thyroid microcarcinoma (PTMC) and determine the association between LLNM and prognosis. The surgical approach was investigated in a large group of PTMC patients during a 15-yr period from single institution with a focus on the management of lymph node metastasis. A total of 1989 patients met the inclusion and exclusion criteria of the study. All patients underwent a routine central lymph node dissection (CLND), while 330 patients received lateral lymph node dissection (LLND). The prevalence of central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM) were 44.6% and 14.2%, respectively. Our multivariate logistic regression analysis identified variables associated with LLNM, including a younger age ( £ 45 yr), greater tumor size, multifocal, bilateral, extrathyroidal extension, and CLNM. In patients with a solitary primary tumor, a location in the upper third of the thyroid lobe conferred a higher risk for LLNM. Extrathyroidal extension was a significant predictor of recurrence according to multivariate analysis, whereas LLNM was not significantly associated with either recurrence or survival. Given the prevalence of LLNM in PTMC, a thorough inspection of the lateral compartment is recommended in PTMC patients with risk factors, while prophylactic LLND may not be an appropriate option for these patients.

Poster 707 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM CAN SERUM PHOSPHATE PREDICT TRANSIENT HYPOPARATHYROIDISM FOLLOWING THYROIDECTOMY? T.M. MADKHALI2, C.J. Balentine1, D. Schneider1, H. Chen1, R.S. Sippel1 1 Endocrine Surgery, UW-Madison, Madison, WI; 2Endocrine Surgery, University of Wisconsin, Madison, WI Hypoparathyroidism is the most common complication following thyroidectomy and can occur in up to 46% of cases. Parathyroid hormone (PTH) measurements can be used to predict this complication; however, rapid PTH measurements are not available in all facilities. In contrast, serum calcium and phosphate levels are widely available, and inexpensive to perform. Since calcium levels often take several days to nadir after surgery, we sought to determine if serum phosphate levels could be used to help predict the presence of transient hypoparathyroidism following thyroidectomy. We retrospectively evaluated all patients who had total or completion thyroidectomy performed between 2007 and 2013 and had serum calcium, phosphate and PTH levels measured post-operatively. Transient hypoparathyroidism was defined as PTH level £ 10 pg/ml at 4 hours post-thyroidectomy and lasted less than 6 months. 260 patients that underwent a total (n = 237) or completion thyroidectomy (n = 23) were included. Transient hypoparathyroidism was found in 18.1% (n = 47), and persisted > 6 months in 3 patients (1.2%). Comparing patients with hypoparathyroidism to those with normal parathyroid function, there were no differences in preoperative calcium levels. However, patients with hypoparathyroidism had significantly lower calcium (8.0 vs. 8.6, p < 0.001) and higher phosphate levels (3.9 vs. 3.5, p < 0.001) on postoperative day 1 (POD1). A POD1 Calcium < 8.0 mg/dl only identified 44% of patients with hypoparathyroidism. However, a POD1 phosphate level ‡ 3.5 mg/dl identified 72% of hypoparathyroidism patients. Using a combination of either a calcium < 8.0 mg/dl or a phosphate ‡ 3.5 mg/dl on POD1, 80% of patients with hypoparathyroidism were able to be identified. Measuring serum calcium levels alone after thyroidectomy will miss a significant number of patients with hypoparathyroidism.

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However, an elevated phosphate level after thyroidectomy is associated with a high risk of hypoparathyroidism and can be used to identify the majority of patients at risk for such complication. This can be a useful alternative when PTH measurements are not readily available.

Poster 708 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM INFLUENCE OF NITRATE IN DRINKING WATER IN OPEN WELLS ON CHILDHOOD THYROID CANCER RATES IN BELARUS AND UKRAINE AFTER THE CHERNOBYL ACCIDENT V. Drozd1,2, V. Saenko3, A. Brenner4, V. Drozdovitch4, M. Tronko5, V. Shpak5, T. Bogdanova5, A. Serduk8, I. Chernychenko5, S. Tsymbaliuk5, V. Pashkevich6, A. Kudelsky6, D. Branovan1, N. Shiglik1, T. Rogounovitch3, S. Yamashita3, J. Biko7, C. Reiners7 1 Project Chernobyl, New York, United States, Brooklyn, NY; 2The International fund ‘‘Help for patients with radiation-induced thyroid cancer ‘‘Arnica’’, Minsk, Belarus; 3Department of Molecular Epidemiology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan; 4Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, US DHHS, Bethesda, MD; 5State Institution, VP Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine; 6Laboratory of Hydrogeology and Hydroecology, Institute for Nature Management of National Academy of Sciences, Minsk, Belarus; 7Clinic and Polyclinic of Nuclear Medicine, University of Wuerzburg, Wuerzburg, Germany; 8State Institution, OM Marzeev Institute of Hygiene and Medical Ecology of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine The incidence of thyroid cancer increased markedly in the past 20 years in countries exposed to radiation after Chernobyl accident. This increase has been directly linked to iodine-131 (131I) thyroid doses. However, there remains limited understanding of factors that modify the 131I-related risk such as endocrine disruptors. The aim of the study was to investigate the incidence of radiation induced thyroid cancer in children after Chernobyl accident in Belarus and Ukraine with respect to thyroid radiation dose and drinking water nitrate concentration. Our data suggest that intake of nitrate with drinking water may potentially modify the effects of radiation exposure on thyroid cancer rates in populations exposed to ionizing radiation. Analytic epidemiological studies aimed at quantification of the joint effect of nitrate content in groundwater and radiation present a promising approach to understanding the impact of environmental factors on the growing incidence of thyroid cancer. Mean 131I thyroid dose for the children in most contaminated areas of Belarus were in Gomel-320, Mogilev-65, and in Brest-51 mGy. Average concentration of nitrates in open wells water in the early nineties were in Gomel-112, Mogilev-40, Brest-185 mg/l. An increase in thyroid cancer incidence rate was observed in Gomel-11.0 and Brest - 5.4, and was less pronounced in Mogilev-1.5 (per 100,000 PY). Mean 131I thyroid dose for the children in most contaminated areas of Ukraine were in Zhytomyr-87, Kyiv-81, and Chernihiv-58 mGy. Average concentration of nitrates in open wells water were 39, 169, and 174 mg/l, respectively. Thyroid cancer incidence rates per 100,000 PY were in Zhytomyr-1.2, Kyiv-1.8, and Chernihiv-1.6. Statistical regression models indicated that the relationship of radiation dose with thyroid cancer incidence may vary depending on nitrate concentration. Our data suggests that intake of nitrate with drinking water is potentially modify the rates of thyroid cancer in populations exposed

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to ionizing radiation. Analytic epidemiological studies designed to evaluate joint effect of nitrate content in groundwater and radiation present a promising avenue of research and may provide useful insights into etiology of thyroid cancer.

Poster 709 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM A SYSTEMATIC REVIEW OF THE TRENDS IN THYROID CANCER INCIDENCE J.J. Wiltshire1, T.M. Drake1, L. Uttley2, S. Balasubramanian1,3 1 The Medical School, University of Sheffield, Sheffield, United Kingdom; 2HEDS, ScHARR, The University of Sheffield, Sheffield, United Kingdom; 3Sheffield Teaching Hospitals, Sheffield, United Kingdom A significant proportion of the global increase in thyroid cancer (TC) incidence has been attributed to increased detection of papillary thyroid cancer (PTC). Nonetheless there are some reports supporting a real increase in incidence. We aimed to document the changing trends in thyroid cancer incidence in the published literature and summarise the evidence on potential risk factors predisposing to this trend. The English language literature published between 1980 and 2014 was searched via PubMed (MEDLINE database) and OvidSP (EMBASE database). We included original studies reporting changes in thyroid cancer incidence in a defined geographic area. Only studies that described clear methods of case selection and population estimates were included. Full texts of relevant articles were reviewed and data on incidence rates and risk factors were collected. The review was registered as follows-PROSPERO 2014:CRD42015013916 Of 4719 manuscripts reviewed, 60 studies were included - 31 from Europe, 13 from North America and the rest from Asia (9), Oceania (4) and South America (3). The number of publications on the topic has increased several fold over the last 30 years. 53 of 60 articles reported a significant increase in incidence (the highest was a 10 fold increase in South Korea), 6 reported stable rates and 1 (from Bosnia) noted a decrease (probably related to war). PTC was the commonest TC type reported to have increased in incidence (in 10 studies that reported sufficient detail to allow comparison). FTC increased in incidence (in 4 studies); albeit at a lower rate compared to PTC. There was limited data on risk factors; the commonest factors discussed included ionising radiation exposure, changes to diagnostic practices and effects of iodine deficiency and/or supplementation. The results of this review strongly support a widespread and persistent increase in thyroid cancer incidence. Evidence for over detection of PTC as being the predominant influence on increasing rates included rising numbers of smaller sized tumours and improved or unchanged survival rates.

Poster 710 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM THYROID CANCER - INCIDENCE TRENDS AND DISTRIBUTION PATTERNS IN SOUTH YORKSHIRE, UNITED KINGDOM J.J. Wiltshire1, B.J. Harrison2, J. Wadsley3, S. Balasubramanian1,2 1 The Medical School, University of Sheffield, Sheffield, United Kingdom; 2Sheffield Teaching Hospitals, Sheffield, United Kingdom; 3Weston Park Hospital, Sheffield, United Kingdom The global increase in the incidence of thyroid cancer (TC) is largely attributed to increased detection of papillary thyroid cancer (PTC); especially papillary micro cancer. The epidemiology of thyroid

cancer and patient level information on types and subtypes in UK population have not been reported. The aim was to study the incidence, distribution, management and outcome patterns of thyroid cancer in North Trent over a fifteen-year period. The demographics and relevant clinic-pathological details of all patients in the North Trent Cancer Network (population > 1.5 million) were collected from electronic and paper records. Incidence rates were calculated from population estimates from the 2001 and 2011 consensus. 637 patients had a first time diagnosis of thyroid cancer between January 2000 and December 2014. Overall crude incidence rates increased from 1.02 per 100,000 persons per year in 2000 to 2.98 in 2014 per 100,000 per year. Incidence rates were highest for PTC. 87% patients had differentiated thyroid cancer (DTC); 3.3% had medullary thyroid cancer; 7.4% had poorly differentiated or anaplastic thyroid cancer and 2% had thyroid lymphoma. 2 others had thyroid metastases from other sites. Of patients with DTC, 78.8% had PTC. Comparisons with historical cohorts from this region shows a significant increase in the proportion of DTC (65% in the 1960s, 58% in the 1980s and 87% currently. The incidence of thyroid cancer in South Yorkshire is lower than many other parts of Europe. Age and gender distribution of each type is similar to published series and the causes of increased incidence are explored.

Poster 711 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM PRE-ABLATION STIMULATED THYROGLOBULIN IS BETTER PREDICTOR OF RECURRENCE IN PATHOLOGICAL N1A PAPILLARY THYROID CARCINOMA THAN LYMPH NODE RATIO Y. Chang1,4, H. Kim1,4, S. Jung2,4, H. Kim2,4, J. Lee3,4, J. Bae2,4, G. Son1,4 1 Breast Endocrine Surgery, Korea University Medical Center, Ansan, Korea (the Republic of); 2Breast Endocrine Surgery, Korea University Medical Center, Anam, Korea (the Republic of); 3Breast Endocrine Surgery, Korea University Medical Center, Guro, Korea (the Republic of); 4Surgery, Korea University College of Medicine, Seoul, Korea (the Republic of) Papillary thyroid carcinoma (PTC) with node metastasis is likely to recur. In the present study, we analyzed lymph node ratio (LNR) and pre-ablation stimulated thyroglobulin (sTg) level as predictive risk factors for recurrence in pathological N1a PTC. This study involved 209 patients with pathologically confirmed PTC and central neck lymph node metastasis who underwent total thyroidectomy with central neck dissection. Clinico-pathologic characteristics, pre-ablation sTg level and post treatment recurrences were examined. Univariate and multivariate analyses were performed to identify factors associated with recurrence in the patients. During a median follow-up pf 55 months, 19 patients had locoregional recurrences. ROC curve analysis showed that 0.48 was the appropriate cut-off value of LNR and 9.3 ng/mL was the one of preablation sTg level. Patients with LNR ‡ 0.48 had significantly worse disease-free survival (DFS) compared to those with LNR < 0.48 (P = 0.03), and patients with pre-ablation sTg ‡ 9.3 had also significantly worse DFS compared to those with pre-ablation sTg level < 9.3 ng/mL (P < 0.01). Relative to patients with LNR < 0.48, those with LNR ‡ 0.48 had higher median pre-ablation sTg level (0.50 vs. 4.05, P < 0.01). The correlation covariant between LNR and pre-ablation sTg level was r = 0.45, P < 0.01. Multivariate analysis showed that LNR ‡ 0.48 (P = 0.63) was not independent risk factor

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Poster 713 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM VALUE OF BASELINE THYROGLOBULIN IN PREDICTION OF SUCCESSFUL ABLATION IN THYROID CANCER A.A. Nawwar1, S. Elrasad1, A. Tawakol1, Y. Abdelhafez2, S. El-Refaei1 1 Nuclear Medine, Faculty of medicine, Cairo University, Cairo, Egypt; 2Nuclear Medine, South Egypt Cancer Institute, Assuit, Egypt

for recurrence, but pre-ablation sTg level ‡ 9.3 ng/mL (P < 0.01) remained as only independent risk factor. Pre-ablation sTg level is better predictors of recurrence in pathological N1a PTC than LNR. Careful follow-up of patients with this risk factor is recommended.

Poster 712 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM ONCOCYTIC VARIANT OF PAPILLARY THYROID CARCINOMA: AN INSTITUTIONAL REVIEW OF OUTCOMES D.I. Ortiz1, G.G. Fareau2, B.C. Hunt3, B.L. Massey4, B.H. Campbell4, A.A. Carr1, D.B. Evans1, T.W. Yen1, T.S. Wang1 1 Surgery, Medical College of Wisconsin, Milwaukee, WI; 2Endocrinology, Medical College of Wisconsin, Milwaukee, WI; 3Pathology, Medical College of Wisconsin, Milwaukee, WI; 4 Otolaryngology, Medical College of Wisconsin, Milwaukee, WI Previous studies have suggested that variants of PTC, including the oncocytic variant, may be more aggressive, with higher rates of recurrent disease. The aim of this study was to evaluate characteristics and outcomes of patients with oncocytic variant of PTC in a contemporary cohort. Patients with oncocytic variant of PTC were retrospectively identified from 507 patients who underwent thyroidectomy between 5/09-3/15 with a diagnosis of PTC. Data collected included patient demographics, laboratory and pathology findings, imaging studies, and treatment. The cohort included 26 patients; 23 (88%) were female with a median age of 55 years (range, 27–76). All patients underwent total thyroidectomy and 21 (81%) had a central compartment neck dissection (CND; 11 [52%] prophylactic). Median tumor size was 1.8 cm (range, 0.9–6.5) and 5 (19%) patients had extrathyroidal extension. Of those who underwent CND, malignant lymph nodes (median 2 [range, 0–15]) were found in 13 patients. Lateral neck dissection was performed in 5 (19%) patients; 4 had metastatic lymphadenopathy (median 2 malignant lymph nodes [range, 0–6]). Radioactive iodine was administered to 19 (73%) patients. At a median follow-up of 21 months (range, 0.3–70), 3 (12%) patients had recurrent PTC with a median time to recurrence of 23 months (14–28). One patient with recurrent PTC underwent reoperative lateral neck dissection and died from unrelated causes, 1 has not yet had additional treatment (thyroglobulin [Tg] 13 ng/mL with biopsy-proven lateral neck disease), and 1 has Tg of 6.9 ng/mL with no imageable disease. One patient with possible persistence has a suppressed Tg of 3 ng/mL, with detectable Tg antibodies and no imageable disease. One patient with metastatic disease at the time of initial treatment died of disease at 25 months. Oncocytic variant of PTC was present in 5% of PTC patients. Although longer follow-up is needed, most (81%) patients remain disease-free, suggesting that the oncocytic variant may not represent a more aggressive variant.

Thyroglobulin is commonly used to monitor patients with differentiated thyroid cancer. It has also become an excellent biological marker for tumor persistence or recurrence. The aim is to study the prognostic value of baseline thyroglobulin levels early after near total thyroidectomy and before I131 ablation in patients with papillary thyroid cancer. Baseline neck u/s, serum thyroglobulin and anti-thyroglobulin antibodies levels were performed prospectively after near total thyroidectomy and before iodine ablation on 135 patients. Patents’ ages ranged from18 to 77. All patients had intermediate risk papillary thyroid cancer. Inclusion criteria also included absence of lymph node metastasis or bulky thyroid residual on baseline neck u/s. The study design consisted of follow up neck u/s, I131 whole body scan, serum thyroglobulin and anti-thyroglobulin levels 6 months after a high ablative dose of I131 ranging from 80 to 120mCi. Results were available for 123 patients. Successful ablation on follow up was defined as negative I131 whole body scan and neck u/s as well as serum thyroglobulin level less than 2ng/ml. Residual functioning thyroid tissue was found in 27 out of 123 cases (22%). On comparing the baseline and follow up thyroglobulin using paired t-test, a statistically significant decrease was noticed (p = 0.005). The mean baseline thyroglobulin in patients with residual functioning thyroid tissue was 39.42 and was found to be significantly higher than that of patients with no evidence of disease on follow-up (P = 0.001). The patients were then classified into 3 groups by baseline thyroglobulin level: 100. Higher levels were related to residual functioning thyroid tissue (p = 0.001). The incidence of residual functioning thyroid tissue was high in the > 100 TG group (4/5; 80%) and was found to be statistically higher than that in the < 10 and 10-100 groups; 12.3% and 31.8% respectively (p = 0.001). On multivariate analysis, the patient’s age and gender had no statistically significant predictive value (Pearson correlation - 0.161). Post-thyroidectomy baseline thyroglobulin levels in well differentiated thyroid cancer < 10 are associated with high probability of successful I131 ablation and can therefore guide further treatment and follow up planning.

Poster 714 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM LARYNGOSCOPY IN THYROID SURGERY BY GENERAL SURGEON Y. CHOI, J. LEE Surgery, Samsung Changwon Hospital, Sungkyunkwan University, Changwon, Korea (the Republic of) Preoperative and postoperative laryngoscopy has been recommended for diagnostic and treatment plans of vocal fold dysfunction, a standard procedure in all patients who undergo thyroid surgery. Laryngoscopy is a very simple procedure, performed by a trained general surgeon is sufficient. The aim of this study was to find a more selective approach by defining patients at risk of developing vocal fold palsy (VFP).

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The history of neck explorations, voice symptoms, results of laryngoscopy, and pathology were registered in all patients who underwent thyroid surgery at our institution between March and September, 2013. Patients with pathologic findings at postoperative laryngoscopy underwent reassessment of voice and vocal fold mobility 2 weeks, 3 months later. Preoperative pathologic laryngoscopy findings was detected in 5 of 568 patients (0.88%). Of the 5 patients, all patients had no history of neck surgery, 4 patients had voice symptoms. 2 patients had unilateral vocal nodule. 3 patients had unilateral VFP. 1 patient had no suspected malignancy and no voice symptoms. Postoperative laryngoscopy revealed a new development of VFP in 41 of 568 patients (7.2%). Of the 41 patients, 4 patients were performed recurrent laryngeal nerve (RLN) resection and anastomosis due to direct tumor invasion, 4 patients were performed shaved RLN methods, 2 patients had iatrogenic RLN injury. Of the 41 patients, 6 patients had no symptoms at postoperative assessment. Among then 3 patients had a new development of symptoms, and persistent VFP at reassessment of 2 weeks later. 20 patients had persistent voice symptoms and VFP at postoperative 2 weeks later. 3 months later, 5 of the 11 reassessment patients had persistent symptoms and VCP. All patients with a permanent VFP had symptoms immediately after operation, asymptomatic VFPs always recovered. Preoperative laryngoscopy is justified in symptomatic patients. Postoperative laryngoscopy is essential standards in thyroid surgery patients. It is simple procedure and helpful for decision of early voice treatment. Postoperative laryngoscopy should be reserved for symptomatic patients.

Poster 715 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM NODULAR GOITER WITH BETHESDA III CYTOLOGY. WHEN CARRYING OUT SURGERY? M. Jimenez1,2, J. Sapunar1,2, V. Iturrieta1, C. Granzotto1, G. Aguilera1 1 Medicina Interna, Universidad Frontera Temuco, Temuco, Chile; 2 Unidad Endocrinologia y Diabetes, Clinica Alemana Temuco, Temuco, Chile Thyroid nodular disease is common; therefore efforts have been made in order to bring together the US criteria to define which are the riskier. The Bethesda cytological classification has been supportive when deciding the surgical treatment; however, in patients with Bethesda III cytology, it continues to being difficult to define when to derive them to surgery. Objective: The objective of this research is the assessment of the TIRADS classification as a cancer predictor in patients with Bethesda III cytology from the ‘La Araucanı´a’ region in Chile. 41 patients with Bethesda III cytology that underwent surgery in the Clinica Alemana Temuco, between June 2012 and April 2015. The following clinical data were registered: age, sex, associated thyroid disease, and their classification according to TIRADS. The average age of the sample is 49.8 – 13.3 years and the 85.3% of the subjects were women. The T Hashimoto and familiar thyroid cancer were a 46.3 and 12.2% respectively. Carcinoma distribution according to TIRADS.

The analysis of each of the US characteristics did not show to be statistically significant to predict TC except for the microcalcifications (OR 7.5), nevertheless, when they were grouped in TIRADS, correlation was noticed. 91% of TC in nodules TIRADS 3 can be explained since they had carcinoma suspicious cytologies that triggered the surgical indication. TIRADS is a good predictor of thyroid carcinoma for this population and we believe that it could be useful to the treatment of nodular disease by general practitioners.

Poster 716 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM MICROCALCIFICATIONS ARE A GOOD INDIVIDUAL PREDICTOR OF THYROID CANCER (TC). THE ASSOCIATION OF US CHARACTERISTICS ENHANCES THE PREDICTIVE VALUE FOR THYROID CANCER M. Jimenez2,1, J. Sapunar1,2, V. Iturrieta1, G. Aguilera1, C. Granzotto3 1 Medicina Interna, Universidad Frontera Temuco, Temuco, Chile; 2 Unidad Endocrinologia y Diabetes, Clinica Alemana Temuco, Temuco, Chile; 3Radiologia, Hospital Clinico U Mayor, Temuco, Chile Thyroid nodular disease is common. The US characteristics (echogenicity, halo, calcifications, flux characteristics and adenopathies) are helpful in defining a higher risk of TC and they require cytological study. Objetive: to assess clinical and US characteristics in predicting TC, in the ‘La Araucanı´a’ region. FNAs carried out in the Clinica Alemana that were derived to surgery between June 2012 and April 2015 were studied. Clinical data were registered: age, sex, associated thyroid disease and characteristics US, cytological study (extended and cellular block) was informed according to Bethesda and were compared with biopsy. 157 FNAs, average age 45 – 14.7 years, 84.5% women, 45.8% of Hashimoto antecedent and 9% of patients with a family member that underwent surgery due to TC. Univariate analysis of the US individual characteristics did not show a significant difference, except for the analysis for microcalcifications OR 7.5 (CI: 2.63-26.4). However, when the characteristics where associated utilising TIRADS classification a positive correlation with risk of cancer was observed (Table 1) The analysis of each of the US characteristics did not show to be statistically significant to predict TC except for the microcalcifications (OR 7.5), nevertheless, when they were grouped in TIRADS, correlation was noticed. 91% of TC in nodules TIRADS 3 can be explained since they had carcinoma suspicious cytologies that triggered the surgical indication. TIRADS is a good predictor of thyroid carcinoma for this population and we believe that it could be useful to the treatment of nodular disease by general practitioners

Poster 717 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM EXPANDING THE INDICATION FOR ROBOTIC THYROIDECTOMY IN DIFFERENTIATED THYROID CARCINOMA MANAGEMENT Y. Chai1, H. Suh2, J. Woo3, H. Kwon4, J. Yi4, H. Yu4, R. Song4, J. Lee5, J. Choi5, S. Kim4, K. Lee4

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Surgery, Seoul National University Boramae Medical Center, Seoul, Korea (the Republic of); 2Surgery, Mount Sinai Beth Israel Hospital, Icahn School of Medicine at Mount Sinai, New York, NY; 3 Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of); 4Seoul National University Hospital and College of Medicine, Seoul, Korea (the Republic of); 5Seoul National University Bundang Hospital and College of Medicine, Seoul, Korea (the Republic of) Feasibility of robotic thyroidectomy (RT) is evolving in thyroid carcinoma management. Its efficacy, safety, and cosmetic benefits have been well established for an early stage differentiated thyroid carcinoma as the indication for RT has been generally limited to T1 ( £ 2cm) tumors. Although RTs are selectively performed for larger tumors, its safety and efficacy have not been well investigated. A retrospective review of consecutive differentiated thyroid carcinoma cases (n = 86) from 2009–2014 at a single institution with tumor size 2-4cm, excluding N1b (AJCC TNM), were performed comparing the bilateral axillo-breast approach (BABA, n = 21) RT versus the conventional open thyroidectomy (OT, n = 65). The average tumor size for both groups were equal (2.8 – 0.6 cm, p = 0.991). BABA RT had increased operation time (165.1 – 43.9 vs. 93.5 – 30.8 min, p = < 0.001). Vocal cord paralysis rate based on a routine POD 14 laryngoscopy evaluation were comparable for BABA and OT (transient, 19.0% vs. 9.2%, p = 0.250; permanent, 0% vs. 1.5%, p = 1.00). Postoperative hypoparathyroidism rate difference were not statistically significant for BABA RT and OT (transient, defined as PTH level < 8 pg/ml on a routine POD 1 test, 19.0% vs. 33.8%, p = 0.199; permanent, 0% for both). There were no cases of neck hematoma or mortality. The average number of retrieved central neck lymph nodes for BABA vs. OT were 2.1 – 3.3 and 1.5 – 1.9 (p = 0.757), respectively. At the time of initial radioactive iodine treatment, 11/16 (68.8%) BABA RT group had stimulated thyroglobulin level of < 1.0 ng/ml compared to 35/53 (66.0%) in OT (p = 1.00). Neither group had recurrences during the median follow up period of 32.3 months for BABA and 29.3 months for OT. BABA robotic thyroidectomy is a safe and oncologically sound treatment option for 2-4cm differentiated thyroid carcinoma for a selected group of patients. The indication for RT should not be limited based on the tumor size alone, and its role in advanced thyroid carcinoma management should be continually evaluated as the RT experience and technology evolve.

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1

Division of Endocrinology, Department of Medicine, University of Texas Health Science Center in San Antonio, San Antonio, TX; 2 Pathology, University of Texas Health Science Center in San Antonio, San Antonio, TX; 3Endocrine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY Malignancy rate of cytopathological samples classified as indeterminate (suspicious for follicular neoplasm/Hurthle cell neoplasm), Atypia of undetermined significance (AUS)/Follicular Lesion of Undetermined Significance (FLUS) varies by institution. This presents a major challenge in the era where accurate cancer diagnosis is required to minimize morbidity, decrease mortality, avoid excessive psychological burden to patients and prevent medical costs of unnecessary surgery. Our aim was to determine if the combination of ultrasound findings and FNA is better predictor of thyroid cancer in these patients. We retrospectively reviewed the electronic chart of 229 patients at our institution who had indeterminate cytology of thyroid nodules between 2008–2015 and who subsequently received either lobectomy or total thyroidectomy. The preoperative neck ultrasound images were reviewed by ECNU certified endocrinologist. All nodules were classified into four grades. Grade 1: Spongiform nodule, cystic/ solid with cystic areas in solid component, Grade 2: hyperechoic or isoechoic with regular border, cystic/solid with eccentric solid component, Grade 3: hypoechoic with regular border, Grade 4: hypoechoic with micro-calcification, irregular border, interrupted rim calcification, extra-thyroidal extension. Hyperechoic/isoechoic nodule with micro/coarse calcification, eggshell calcification and lobulated nodules were classified as grade 3.5. Patients were 20–82 years old with 89% cases females, predominantly Caucasian (60%). Preliminary data analysis of 232 nodules revealed that 47 (20%) were cancerous, of which 17 (27%) classified as classic papillary thyroid cancer (PTC) and 23 (64%) follicular variant-PTC. Our preliminary results revealed that the risk of malignancy in thyroid nodules with indeterminate cytology increases in the presence of suspicious ultrasound findings. To date, all patients with grade 4 nodules had thyroid cancer as compared to close to 20% of those with grade 2–3 nodules and none with grade 1 nodules. We hope that this classification will be helpful in identifying patients with indeterminate cytology who will benefit of observation vs surgery.

Poster 719 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM CRIBRIFORM MORULAR VARIANT OF PAPILLARY THYROID CANCER: A CLINICAL CURIOSITY S.N. Agosto Salgado1, M. Policarpio2, A. Santillan3, J.M. Bruder1, S. Ahmadi1 1 Endocrinology, University of Texas Health Science Center San Antonio, San Antono, TX; 2Pathology, University of Texas Health Science Center San Antonio, San Antonio, TX; 3Surgery, University of Texas Health Science Center San Antonio, San Antonio, TX

Poster 718 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM FINE NEEDLE ASPIRATION OF THYROID NODULES AS A PREDICTOR FOR THYROID CANCER: RETROSPECTIVE REVIEW OF 7 YEARS CYTOPATHOLOGY RESULTS AND CORRELATION WITH THYROID ULTRASOUNDS S.N. Agosto Salgado1, M. Policarpio-Nicolas2, D. Avery2, J. Bruder1, M. Sabra3, S. Ahmadi1

Papillary Thyroid Cancer (PTC) is the most common type of thyroid cancer. We present a rare case of cribriform morular variant of papillary thyroid cancer (CMV-PTC), which has an estimated prevalence 0.16% of all PTC. A 39-year-old Hispanic woman with a history of toxic adenoma treated with radioactive iodine in 2001, presented in 2014 with an ultrasound demonstrating a multi-nodular goiter with a 1.6 cm highly suspicious nodule in the right lobe. A fine needle aspiration was consistent with PTC. She underwent a total thyroidectomy with central neck dissection in 8/2014 without complications. Pathology report revealed multiple foci of carcinoma: right lobe CMV-PTC

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(1.5 cm) and two separate foci (0.1 and 0.2 cm) of well-circumscribed follicular variant of PTC; left lobe with minimally invasive 1.7cm follicular carcinoma. Immunohistochemistry was positive for TTF-1, ER, PR, beta-catenin and negative for thyroglobulin confirming the diagnosis of CMV-PTC. Four weeks after surgery the un-stimulated thyroglobulin antigen (Tg Ag) and thyroglobulin antibodies (Tg Ab) were undetectable. I131 with low dose 29.9mCi was administered in 9/2014 since non-aggressive behavior has been reported in most cases of CMV-PTC. Uptake in the thyroid bed was seen on the whole body scan. Genetic testing for familial adenomatosis polyposis (FAP), which can be associated with CMV-PTC, was negative. This case highlights the importance of special attention to the cytological and histo-pathological examination in order to render an accurate diagnosis as most reports indicate a low risk of recurrence after appropriate surgery in patients with CMV-PTC. Our patient had excellent response to initial therapy and has remained free of disease 6 months later with an undetectable TgAg and negative US. However, there is a reported case with aggressive CMV-PTC associated with paraneoplastic syndrome, which prompts further investigation in these cases.

Poster 720 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM ENDOSCOPIC THYROID CANCER SURGERY ALREADY HAVE SURPASSED THE CONVENTIONAL OPEN SURGERY - BIDIRECTIONAL APPROACH OF VIDEO ASSISTED NECK SURGERY (BAVANS) A. Nakajo, H. Arima, Y. Takae, M. Hirata, Y. Shinden, Y. Eguchi, Y. Nomoto, M. Wada, N. Hayashi, Y. Kijima, S. Natsugoe Breast & Thyroid Surgery, Kagoshima University Hospital, Kagoshima, Japan Endoscopic thyroid surgery with extracervical approaches is a safety and well-accepted technique. We have to apply these endoscopic techniques widely in thyroid cancer treatment, and aim to establish the technique of complete lymph node dissection with same or further quality than conventional open surgery. Now, we developed a new Bidirectional Approach of Video Assisted Neck Surgery (BAVANS) for endoscopic thyroid cancer surgery, and report that craniocaudal approach is extremely useful for endoscopic complete central node dissection (CCND) around the trachea. BAVANS combines different approaching pathway to the cervical lesion. Initially we performed thyroidectomy via gasless precordial approach. After thyroidectomy, only 2 small ports (2 & 5 mm)

inserted at upper neck area to get the cranio-caudal view for CCND. We could have reduced surgical port on the neck via using a new rigid laparoscope featuring variable viewing direction. Total of 32 patients with papillary thyroid cancer received BAVANS and were greatly satisfied after surgery. The average number of retrieved lymph nodes was more than conventional open surgery. There is no patient with recurrent laryngeal nerve injury and palsy. One patient had Horner syndrome by injury of cervical sympathetic nerve. BAVANS has not only a great cosmetic advantage but also provides easy access to the central node compartment. With the advent of BAVANS, endoscopic thyroid cancer surgery already have surpassed the conventional open surgery.

Poster 721 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM COMPARATIVE STUDY OF THE QUALITY OF LIFE BETWEEN CONVENTIONAL OPEN AND ROBOTIC TOTAL THYROIDECTOMY USING A BILATERAL AXILLO-BREAST APPROACH W. Kim, J. Jung, J. Lee, S. Hwang, H. Park Surgery, Kyungpook National University, Daegu, Korea (the Republic of) Robotic thyroidectomy is known to be effective and comparable to conventional open thyroidectomy in the clinicopathologic oncological outcome of papillary thyroid carcinoma (PTC). The purpose of this study was to compare the long-term quality of life (QoL) between conventional open and robotic total thyroidectomy from retrospective review. From January 2011 to July 2013, 229 patients who were followed up for at least 1 year after thyroidectomy and randomly selected were enrolled in this study. One hundred twelve patients had robotic thyroidectomy, and 117 patients received open thyroidectomy, due to PTC. QoL, including overall satisfaction, cosmetic results, voice/ sensory change, postoperative pain and impairment of swallowing, neck/shoulder movement, and physical/psychological activity, were recorded through telephone conversations. The follow-up period was 32.3 – 6.3 months. The satisfaction levels of the overall and cosmetic results were 8.95 – 1.23, 8.40 – 1.20 and 3.86 – 0.04 and 3.21 – 0.10, for robotic and open surgery, respectively; these differences were statistically significant (p = 0.002 and < 0.001 for robotic and open surgery, respectively). The sensory change might be more noticeable with robotic thyroidectomy (p = 0.064). There were no differences in the results concerning voice/sensory change, pain, other impairment of swallowing, neck/ shoulder movement, and physical/psychological activity among the two groups. Regarding transient hypocalcemia, 29 patients (25.8%) and 42 patients (35.8%) showed complications after robotic and open

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 thyroidectomy (p = 0.001). The same results were obtained for recurrent laryngeal nerve palsy. A serum stimulated Tg level was 1.52 – 0.62 ng/ml and 1.12 – 0.52 ng/ml in the robot and open groups, respectively, showing no difference. Robotic thyroidectomy shows comparable results to conventional open thyroidectomy in terms of the postoperative clinicopathologic outcome and long-term QoL.

Poster 722 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM MACMILLAN NATIONAL THYROID CANCER NURSE SPECIALISTS: NEW MODELS OF WORKING IN THE UK L. Moss Clinical Oncology, Velindre Cancer Centre, Cardiff, United Kingdom A national survey by Thyroid Cancer Forum-UK in 2009 demonstrated wide variation in access to clinical nurse specialist (CNS) support for thyroid cancer patients in the UK. Patients in some areas had no access while others were referred to CNSs in vascular surgery, general endocrinology, sarcoma and palliative care. Due to relatively small patient numbers and financial constraints within the NHS it is not feasible for every hospital to fund a thyroid cancer specific CNS. An alternative way of working was therefore developed in cooperation with Macmillan Cancer Support in order to plug the gaps and optimise patient support across the UK. Two posts have been created in a pilot project - i) national thyroid cancer CNS, who has a local clinical case load in Cardiff plus providing telephone and email support for patients in the pilot centres (Oxford, Norwich, Glasgow) and ii) thyroid cancer information nurse specialist based on the Macmillan Support Line providing information and support to patients and their families across the UK. The posts are funded for 3 years and 2 years respectively by Macmillan Cancer Support. The National Thyroid Cancer CNS post holder has developed excellent links at the 3 pilot sites and is actively involved via videolinkage with the mutidisciplinary team meetings. Support is being provided by telephone and email to patients. Links are also being developed with other UK teams. The information nurse specialist is busy providing telephone support to callers across the UK and is maintaining an up to date information resource. Both nurses are involved in the development of educational resources for CNSs through national meetings and on line CPD modules via the Macmillan LearnZone as well as working towards standardising patient information across the UK and strengthening of the network of CNSs supporting thyroid cancer patients. The project will increase UK patients’ access to a thyroid cancer specific CNS and will improve provision of information and support for patients and their families. If this innovative model of working proves effective it is hoped to expand it to other centres and also to utilise a similar process to help support patients across the UK with other rarer cancers.

Poster 723 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM THYROID CANCER FORUM - UK (TCF-UK): THE FIRST 10 YEARS L. Moss Clinical Oncology, Velindre Cancer Centre, Cardiff, United Kingdom Thyroid Cancer Forum-UK (TCF-UK) was established in 2005 as an electronic discussion forum and support network for senior thyroid

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cancer specialists across the UK in order to facilitate patient management, service delivery, data collection and research. No national thyroid-cancer-specific organisation previously existed in the UK. Membership is free and multidisciplinary and open to consultants and senior scientists. In 2007, TCF-UK changed from an e-mail-only to a web based organisation and added: document library, secure databases for ATC and MTC, information for the general public. In 2009, membership was extended internationally and includes Australia, Belgium, Canada, Czech Republic, Netherlands, Panama, Republic of Ireland and USA. Users can access opinions from its 250 + members, to discuss difficult cases, management protocols and research ideas. Members receive journal abstracts and meeting announcements via e-mail, and can log in to the website to access the complete archive. A survey was undertaken in 2015 to gain feedback from members. Member specialty: clinical oncology 37%, surgery ENT-23%, endocrine-16%, pathology 11%, endocrinology 7%, radiology 4%, nuclear medicine 2% - Journal abstracts useful? 100% - Have you found case discussions informative? Yes 93% - Have you been made aware of the following: -articles you would not have seen otherwise? Yes 98% - thyroid cancer meetings? Yes 66% - clinical trial availability? Yes 70% - clinical trial results? Yes 79% - new research funding options? Yes 52% - Do you feel TCF-UK provides impartial information? Always 68%, Mostly 32% - Have you requested a journal article based on the abstract service? Yes 77% - Have you changed any aspect of your practice based on TCF-UK activities? Yes 39% The 2015 user survey demonstrates that TCF-UK raises awareness of abstracts, research areas and clinical trials, and effectively disseminates information on meetings as well as published guidelines. More than a third of respondents stated they had changed their clinical practice as a result of TCF-UK activities. The reported changes included individual case discussions, risk stratification, radioiodine activity, USS staging, pathological staging, prophylactic nodal surgery.

Poster 724 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM ONE SIZE DOES NOT FIT ALL; A DOSIMETRY CASE REPORT T.V. Bogsrud, C. Stokke Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway Radioiodine treatment of metastatic differentiated thyroid cancer is most commonly performed with a fixed activity of 100-200 mCi. The resulting absorbed doses to metastases and organs at risk are usually not considered. We have treated a 55 year old female with follicular thyroid cancer with a large metastasis to the skull and brain abutting the optical nerve with a high dosage of I-131 based on a dosimetric planning study. The patient was previously treated with 100 mCi I-131 without clinical or volumetric tumor response. A dosimetric planning study with 0,7 mCi I-131 was therefore performed prior to a second therapy. SPECT/CT and planar scans were obtained on the day of oral administration and on 4 consecutive days. Uptake and washout curves were used to calculate absorbed doses per administered unit activity. The optical nerve was identified as the dose limiting organ (tolerance < 52 Gy) for this patient. Based on the calculations treatment with 380 mCi under stimulation with rhTSH was performed 3 months after the planning study. I-131 uptake and washout were also investigated during treatment. The dosage of 380 mCi I-131 resulted in an tumor dose of 60 Gy and the dose to the surface of the optical nerve was 35 Gy. The

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Poster 726

agreement between planning and treatment kinetics was excellent. The treatment effect was good with almost 40% tumor volume shrinkage measured on CT, reduced FDG uptake on PET/CT (see figure), and reduced headache and visual improvement. Retrospective analyses of the first treatment (100 mCi) were also performed, revealing an absorbed tumor dose of < 10 Gy, which explains the lack of response at that point. Based on planning dosimetry a patient with FTC with a large brain and skull metastasis was treated with 380 mCi per oral I-131 under stimulation with rhTSH. The high dosage resulted in a tumor dose of 60 Gy, was well tolerated, and the treatment response was very good. A standard dosage of 100-200 mCi would probably have resulted in a too low tumor dose.

Poster 725 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM SECOND PRIMARY MALIGNANCY IN PATIENT WITH THYROID CARCINOMA N. Cihangiroglu, S.N. Sendur, B. Erbas, S. Dagdelen, T. Erbas Hacettepe University, Medical School, Ankara, Turkey Differentiated thyroid carcinoma is the most commonly diagnosed endocrine malignancy. The incidence in thyroid cancer is rising throughout the world. Furthermore, thyroid cancer survivors have an increased risk of developing second primary malignancies relative to the general population. The purpose of this study was to evaluate the prevalence of a second malignancy in patients treated for thyroid cancer. Medical records of patients with diagnosis of papillary or follicular thyroid cancer were reviewed. The data of 69 patients [73.9% females (age 55.1 – 13.7 years), 26.1% males (age 47.3 – 14.8 years)] were included. During the study period, 23 patients (33.3%) were diagnosed with second primary malignancy either preceding or following the thyroid cancer. Second primary malignancy was observed in 17.6% of men and 41.7 % of women; however difference was not statistically significant. Twenty tumors (86.9%) preceded the thyroid cancer and three tumors (13.1%) occurred after thyroid cancer. The mean interval between first and second malignancy was 9.23 – 9.6 years. The most common secondary primary cancers were breast (n: 13), renal cell carcinoma (n:3), gynecologic cancer (n:2), parotid cancer (n:1), Hodgkin lymphoma (n:1), neuroblastoma (n:1), stomach cancer (n:1), and mycosis fungoides (n:1). The following characteristics were not significantly different between the patients with second primary malignancy and thyroid carcinoma: thyroid tumor size, thyroid cancer stage and thyroid cancer histology. Developing thyroid cancer after a primary breast cancer has a higher risk than developing breast cancer after thyroid cancer. To

Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM DIAGNOSIS OF FOLLICULAR VARIANT OF PAPILLARY THYROID CANCER: IS FROZEN SECTION A GUIDE FOR THE SURGEON H. Kaya2, B. Ertas1, N. Kurtulmus5, U. Ince3, S. Giray4, M. Duren2 1 Otorhinolaryngology, Acibadem University Medical School, Istanbul, Turkey; 2General Surgery, Acibadem Maslak Hospital, Istanbul, Turkey; 3Pathology, Acibadem University Medical School, Istanbul, Turkey; 4General Surgery, Florence Nightingale Hospital, Istanbul, Turkey; 5Endocrinology, Acibadem University Medical School Istanbul-Turkey, Istanbul, Turkey Fine needle aspiration biopsy (FNAB) is a useful tool in diagnosis of papillary thyroid cancer (PTC). Follicular variant of PTC (FVPTC), however, is difficult to diagnose preoperatively with FNAB as well as peroperatively with frozen section (FS). In this retrospective study we aimed to determine the sensitivity and agreement ratio of these two tests in patients who have the final diagnosis of FVPTC. In Thyroid Clinic of Acibadem Hospital 100 patients were operated and had the diagnosis of FVPTC between the period of November 2013 to November 2014. The patients were operated by the same surgeon, the FNAB and FS examinations were evaluated by the same cytopathologist and histopathologist, respectively. The sensitivity of FNAB and FS was determined, Kappa test was used to determine the agreement ratio of these two tests. 78 patients were operated with bilateral total thyroidectomy, 22 patients with diagnostic lobectomy underwent completion thyroidectomy. FNAB results were benign (25%), atypical cells/follicular lesion of unknown significance (AFCUS) (14%), follicular neoplasia (31%), suspicious for PTC (18%), PTC (12%). FS results were benign (27%), follicular neoplasia (46%), suspicious for PTC (13%), PTC (14%). Surgery was performed for patients with larger than 3 cm nodules and benign FNAB, with nodules of any size and twice AFCUS FNAB, with nodules of any size and FNAB results of follicular neoplasia, suspicious for PTC and PTC. The sensitivity for FNA for FVPTC is 32.4% and the sensitivity for FS for FVPTC is 34.1%. There is a moderate agreement among these two tests. K: 0.423 (95% CI 0.078-0.747). Patients whose FS diagnosis were determined as suspicious for PTC or PTC were operated with bilateral total thyroidectomy as initial surgery. Initial surgical strategy was changed in 17% of the patients after receiving the FS diagnosis of suspicious for PTC or PTC. Although frozen section is debatable in patients who undergo thyroid surgery for thyroid nodule, our results show that FS may change the initial surgical strategy and decrease the risk of a completion thyroidectomy.

Poster 727 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM ADULT THYROGLOSSAL DUCT CARCINOMA: A CASE SERIES R. Akram1, J.J. Wiltshire1, J. Wadsley2, S. Balasubramanian1,3 1 The Medical School, University of Sheffield, Sheffield, United Kingdom; 2Weston Park Hospital, Sheffield, United Kingdom; 3 Sheffield Teaching Hospitals, Sheffield, United Kingdom Thyroglossal duct carcinoma (TGDC) is extremely uncommon. Most such cancers are of thyroid origin. It is unclear whether the

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 presentation and prognosis of TGDC are different to thyroid cancer. Although current treatment protocols follow those of primary thyroid cancer, there is controversy over the need for and extent of thyroid and lymph node surgery in these patients. The aim of this study was to study the presentation, treatment strategies and clinical outcomes in a series of patients with TGDC in a specialist thyroid oncology unit. Of 637 patients with a new diagnosis of thyroid cancer over a 15 year period, 4 patients (0.6%) with TGDC were identified. One further patient diagnosed before this period was also included. Details of demographics, presentation, diagnosis, management and outcomes were collected. 4 females and 1 male with a median (range) age of 39 (21-45) years were treated for papillary carcinoma arising in the thyroglossal duct. Treatment usually involves cyst excision or Sistrunk’s procedure, followed by a total thyroidectomy (TT), I131 therapy and TSH suppression therapy (TST). 3 patients underwent Sistrunk’s procedure; the other 2 had cyst excision only. 4 patients then proceeded to TT. 1 patient underwent central compartment neck dissection. The patient who didn’t undergo TT later had 1 lymph node excised, which turned out to be benign. All 4 patients who underwent TT went on to have I131 therapy. All patients are either continuing under TST or have received at least 4 years of TST. Tumours were staged pT1 (n = 1), pT1b (n = 2), pT3 (n = 2), pN0 (n = 1), pNx (n = 4), R0 (n = 4) pR1 (n = 1). Additional tumour foci in the thyroid were found in two patients, these cases were considered to be multifocal. No patients had clinical evidence of lymph node involvement at presentation. Recurrence occurred in 1 patient at 6 months. At a median follow up of 81 months, all patients were disease free. Patients with TGDC have papillary subtype and do well with standard treatment in accordance to thyroid cancer guidelines. There are only a few published series and a systematic review will help summarise the existing knowledge base and clarify the similarities and differences with primary thyroid cancers.

Poster 728 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM SERIAL THYROGLOBULIN MONITORING AFTER RADIOIODINE THERAPY IN PTC PATIENTS WITH LOW TO INTERMEDIATE RISK OF RECURRENCE M. Hou, Y. Lin Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China The undetectable thyroglobulin level (Tg £ 0.1ng/mL) on LT4 suppression therapy (TSH < 0.01mU/L) holds high negative predictive value in disease-free survival of papillary thyroid cancer (PTC) patients. Data regarding short-term serial surveillance on Tg after radioactive iodine (RAI) therapy has rarely been reported. The present study aims to observe the changing of Tg within 4 weeks after RAI in PTC patients with low to intermediate recurrence risk. A total of 62 patients with PTC who have undergone total thyroidectomy were enrolled in this study. They were stratified as low to intermediate risk of recurrence according to ATA guidelines. Tg, Tg antibody (TgAb) and corresponding thyrotropin (TSH) were collected before and the 1st,2nd,3rd,4th week after RAI therapy, which were defined as Tg0*4 respectively, and so were the definition of TSH and TgAb. The index of remnant thyroid RAI uptake was measured and reviewed by 3 experienced nuclear medicine physicians. Patients were divided into 2 groups according to their Tg4 levels: G1( £ 0.1ng/mL, negative), G2 ( > 0.1ng/mL, positive). Then the proportion varying-trend curve of undetectable-Tg from Tg1 to Tg4 was obtained. Univariate and

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The proportion of patients with undetectable-Tg in all was showed in the graph.The proportion rises with time. multivariate analyses were done for the correlations between undetectable Tg and tumor features. At the end of the 4-week observation, 47% patients manifested undetectable Tg. On the one hand, it provides new evidence to foreknowing disease-free survival earlier in clinical management of DTC with low to intermediate risk of recurrence. On the other hand, it helps ease patients’ anxiety. At a specific time point short after RAI therapy, the proportion that Tg turns negative has convincing correlations to thyroid remnant index (p = 0.001),TNM staging (p = 0.007), and age (p = 0.016). Among which, remnant thyroid is significantly related (OR = 15.819). During the observation, the proportion of Tg-turning-negative keeps rising. The Tg level in near-half patients ended undetectable 4 weeks after RAI, which provides convincing evidence to foreknowing disease-free survival. Remnant thyroid is significantly related to Tg turning negative.

Poster 729 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM CONTINUED CARE OF THYROID CANCER PATIENTS THROUGH TELEMEDICINE FROM A TERTIARY CARE CENTRE: EXPERIENCE OF MORE THAN ONE DECADE IN A RESOURCE CRUNCH ENVIRONMENT P. Pradhan1, B. Mohanty2, A. Mohanty2, A. Prashant1, A. Singh1, S. Verma1, M. Raveena1, N. Kumar1, A. Arya1, S. Mishra3,4 1 Nuclear medicine, SGPGIMS, Lucknow, India; 2SCB Medical college, Cuttack, India; 3Endocrine surgery, SGPGIMS, Lucknow, India; 4School of Telemedicine and Bioinformatics, SGPGIMS, Lucknow, India Radioiodine therapy is an essential component of thyroid cancer management besides surgery and thyroxine and most of the patients require lifelong follow up at timed intervals.This follow up interval is decided on risk status of thyroid carcinoma and it needs visit to hospital in person along with family members. Nuclear medicine therapeutic facility for high dose radioiodine therapy is not available in the eastern zone of India. This is a retrospective study to assess management of thyroid cancer patients following surgery in a resource crunch environment through telemedicine. Tele-referral, tele-consultation and tele follow up modules were adopted in 252 patients (both new and previously treated with radioiodine) since 2004 to 2014 which was done twice in a month. Interactive video-conference through tele link was done

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between the surgeon, patient and Nuclear Physician followed after exchange of medical data over satellite based communication (256kbps) provided by ISRO and also with 100 mbps bandwidth leased line provided by National Knowledge Network (NKN) between SGPGIMS, Lucknow, India and SCB medical college, Cuttackwhich is at a distance of 1500 kms. Radioiodine therapy scheduling was done in 242 thyroidectomy patients.Tele-follow up in 224 post-therapy patients covered all the elements as per the protocol e.g. review of serum thyroglobin level, TSH level, radiology of the chest etc and there were 832 tele follow ups which includes early recurrence detection, thyroxine dose titration and assurance of well being. 74 patients didn’t came to Lucknow after 3 visits because of free of disease and continued to be in telefollow up at timed interval. Eighteen patients who were lost to follow-up on physical visits turned up for tele-visits. There is increase in the number of tele-follow ups over long period in more than 10 years which implies patient acceptance because of reasonable satisfaction, saving travel time and cost. The amount of cost incurred in televisits is one third of personal visits to the hospital. This study provides an alternative way of continued care of thyroid cancer patients following surgery permitting better resource utilisations by avoiding significant travel time and cost.

Poster 730 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM OPTIMAL TIMING OF MULTIKINASE INHIBITOR INITIATION IN RADIOACTIVE IODINE REFRACTORY ASYMPTOMATIC PATIENTS WITH DIFFERENTIATED THYROID CANCER - A GLOBAL NON-INTERVENTIONAL STUDY (RIFTOS MKI) M.S. Brose1, J.W. Smit2, C. Lin3, F. Pitoia4, M. Fellous5, M. Schlumberger6, I. Sugitani7 1 Department of Otorhinolaryngology: Head and Neck Surgery, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; 2Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; 3Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; 4 Division of Endocrinology - Hospital de Clı´nicas, Universidad de Buenos Aires, Buenos Aires, Argentina; 5Bayer Healthcare Pharmaceuticals, Whippany, NJ; 6Institut Gustave Roussy, Villejuif, France; 7Department of Endocrine Surgery, Nippon Medical School Graduate School of Medicine, Tokyo, Japan There are limited treatment options for patients (pts) with Radioactive Iodine (RAI)-refractory progressive Differentiated Thyroid Cancer (DTC). Although there is consensus that multikinase inhibitor (MKI) therapy should be considered in pts with progressive disease with considerable tumor load or symptomatic disease, uncertainty exists on optimal timing to treat with a MKI for asymptomatic pts with RAI-refractory progressive DTC. RIFTOS is an international prospective, open-label, multicenter, non-interventional study with a primary objective to compare the time to symptomatic progression (TTSP) from study entry in asymptomatic pts with RAI-refractory progressive DTC for whom there is a decision to initiate MKIs at study entry with asymptomatic pts with RAI-refractory progressive DTC for whom there is a decision to not initiate MKIs at study entry. Secondary objectives are overall survival, progression free survival, post progression survival, tumor response, dosing and treatment duration, and safety. Pts aged ‡ 18 years with histologically/cytologically documented DTC, who do not have symptoms related to DTC and have not received previous treat-

ment with MKIs for advanced disease are eligible. Patients may receive any therapy for RAI-refractory DTC including sorafenib or other MKI if indicated and decided upon by the treating physician. Planned enrollment is approximately 700 pts from about 30 countries across the world. As of June 2015, enrollment is approximately 18 patients. Final analysis will be performed once the last enrolled pt has been followed for 24 months. Planned enrollment is approximately 700 pts from about 30 countries across the world. As of June 2015, enrollment is approximately 18 patients. Final analysis will be performed once the last enrolled pt has been followed for 24 months.

Poster 731 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM LENVATINIB AND THE EFFECT OF AGE ON OVERALL SURVIVAL FOR PATIENTS WITH RADIOIODINEREFRACTORY DIFFERENTIATED THYROID CANCER M.S. Brose1, A. Teng2, P. Rietschel2, M.A. Habra3 1 Department of Otorhinolaryngology: Head and Neck Surgery, The Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; 2Eisai Inc., Woodcliff Lake, NJ; 3Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houtson, TX We recently described for the first time that lenvatinib (LEN) improved overall survival (OS) in older ( > 65 years) patients (pts) compared with placebo (PB; hazard ratio 0.53; 95% confidence interval 0.31-0.91; P = 0.020) using data from pts with radioiodinerefractory differentiated thyroid cancer (RR-DTC) from the phase 3 SELECT trial. Median OS for older and younger ( £ 65 years) pts, respectively, was: LEN, not reached in either age group; PB, 18.4 months and not reached. Median progression-free survival (PFS; months) for older and younger pts, respectively, was: LEN, 16.7 and 20.2; PB, 3.7 and 3.2. Here we identify additional factors that may have contributed to this finding. Pts with progressive RR-DTC stratified by region, prior VEGFtargeted therapy, and age, were randomized 2:1 to LEN or PB (younger: LEN, n = 155; PB, n = 81 and older: LEN, n = 106; PB, n = 50). The initial subgroup analysis of efficacy by age was prespecified; the current exploratory analyses further investigates additional factors that may have contributed to, or been associated with, the improvement in OS in pts aged > 65 years. There was a significant correlation between PFS and OS in both age groups (P < 0.001 for both), as well as a significant correlation between maximum percent change in tumor size and OS (younger, P = 0.004; older, P < 0.001). In an analysis of age as a continuous variable across both arms, and its correlation with OS, a trend for significance was observed (P = 0.082). There was no significant correlation between baseline or maximum postbaseline thyroglobulin levels and OS in either age group. The duration of LEN treatment was similar for both older (13.5 months) and younger (13.9 months) pts, although older pts had a shorter median time-to-first-dose reduction compared with younger pts (1.4 months and 3.1 months, respectively). This likely contributed to the significantly lower median LEN dose intensity observed in older vs younger pts (15.9 mg/ day vs 17.5 mg/day; P < 0.001). LEN improved OS in older pts with RR-DTC from the SELECT trial in spite of a lower median dose intensity of LEN in this group. Decrease in overall tumor size and PFS correlated with OS in both age groups.

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Poster 732 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM EPIDEMIOLOGICAL DATA ON THYROID CANCER FROM A SINGLE PORTUGUESE TERTIARY REFERRAL CENTER, 1998–2007 D. Macedo, A. Mayer, J. Simo˜es-Pereira, H. Vilar, E. Limbert, V. Leite Endocrinology, Instituto Portugueˆs de Oncologia de Lisboa, Francisco Gentil, Lisboa, Portugal Thyroid cancer incidence is increasing worldwide over the last few decades. The widespread use of thyroid imaging, particularly ultrasound is partially responsible for this trend, but the causes are still highly debated. The aim of this study was to examine thyroid cancer prevalence patterns and characteristics in Lisbon Portuguese Oncology Institute (LPOI). Data from patients diagnosed with thyroid cancer between 1998 and 2007 from the database of the South Region of Portugal Oncology Registry and Endocrinology Department of LPOI. A Retrospective analysis of the histological patterns by sex, age, staging and cause-specific survival was performed. Cause-specific survival was estimated and stratified according to age and sex in each stage. Thyroid cancer was diagnosed in 2146 patients between 1998– 2007. The mean age at diagnosis was 50.0 – 16.3 years; 79.4% were women. 83.7% presented papillary thyroid carcinoma (PTC), 9.4% follicular thyroid carcinoma (FTC), 3.2% medullary thyroid carcinoma (MTC) and 1.4% anaplastic thyroid carcinoma (ATC). The prevalence rate increased by 7.3% per year (1998: n = 138; 2007: n = 283), which ocurred mainly due to PTC (prevalence rate increase of 7.9% per year). PTC, FTC and MTC were mostly diagnosed at the 5th decade of life, while ATC was mostly diagnosed between 70–79 years. Overall, the prevalence of thyroid cancer increased for all ATA risk stratification groups, more pronounced for ATA stage I cases (1998: n = 57; 2007: n = 134). The 5-years cause-specific survival was 92.5% (PTC: 95%; FTC: 89%; MTC: 77%; ATC: 6%). Cause-specific survival according to sex and age was associated with a better prognosis for female gender and younger age at diagnosis ( < 45 years), respectively. In our series, the increasing prevalence of thyroid cancer is mainly due to PTC. The increase was more prevalent in women and occurred for all ATA risk stratification subgroups. The cause-specific survival rate is globally similar to the rates reported in the literature for all histotypes. Female gender and younger age at diagnosis appear to be related with a better outcome.

Poster 733 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM CLINICOPATHOLOGICAL FEATURES OF SURGICAL CASES FOR LONG FOLLOWED-UP HASHIMOTO’S DISEASE S. Kikuchi1, S. Uchino1, K. Ishikawa1, S. Watanabe1, H. Takahashi1, S. Noguchi1, Y. Hiroto2 1 Surgery, Noguchi Thyroid Clinic, Beppu, Japan; 2Pathology, Noguchi Thyroid Clinic, Beppu, Japan We examined the clinicopathological features of surgical cases for long followed-up Hashimoto’s disease (HD). Points of interest 1. Patient’s age, gender 2. Preoperative follow-up period between onset of symptom and surgery 3. Preoperative follow-up period between beginning of thyroid hormone therapy and surgery 4. Histological characteristics of HD

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334 cases of Patients with HD and a grossly enlarged thyroid who underwent surgery in 2004-2013 at our clinic, with resected thyroid tissue weighing ‡ 90 g (mean 163.5 – 70.6 g), were included (G). 33 cases of patients with HD and malignant lymphoma (ML), and 82 cases of patients with HD and papillary thyroid carcinoma (PC) in same periods were also included as a control. Patients with HD were followed-up ‡ 5 years by annual thyroid function tests, ultrasonography with fine needle aspiration cytology when necessary. Patients age, gender of group G was 59.0 – 11.8 (37–84) years old, male/female = 6/28, group ML was 72.2 – 8.2 (53–84) years old, male/female = 3/30, group PC was 55.2 – 14.6 (16–87) years old, male/female = 1/81. Age of Group ML was significantly higher than that of group G and PC. (p < 0.05) The durations between surgery and symptom onset in group G, ML and PC were 15.3 – 11.3, 25.1 – 14.2, and 18.8 – 12.7 years, respectively. The duration of group ML was significantly longer than that of group G. (p < 0.05) The durations between surgery and HD diagnosis in group G, ML and PC were 13.7 – 11.5, 16.8 – 10.7, and 15.8 – 10.0 years, respectively. There was no significant difference between 3 groups. Severe lymphocyte infiltration were observed in background HD on final pathology of group G, ML and PC were 61.8 % (21/34), 48.5 % (16/33) and 13.4 % (11/82), respectively. Background HD in group G and ML was significantly severely progressed than that in group PC. Some patients with HD should be followed-up as long as possible because they may have a grossly enlarged thyroid and malignancy for more than 13 years and 16 years followed-up. As most cases with a grossly enlarged thyroid showed severe lymphocyte infiltration at final histology, and may progress to malignant lymphoma in future, surgery should be necessary.

Poster 734 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM RAI UPTAKE IN THE PELVIS: FALSE POSITIVE OR THYROID CANCER METASTASES? S. Khare1, C. Veloski2, J. Yu3 1 Department of Endocrinology, Temple University Hospital, Philadelphia, PA; 2Department of Endocrinology, Fox Chase Cancer Medical Center, Philadelphia, PA; 3Department of Nuclear Medicine, Fox Chase Cancer Center, Philadelphia, PA Radioiodine whole body scintigarphy (RAI WBS) is often used to evaluate for persistence or recurrence after total thyroidectomy (TT) for differentiated thyroid cancer (DTC). A thorough understanding of physiologic and pathologic uptake is crucial to avoid diagnostic error leading to unnecessary treatment or incomplete evaluation. We present a case of RAI uptake in the pelvis due to an ovarian mass after TT for papillary thyroid cancer (PTC). A 33 year old woman presented with a 3cm thyroid nodule. FNA was + for PTC and BRAF V600E mutation. Findings after TT with CCLND: Stage I T2N0Mx PTC, TSH-0.11, FT4-1.7, Tg-0.8, TgAb < 1. Since the risk for persistence /recurrence was intermediate due to + BRAF, RAI ablation with 53 mCi of I-131 was performed. Both pre and post treatment scans showed no evidence of iodine avid tissue in neck, but midline activity in the pelvis was present. The intensity was greater in posterior view and thought to be retained menstrual blood in the uterus. Since pelvic activity persisted after ablation, CT of the pelvis was performed that showed an ovarian mass. Differential diagnosis includes ovarian cystadenoma or adenocarcinoma, teratoma, or struma ovarii. DTC metastases to ovary and uterus have been reported but are extremely rare. Surgery to resect the mass is scheduled. We await final surgical pathology to provide definitive diagnosis. RAI WBS is a sensitive technique for the detection of DTC, but it is not specific for thyroid tissue. Accurate interpretation requires an

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understanding of the normal physiologic distribution of RAI and physiologic and pathologic variants of RAI uptake. False positives can occur due to retention of RAI in body fluids, contamination, RAI uptake in non-thyroidal neoplasms, inflamed tissues, or in tissues with the ability to trap iodine or metabolize thyroid hormone. The experienced nuclear medicine physician can usually differentiate malignant from physiologic RAI uptake; however, some findings require additional imaging/evaluation. A thorough knowledge of non-thyroidal causes of false + RAI uptake and clinical judgement should guide the interpretation and evaluation.

Poster 735 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM PAPILLARY THYROID CARCINOMA IN INSULINOMA PATIENTS: SIMPLE COINCIDENCE, MEN 1 SYNDROME OR EFFECT OF HYPERINSULINEMIA? R.A. Trifanescu1,2, I. Baciu1,2, D. Ioachim3, A. Dumitrascu4, A. Goldstein5, D. Neamtu5, O.G. Trifanescu6,7, C. Poiana1,2 1 Endocrinology, ‘‘Carol Davila’’ University of Medicine and Pharmacy, Bucharest, Romania; 2Pituitary disease and neuroendocrine tumors, ‘‘C.I. Parhon’’ National Institute of Endocrinology, Bucharest, Romania; 3Pathology, ‘‘C.I. Parhon’’ National Institute of Endocrinology, Bucharest, Romania; 4Radiology and Medical Image, ‘‘C.I. Parhon’’ National Institute of Endocrinology, Bucharest, Romania; 5Nuclear Medicine, ‘‘C.I. Parhon’’ National Institute of Endocrinology, Bucharest, Romania; 6Medical Oncology, ‘‘Al. Trestioreanu’’ Institute of Oncology, Bucharest, Romania; 7Medical Oncology, ‘‘Carol Davila’’ University of Medicine and Pharmacy, Bucharest, Romania Insulin stimulates proliferation of thyroid cells in culture. Hyperinsulinemia is associated with increased thyroid volume and nodule prevalence. Aims: To assess prevalence of thyroid nodules and differentiated thyroid carcinoma in patients with insulinoma. Twenty-five patients (14 F/11 M), aged 49.1 – 14.1 years, diagnosed with insulinoma between 2000–2014 were retrospectively reviewed. Seven patients were resident in iodine deficient areas. Thyroid function tests (TSH, FT4), thyroid ultrasound were performed; fine needle aspiration biopsy (FNAB) was performed in suspicious nodules. Histology confirmed the diagnosis of differentiated thyroid carcinoma. Body mass index was 30.4 – 7.5 kg/m2 at diagnosis; 9 patients were obese. Morning fasting glucose was 49.7 – 24.6 mg/dL; median morning fasting insulinemia was 34.8 lIU/mL (25th percentile: 33.5, 75th percentile: 65.25 lIU/mL). Median duration of hyperinsulinemia, estimated as time between the onset of hypoglycemic symptoms and diagnosis, was 2 years. Median insulinemia recorded simultaneously with hypoglycemia nadir during 72-hour fast was 28 lIU/mL. All patients, but one, were euthyroid, with median TSH = 0.77 mIU/L (25th percentile:0.47, 75thpercentile: 1.3 mIU/L). Median thyroid volume was 10.5 ml (25th percentile:8.8, 75th percentile:13.1 ml). Non toxic multinodular goiter was present in 8 patients (32%) and toxic multinodular goiter in one patient (4%). Differentiated thyroid carcinoma was diagnosed in 3 patients (12%). Pathology was: follicular variant of papillary thyroid cancer (3/1.2 cm diameter) in one patient, submitted to radioiodine therapy (150 mCi 131I, Tgl = 0.9 ng/mL, antiTgl Ab = 7 IU/ml); bilateral, encapsulated multifocal sclerosing variant of papillary thyroid carcinoma in a patient with MEN1 syndrome (associating primary hyperparathyroidism, nonfunctional pituitary adenoma); unifocal papillary microcarcinoma in one patient. Insulinoma patients may have an increased prevalence of nodular goiter and thyroid carcinoma. Further larger, multicentric studies are necessary to confirm this association and to identify underlying mechanisms.

Poster 736 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM PAPILLARY THYROID MICROCARCINOMA: IS SMALLER REALLY BETTER? A. Gargya1,2, E. Tabet1,3, E. Chua1,3 1 ENDOCRINOLOGY, ROYAL PRINCE ALFRED HOSPITAL, Sydney, NSW, Australia; 2University of New South Wales, Sydney, NSW, Australia; 3University of Sydney, Sydney, NSW, Australia Papillary thyroid microcarcinoma (PTMC) is defined as a papillary carcinoma (PTC) measuring £ 10mm in diameter according to the WHO classification. Gross lymph node (LN) metastases can be present in approximately 35% of patients with differentiated thyroid cancer. PTMC rates of LN and distant metastases occur with lower frequency compared with classical PTC. We herewith present a patient, along with our institution’s case series of PTMC (see Table 1), where the initial clinical presentation was of a lateral neck mass due to gross LN PTC metastases. Our index patient (Patient 1) presented with a two-month history of a right supraclavicular neck mass. Ultrasound of this region showed a 4cm cystic lesion. Fine needle aspiration thyroglobulin was strongly positive; cytology was inconclusive. A repeat neck ultrasound showed three abnormal subcentimetre LN in the right lateral neck with no intrathyroidal lesion detected. Post-surgical histopathology demonstrated a strikingly small unifocal 0.5mm classic PTMC in the right hemithyroid, 0.7mm from the surgical margin. There were multiple foci of lymphovascular invasion but no extrathyroidal extension or tumour fibrosis and BRAF mutation was negative. Metastatic PTC was found in 16 of 65 lateral cervical LN. Metastatic PTC was found in 8 of 13 level VI LN, one with extranodal extension. The tumour was staged IVA by AJCC 2010 parameters. In our institution we have previously reported an incidence of lateral LN metastases of 11.6% in ‘non-incidental’ (i.e. with a pre-operative diagnosis) PTMC; metastases showed association with extrathyroidal extension (OR 4.7) and lymphovascular invasion. Other published risk factors for lateral LN metastases in PTMC include male sex, age < 45 years, tumour fibrosis, superficial tumour location and BRAF mutation positivity. This case highlights that there remains a minority of PTMC that behave aggressively despite displaying few, if any, of the published clinicopathological characteristics associated with cervical LN metastases.

Poster 737 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM INMATE ATTACK: CULPRIT OR SAVIOR? A CASE OF METASTATIC FOLLICULAR THYROID CARCINOMA L.S. Chertman1, M.M. Chertman2,3 1 Internal Medicine-Medical Teaching Service, Mount Sinai Medical Center, Miami Beach, FL; 2Endocrinology Private Practice, University of Miami Hospital, Miami, FL; 3Clinical Preceptorship, University of Miami Miller School of Medicine, Miami, FL

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 Well differentiated thyroid cancers are confined to the thyroid at presentation with only 4% having distant metastases. Follicular thyroid carcinoma (FTC), the 2nd most common thyroid cancer, usually presents as a single tumor. Incidence of metastasis is 11– 25%, primarily to lung followed by bone, via hematogenous spread. A 39 year old male prison guard was attacked by an inmate, causing left shoulder pain, swelling, and limited range of motion. MRI confirmed pathologic fracture of the humerus with destruction of the cortex. Core biopsy showed metastatic follicular carcinoma. He then revealed 6 months of back and hip pain with right upper and lower extremity numbness. Imaging showed ostelytic lesions in the right clavicle, inferior pubic ramus, left hilum and T2-T3 with cord compression. Emergent radiotherapy improved symptoms. Thyroid UG-FNA of right and left nodules showed follicular lesions of undetermined significance with negative molecular analysis. Total thyroidectomy revealed 2.5 cm FTC with capsular and angiolymphatic invasion, pT2NxM1. 24 hours later he developed tetany, DVTs and saddle central pulmonary embolus treated with heparin, and then a large seroma of the neck causing respiratory distress that resolved. After prophylactic dexamethasone, I-131, 150 mCi was given and post therapy scan confirmed I-131 avid bone metastases. 1 year later, thyroglobulin decreased from 25,620 to 2,280 ng prompting a 2nd dose of I-131, 150 mCi, with an unchanged post therapy scan, and stable clinical course. At diagnosis, 10% of FTC’s have distant metastases and only 1% of those are < 45 years old. Isolated cases of pathologic fractures as the initial presentation have been reported. Even with metastases, 10–30% of thyroid FNA’s are indeterminate. RAS and NRAS mutations are found in only 40% of FTC, and PAX8/PPARG translocation in 25–50%. Treatment includes total thyroidectomy, thyroxine suppression, I-131, possible external beam radiation and tyrosine kinase inhibitors for non-responders. Simultaneous pathologic fracture and impending cord compression as initial presentation for FTC is rare and requires high index of suspicion with multimodality treatment. Long-term survival is 43% versus 86% in localized disease.

Poster 738 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM GENETIC HETEROGENEITY OF MEDULLARY THYROID CARCINOMA C. Romei1, R. Ciampi1, A. Tacito1, F. Casella1, C. Ugolini2, M. Porta1, L. Torregrossa2, F. Basolo2, R. Elisei1 1 Departement of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 2Department of Surgical Pathology, University of Pisa, Pisa, Italy Genetic intratumor heterogeneity has been recently demonstrated in some solid human cancers and a few years ago RET mutated and not mutated cells were described in medullary thyroid carcinoma (MTC). Nobody reported the presence of two different RET mutations Aim of our study was to investigate the RET somatic mutation profile in primary MTC (pMTC) and in the corresponding metastatic tissues (mets). We studied pMTC and mets of 22 MTC sporadic cases. Altogether 86 samples were screened for the presence of a RET somatic mutations in exons 10, 11, 13–16. In 18 cases (81.8%), 57 tissues, a correspondent mutation profile was found in the pMTC and in their mets. In 4 cases (18.2%), 29 tissues, a different RET mutation profile was observed in pMTC and in their mets. In particular in one case a M918T was found in the pMTC but only in 3/5 lymphnode mets; in another case, a 3 bp in frame deletion in exon 15 was found in 8 mets but not in the primary tumor and in 4 additional mets. Interestingly we found one patient

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with a S891A somatic mutation in the primary tumor that was absent in a kidney distant metastases that was indeed characterized by the presence of a M918T mutation. A complex genetic heterogeneity was finally demonstrated in one MTC patient with a very severe disease. The primary tumor displayed a heterozygous 6 bp in frame deletion in exon 11 that was found also in 4/5 lymphnode metastases and in 1/2 liver met. In 1/5 lymphnode and in 1/2 liver metastasis the deletion was homozygous. The analysis of several RET SNPs demonstrated that in this case one RET allele was missing determining loss of heterozigosity. In addition both the primary tissue and 4 lymph node metastases harbored a V804M mutation. In conclusion our study shows that a) 82% of cases had a correspondent RET mutation profile, although in these cases we cannot exclude the simultaneous presence of RET positive and RET negative cells; b) 19% of cases are clearly heterogeneous and among them 2/4 have different RET mutations in different tissues. This information should be taken into consideration in the planning of personalized target therapies and raise the question of whether RET mutations play a real driving role in the development of MTC.

Poster 739 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM AUTOPHAGY ACTIVITY IN MALIGNANT THYROID CELLS IS ASSOCIATED WITH MEMBRANOUS HUMAN SODIUM IODIDE SYMPORTER EXPRESSION AND CLINICAL RESPONSE TO RADIOACTIVE IODINE ABLATION THERAPY IN NON-MEDULLARY THYROID CARCINOMA PATIENTS T.S. Plantinga1,2, M. Tesselaar2, H. Morreau3, E.P. Corssmit4, B. Kusters1, I.C. van Engen-van Grunsven1, R.T. Netea-Maier2, J.W. Smit2 1 Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands; 2Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, Netherlands; 3Department of Pathology, Leiden University Medical Center, Leiden, Netherlands; 4Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands Although non-medullary thyroid cancer (TC) has in general a good prognosis and high cure rates, 30–40% of patients with distant metastases develop resistance to radioactive iodine (RAI) therapy due to tumor dedifferentiation. For these patients, treatment options are limited. Autophagy is a central cellular process involved in cell survival and differentiation. In the present study, abundance and activity of autophagy was assessed in a large set of normal, benign and malignant thyroid tissues and was correlated with thyroid pathology, human sodium iodine symporter (hNIS) protein expression and with the clinical response to RAI ablation therapy in patients with TC. Formalin-fixed, paraffin-embedded blocks routinely prepared from the surgical specimens of 100 benign (64 normal, 10 Graves’ disease, 14 goiter, 12 follicular adenoma) and 77 malignant (53 papillary TC, 24 follicular TC) thyroid tissues were selected for this study. Fluorescent immunostaining for the autophagy marker LC3 was performed and a semi-quantitative immunohistochemical scoring was generated taking into account both the intensity of diffuse LC3 staining and the number of LC3 positive punctae in thyroid cancer cells. These data were correlated with hNIS protein expression and with clinical parameters. Statistical analysis was performed with Chi-square tests. Degree of diffuse LC3 intensity and number of LC3 positive punctae scoring were not discriminative for benign vs. malignant

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thyroid pathologies. Interestingly however, in patients with TC significant associations were observed between diffuse LC3 intensity and LC3 positive punctae scoring on the one hand and the clinical response to RAI therapy on the other (P = 0.01 and P = 0.002, respectively). Mechanistically, only the number of LC3 positive punctae correlated with membranous hNIS expression (P < 0.001), number of RAI treatments required to reach remission (P = 0.014), cumulative RAI dose (P = 0.027) and with overall remission and recurrence rates (P = 0.031). Activity of the autophagy machinery is strongly correlated with the clinical response of TC to RAI therapy, most probably by its capacity to maintain tumor cells in a well differentiated state and to preserve functional iodine uptake.

Poster 740 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM GENETIC VARIATION IN AKT1 LEADS TO ENHANCED AKT1 SIGNALLING AND IS ASSOCIATED WITH SUSCEPTIBILITY TO NON-MEDULLARY THYROID CANCER T.S. Plantinga1,2, M. Petrulea3, J.W. Smit1, C. Georgescu3, R.T. Netea-Maier1 1 Internal Medicine, Radboud University Medical Center Nijmegen, The Netherlands, Nijmegen, Netherlands; 2Pathology, Radboud University Medical Center Nijmegen, The Netherlands, Nijmegen, Netherlands; 3Endocrinology, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania The intracellular signalling kinases mTOR, PI3K and Akt play a central role in oncogenic pathways driving (thyroid) carcinogenesis. Common germline genetic variation that modulates the expression or functional characteristics of these protein kinases are associated with altered signalling and could therefore influence susceptibility towards malignant transformation and tumor development. In the present study, it was assessed whether common genetic variants of mTOR, PI3K, Akt1, Akt2 and Akt3 influence thyroid cancer (TC) susceptibility and/or disease progression and outcome. A Romanian discovery cohort (159 TC patients, 259 controls) and a Dutch validation cohort (154 TC patients, 188 controls) were genotyped for ten single nucleotide polymorphisms in the genes mTOR, PI3K, Akt1, Akt2 and Akt3 and were selected based on genetic associations with other diseases reported previously. Furthermore, the influence of genetically associated variants on both expression and degree of activation of the encoded proteins by phosphorylation was assessed. We also correlated the genetic data with clinical characteristics of the patients including outcome and response to conventional therapy. A statistically significant association was observed for the intronic Akt1 rs3803304 polymorphism in both the discovery cohort (dominant model; OR (95%CI) 1.57 (1.053-2.336); P = 0.027) and the validation cohort (dominant model; OR (95%CI) 1.59 (1.032-2.439); P = 0.035). Furthermore, we found that the risk allele of this Akt1 polymorphism results in elevated amounts of phosphorylated Akt1 upon activation of this pathway by Toll-like receptor 4 signalling in human primary monocytes. However, we observed no assocations with clinical parameters, including TNM stageing, response to radioactive iodine therapy and clinical remission rates. Furthermore, the other selected genetic variants were not reproducibly associated with either susceptibility nor clinical outcome. The risk allele of the Akt1 rs3803304 polymorphism is associated with increased susceptibility to develop TC, which is functionally explained by the increased phosphorylation of Akt1 in the presence of the risk allele and thereby acts as an amplifier of oncogenic signalling.

Poster 741 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM MIRNA EXPRESSION DIFFERENTIATES MUTATION NEGATIVE FOLLICULAR THYROID CARCINOMAS FROM FOLLICULAR THYROID ADENOMAS T. Stokowy2, B. Wojtas3, B. Jarzab4, K. Krohn1, L. Hegedu¨s5, R. Paschke1, M. Eszlinger1 1 University of Leipzig, Leipzig, Germany; 2University of Bergen, Bergen, Norway; 3Nencki Institute of Experimental Biology, Warsaw, Poland; 4M. Sklodowska-Curie Memorial Cancer Center, Gliwice, Poland; 5Odense University Hospital, Odense, Denmark Diagnostics of thyroid fine needle aspiration (FNA) is challenging for the ‘‘indeterminate’’ category and can be supported by molecular analyses. We set out to identify miRNA markers that could be used in a diagnostic setting to improve the discrimination of mutation negative indeterminate FNAs. miRNA high-throughput sequencing (HTS) was performed for freshly frozen tissue samples of 19 RAS and PAX8/PPARG mutation negative follicular thyroid carcinomas (FTCs) and 23 RAS and PAX8/PPARG mutation negative follicular adenomas (FAs). Candidate miRNAs and miRNA classifiers were validated by quantitative PCR in an independent set of 24 mutation negative FTCs and 20 mutation negative FAs. 26 miRNAs characterized by a significant differential expression between FTCs and FAs were identified (FDR < 0.05, fold change > 1.25 or fold change < 0.8). 15 miRNAs were down- and 11 upregulated in FTCs. Nevertheless, since no single miRNA marker had satisfactory predictive power, classifiers comprising two differentially expressed miRNAs were designed with the aim to improve the classification statistics. Seven two-miRNA-classifiers were established and qPCR validated in an independent sample set. The best classifier consisting of hsa-miR-484 and hsa-miR-139-5p identified thyroid malignancy with a sensitivity of 88% and a specificity of 80%. HTS allowed the identification of subtle differences in the miRNA expression profiles of FTCs and FAs. While none of the differentially expressed miRNAs could be used as a standalone malignancy marker, the validation results for two-miRNA-classifiers in an independent sample set are very promising. Finally, the ultimate evaluation of these classifiers for their capability of discriminating mutation negative indeterminate FNAs will require the evaluation of a sufficiently large number of indeterminate FNAs with histological confirmation.

Poster 742 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM CELL CYCLE M-PHASE GENES ARE HIGHLY UPREGULATED IN ANAPLASTIC THYROID CARCINOMA P. Weinberger1,2, H. Xu1, S. Bai1, S.R. Ponny1, J.A. Copland3, R.C. Smallridge3, A. Sharma1 1 Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA; 2Otolaryngology, Georgia Regents University, Augusta, GA; 3Mayo Clinic, Jacksonville, Jacksonville, FL Anaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet is responsible for 40% of thyroid cancer deaths. There are currently no effective therapies. In an effort to identify ATCspecific therapeutic targets, we analyzed data from multiple gene expression microarray studies to identify globally altered genes. The NCBI GEO database was searched for high-throughput gene expression microarray studies that included human ATC tissue as well as

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normal thyroid and/or papillary thyroid cancer (PTC) tissue. Gene expression levels in ATC were compared to normal thyroid or PTC using seven separate comparisons, and an ATC-specific set of genes altered in all seven comparisons were identified and further investigated. There were 3 studies meeting inclusion criteria, encompassing n = 37 ATC patients, 69 PTC and 83 normal tissue samples. There were 259 upregulated genes and 286 downregulated genes in ATC with at least 2-fold change in all seven comparisons. Using a 5-fold filter, 36 genes were upregulated in ATC while 40 genes were downregulated. Of the top globally upregulated genes in ATC, 4/10 (MMP1, ANLN, CEP55, TFPI2) are known to play a role in ATC progression, however 7/10 genes had not been specifically implicated in ATC. Similarly, 3/10 most globally downregulated genes were novel in this context. Next, we examined gene ontology clustering of globally altered genes. ‘‘Mitotic Cell Cycle’’ is highly enriched in the globally upregulated geneset (44% of top upregulated genes, p-value < 10 - 30 ). The biological processes enriched in globally downregulated genes are ‘‘Endocrine System Development’’, ‘‘Hormone Metabolic Process’’, and ‘‘Neuron Differentiation.’’ Examination by cellular component (CC) revealed ‘‘Spindle’’, ‘‘Microtubule Cytoskeleton’’, and ‘‘Chromosome Centromeric Region’’ are the most enriched CCs in the upregulated genes (p-value < 10 - 12). Of note, these CCs are all involved in the M-phase of cell division. By focusing on globally altered genes, we have identified a set of consistently altered biological processes in ATC. Our data are consistent with an important role for M-phase cell cycle genes in ATC, and may provide direction for future studies to identify novel therapeutic targets for this disease.

Poster 743 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM DREAM EXPRESSION MAY BE A VALUABLE AUXILIARY TOOL IN THE DIAGNOSIS OF THYROID NODULES C. Torricelli1, L.S. Ward1, F.A. Batista1, M.A. Marcello1, M.B. Martins1, N.E. Bufalo1, K.C. Peres1, F.A. Soares3, M.J. Silva2, L.V. Assumpc¸a˜o1 1 Laboratory of Cancer Molecular Genetics, University of Campinas, Campinas, Brazil; 2Molecular Biology and Genetic Engeneering Center, University of Campinas, Campinas, Brazil; 3Department of Anatomic Pathology, A. C. Camargo Cancer Center, Sa˜o Paulo, Brazil DREAM gene encodes a transcriptional repressor involved in thyroid differentiation and apoptosis. Increased DREAM expression in thyroid has been related to thyroid growth and nodular development but its relationship with other thyroid specific genes and its role in thyroid tumorigenesis is still confusing. We aimed to look for DREAM expression clinical utility correlating it with patients’ clinical and pathological characteristics and comparing it to TTF1, FOXE1 and PAX8 genes expression in thyroid tissues.

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We analyzed 205 samples of thyroid tissues including 50 follicular adenomas (FA), 49 colloid goiters (CG), 63 classic papillary thyroid carcinomas (CPTC), 36 follicular variant papillary thyroid carcinomas (FVPTC), 2 anaplastic carcinomas (AC) and 4 non-neoplastic thyroid tissues. RNA extraction of the samples was performed, followed by RT-PCR and qPCR techniques. The reaction was standardized by using GAPDH as endogenous control. The values of relative gene expression were obtained by DDCt method. There was no DREAM expression in AC. DREAM expression was higher in benign nodules (median 1.153 AU) than in malignant thyroid nodules (median 0.2490 AU, p = 0.0261), being able to distinguish them with accuracy of 78% (sensitivity = 82%, specificity = 67%, PPV = 72% and NPV = 79%) using a ROC curve with a cutoff 0.528 AU. DREAM expression also distinguished follicular patterned lesions (CPTC vs. FA; FA vs. FVPC; CPTC vs. CG; CG vs. FVPTC, all p < 0.001), and differentiated follicular lesions (FA versus FVPTC) with an accuracy of 75% (sensitivity = 56%, specificity = 86%, PPV = 74% and NPV = 73%) using a ROC curve with a cutoff 0.405 AU. DREAM expression was directly associated to the expression of TTF1 (p < 0.0001, r = 0.4), FOXE1 (p < 0.0001, r = 0.7) and PAX8 (p < 0.0001, r = 0.7) genes. There was no correlation between DREAM expression values and any clinical data or patients outcomes. We suggest that DREAM expression may be clinically helpful differentiating follicular lesions and establishing thyroid nodules malignancy. Functional studies are necessary in order to explore the role of this gene and its association with other thyroid differentiation gene in the pathogenesis of nodular thyroid diseases.

Poster 744 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM USE OF DROPLET DIGITAL PCR FOR DETECTION OF GENETIC ALTERATIONS FROM THYROID FINE NEEDLE ASPIRATE BIOPSIES A.E. Matkin, M. Kostiuk, D. O’Connell, H. Seikaly, D. Cote, J. Harris, V. Biron Surgery, University of Alberta, Edmonton, AB, Canada Fine needle aspiration biopsies (FNABs) are the gold standard test for diagnosis of thyroid nodules. Unfortunately, up to 25% of FNAB cytology reports are indeterminate resulting in repeat testing and, occasionally, precautionary thyroidectomy. These additional procedures present a burden on both the patient and the healthcare system. Advancements in molecular diagnostic technology and increased understanding of molecular mechanisms contributing to thyroid cancer can enhance the ability to detect and treat early stage thyroid cancers. We propose the use of droplet digital PCR (ddPCR) to identify pathogenic mutations and abnormal gene expression levels obtained from FNABs. Ultrasound-guided FNABs were collected from patients with thyroid nodules presenting to a tertiary care centre. FNAB samples were stored in RNA-preserving reagent for later nucleic acid extraction and ddPCR was performed using ‡ 1 ng of cDNA with the following FAM/HEX-labelled probes. Gene expression levels were measured relative to an internal control (EEF) for PTEN, PIK3CA, MET, CCND1, MKI67, TSHR, LGALS3 and EGFR. Mutational analysis was performed with comparison to wild type control for HRAS pG12V, HRAS Q61R, HRAS Q61K, NRAS Q61R, NRAS Q61K and BRAF V600E. Genetic profiling results were compared to histopathology from FNAB and final surgical pathology for patients who later received hemi/total thyroidectomy. FNAB samples for ddPCR analysis have been collected from 24 patients (3:1 female; mean age 55 years, range 17–79) to date. Compared to other methods of FNAB sample biomarker analysis, mutational and gene expression data was reliably obtained with small amounts of nucleic acid. Gene expression profiles demonstrated

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broad expression ranges and mutations were identified in non-diagnostic and benign FNAB specimens. The detection of thyroid cancer molecular biomarkers using ddPCR is a process that has the potential to become a new diagnostic tool. With this method, we are able to detect specific mutations in thyroid nodules the same day the sample is obtained from the patient. This ongoing study will correlate genetic ddPCR analysis with current FNA pathology reports and final histopathology specimen on patients receiving thyroid surgery.

Poster 745 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM ERa IMMUNOSTAINING: AN AUXILIARY DIAGNOSTIC TOOL OF FOLLICULAR THYROID LESIONS N.E. Bufalo1, A.H. Campos2, A.G. Rocha1, L.L. Cunha1, G.D. Pimentel3, F.A. Batista1, L.V. Assumpc¸a˜o1, L.S. Ward1 1 Laboratory of Cancer Molecular Genetics, University of Campinas, Campinas, Brazil; 2Department of Anatomic Pathology, A. C. Camargo Cancer Center, Sa˜o Paulo, Brazil; 3Department of Internal Medicine, University of Campinas, Campinas, Brazil Evidence indicates an important role of estrogen in thyroid tumorigenesis, stimulating growth and amplifying its growth-promoting effects by upregulation of estrogen receptor alfa (ERa). The isoform ERa was demonstrated in goiter tissues, thyroid carcinomas, and different thyroid carcinoma cells; however, ERa immunohistochemistry is still dubious in adenomas and goiters. We aimed to investigate ERa utility as a diagnostic and prognostic marker of thyroid cancer. ERa nuclear immunohistochemical expression was analyzed in 110 benign nodules [79 goiters and 31 follicular adenomas (FA)] and 111 thyroid carcinomas [8 follicular carcinomas (FC) and 103 papillary thyroid carcinomas (PTC), including 79 classic (CPTC), 10 tall cell (TCPTC), and 14 follicular variant (FVPTC)]. All cases were managed according to current guidelines and followed up for 75 – 63 months. There were 123 patients classified as free-of-disease and 27 of poor outcome (1 death), according to their serum Tg levels and image evidences. ERa was identified in 50.63% CPTC, 60% TCPTC and 78.57 % FVPTC, 12.5% FC, 32.25% FA, and 34.17 % benign tissues. ERa expression differentiated malignant from benign thyroid tissues (p = 0.0065), FVPTC from goiter (p = 0.0027; PPV = 0.2895 - NPV = 0.9455), FVPTC from AF (p = 0.0085; PPV = 0.5238 - NPV = 0.8750), FVPTC from FC (p = 0.0062; PPV = 0.9167 - NPV = 0.7000). Furthermore, ERa was more expressed in female cancer patients using hormonal contraception (85%) (p = 0.003) and in well differentiated carcinoma (95.8%) when compared to poorly differentiated (4.2%) (x2 = 0.03). However the presence of ERa was not associated with outcome or any feature of tumor aggressiveness. We suggest that ERa staining may help diagnose thyroid nodules, characterize follicular-patterned thyroid lesions, and is associated with oral contraceptive use in thyroid cancer patients, but is not a parameter of thyroid tumors’ aggressiveness.

Poster 746 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM FAMILIAL NONMEDULLARY THYROID CANCER: A CLINICAL AND MOLECULAR STUDY F.Y. Miasaki1, J.C. Ricarte-Filho2, G.A. de Carvalho1, E.T. Kimura2 1 SEMPR, HC-UFPR, Curitiba, Brazil; 2ICB1, USP, Sa˜o Paulo, Brazil Familial nonmedullary thyroid cancer (FNMTC) is characterized by two or more first-degree relatives affected by thyroid cancer of fol-

licular cell origin and no other syndrome associated (Cowden, Carney, Werner syndrome,.). Presumably it represents 5 to 10% of all thyroid cancers; however, the clinical and genetic characteristics related with FNMTC pathogenesis remain to be elucidated. We have studied a Brazilian family affected by FNMTC, consisted by 5 siblings and 3 cousins of second generation. Anamnesis and histology review were performed, as blood samples were collected for exome sequencing from 6 of 8 patients. Blood samples and thyroid ultrasound were also taken from healthy relatives for the negative control. After extraction of DNA from leucocytes, exomes of 3 patients with thyroid cancer were performed by Illumina HiSeq2500. Genome alignment (hg19), variants detections (SNPs, indels) and gene-based annotation were performed by BWA, GATK and ANNOVAR respectively. Only rare potentially deleterious functional variants were considered (MAF < 1%). All patients presented papillary thyroid cancer (1 moderately differentiated, 3 classical variants, 1 follicular variant and 1 a mixed classical and follicular variant). It was identified 2/6 multifocal involvement, 1/6 extra-thyroidal invasion, 3/6 lymph nodal involvement. It was also observed ‘‘anticipation’’ phenomenon: in the first-generation, median of age was 48.5 years old; while in the second-generation, 24 years old. All patients are disease-free at this moment. The exoma sequencing presented 100 · average coverage (2 · 76 pb reads) for target exonic regions. Genes related to syndromes (as PTEN, WRN, PRKAR1A, APC), thyroid function (FOXE1, NKX2-1, PAX8, TG, TPO, SLC26A4, NIS, TSHR) and sporadic thyroid cancer (RET, BRAF, N-K-HRAS) were sequenced manually. No germline variants were found. Twelve non-synonymous variants from different genes related to cell survival, proliferation and migration were selected for validation. None of these genes/variants were associated with FNMTC previously. We have performed clinical and genetic analysis and have uncovered the alterations which could be potencially associated with FNMTC in this family.

Poster 747 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM WHOLE EXOME SEQUENCING OF MEDULLARY THYROID CARCINOMAS DID NOT IDENTIFY ONCOGENIC DRIVERS ALTERNATIVE TO RET AND RAS GENES R. Ciampi1, C. Romei1, A. Tacito1, F. Casella1, G. materazzi2, C. Ugolini2, F. Basolo2, P. Vitti1, R. Elisei1 1 Department of Clinical and Experimental Medicine-Unit of Endocrinology, University of Pisa, Pisa, Italy; 2Department of Surgical Pathology Medical, Molecular and Critical Area, University of Pisa, Pisa, Italy About 60% of sporadic Medullary Thyroid Carcinomas (MTC) harbor somatic mutations in RET and RAS genes while roughly 40% of cases are still orphan of an oncogenic driver. Aim of this study was to investigate putative novel genetic alterations leading to pathogenesis of MTC from Whole Exome Sequencing (WES) data obtained in RET + and RET- cases. WES analysis was performed on 6 sporadic MTC cases (2 RET + , 4 RET-) using an Illumina platform. Analyzing the list of Single Nucleotide Variations (SNV) shared by the RET- cases, we studied the gene CNOT1 presenting different SNV in the 4 RET- cases; among these SNV we chose a SNP, the R299Q, with a Minor Allele Frequency (MAF) £ 0.1. We first performed a validation panel of 83 sporadic MTC cases and 94 healthy controls. A larger case-control study was then performed on 874 MTC cases and 896 healthy controls. Genotyping was performed using a TaqMan SNP Assay (Life Technologies) on genomic DNA extracted from the blood of the patients. We also analyzed the presence of mutations in genes belonging to a panel of 344

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 oncogene panel list (NuGEN). We chose 7 SNV not present in dbSNP database as somatic mutation candidates: RB1 (R787Q), MSH2 (A189T), HIF1A (K334R), PCNA (V102I), FES (R764Q), THBS1 (G26A), NSD1 (P702S). These SNV were studied by direct sequencing on genomic DNA extracted from tumoral tissue and blood in order to evaluate their somatic or germinal nature. On a first step of validation, we found that the frequency of the mutated allele (allele A: CGA/CAA) of the CNOT1 R299Q in our total series of 89 MTC cases was significantly higher than in the 94 healthy controls (0.045 vs 0.011, v2 = 4.04, p = 0.04); despite this, further validation on a larger case-control panel did not confirm the significant difference (0.0215 vs 0.0189, v2 = 0.12, p = 0.729). The validation obtained in the tissue and blood DNA of patient harboring the 7 oncogene SNV, revealed their germinal nature and they were not further studied. Despite the great potentiality of WES, in sporadic MTC cases it was unable to find any oncogenic driver alternative to RET and RAS. Nevertheless, the huge amount of data generated by WES will be further analyzed to complete the study.

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Poster 749 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM TARGETING IMMUNE SYSTEM IN ANAPLASTIC THYROID CANCER (ATC): A POTENTIAL TREATMENT APPROACH R. Dadu1, J. Rodriguez Canales2, I.I. Wistuba2, W. Tian2, H. Lui2, M.D. Williams3, M. Cabanillas1 1 Endocrine Neoplasia and HD, MD Anderson cancer Center, Houston, TX; 2Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; 3Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX In differentiated thyroid cancer, recent studies have uncovered a dysfunctional immune response associated with both primary and metastatic disease. In this study, we sought to analyze the immune signature associated with ATC, with the hope of targeting the immune system as a potential treatment. We analyzed formalin fixed paraffin embedded ATC specimens for 8 immune markers: CD4 (T helper cells), CD8 (cytotoxic T cells), Foxp3 (regulatory T cells), CD45Ro (activated & memory

Poster 748 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM A NOVEL FUSION RET/PTC3 INVOLVING NCOA4 AND RET GENES IN A PEDIATRIC CASE OF PAPILLARY THYROID CARCINOMA R. Ciampi, C. Romei, A. Tacito, F. Casella, E. Molinaro, L. Agate, V. Bottici, A. Matrone, P. Vitti, R. Elisei Department of Clinical and Experimental Medicine-Unit of Endocrinology, University of Pisa, Pisa, Italy Papillary thyroid carcinoma (PTC) originates from follicular cells of thyroid gland and it represents the most common type of thyroid cancer. About 10–20% of PTC cases harbor a RET/PTC rearrangement and the presence of these rearrangements is strongly associated to exposure to ionizing radiations and younger age. In this study, we present the case of a 4 years old patient affected by classic variant PTC with lymph-node metastasis. After surgery, RNA and DNA were extracted from the primary tumor and 2 metastatic lymph-nodes. The cDNA was examined for the presence of RET/PTC 1 and 3 rearrangements by multiplex RT-PCR; amplicons obtained were then sequenced by Sanger method. The method of chromosome walking in the intronic regions of the genomic DNA of tumoral tissues was used to identify the breakpoint sites. The results obtained on the primary tumor and metastatic tissues demonstrated the absence of a RET/PTC1 rearrangement but the presence of a RET/PTC3 rearrangement resulting in a shorter band length when compared to the positive control (300bp vs 430bp). Direct sequencing of the band obtained revealed a fusion between NCOA4 exon 6 and RET exon 12 with a skip of exon 7 of NCOA4 that is characteristic of the classic RET/PTC3 rearrangement. In order to further characterize the fusion on genomic DNA, we performed PCR with different primers located within intron 6-7 of NCOA4 and intron 11-12 of RET and the data obtained reveled a breakpoint within exon 11-12 of RET and within exon 7 of NCOA4, lost in the transcript after the splicing process. The patient’s personal and medical history did not show any link to radiation exposure or to other disruptors. Currently, a screening for this type of rearrangement on pediatric PTC patients with no history of radio exposure, is ongoing and chromosome fragility induced by other causes than radiation exposure are taken into consideration. In conclusion, in this study we described an alternative and new RET/PTC3 rearrangement in a pediatric PTC patient. Apparently, the occurrence of this rearrangement is not linked to radiation exposure and other mechanisms are still under investigation.

Figure 1: ATC case, highly infiltrated by inflammatory cells and tumor cells is expressing PD-L1 (PD-L1 H score = 80; PD1 density = 32; CD4 density = 43; CD8 density = 49; Foxp3 density = 16; CD45Ro = 70; Granzyme B density = 23).

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T lymphocytes), Granzyme B (cytotoxic T & NK cells), CD68 (macrophages), PD-1 (T cell exhaustion), PD-L1 (known to suppress the immune system). Slides were analyzed using Aperio Image Toolbox. 5 random 1 mm2 areas in the tumor center (CT) and in the peritumoral (PT) area were chosen. The score for each marker was expressed as average score of 5 areas. PD-L1 expression was evaluated in the tumor cells using H-score [% of positive cells showing membrane staining combined with intensity of staining]. The other markers (inflammatory cell markers) were evaluated as density [number of positive cells/area regardless of intensity]. Analysis of 4 untreated primary ATC tumors was performed. In CT area, PD1 + density = 22-95 cells/mm2, CD8 + density = 49-319 cells/ mm2, CD4 + density = 43-604 cells/mm2, FoxP3 + density = 5-60 cells/ mm2, CD45 + density = 37-251 cells/mm2, Granzyme B + density = 12-82 cells/mm2, CD68 + density = 82-135 cells/mm2. Furthermore, tumor cells express high levels of PD-L1 (H-score = 5-80). The CT immune markers expression in one ATC case is shown in Figure 1. In PT area, PD1 + density = 3-20 cells/mm2, CD8 + density = 29-75 cells/mm2, CD4 + density = 27-84 cells/mm2, FoxP3 + density = 9-16 cells/mm2, CD45 + density = 40-80 cells/mm2, Granzyme B + density = 3-19 cells/ mm2, CD68 + density = 25-60 cells/mm2. PT PD-L1 H-score = 2-44. Immune analysis of a small ATC cohort shows that ATCs are highly infiltrated by inflammatory and immune cells which may exert both pro-(T cells expressing PD-1, Regulatory T cells expressing FoxP3) and anti-tumor effects (cytotoxic T cells). Tumor cells highly express PD-L1 which also contributes to the exhausted phenotype. These findings should be replicated in a larger cohort. Preliminary results support the use of checkpoint blockade in ATC.

Poster 750 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM PESTICIDES CAUSE DNA DOUBLE STRAND BREAKS IN HUMAN THYROID CELLS J.M. Hershman1,2, K. Hon1, B. France3, R. Damoiseaux3 1 Endocrinology, VA Greater Los Angeles Healthcare System, Los Angeles, CA; 2Medicine, UCLA School of Medicine, Los Angeles, CA; 3California Nanosystems Institute, UCLA School of Medicine, Los Angeles, CA The basis for the dramatic increase in the incidence of papillary thyroid cancer during the past two decades is unknown. We propose the hypothesis that environmental toxins, especially pesticides, may be responsible for the increased incidence of thyroid cancer. Chemicals and ionizing radiatiion may cause DNA double strand breaks (DSB) in various cells. Repair of DNA DSB can lead to oncogenic rearrangements and mutations that could result in cancer. For example, Agent Orange has been linked to thyroid cancer in Veterans. The purpose of this study is to determine whether pesticides cause DNA DSB in thyroid cells. To pursue this concept, we developed a high throughput screening assay for DSB in the H-tori-3 human thyroid cell line. After incubation of the cells with each compound, the DSB were detected by an immunofluorescent assay for the phosphorylation of nuclear histone H2AX (gH2AX), a specific indicator for the presence of DSB. This assay employs a laser scanning cytometer to quantify directly the phosphorylation on a cell by cell level; the readout is multiplexed with total cell number measured using the nucleic acid stain, propidium iodide, and the percentage of cells with DSB is calculated. The assay was validated using etoposide as a positive control. Using this assay, we tested the Toxcast Phase 1 chemical library of 309 compounds, mainly pesticides, and several additional compounds for their ability to cause DNA DSB.Twenty of the compounds tested caused DNA DSB in a dose-dependent manner in multiple assays. Among them were the following compounds: abamectin, amitraz,

captafol, captan, difenconazole, diquat, fluazinam, naled, prallethrin, prodiamine, propargite, rotenone, tebupirimfos, TCDD (dioxin), tribufos, and triclosan. Our resutls may serve as a basis for epidemiologic studies relating thyroid cancer to pesticide exposure. The data suggest that exposure to some of these pesticides may be a cause of the increased incidence of thyroid cancer.

Poster 751 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM THE ARYL HYDROCARBON RECEPTOR (AHR) IS OVEREXPRESSED IN THYROID CARCINOMA E. Puxeddu, S. Moretti, E. Menicali, S. Morelli Department of Medicine, University of Perugia, Perugia, Italy AHR is a ligand-activated transcription factor. It influences the major stages of tumorigenesis. The products of tryptophan transformation by Indoleamine-2,3-dyoxygenase 1 (IDO1) are known AHR agonists. Conversely, IDO1 and cytochrome P4501B1 (CYP1B1) are known AHR target genes. Purpose of the present study was the evaluation of AHR relevance in thyroid carcinoma tumorigenesis. AHR, IDO1 and CYP1B1 expression levels were evaluated by QPCR in 90 papillary thyroid carcinomas (PTC), 11 medullary thyroid carcinomas (MTC) and 6 anaplastic thyroid carcinomas (ATC), and compared with those of a control normal thyroid pool. All samples were genotyped for the occurrence of the most common driver mutations, including those of RET, BRAF and all 3 RAS isoforms. AHR and IDO1 expression resulted higher in all thyroid cancer histotypes compared to normal thyroid (PTC: AHR 26.91 – 15.45 folds [P < 0.00], IDO1 10.75 – 40.9 folds [P = 0.02]. MTC: AHR 8.96 – 4.28 folds [P < 0.00], IDO1 4.84 – 2.95 folds [P = 0.0014]. ATC: AHR 8.22 – 3.81 folds [P < 0.00], IDO1 50.13 – 42.50 folds [P = 0.0046]). CYP1B1 expression resulted higher in PTC (2.29 – 3.39 folds [P = 0.0004]), but lower in ATC (0.36 – 0.75 folds [P = 0.036]). A statistical significant positive correlation could be found between AHR and CYP1B1 expression levels (R = 0.29, P = 0.004). On the contrary, a statistical significant negative correlation could be found between AHR and IDO1 (R = -0.24, P = 0.015). AHR expression resulted higher in BRAF mutation-positive PTC than in the BRAF-negative counterpart (29.22 – 16.37 vs 20.91 – 10.9, P = 0.03). These data indicate that AHR is overexpressed and functional in all thyroid carcinoma histotypes. BRAF mutation-activated signaling appears as one of the possible pathways regulating AHR expression. The negative correlation between AHR and IDO1 might underscore the complex regulation of AHR and IDO1 expression, but also a possible overlapping of functions of two molecules placed in sequence on the same functional pathway. In summary, these data indicate a possible role of AHR in thyroid tumorigenesis and a potential for therapeutic modulation of its activity in this cancer type.

Poster 752 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM CLINICAL RELATIONSHIP BETWEEN IGG4-POSITIVE HASHIMOTO’S THYROIDITIS AND PAPILLARY THYROID CARCINOMA Y. Yu1, G. Lu1, J. Zhang2, T. Li3, Y. Gao1, Y. Gao1, X. Guo1 1 Department of Endocrinology, Peking University First Hospital, Beijing, China; 2Department of Geriatrics, Peking University First Hospital, Beijing, China; 3Department of pathology, Peking University First Hospital, Beijing, China

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Hashimoto’s thyroiditis (HT) can be divided into IgG4-positive HT and IgG4-negative HT on the basis of immunohistochemistry. The association between IgG4-positive HT and papillary thyroid carcinoma (PTC) was reported in limited literature. The aim of our study was to investigate the relationship between IgG4-positive HT and PTC, and compare the parameters and prognosis of PTC between PTC with IgG4-positive or negative HT. A total of 66 HT cases with stored serum samples before operation were collected to detect IgG4 and IgG expression by immunohistochemical staining from 2009 to 2014 in Peking University First Hospital. 18 of the 66 cases were HT alone, and the remaining 48 were diagnosed as HT with PTC. Serum TgAb IgG, TgAb IgG4 levels were detected by ELISAs. 18 PTC patients without HT were collected as control group. 17 (35.4%) in the 48 HT with PTC group and one (5.6%) in HT alone group were IgG4-positive HT. The association of IgG4positive HT and PTC was statistically significant (P < 0.05). In contrary, there were only scant to absent IgG4-positive plasma cells in patients with PTC alone. The levels of TgAb IgG4 and the ratios of TgAb IgG4/TgAb IgG were significantly higher in HT with PTC group and PTC alone group than in HT alone group (P < 0.05, respectively). Furthermore, in the HT with PTC group, the average tumor diameter in IgG4-positive HT with PTC cases was 1.7 cm while that in IgG4-negative HT with PTC cases was 1.2 cm. A considerably higher percentage of lymph node (LN) metastasis (41.2% vs. 12.9%; P = 0.026) was found in IgG4-positive HT with PTC group compared to that in IgG4-negative HT and PTC group. We proposed that IgG4-positive plasma cells might contribute to the development of PTC in the background of chronic inflammation. The coexistence of IgG4-positive HT in PTC cases might indicate poor clinical outcomes compared with those of IgG4-negative HT with PTC. High TgAb IgG4 levels might be a useful predictor for PTC.

Poster 753 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM INVESTIGATION ON THE CLINICAL UTILITY OF SERUM INTERLEUKIN-2 (IL-2) LEVELS AND INTERLEUKIN-2 RS2069762 POLYMORPHISM IN DIFFERENTIATED THYROID CANCER M.B. Martins1, M.A. Marcello1, F.D. Batista1, K.C. Peres1, M. Meneghetti1, M.A. Ward1, L.V. Assumpc¸a˜o2, L.S. Ward1 1 Laboratory of Cancer Molecular Genetics, University of Campinas (Unicamp), Cosmopo´lis, Brazil; 2Division of Endocrinology, Department of Medicine, Faculty of Medical Sciences, Campinas, Brazil Cytokines are produced by different cells of the immune system and can perform various functions, including the mediation of immune

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and inflammatory responses. Thus, cytokines influence the activity, differentiation, proliferation and survival of immune cells. Interleukin2 (IL-2) is a potent immunoregulatory cytokine involved in mediating cells in the immune response by activated T lymphocyte proliferation, once redirected to differentiated thyroid carcinoma (DTC) can modulate tumor growth. In order to investigate the clinical utility of IL-2 as diagnostic and prognostic markers for DTC, we studied 300 patients with malignant nodules (272 Papillary Thyroid Cancer and 28 Follicular Thyroid Cancer); 60 patients with benign nodules and 300 healthy controls. DTC patients were treated and followed according to a standard protocol for 88.51 – 54 months. Serum IL-2 levels were measured by ELISA and rs2069762 polymorphism was analysed by TaqMan SNP Genoptyping. IL-2 levels differentiated malignant nodules (16.26 pg/mL) from benign (7.95 pg/mL, p > 0,0001). A ROC curve with a cutoff £ 12.16 pg/ mL, showed a sensitivity of 71%, specificity 91%, positive predictive value of 96.61%, negative predictive value of 78.78% and accuracy of 75.78%. Patients with multifocal tumors produced higher levels of IL-2 (17.25 – 7.95 pg/mL), than patients with unifocal lesions (15.46 – 8.11 pg/mL, p = 0.0255). Likewise, patients without thyroiditis (25.84 – 8.39 pg/mL) had higher IL-2 levels than patients with thyroiditis (15.46 – 9.06 pg/mL, p = 0.0461). Patients who had the AA allele of the rs2069762 SNP had a higher serum production of IL-2. IL-2 genotype distribution did not differentiate the group of patients with DTC from the control group (p = 0.4077), and did not demonstrate association with any clinicopathological characteristic of the patients. In conclusion, serum IL-2 levels may help diagnose malignancy, but do not appear to be useful in the definition of DTC patients’ outcome.

Poster 754 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM INVESTIGATION OF FOXE1 EXPRESSION AND METHYLATION PATTERN IN DIFFERENTIATED THYROID CARCINOMA E.U. de Lima3, L. Morais1,6, J.C. Silva Jr.2, F.F. dos Santos3, I.C. da Silva4, C.A. de Lima4, A. Bezerra5, J.M. Cerutti6, H.E. Ramos2, I. Rubio3 1 Department of Morphology and Genetics, UNIFESP, Sa˜o Paulo, Brazil; 2Biorregulation Department, Health and Science Institute, Universidade Federal da Bahia (UFBA), Thyroid Study Laboratory, Salvador, Brazil; 3Department of Biological Sciences, Federal University of Sa˜o Paulo (UNIFESP), Sa˜o Paulo, Brazil; 4Monte Tabor - Hospital Sa˜o Rafael, Salvador, Brazil; 5Universidade de Fortaleza - Unifor, Fortaleza, Brazil; 6Genetic Bases Laboratory of Tumor of the Thyroid, Sa˜o Paulo, Brazil Forkhead box E1/thyroid transcription factor 2 (FOXE1) is a thyroidspecific transcription factor and has been recently identified as a risk factor for thyroid cancer. However more studies are needed to understand its role in thyroid cancer. Aberrant DNA methylation is a frequent event observed in thyroid tumor leading to aberrant gene expression. Recently, it was shown that hypermethylation of FOXE1 promoter lead to reduced FOXE1 expression in leukocytes as compared to non tumoral thyroid tissue. This study aims to evaluate FOXE1 expression in DTC tumors and the involvement of the promoter methylation in its gene expression. We evaluated 23 pairs of thyroid samples: DTC tumor (T) and surrounding nontumor (NT) samples. FOXE1 expression was investigated by real-time PCR and the methylation of 24 CpG sites, between positions -1.600 and 1.140 relative to the ATG, were quantified by Bisulfite sequencing. For in vitro studies FTC133,

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FTC236, FTC238, WRO and NPA cell lines were treated with 5-aza2¢-deoxycytidine(5-Aza) demethylating agente or DMSO (control). The FOXE1 expression in thyroid tumors was reduced in 32% when compared to NT samples (p = 0.0125). At all 74% (17/23) of the tumor samples showed the T < NT pattern expression. After treatment of WRO cell with 5Aza (WRO5aza) the FOXE1 expression increased 6,8 times when compared to control (WROdmso) (p = 0.005). However, in NPA5’aza cells the FOXE1 expression was similar to NPAdmso. The FOXE1 methylation status in WROdmso was higher (90,2 – 5.3%) than in WRO5’aza (71.5 – 33.6%) (p = 0.03), while in NPAdmso and NPA5’aza FOXE1 methylation status was similar (60,6 – 11%; 55,6 – 20.4%;p = 0.44). In WROdmso we observed that 21 of 24 CpG sites had higher methylation degree when compared to WRO5’aza and in NPAdmso only 11 of 24 sites showed higher methylation than NPA5aza. FOXE1 expression also increased after 5’aza treatment of FTC133, FTC236, FTC238 cell lines. These data shows that the expression of FOXE1 is reduced in DTC tumors as compared to not tumor samples and suggest that methylation may be one of the mechanism involved in the regulation of FOXE1 expression in thyroid cancer. To confirm this statement the methylation status of the other cell lines and of T and NT patients samples are being investigated.

Poster 755 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM FDG AND FLT PET CT IMAGING IN DIFFERENTIATED THYROID CANCER (DTC) REFRACTORY TO RADIOIODINE: THRIFT STUDY R. pearson1,2, J. Snell1, G. Petrides1,2, U. Mallick1, S. Atkinson1, D. Newell2, R. Maxwell2, R. Plummer2,1, S. Johnson1 1 Northern Centre for Cancer Care, Freeman Hospital, Gateshead, United Kingdom; 2NICR, Newcastle University, Newcastle, United Kingdom Accelerated repopulation of tumour cells during radiotherapy (RT) is an important cause of radioresistance and consequent local relapse. 18F-Fluorothymidine (FLT) is a thymidine analogue which measures cell proliferation (Ki-67 score); its uptake reflects the fraction of tumour cells in S-phase and is high in many cancers. Increased uptake on FLT-PETCT identifies tumour subvolumes with a high density of actively proliferating cells which has been targeted for focused RT dose escalation (RDE) to improve local control in some cancers but not DTC. THRIFT is a single-centre study to assess the feasibility of a single pre-treatment FLT-PETCT scan in the RT treatment position in refractory DTC patients who are being planned for high dose RT for recurrence in the neck. Dose-escalated RT plans will be generated in patients with FLT-avid disease. Two patients with pT3N1b papillary thyroid carcinoma with recurrence after total thyroidectomy, level VI neck dissection, radioiodine ablation, surgery and radioactive iodine therapy have been recruited in the study. In patient 1 Ki67 was 5% and FLT-PETCT showed no focal uptake within the thyroid bed /neck. FDG-PETCT demonstrated marked focal uptake within the thyroid bed (SUVmax 6.9) and right supraclavicular fossa (SUVmax 10.3) consistent with disease on CT. In Patient 2 Ki67 was 20% and mild FLT uptake was present within a mass in thyroid bed (SUVmax 2.5) Consistent with low proliferative indices, FLT-PETCT scans acquired in two patients with recurrent DTC did not have sufficient uptake required to guide RT volume definition. Larger studies are required to evaluate its role in RDE for DTC patients.

Poster 756 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM MOLECULAR FEATURES OF ATYPICAL ADENOMA OF THE THYROID IN COMPARISON WITH ANAPLASTIC CARCINOMAS H. Hatakeyama, K. Hoshino, A. Homma, S. Fukuda Hokkaido University, Sapporo, Japan Atypical adenoma of the thyroid is a rare form of tumor, and its accurate diagnosis prior to surgical resection is difficult as the histological and pathological morphology are very similar to those of anaplastic thyroid carcinoma (ATC), and its anaplastic transformation remains to be elucidated. In this study, we showed a case of atypical adenoma which dignosed as ATC with the cytology and compared the expression of the molecules associated with aggressiveness of tumor with ATC. Patient findings: We reported a case of a 75-year-old female with a thyroid isthmus nodule diagnosed repeatedly by FNAC as anaplastic carcinoma with a concurrent papillary carcinoma in the right lobe. Both the first and second FNAC specimen slides showed a large number of scattered or aggregated atypical cells consisting large, pleomorphic nucleoli with irregular membranes, chromatin clumps and prominent nuclei. The surgical specimen contained an atypical adenoma at the isthmus, and a papillary carcinoma in the right lobe with metastasis to 2 paratracheal lymph nodes. Methods: To investigate the molecular biological features of atypical adenoma, we undertook immunohistochemical staining with several molecular markers associated with tumor aggressiveness and compared the results obtained for atypical adenoma and 9 anaplastic cancer samples. Less than 1% of cells were stained in the atypical adenoma, whereas 30–90% of cells in the ATC samples were stained with Ki-67. Betacatenin and E-cadherin were highly expressed in the atypical adenoma; however, E-cadherin expression was lost in eight of 9 ATC samples and 5 of 9 ATC samples showed low beta-catenin expression. Vimentin is used as a mesenchymal marker. Vimentin expression was low in the atypical adenoma, but 5 of 9 ATC samples showed high levels of vimentin expression. EGFR expression was high in the atypical adenoma and in 89% of ATCs, whereas VEGF expression was moderate in the atypical adenoma and varied among the ATC samples. Based on the current results as well as those of other reports of genetic analyses, ATCs are speculated to be derived from atypical adenomas with EMT.

Poster 757 Thyroid Cancer Wednesday & Thursday Poster Translational 9:00 AM ID1 AND ID3 EXPRESSION IN THYROID TUMORS L.P. Amaral1, F.A. Batista1, N.E. Bufalo1, C. Torricelli1, A.H. Campos2, L.S. Ward1, A.J. Tincani1, P.P. Arau´jo1 1 Laboratory of Cancer Molecular Genetics, University of Campinas, Campinas, Brazil; 2Anatomic Pathology, A. C. Camargo Cancer Center, Sa˜o Paulo, Brazil Malignant and benign thyroid nodules have been increasing in frequency, leading to the search for markers that could help diagnose malignancy and predict prognosis. Inhibitors of DNA binding proteins (IDs) are part of the family of helix-loop-helix transcription factors and play a fundamental role in the induction of cell proliferation and migration, as well as in the inhibition of cell differentiation and apoptosis. ID genes act as oncogenes or tumor suppressors in different types of carcinomas. They are also involved in cell cycle control and in the regulation of transcription pathways found in differentiated thyroid cancer (DTC) such as PI3K/Akt and NF-kB, with the ID1 already being associated with this cancer.

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In order to investigate the clinical use of the ID1 and ID3 mRNA expression as markers of diagnosis in thyroid nodules, we performed a RT-PCR followed by relative quantification through qPCR technique. Until this moment we investigated 95 thyroid nodules: 15 Follicular adenomas (FA), 65 colloid goiters (G), 7 classic papillary thyroid carcinomas (PTC), 4 follicular variants of PTC (FVPTC), 1 follicular carcinoma, 2 normal thyroid tissues and 1 anaplastic thyroid carcinoma (ATC). All DTC patients were treated and followedup according to a standard protocol for 88.51 – 54 months. There was no difference between ID1 expression in benign (0.37 – 72 AU) and malignant thyroid nodules (0.21 – 12 AU) (p = 0.2527); PTC (0.18 – 6 AU) and G (0.49 – 60 AU) (p = 0.0582); and PTC (0.18 – 6 AU) and FA (0.36 – 14 AU) (p = 0.2552). We also did not find difference in the expression of ID3 comparing benign (0.47 – 76 AU) and malignant (0.28 – 13 AU) (p = 0.6631); PTC and G (0.23 – 7 AU versus 0.53 – 62 AU, p = 0.3873); PTC and FA (0.23 – 7 AU versus 0.20 – 14 AU, p = 0.2245). A larger number of cases and the ongoing analysis of ID2 and ID4 proteins expression will complement these preliminary data that do not indicate, at this point, any important role of the proteins ID1 and ID3 in the pathogenesis of DTC.

and the decrease of POLG indicate that there is greater oxidative damage and that the reduced mtDNA lesion frequency might be a consequence of increased mitochondrial biogenesis Taken together these data demonstrate that both T2 and T3 are able to reduce mtDNA oxidative damage but they act via different mechanisms.

Poster 758

Maternal hypothyroxinemia is characterized by a reduction in the plasmatic levels of thyroxine (T4) having normal levels of 3,3’5’triiodo-L-thyronine (T3) and thyroid stimulating hormone (TSH). It has been shown in humans and other mammals that maternal hypothyroxinemia is asymptomatic for the pregnant woman but causes irreversible damage in the central nervous system of their offspring. We have published that maternal hypothyroxinemia increases the intensity of experimental autoimmune encephalomyelitis (EAE) an animal model for multiple sclerosis (MS). In order, to understand the mechanisms that underlie these alterations, we analyzed the reactivity of microglia and astrocytes in their offspring. Primary cell cultures of microglia and astrocytes from the offspring gestated in hypothyroxinemia were challenged with LPS and TNF-a respectively. Immunofluorescence analysis was used to evaluate reactivity and morphology of microglia and astrocytes. NO, ROS and cytokines production were determinate in the supernatant of stimulated or not cell cultures. qRT-PCR was used to analyze transcript expression of ROS production related enzymes. The effect on cell death was also analyzed by immunofluorescence and TUNEL. By using specific markers for microglia we found only less reactive number of microglia from the offspring gestated in hypothyroxinemia and less production of NO, ROS and low levels of ROS enzymes in the microglia cell culture compared with higher production in astrocytes derived from the offspring gestated in hypothyroxinemia. An alteration pattern of secreted cytokines was found in both cell types derived from the offspring gestated in hypothyroxinemia. Finally, astrocyte but not microglia derived from the offspring gestated in hypothyroxinemia were highly inductors of cell death. Our work suggests that maternal hypothyroxinemia alters the function of astrocytes and microglia, making the microglia cells less reactive and the astrocytes more reactive to an insult. These alterations in part can be responsible for the high intensity of EAE in the offspring gestated in hypothyroxinemia.

Thyroid Hormone Action Wednesday & Thursday Poster Basic 9:00 AM THE EFFECT OF 3,5-DIODO-L-THYRONINE AND 3,5,3’TRIIODO-L-THYRONINE ON MITOCHONDRIAL DNA INTEGRITY F. Cioffi1, P. Lasala1, A. Ziello2, L. Iannucci2, A. Giacco1, F. Goglia1, A. Lanni2 1 Department of Sciences and Technology, University of Sannio, Benevento, Italy; 2Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Caserta, Italy Thyroid hormones (THs) are a major factor controlling metabolic rate in virtually all cell types in mammals. Due to their capacity to stimulate respiratory rate in mitochondria, THs play a significant role in ROS production. But, as they simultaneously affect various aspects of the oxidative stress, inducing different and even opposite effects, several inconsistencies are found in the literature. Moreover, other iodothyronine, such as 3,5-diiodo-l-thyronine (T2), has been shown to exert marked effects on energy metabolism and on oxidative stress. Being the mitochondria the major site of ROS production and target of TH, the purpose of this study was evaluate the effect of T2 and triiodothyronine (T3) on rat liver mitochondrial DNA (mtDNA) oxidative damage and repair. Control rats, rats receiving a daily injection of 25 ug T2/100g BW (N + T2) for 1 week and rats receiving a daily injection of 15 ug T3/ 100 g BW (N + T3) for 1 week, were used troughout. In liver, mtDNA oxidative damage [by measuring mtDNA lesion frequency and expression of DNA polymerase c (POLG), a selected mtDNA repair enzyme], mtDNA copy number, mitochondrial biogenesis [by measuring amplification of mtDNA/nDNA and expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1a)] and oxidative stress [by measuring serum levels 8-hydroxy-2’-deoxyguanosine (8-OHdG)] were detected. T2 reduces mtDNA lesion frequency, increases expression of POLG, does not change mtDNA copy number and expression of PGC1a, and does not alter serum levels of 8-OHdG. Therefore, T2 by stimulating the major mtDNA repair enzyme maintains genomic integrity. Like T2, T3 reduces mtDNA lesion frequency, but increases serum levels of 8-OHdG and decreases expression of POLG. Moreover, as expected, it increases mtDNA copy number and expression of PGC1a. Thus, in T3 treated rats the increase of 8-OHdG

Poster 759 Thyroid Hormone Action Wednesday & Thursday Poster Basic 9:00 AM MATERNAL HYPOTHYROXINEMIA ALTERED ASTROCYTES AND MICROGLIA REACTIVITY IN THEIR OFFSPRING M.C. Opazo1,2, P. Gonzalez1,2, L.F. Venegas1,2, K. Bohmwald2, N. Mun˜oz2, A. Becerra3,2, K. Buguen˜o1,2, E. Jara2, P.A. Cisternas1, F. Simon3,2, S. Bueno2, A.M. Kalergis2, C.A. Riedel1,2 1 Cell Biology and Pharmacology Laboratory, Universidad Andres Bello, Santiago, Chile; 2Millenium Institute on Immunology and Immunotherapy, Santiago, Chile; 3Integrative Physiopathology Laboratory, Universidad Andres Bello, Santiago, Chile

Poster 760 Thyroid Hormone Action Wednesday & Thursday Poster Basic 9:00 AM SEX-DEPENDENT INFLUENCE OF HYPOTHYROIDISM ON CLAUDIN-2 IN MOUSE LIVER D. Zwanziger, H. Rakov, K. Engels, L.C. Moeller, D. Fu¨hrer Endocrinology and Metabolism, University Duisburg-Essen, Essen, Germany

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Hypothyroidism affects liver cholesterol synthesis and lipid metabolism. Furthermore, the prevalence of gallstones is increased in hypothyroidism, however this only applies for men and is in contrast to the female preponderance of biliary disease in the general population. The tight junction protein claudin-2 plays an important role in bile secretion by regulating the paracellular water transport and has recently been linked to increased gallstone susceptibility in a claudin2 deficient murine model. Here, we hypothesized, that hypothyroidism could affect claudin-2 expression in mouse liver. Claudin-2 was analyzed in liver of eu- and hypothyroid male and female C57BL/6 mice by real-time PCR, Western blot and immunofluorescence. In addition, the impact of hypothyroidism on hepatic aquaporins, liver lipid metabolism including bile cholesterol, and liver morphology was investigated. Under hypothyroid condition, livers of female mice showed elevated claudin-2 expression, while reduced claudin-2 expression was found in males compared to euthyroid controls. Furthermore hypothyroidism resulted only in females in increased hepatic aquaporin expression. Induction of hypothyroidism increased serum total cholesterol concentration in mice of both sexes. Interestingly, bile cholesterol content was only elevated in male hypothyroid mice, whereas reduced cholesterol content was found in bile of female hypothyroid mice. Murine hepatic claudin-2 expression is influenced by hypothyroidism in a sex-dependent manner. Diminished claudin-2 expression in male hypothyroid liver tissue could confer disturbed paracellular water transport in line with increased bile cholesterol content. This appears not to be compensated by transcellular water transport mediated through aquaporins. In contrast, female hypothyroid mice show both hepatic claudin-2 and aquaporin upregulation, which may explain lower bile cholesterol content despite effects of hypothyroidism on serum cholesterol levels. Our observations in a murine model provide first hints why gallstone diseases are more frequent in hypothyroid men but not women and suggest a role of hepatic claudin-2 for compartment-specific regulation of serum and bile cholesterol concentrations.

Poster 761 Thyroid Hormone Action Wednesday & Thursday Poster Basic 9:00 AM UTILIZING THYROID HORMONE ACTION TO PROMOTE MYELIN REPAIR IN DEMYELINATING DISEASE M.D. Hartley1, D. Galipeau2, E. Calkins2, L. Kirkemo1, P. Chaudhary2, E. Pocius2, G. Marracci2, D. Bourdette2, T. Scanlan1 1 Physiology and Pharmacology, Oregon Health & Science University, Portland, OR; 2Neurology, Oregon Health & Science University, Portland, OR For demyelinating diseases such as multiple sclerosis, currently no therapies are available that promote remyelination. Successful myelin repair may halt neurodegeneration and help restore neurological function. One possible route to promoting remyelination is through the action of thyroid hormone. During development, rising levels of thyroid hormone induce differentiation of oligodendrocyte precursor cells (OPCs) into mature, myelinating oligodendrocytes. Thyroid hormone can also promote remyelination in animal myelin disease models including the cuprizone model of demyelination and experimental autoimmune encephalomyelitis (EAE). We are exploring thyroid hormone signaling pathways for promoting remyelination in models of multiple sclerosis. Thyroid hormone action in demyelination was evaluated by injecting lysolecithin directly into the corpus callosum of mice to induce demyelination. The ability of thyroid hormone to promote remyelination was evaluated using histology, immunohistochemistry (IHC), and electron microscopy (EM). Lesion volume was measured as a function of thyroid treatment. The populations of OPCs, oligo-

dendrocytes, microglia and macrophages in the lesion were also determined. We will present data showing that both thyroid hormone and a thyromimetic can promote faster remyelination in the lysolecithin model of demyelination in mice as analyzed by histology and EM. IHC data will show that thyroid hormone perturbs the cellular populations in the lesion area. This study suggests that activating thyroid hormone pathways in the brain with thyromimetics may represent a new therapeutic strategy for treating demyelination diseases.

Poster 762 Thyroid Hormone Action Wednesday & Thursday Poster Basic 9:00 AM THYROID AND BONE: EXPRESSION AND T3-INDUCED REGULATION OF A NOVEL TSH b VARIANT (HTSHbV) IN HUMAN MACROPHAGES R. Baliram1, R. Latif1, M. Zaidi2, T.F. Davies1 1 Medicine, Icahn School of Medicine at Mount Sinai and James J Peters VA Medical Center, New York, NY; 2Medicine, Icahn School of Medicine at Mount Sinai, New York, NY Thyroid stimulating hormone (TSH) and thyroid hormones (T3 &T4) are intimately involved in bone biology. We have previously reported the presence of a murine TSH b variant (mTSHbv) expressed specifically in bone marrow derived macrophages and which exerts an osteoprotective effect by inducing osteoblastogenesis. In order to extend this observation and its relevance to human bone biology, we set out to identify and characterize a human macrophage derived TSH-b variant in human PBMC, bone marrow and the pituitary. RT-PCR analysis using variant specific primers identified a 364bp product in bone marrow that was sequence verified and homologous in gene organization to the hTSHbv reported by Klein et al in PBMC (General and Comparative Endocrinol 162:241, 2009). We then characterized TSH-bv regulation using a human monocytic leukemia cell line (THP-1) which we matured into macrophages using PMA (100ng/ml). After 4-days, 41.6% of the THP-1 cells expressed the macrophage markers CD-14 and MCSF and attached to the plastic dish with morphological characteristics of macrophages. RT-PCR analysis of these macrophages treated with T3 (50ng/ml for 1 hour) showed a 50-70 fold induction of hTSHbv mRNA. Furthermore, these hTSHbv positive cells derived by T3 exposure categorized into the M2 phenotype as evidenced by MARC-1 and CCL22 expression. These accumulating data indicate that in hyperthyroidism, macrophages have the potential to exert osteoprotective effects by inducing bone resident macrophages to secrete local hTSHbv which may exert its osteoprotective role via osteoblast TSH receptors.

Poster 763 Thyroid Hormone Action Wednesday & Thursday Poster Basic 9:00 AM MOLECULAR MECHANISM OF THYROID HORMONEMEDIATED CELLULAR ENERGY METABOLISM: ROLE OF MITOCHONDRIAL ADENINE NUCLEOTIDE TANSLOCATORS Y. Iwasaki, M. Nishiyama Endocronology & Metabolism, Kochi University, Kochi, Japan Thyroid hormone profoundly influences cellular energy metabolism of the whole body, at least partly via acting on mitochondrial function. However, the precise molecular metabolism(s) remains elusive.

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 Here, we examined the effects of thyroid hormone (T3) on the transcriptional activity of genome-coded mitochondrial genes. We found that the transcriptional activity of adenine nucleotide translocator (ANT) genes is potently induced by T3 in HepG2 human hepatocyte cell line. Among the four isoforms of ANTs (ANT1-ANT4), most remarkable effect was obtained in ANT1 (more than 3-fold increase in response to 10 nM T3). Thyroid hormone-response element was recognized in the 5’-promoger region of the ANT1 gene. Since ANTs export ATP from mitochondrial matrix, we assume that enhanced activity of ANT increases cytosolic levels of ATP, thereby enhances energy metabolism of the cells, and also sensitize the cells in response to extracellular stimuli such as catecholamines. Altogether, our results suggest that ANT1 is supposed to be at least partly involved in the thyroid hormone-mediated cellular energy metabolism.

Poster 764 Thyroid Hormone Action Wednesday & Thursday Poster Basic 9:00 AM SUBACUTE EXPOSURE TO METHYLMERCURY IMPAIRS LEARNING AND DECREASES GENE EXPRESSION OF THYROID HORMONE TRANSPORTERS IN HIPPOCAMPUS OF RATS G.R. Mundstock Dias1, E. Lima de Souza1, L. Miranda Alves2, A. Freitas Ferreira1, D.P. Carvalho1 1 CCS-IBCCF, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 2CCS-ICB, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Thyroid hormones (TH) are essential for the development and maintenance of the central nervous system (CNS) activities. Central bioavailability of TH is controlled through OATP1C1 and MCT-8 transporters. The toxic compound methylmercury (MeHg) is a commonly encountered form of mercury in the environment resulting from the methylation of inorganic mercury. Adult male rats (n = 30, 2 months old, 250-300g) received via gavage an aqueous solution of MeHg at doses of 1 mg/ kg and 2.5 mg/ kg (6 administrations/14 days). The animals were tested in OpenField, in Object Recognition Test and in the Inhibitory Avoidance Test. Cerebral cortex and hippocampus were removed and used for the evaluation of mRNA expression of OATP1C1 and MCT-8 transporters by q-PCR (Ethics Committee Approval Number 19607/16). Evaluation of gene expression of TH transporters through qPCR in the hippocampus showed a significant decrease in mRNA levels of OATP1C1 and MCT-8. Behavioral analysis related to locomotor activity through the Open Field Test showed no significant alterations. Behavioral analysis related to learning and memory showed longer time of exploration of the old object among the group treated at a dose of 2.5 mg/kg and the control group (Object Recognition Test-short-term memory), lower total time and time of exploration of the new object (Object Recognition Test-long-term memory). In the Inhibitory Avoidance Test there was less time spent for the down of the platform between the treated groups and the control group. In conclusion, the present study showed that subacute exposure to MeHg promotes a significant reduction in mRNA levels of TH transporters in rat hippocampus. In addition, there was significant impairment to learning and memory evidenced through behavioral tests. Finally, it can be postulated that the reduction in the levels of the TH in the CNS may be related to the deleterious effects of MeHg on learning and memory.

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Poster 765 Thyroid Hormone Action Wednesday & Thursday Poster Basic 9:00 AM INCREASE OF T3 SIGNALING IN BRAIN OF EPILEPTIC MICE B.P. Nascimento1,2, A.C. Bianco3, M.O. Ribeiro2 1 Translational Medicine, Sao Paulo Federal University, Sao Paulo, Brazil; 2Department of Health and Biological Sciences, Mackenzie Presbyterian University, Sao Paulo, Brazil; 3Internal Medicine, Rush University Medical Center, Chicago, IL Epilepsy is a reversible temporary disorder of brain activity characterized by the occurrence of spontaneous and recurrent seizures. This disorder is one of the most common neurological conditions in the worldwide population. Thyroid hormones (TH) play an important role in the development and maintenance of Central Nervous System (CNS) through the control of gene expression. Although serum concentration of TH is remarkably stable, deiodinases regulate their signaling in a precise spatio- and temporalmanner by controlling the activation and inactivation of TH. Respiratory abnormalities frequently occur in seizures, which may lead to changes in expression and activity of deiodinases in some brain regions. Thus, we have studied whether epilepsy causes changes in deiodinases expression and in T3 signaling in the brain of epileptic mice. To that, C57Bl/J6 mice were subjected to pilocarpine model of epilepsy and type 2 and 3 deiodinases (D2; D3), as well as the T3regulated genes mRNA levels in the brain were analyzed by realtime PCR. Notably, C57Bl/J6 in Status Epilepticus show an increase in type 2 deiodinase (D2) mRNA levels and a decrease in D3 mRNA levels in the hippocampus, amygdala and prefrontal cortex. Accordingly, these animals show a decrease in T3-negative regulated genes mRNA levels, although the mRNA levels of T3-positive regulated genes show a tendency to decrease. We conclude that epilepsy increases intracellular thyroid hormone signaling.

Poster 766 Thyroid Hormone Action Wednesday & Thursday Poster Basic 9:00 AM RECURRENT LARYNGEAL NERVE INJURY IN THYROID SURGERY: CLINICAL PATHWAYS AND RESOURCES CONSUMPTION G. Dionigi1, C.C. Ferrari1, H. Kim2, C. Wu3, M. Lavazza1, A. Leotta1, F. Chiang3, M.L. Tanda4, E. Piantanida4, V. Pappalardo1, D. Inversini1 1 Department of Surgical Sciences and Human Morphology, University of Insubria, 1st Division of Surgery, Research Center for Endocrine Surgery, Varese, Italy; 2Department of Surgery, Korea University, Anam Hospital, Division of Breast and Endocrine Surgery, Minimally Invasive Surgery and Robotic Surgery Center, Seoul, Korea (the Republic of); 3Kaohsiung Medical University Hospital, Kaohsiung Medical University, Department of Otolaryngology, Kaohsiung, Taiwan; 4University of Insubria (Varese-Como), Department of Endocrinoly, Varese, Italy Aim of this study is to assess resources consumption in patient with Recurrent Laryngeal Nerve (RLN) injury management versus non-injured patient management. Three perspectives were investigated: patient, National Healthcare System (NHS) and society.

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Direct and indirect costs in RLN injury management were estimated. The analysis includes costs associated with hospitalizations, medications, diagnostic tests, outpatient visits, rehabilitation and general practitioner visits. Five clinical pathways were identified, based on the result of the RLN injury with vocal fold paralysis: vocal folds function recovery within one, three and six months and vocal fold permanent paralysis after six months until one year without and with phono-surgery. From the societal perspective, indirect costs were valued in terms of productivity losses (Human Capital Approach). Both from NHS and patient perspectives, the analysis shows a significant increase in costs related to the injured patient management, depending on the duration and severity of the damage. Direct medical costs supported by NHS range from a minimum of e 80,58 (vocal fold recovery within one month) to a maximum of e 3.261,95 in the case of permanent paralysis with phono-surgery. From patient perspective, the analysis shows an increase of direct medical costs supported by the patient from a minimum of e 3,60 to a maximum of e 506,75. Productivity losses were accounted in e 156 per day per patient. A comparison analysis was performed considering the noRLN injury clinical pathway as the baseline. Minimum and maximum values related to direct costs supported by NHS and by the patient for each clinical pathway were considered. From NHS perspective, the percentage increase ranging from 43,25%. From patient perspective, the percentage increase ranges from 51,56% to 80,88% respectively. The analysis shows a significant economic impact of RLN injury management, the weight of which is variable depending on the duration and severity of the damage. This involves considerable additional costs supported by NHS and by the patient.

Poster 767 Thyroid Hormone Action Wednesday & Thursday Poster Basic 9:00 AM OBESITY LEADS TO AN INCREASE IN D3 EXPRESSION IN HIPPOCAMPUS OF RATS. F.B. Lorena1,2, J.D. Panizza2, B.P. Nascimento1, P.D. Braga2, C.P. Marcelino1, E.L. Camargo2, A.C. Bianco3, M.O. Ribeiro2 1 Translational Medicine, Sao Paulo Federal University, Osasco, Brazil; 2Department of Health and Biological Sciences, Mackenzie Presbyterian University, Sao Paulo, Brazil; 3Internal Medicine, Rush University Medical Center, Chicago, IL Thyroid hormone is very important for the development and maintenance of the central nervous system. Hypothyroidism in adult human being leads to depression and impaired memory formation. Obesity also impairs memory and learning processes and leads to behavioral changes such as depression and anxiety. Therefore, our hypothesis is based on the possibility that obesity may decrease T3 signaling in the brain through the increase in D3 expression. For this, Wistar rats were treated with high fat diet (40%) for 8 months. Obese animals did not show deficits in memory acquisition, but longer immobility during the forced swimming test, gold standard test to assess depression in animals (31.1 – 2.9 sec vs. 0.5 – 0.1 in non-obese rats). Immunohistochemistry analysis showed that there is an increased expression of D3 in the hippocampal region of obese animals. Taken rogether, these data suggest that the smaller obesity reduces T3 signaling in the brains of obese rats and may be related to the depression observed in these animals.

Poster 768 Thyroid Hormone Action Wednesday & Thursday Poster 9:00 AM DEMOGRAPHIC AND CLINICAL FEATURES IN THYROTOXIC PERIODIC PARALYSIS: A CASE SERIES OF 15 PATIENTS I. Hussain UT Southwestern, Dallas, TX Thyrotoxic periodic paralysis (TTP) is an uncommon channelopathy, associated with hypokalemia and flaccid paralysis or muscle weakness, which manifests in the presence of hyperthyroidism. This case series reviews 15 patients with thyrotoxic hypokalemic periodic paralysis seen at Parkland Memorial Hospital, Dallas, Texas between 2009 and 2014. The patients were all males with thyrotoxicosis secondary to Graves’ disease. They presented with varying degrees of muscle weakness ranging in duration from 1 hour to 24 hours. Bilateral upper and lower extremity paralysis occurred in 8 patients; only lower extremities were involved in 5 patients; 2 patients had generalized involvement with one of them only able to move his eyes from side to side; and 1 patient had hemiplegia. Five of the patients had associated cramping and muscle pain. Precipitating factors for TTP were identified in only 6 of the cases, and included heavy exercise in 2 cases, high carbohydrate meals in 2 cases, heat exhaustion in one case and alcohol binge drinking in one case. They were all found to be hypokalemic with laboratory results consistent with hyperthyroidism (Table). The patients were between 17 to 44 years of age at time of presentation. Most of the patients were Hispanic, with only 2 Asian and one African-American patient. Only 4 of them had a family history of auto-immune thyroid disease. All patients were treated with betablockers and either methimazole or propylthiouracil. Potassium was normalized resulting in resolution of symptoms. Thyrotoxic periodic paralysis is most commonly reported in Asians, followed by those of Latin American descent. Demographics in this series can be attributed to the large Hispanic population in the service area of Parkland Memorial Hospital. TTP occurs predominantly in males, with few female cases in the literature. Although other causes of hyperthyroidism can cause TTP, Graves’ disease is by far the most common etiology.

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 This series highlights the importance of suspecting TTP in patients presenting with weakness, especially in males of Hispanic origin. Early diagnosis and reversal are essential to avoid life threatening complications, including development of bulbar weakness, respiratory weakness and arrhythmias.

Poster 769 Thyroid Hormone Action Wednesday & Thursday Poster Clinical 9:00 AM NATURAL HISTORY OF SUBCLINICAL HYPOTHYROIDISM IN CHILDREN AND ADOLESCENTS A. Bianchini1, C. Acras1, G. Viani2, H.C. Villar1, J.A. Sgarbi1 1 Division of Endocrinology and Metabolism, Faculdade de Medicina de Marilia, Marilia, Brazil; 2Division of Oncology, Faculdade de Medicina de Marilia, Marilia, Brazil There are limited data about the natural history of subclinical hypothyroidism (SH) in children and adolescents, and treatment is controversial. We investigated a retrospective cohort of children and adolescents (4–18 y) with persistent SH (TSH ‡ 4.5–20 mU/L and normal FT4 for at least three months) to evaluate the spontaneous course of SH, and potential factors associated with the progression to overt hypothyroidism (OH) or to persist in SH. After exclusions, 43 patients (62.8% female) with a mean age of 8.8 – 3.2 y were identified. Median (range) TSH and FT4 concentrations at diagnosis were 6.9 (4.6–15.6 mU/L) and 1.2 (0.8–1.7 ng/ dL), respectively. Familiar history of thyroid disease was present in 11 (25.6%), antithyroid peroxidase antibody (TPOAb) was positive in seven (16.3%), and goiter was palpable in five (11.6%) patients. Symptoms associated with hypothyroidism were identified in 18 (49%) patients, and 29 (67.4%) had short stature. In a mean follow-up of 21.3 months, 24 (55.8%) patients persisted in SH, 18 (41.9%) reverted to euthyroidism, and only one (2.3%) patient progressed to OH. Any studied potential risk factor (sex, age, familiar history of thyroid disease, goiter, positive TPOAb, symptoms, serum TSH and FT4 levels at diagnosis) were significantly associated with progression to OH. However, TSH at diagnosis was significantly higher in patients who persisted in SH compared to those who reverted to euthyroidism (7.15 – 1.7 vs. 6.18 – 0.96, p < 0.05). In addition, patients with TSH > 8.0 mU/L at diagnosis were more likely to persist in SH compared to those with TSH £ 8.0 mU/L (32% vs. 5.6%, p < 0.05). Our results confirm previous studies showing that SH in children and adolescents rarely progress to OH. Patients with TSH > 8.0 mU/L were more likely to persist in SH.

Poster 770 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM NATURAL HISTORY OF SUBCLINICAL HYPOTHYROIDISM IN CHILDREN WITH DOWN SYNDROME C. Acras1, A.L. Bianchini1, G. Viani2, H.C. Villar1, J.A. Sgarbi1 1 Division of Endocrinology and Metabolism, Faculdade de Medicina de Marilia, Marilia, Brazil; 2Division of Oncology, Faculdade de Medicina de Marilia, Marilia, Brazil Subclinical hypothyroidism (SH) is the commonest thyroid abnormality in children with Down syndrome (DS). However, there are sparse data regarding the natural course, and whether treatment is required remains controversial and object of debate in the literature.

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We retrospectively investigated the natural course of persistent SH (TSH ‡ 4.5–20 mU/L and normal FT4 for at least three months) in healthy children with DS. After exclusion, 15 patients (60% female) were identified, with an average age of 3.7 – 3.4 y, median (range) TSH at diagnosis 7.1 (5.4 - 9.3 mU/L), and median (range) FT4 1.2 (1.05–1.5 ng/dL). Familiar history of thyroid disease was present in three (20%) patients, antithyroid peroxidase antibody (TPOAb) was positive in two (13.3%), positive antithyroglobulin antibody (TgAb) in two (13.3%), and goiter was palpable in only one (6.7%) patient. Symptoms associated to hypothyroidism were identified in twelve (80%), and obesity or overweight in two (13.3%) patients. In a mean follow-up of 24.2 months, only one (6.7%) patient progressed to overt hypothyroidism (OH), and another one p (6.7%)patient reverted spontaneously to euthyroidism while most of them (n = 13, 66.7%) persisted in SH. Nine (60%) of patients were treated for hypothyroidism. From them, L-T4 therapy was started when serum TSH reached values ‡ 10 mU/L in four (44.4%) or due to progressive increase of TSH levels in five (55.6%) patients. There was no significant difference between TSH levels at diagnosis amongst treated and untreated patients. Except the patient who progressed to OH, other patients only showed a slow increase in TSH levels at the end of follow-up compared to TSH levels at diagnosis (8.23 – 2.7 vs. 7.14 – 1.15; p = 0.19). We were not able to find any association between studied potential factors with the risk for progression to overt disease. Our results suggest that SH in children with DS seems to be a persistent condition rarely progressing to OH or reverting to euthyroidism.

Poster 771 Thyroid Hormone Action Wednesday & Thursday Poster Clinical 9:00 AM ASSAY OF CEREBRO-SPINAL FLUID LEVELS OF T4, T3 AND RT3 IN PATIENTS WITH DEMENTIA A. Accorroni1,2, F. Giorgi1, R. Donzelli1, L. Lorenzini1, A. Saba1, A. Vergallo1, G. Tognoni1, U. Bonuccelli1, R. Zucchi1 1 University of Pisa, Pisa, Italy; 2Scuola Superiore S. Anna, Pisa, Italy Thyroid hormones (TH) play a role in the regulation of cognitive performances and it has been suggested that abnormalities in neuronal TH availability might be involved in the development of dementia. Since serum TH levels may not correlate with neuronal ones, due to the effects of local TH transport and metabolism, we investigated the relationship between dementia and cerebrospinal fluid (CSF) TH concentration. We selected a series of 35 subjects, with a diagnosis of Alzheimer’s disease (AD, n = 15), Fronto-temporal dementia (FTD, n = 10) and normal cognitive function (n = 10). TH levels were assayed in the CSF using HPLC coupled to mass spectrometry. Serum TH levels were determined with standard immunological technique. Moreover, we evaluated the correlations between CSF TH levels and mini mental state score examination (MMSE), a clinical index of general cognitive function that is routinely used to assess the severity of dementia. The average values of CSF T4, T3 and rT3 in the whole series were 1.60 – 0.10 nM, 15.0 – 1.2 pM and 152.0 – 12.1 pM, respectively, showing that rT3/T3 ratio was much higher than in serum. There were no significant differences between groups for any of these variables. When CSF and serum TH concentrations were compared, significant correlations were observed in the whole series for T3 (r = 0.538 with total serum T3, P = 0.001; r = 0.408 with serum fT3, P = 0.015), but not for T4. Interestingly, group analysis showed a significant correlation between CSF T3 and serum fT3 in the control and FTD groups, but not in the AD group. Within the group of AD

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patients, a significant negative correlation was observed between MMSE and CSF rT3 (r = 0.661, P = 0.007) and rT3/T3 ratio (r = 0.606, P = 0.017), while no significant correlation was found between MMSE and CSF TH in FTD patients. Moreover, neither the CSF content of beta amyloid nor that of tau protein significantly correlated with the MMSE score in both AD and FTD groups. Our results confirm the complexity of brain TH metabolism and suggest that brain dysthyroidism may be involved in the progression of dementia in AD. Alteration of CSF TH levels (namely rT3 and rT3/T3 ratio) may represent a biomarker of cognitive decline specific to AD patients.

Poster 772 Thyroid Hormone Action Wednesday & Thursday Poster Clinical 9:00 AM ASSOCIATION OF LOW BASELINE FREE THYROXIN LEVELS WITH PROGRESSION OF CORONARY ARTERY CALCIFICATION OVER FOUR YEARS IN EUTHYROID SUBJECTS: THE KANGBUK SAMSUNG HEALTH STUDY H. Park, J. Kim, E. Han, S. Park, C. Park, K. Oh, S. Park, E. Rhee, W. Lee Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of) Overt and subclinical hypothyroidism are risk factors for atherosclerosis and cardiovascular diseases. It is unclear whether thyroid hormone levels within the normal range are also associated with atherosclerosis measured by coronary artery calcium (CAC). This study aimed to examine the relationship between normal variations in thyroid function and changes in coronary artery calcium. We conducted a 4-year retrospective study of 2,311 apparently healthy men and women with normal thyroid hormone levels. Their free thyroxin (FT4), free triiodothyronine (FT3), and thyroidstimulating hormone (TSH) levels were measured by electrochemiluminescent immunoassay. The CAC score (CACS) of each subject was measured by multi-detector computed tomography in both 2010 and 2014. Progression of CAC was defined as a CACS change over four years greater than 0. The mean CACS progressions by quartile (lowest to highest) in subjects with normal FT4 levels were 12.90, 8.43, 7.82, and 7.81 (P = 0.028). CACS progression was not significantly associated with either the FT3 or TSH level. The odds ratios for CACS progression over four years (highest versus lowest quartile for each thyroid

hormone) were 0.63 (95% CI 0.46 - 0.87) for FT4, 1.1 (95% CI 0.76 -1.59) for FT3, and 1.01 (95% CI 0.74–1.37) for TSH. In this cohort of euthyroid men and women, a low baseline FT4 level within the normal range was associated with a high risk of CACS progression over four years.

Poster 773 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM TEN-YEAR EXPERIENCE IN MOLECULAR AND DIFERENTIAL DIAGNOSIS OF RESISTANCE TO THYROID HORMONE, THYROTROPINOMA AND FAMILIAL DYSALBUMINEMIC HYPERTHYROXINEMIA: A BRAZILIAN MULTICENTER STUDY L.S. Ramos1, M.M. Kizys1, I.S. Kunii1, J.R. Martins1, M.R. Dias da Silva1, A.M. Spinola e Castro2, R.M. Maciel1,3, M.I. Chiamolera1,3 1 Laboratorio de Endocrinologia Molecular e Translacional, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; 2Disciplina de Endocrinologia Pedia´trica, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; 3Fleury Medicina e Saude, Sao Paulo, Brazil Resistance to thyroid hormone (RTH) is a disorder characterized by variable reduction in tissue sensitivity to TH, associated with mutations in TH receptor beta isoform (THRb) in 85% of cases. RTH is characterized by elevated concentration of TH with inappropriately normal or elevated levels of thyrotropin (TSH). Differential diagnosis comprises TSH producing adenoma (TPA) and alterations of binding proteins such as familial dysalbuminemic hyperthyroxinemia (FDH), caused by mutation in albumin gene (ALB). Therefore, THRb and ALB molecular analysis are important for RTH correct diagnosis. The present study evaluated 26 patients with laboratorial and clinical findings of RTH in the last 10 years. Laboratorial/radiological characteristics and molecular analyses of THRb and ALB were used to classify the subjects. After patients signed informed-consent, the hot spot regions of THRb (exons 8, 9, 10 and 11) and ALB (exon 7) were evaluated by Sanger sequencing analysis from genomic DNA. RTH was identified in 20 subjects and 14 different THRb mutations were identified (70%); 2 patients had the diagnosis of FDH, both with the same ALB mutation; in 4 patients a TPA with adenomas in pituitary MRI were found. Nine THRb + , 5 THRb - (RTH) and both FDH patients had familial history of thyroid dysfunction. Mean age at diagnosis was 20 among THRb + , 30 in THRb - , 26 in FDH and 33 in TPA patients. TPA patients presented more thyrotoxic characteristics than the other groups. Main clinical symptoms for THRb + were tachycardia (42%) and attention disorder/learning disability (42%). Most THRb + and TPA patients presented goiter. One THRb - patient showed an microadenoma on pituitary MRI. Mean TSH and free T4 levels were 3.4 mUI/L and 3.0 ng/dL in THRb + , 6.0 and 2.6 in THRb - , 5.1 and 2.5 in FDH and 36.9 and 3.0 in TPA subjects. In this series, both RTH-THRb + and TPA subjects presented similar characteristics to what is described in literature. However, our series showed 30% of THRb - , while in literature the absence of mutation occurs in 15% of RTH cases. This difference could be explained by misdiagnosis with other conditions, such as FDH, which was confirmed in two patients, the first cases identified in Brazil.

Poster 774 Thyroid Hormone Action Wednesday & Thursday Poster Clinical 9:00 AM TSH CONCENTRATION HAS A STRONG NEGATIVE CORRELATION WITH BREAST CANCER RISK R.C. Dardes4, M.I. Chiamolera1,2, R.M. Biscolla3,2, G.A. Maciel5,2, J.G. Vieira3,2, R.M. Maciel1,2, I.D. Silva4,2

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Laboratorio de Endocrinologia Molecular e Translacional, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; 2Fleury Medicina e Saude, Sao Paulo, Brazil; 3Disciplina de Endocrinologia, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; 4Laboratorio de Ginecologia Molecular - Departamento de Ginecologia e Obstetricia, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; 5Departamento de Ginecologia, Faculdade de Medicina da Universidade de Sa˜o Paulo, Sao Paulo, Brazil Thyroid hormone is involved in breast cell differentiation and also is linked to cancer proliferation. The epidemiological link between thyroid hormone levels and cancer development is still controversial. Recent studies showed a positive correlation with thyroxine (T4) levels and a negative one with the presence of thyroid antibodies against thyroperoxidase (TPO-Ab). However, the link of breast cancer risk and thyrotropin levels (TSH) is still not clear in the literature. The aim of the present study is to analyze if there is a correlation between TSH levels and breast cancer development risk in a Brazilian population. A group of 43 women was included in the study due to elevated breast cancer risk. The assessment of risk was done using the Breast Cancer Risk (Gail Model) and the subjects were evaluated during one year. Clinical evaluation, hormonal and laboratorial tests were performed at time zero (basal), 6 and 12 months. For statistical the results were analyzed using Pearson (r) correlation test, T Statistics, ANOVA and FDR tests. The mean value of TSH of all samples within the period of observation varied from 0.5 to 8.0mUI/L. Correlation between Gail score and the average TSH values (Gail/Average TSH) was significantly negative (p = 6.3914 E-14; correlation = - 0.91711; T Stat = 12.809 and FDR = 2.0382E-12). We found a strong negative correlation between TSH level and the risk of breast cancer measured by Gail score. The higher the TSH levels, the lower the Gail scores. Although the mechanisms of this phenomenon are still elusive, it seems to add support to other studies in the literature linking T4 and breast cancer risk. It could be an alert to improve thyroid status evaluation in women with high risk for breast cancer. Further studies are needed to understand this finding.

Poster 775 Thyroid Hormone Action Wednesday & Thursday Poster Clinical 9:00 AM GLUTEN AND ALUMINUM CONTENT IN SYNTHROID (LEVOTHYROXINE SODIUM TABLETS) R. Espaillat, M. Jarvis, C. Torkelson, B. Sinclair AbbVie Inc., North Chicago, IL Concerns regarding certain excipients in pharmaceutical products and their potential impact on general health have increased as patients and consumers become more exposed to medical information. AbbVie specifically has experienced an increase in inquiries from heath care providers as well as patients regarding gluten and aluminum content in Synthroid. The objective of this study was to review and quantify levels of gluten and aluminum in Synthroid tablets. Gluten content was determined in multiple lots of drug substance and excipients used in the manufacture of Synthroid tablets using the US-RIDASCREEEN Gliadin Test Kit at a third party laboratory. Aluminum level estimations were based on the information from the raw material suppliers, raw material specifications, information from the literature, and scientific judgment using worst case assumptions. All lots evaluated had gluten concentrations of less than 3.0 ppm, which is the lowest detectable limit of the method and below the < 20 ppm threshold the FDA is tentatively considering for defining ‘‘gluten-free’’ in foods. The estimated maximum aluminum levels across the various tablet strengths, ranged from 19 to 137 micrograms per

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tablet. This is an order of magnitude lower than the ATSDR1 chronicduration oral minimal risk level of 1 mg Al/kg/day for aluminum1. Conclusions: Synthroid tablets do not contain gluten or gluten derivatives. Across the various tablet strengths, the estimated maximum aluminum levels were far below the expert determined minimal risk level of exposure to aluminum. 1ATSDR (Agency for Toxic Substances and Disease Registry). Toxicological Profile for Aluminum. U.S. Department of Health and Human Services, Public Health Service. September 2008. Available at http://www.atsdr.cdc.gov/toxprofiles/tp22.html

Poster 776 Thyroid Hormone Action Wednesday & Thursday Poster Translational 9:00 AM NON-GENOMIC EFFECTS OF THYROID HORMONES ON ENDOTHELIAL CELL TUBE FORMATION K.A. Schmohl1, M. Dohmann2, A. Wechselberger2, P.J. Nelson2, C. Spitzweg1 1 Department of Internal Medicine II, University Hospital of Munich, Munich, Germany; 2Medical Policlinic IV, University Hospital of Munich, Munich, Germany Wound healing and tumour stroma formation are dynamic events that are associated with angiogenesis and require interactions of a wide variety of different cell types, including fibroblasts, pericytes, endothelial cells (ECs) and mesenchymal stem cells (MSCs). We and others have shown that MSCs can differentiate into fibroblast-/pericyte-like cells and secrete proangiogenic factors. Thyroid hormone acts as proangiogenic modulator mediated by non-genomic mechanisms via cell surface receptor integrin avb3. The aim of this study is to evaluate the direct stimulative activity of thyroid hormone on endothelial cell tube formation in concert with the assessment of paracrine angiogenic effects of MSCs. Primary human umbilical vein ECs (HUVECs) were seeded on growth factor-reduced Matrigel and cultured in the presence of T3 (0.1 lM) alone or in the presence of primary human bone marrowderived MSC-conditioned medium, with or without tetrac (0.1 lM), a specific inhibitor of integrin avb3-mediated action of T3/T4. Tube formation was analysed after 12 h on microscopic images. Untreated HUVECs formed vessel-like structures with a total tube length (TTL) of 11,988 pixels – 1,457, 87.0 – 10.4 junctions and 16.0 – 4.9 meshes per microscopic field. Treatment with T3 stimulated tube formation with an increased TTL (15,288 pixels – 496), a larger number of junctions (124.2 – 7.2) and meshes (27.2 – 4.7). Additional treatment with tetrac reduced tube formation to basal level (12,457 pixels – 1,540 TTL; 89.0 – 14.1 junctions; 12.3 – 2.5 meshes). HUVECs treated with MSC-conditioned medium in addition to T3 showed even more pronounced effects with 15,784 pixels – 1,689 TTL, 151.8 – 31.8 junctions and 45.2 – 12.7 meshes, while additional treatment with tetrac reduced TTL (13,114 pixels – 1,987), number of junctions (120.4 – 23.3) and meshes (39.0 – 10.4). Our data suggest that T3 stimulates angiogenesis in HUVECs in an integrin avb3-dependent manner, an effect that can be enhanced by additional treatment with MSC-conditioned medium. These studies improve our understanding of the critical role of thyroid hormone in the regulation of angiogenesis, which is important both in the context of wound healing and tumour stroma formation.

Poster 777 Thyroid Hormone Action Wednesday & Thursday Poster Clinical 9:00 AM SYNDROME OF ‘‘INAPPROPRIATE SECRETION OF TSH’’ N.Y. Sviridenko, E. Troshina, V. Volodicheva, T. Grebennikova Clinical Endocrinology Institute, Russian Endocrinological Research Centre Russian, Moscow, Russian Federation

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Differential diagnosis between thyrotropin (TSH)-secreting pituitary adenomas (TSHomas) and resistance to thyroid hormone action (RTH) often represents a significant problem. An incorrect diagnosis can lead to a wrong choice of treatment. 25 year old man with Congenital absence of earflaps, atresia of the left ear canal and the hearing loss appealed to an endocrinologist with complaints on increased neck, increased sweating during physical exercise and a sense of difficulty when swallowing. He was noting palpitations and trembling in the hands since childhood. Analyses: TSH level was 11.6 mIU/L (0.4 - 4), FT4 18.8 pmol/L (0.8 - 2.1), TPO,TG, TRAb were negative. Thyroid volume was 112 ml, with single 29 mm nodule (cytology-follicular adenoma). After administration of MMI 30 mg/day during a month: TSH level was 17.8 mIU/ L, FT4 23.2 pmol/L. After abolition of the MMI, TSH level was 14.2 mIU/L, FT4 28.0 pmol/L FT3 47.3 pmol/L (2.6-5.7), comatomedin C 130 ng/ml (116–358). Thyroid volume increased up to 142 ml. MRI with contrast revealed pituitary microadenoma 6 · 5 mm. After introduction of octreotide: TSH 4.1 mIU/L, FT4 25.9 pmol/L, FT3 9.1 pmol/L. Genetic study: THRB (ERBA2) exon 9 and 10 - pathologically significant changes in the nucleotide sequence were not found. The large thyroid volume with compression of the trachea and follicular tumor were indications to surgical treatment. Thyroidectomia was performed. Levothyroxine was administered 100 mcg. Over 2 months after thyroidectomia TSH level was 43 mIU/L, FT4 15.0 pmol/L, the dose of levothyroxine was increased to 150 mcg. MRI showed the increase in the microadenoma - 6.5 · 5.5 mm. Octreotide LAR was administered in the dose of 20 mg/month. High concentrations of circulation free thyroid hormones in the presence of non-suppressed TSH levels, the presence of pituitary lesions on MRI, decrease of FT4, FT3, TSH after injection octreotide characterize TSHomas. On the other hand, the presence of a birth defect of the auditory conch, the milder symptoms of hyperthyroidism with level FT3 47.3 pmol/L, the small size of the pituitary adenomas do not preclude the existence of RTH.

Poster 778 Autoimmunity Wednesday & Thursday Poster 9:00 AM CLINICAL-TOMOGRAPHIC RELATIONSHIPS IN PATIENTS WITH GRAVES’ OPHTHALMOPATHY (GO) AND DIPLOPIA N.Y. Sviridenko, I. Belovalova, A. Chepurina, M. Sheremeta Clinical Endocrinology Institute, Russian Endocrinological Research Centre, Moscow, Russian Federation The goal of the study is to establish the relationship betw. clinical manifestations of diplopia in diff. phases of GO and tomographic orbit parameters for predicting the efficiency of treatment of diplopia 102 patients were examined: in the active phase of GO (CAS3-7)46 eyes/orbits (e/o), in the inactive (CAS0-2)-32 e/o. Control group21 patient (42 - e/o) without diplopia, 20 e/o with active phase (CAS37) and 22 e/o inactive phase (CAS0-2). Multispiral orbits computed tomography was carried out with 32-slice machine of the Aquilion One (Toshiba). Muscle index (MI) was calculated by Barrett et al. Diplopia has been revealed at 39 patients (38.2%), light non-permanent forms in 36.4% of cases, moderate in 30.3%, severe in 33.3%, moderate and severe forms (80%) predominated in the active phase of GO for up to 14 months and light and moderate forms (53.8%) were prevalent in inactive phase for up to 22 y-s of the disease. Patients with diplopia in active phase (CAS4.3 – 0.9) had more severe form of disease by NOSPECS classif. compared with patients with inactive GO, the level of antibodies to RTSH did not differ. In active phase the MI value, the size of extraocular muscle (EOM) and orbital fat tissue (OFT) were significantly higher compared with inactive phase. The severity of diplopia correlated with the magnitude of MI

(39.5%; 41%; 48%; p = 0.032, r = 0.295). In inactive phase such a correlation has not More severe diplopia predominates (80 %) in active phase of the GO compared to 53,8 % in the inactive phase, due to the increase of EOM. The severity of diplopia correlates with the amount of MI and the increased density of OFT. In the inactive phase of diplopia has been accompanied by increased density of OFT and EOM and does not correlate with the amount of EOM. Understanding causes of diplopia is important to determine the future treatment of the patient.

Poster 779 Thyroid Hormone Metabolism & Regulation Wednesday & Thursday Poster Basic 9:00 AM TRI-IODOTHYRONINE (T3) FORMATION WITHIN THYROGLOBULIN C.E. Citterio, P. Arvan Department of Internal Medicine, Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI The precursor for thyroid hormone synthesis, thyroglobulin (TG), is a large (2746 residue) homodimeric glycoprotein. Hormonogenesis involves monoiodotyrosine (MIT) and diiodotyrosine (DIT) formation by TG iodination; and DIT-DIT or MIT-DIT coupling to form thyroxine (T4) or tri-iodothyronine (T3), respectively. Evolutionary conservation at the N-terminal region of TG appears to be designed specifically for T4 formation (involving Y5), whereas the C-terminal region is enriched in T3. For reasons that remain unknown, in states in which thyroidal TSH receptors are highly activated (such as hypothyroidism caused by iodine deficiency, or hyperthyroidism of Graves’ disease), T3 is formed preferentially over T4 within the thyroid gland. In mouse TG (mTG), Y2519, Y2552, and Y2744 have been suggested to engage in T3 formation (and similar residues are used in the TG of other vertebrates). Interestingly, these tyrosyl residues fall near a region known to be involved in TG homodimerization. We hypothesize that the coupling reaction(s) to form T3 within TG include both intra-monomer and inter-molecular side-chain pairing. To examine T3 formation, we have iodinated native endogenous TG, or recombinant wild-type or mutant TG, in vitro. We find that a mutant TG-Y2744C forms a novel intermolecular disulfide bond, covalently crosslinking TG homodimers—providing evidence for close apposition of the 2744 side chains from two TG monomers. By contrast, neither TG-Y2552C nor TG-Y2519C forms disulfide-linked dimers, indicating that these residues do not crosslink with cognate residues in TG dimers. Upon in vitro iodination of recombinant TG, followed by Western blotting with monoclonal anti-T3, we find that single TG-Y2744C, TG-Y2552C or TGY2519C mutants exhibit diminished T3 formation. Remarkably, upon iodination of a double TG-Y2519C,Y2744C mutant, T3 formation is completely abolished.

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 These data support the hypothesis that there are at least two primary sites of T3 formation at the C-terminus of TG. Work is now needed to understand the relative contributions of these two sites in T3 formation in pathological conditions involving hyperstimulation of thyroidal TSH receptors.

Poster 780 Thyroid Hormone Metabolism & Regulation Wednesday & Thursday Poster Basic 9:00 AM THE MECHANISM OF SELENIUM-DEPENDENT IODOTHYRONINE DEIODINASES: COMPARISON WITH OTHER DEHALOGENATING ENZYMES U. Schweizer1, C. Steegborn2 1 Institut fu¨r Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universita¨t Bonn, Bonn, Germany; 2Dep of Biochemistry, Universita¨t Bayreuth, Bayreuth, Germany The mechanism of iodothyronine deiodinases (Dio) is incompletely understood. While mammalian Dio are selenoenzymes, iodotyrosine dehalogenase is a flavoenzyme, and microbial dehalogenases may contain cobalamin. We have recently determined the atomic structure of the cytoplasmic domain of mouse Dio3 by X-ray crystallography. The structure gives several important clues for the interpretation of the Dio mechanism. We have compared different proposed Dio mechanisms with various dehalogenase mechanisms. Key questions were the nature of the active site, the attack on the halogen-substituted aromatic substrate, the transfer of hydrogen to the ring, and regeneration of the enzyme. Deiodinases/dehalogenases have been proposed to follow quite different mechanisms. Surprisingly, selenium-containing Dio and cobalamin-dependent dehalogenases have several aspects in common: The formation of a halogen-heteroatom bond during which the heteroatom is oxidized, and the transfer of a proton from a protein hydroxyl which is part of a hydrogen bond network. The regeneration of Dio may resemble the regeneration of peroxiredoxins, which are structurally closely related to Dio. The determination of a deiodinase crystal structure was an important step toward the understanding of its mechanism, but a full-length protein structure, ideally with a bound ligand or in the oxidized state will be important to completely understand its function. A better insight into structure and function of mammalian Dio will ultimately allow to design and develop isoenzymespecific inhibitors.

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Poster 781 Thyroid Hormone Metabolism & Regulation Wednesday & Thursday Poster Basic 9:00 AM MICE DEFICIENT IN XB130 DISPLAY MULTIPLE DEFECTS ASSOCIATED WITH THYROID HORMONE SYNTHESIS AND SECRETION Y. Wang1, H. Shimizu1, H. Cho1,2, M. Yoshida1, X. Liao3, S. Refetoff3,4, S. Asa5, M. Liu1,2 1 Latner Thoracic surgery laboratories, University Health Network, Toronto, ON, Canada; 2Departments of Physiology, University of Toronto, Toronto, ON, Canada; 3Department of Medicine, University of Chicago, Chicago, IL; 4Pediatrics and Genetics, University of Chicago, Chicago, IL; 5Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada XB130 is an adaptor protein that regulates cell migration, proliferation and survival. Xb130 KO mice showed transient growth retardation and compensatory hypothyroidism with lower thyroidal TH contents and serum T4. High intrathyroidal non-Tg-T4, high serum TSH and low serum T4 also indicate a defect in Thyroid hormone secretion. Here we attempt to elucidate the mechanism that XB130 plays in maintaining normal thyroid function. Xb130 knockout (KO) mice were used and compared with wild type (WT) control mice in various experiments. 125I was injected into PW5 and PW14 mice fed with LID for two weeks. The TSH level of PW5 WT and KO are 6263 and 8920mU/l and serum T4 are 0.64 and 0.55lg/dl respectively. 4hrs after injection of 125I, 4.69 and 8.52% of dose was measured in excised thyroid gland of WT and KO at PW5. 3.69 and 1.44% of dose was measured in WT and KO at PW14. 20mins after injection of perchlorate, 32 and 41 % washout were detected in WT and KO thyroid at PW5, 0 and 25% washout were detected in PW14 WT and KO. H2O2 assay measured 0.13 and 0.14ng H2O2/lgDNA in WT and KO at PW5 in basal condition, 0.25 and 0.20ng H2O2/lgDNA after ionomycin stimulation. At PW14, 0.056 and 0.034ng H2O2/lgDNA were measured in thyroid of WT and KO in basal condition, 0.27 and 0.13ng/lgDNA were measured after ionomycin stimulation. To investigate if NaI rescue thyroid hormone level in KO mice, both WT and KO mice were fed with 10mg/l NaI water, starting from birth or wean until PW14. Fed with NaI neither elevate the TH level in the serum nor rescue the morphological change in KO thyroid. However, growth retardation was rescued by NaI treatment. The level of TPO, NIS and ER stress marker BIP are highly elevated in KO mice at PW14, compared to WT mice. TSHR in KO and WT have no significant difference, at both PW2 and PW14. MCT8 in KO was slightly down-regulated compared to WT at PW2 and PW14. TEM study shows that KO thyroid have less, short, blunt and bleb like microvilli at the apical membrane, compared to WT thyroid at both PW2 and PW14. Xb130 KO mice has defect in I- organification and H2O2 accumulation. XB130 may play a role in the formation of microvilli on apical membrane of thyrocytes.

Poster 782 Thyroid Hormone Metabolism & Regulation Wednesday & Thursday Poster Basic 9:00 AM TSH AND IGF-1 SYNERGISTICALLY PROMOTE DIFFERENTIATION NOT PROLIFERATION OF HUMAN THYROCYTES IN PRIMARY CULTURE S.J. Morgan, S. Neumann, B. Marcus-Samuels, M. Gershengorn NIDDK, National Institutes of Health, Bethesda, MD

Amino acids likely involved in proton transfer to the iodothyronine ring

It has been widely reported that TSH and IGF-I cooperatively stimulate cell cycle progression and proliferation in various nonhuman in vitro thyroid models, including rat thyroid cell lines (FRTL-5,

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WRT, PCCl3) as well as primary cultures of rat and dog thyrocytes. Specifically, these studies demonstrate synergistic increases in DNA synthesis (as measured via 3H-thymidine incorporation) with combination TSH/IGF-1 treatment. Regardless of the functional consequences, various lines of evidence, including the demonstrated increase in DNA synthesis as well as successful coimmunoprecipitation of IGF-1R with TSHR (and vice versa), strongly support the interaction of these two receptors. Human thyrocytes were isolated from normal thyroid tissue from patients undergoing total thyroidectomy for thyroid cancer. Cells were treated with TSH, IGF-1, and IGF1-R kinase inhibitors alone or in combination and examined for various functional changes. Proliferation was measured via direct cell counting, changes in gene expression via quantitative PCR, and thyroglobulin secretion via ELISA. We found that human thyrocytes in primary cultures stimulated with either TSH, IGF-1, or the combination do not show increased proliferation, as indicated by change in cell number, over control cells. However, TSH/IGF-1 combination treatment does elicit synergistic effects on thyrocyte differentiation, including upregulating the expression of several thyroid-specific genes including sodiumiodide symporter (NIS), thyroperoxidase (TPO) and thyroglobulin (TG), as well as stimulating TG secretion. Linsitinib, an inhibitor of the IGF-1R receptor tyrosine kinase, provides dose-dependent inhibition of TSH-stimulated upregulation of thyroid-specific genes; similar results were obtained using a second IGF-1R kinase inhibitor, PQ-401. IGF-1R kinase inhibition does not affect expression of these same genes modulated by beta-adrenoreceptor stimulation, consistent with the idea that this IGF-1R effect is TSHR-specific and cAMP-independent. TSH/IGF-1 combination treatment synergistically promotes thyrocyte differentiation and function rather than proliferation in a physiologically relevant in vitro model of human thyrocytes.

Poster 783 Thyroid Hormone Metabolism & Regulation Wednesday & Thursday Poster Basic 9:00 AM EFFECT OF THIMEROSAL ON THYROID HORMONES METABOLISM IN RATS T. Pantalea˜o, A.S. Padron, R.A. Louzada, F. Hecht, A. Freitas Ferreira, D.P. Carvalho, D. Rosenthal, V. Correa da Costa Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Mercury seems to exert an inhibitory effect on the deiodinases enzymes activity, but there are few studies using Thimerosal (TM), an antibacterial and antifungal mercurial compound, as the mercury source. The mercury induced deiodinase inhibition may be due to its reaction with the selenol (-SEH) group, directly on the enzyme’s catalytic site and/or by reacting with the (-SH) thiol groups of glutathione, forming a stable complex. This study aimed to elucidate TM’s mechanism on thyroid hormones peripheral metabolism, inclusive the CNS. Adult female Wistar rats received 0.25mg or 250mg Thimerosal/100g of body weight, IM, twice a week, during a month, before euthanasia. Serum T3 and T4 were measured by specific RIAs. D1 activity was measured in liver, kidney and pituitary homogenates using 125I-rT3 as tracer, and D2 activity was measured pituitary, hippocampus, cerebellum, cerebral cortex, and hypothalamus homogenates using 125 I-T4. Inhibition of deiodinase activity in vitro was determined adding different concentrations of TM to the reaction medium. NADPH oxidase activity was measured in liver, kidney, pituitary, pituitary, hippocampus, cerebellum, cerebral cortex, and hypothalamus homogenates by the Amplex-red/HRP method.

Serum T4 and T3 were significantly decreased by the greater dose of TM as was the D1 activity in pituitary and kidney. But no change was seen in hepatic D1 activity, or in the D1 mRNA expression of pituitary, kidney or liver. D2 activity was also significantly decrease by the higher dose of TM in all samples of SNC assayed, excepting the cerebellum, but D2 mRNA expression was unaltered. The in vitro inhibition assay confirmed the D1/D2 inhibitory effects in most tissues. Neither H2O2 nor any NAPH isoform mRNA were affected by TM treatment. Our results indicate that TM (high dose) can inhibit D1/D2 activity probably by binding to their selenium catalytic site, without altering their mRNA expression. NADPH oxidases, are not involved in the reduction of deiodinase activity as previously thought, since the activity of these enzymes is either unaltered or decreased. We believe that mercury forms complexes with thiol residues in glutathione as well as in NOXs inhibiting their activity.

Poster 784 Thyroid Hormone Action Wednesday & Thursday Poster Basic 9:00 AM PHARMACOLOGICAL HYPOTHYROIDISM EFFECT ON LUNG FUNCTION IN WISTAR YOUNG ADULT RATS V.S. Pereira, V.R. Cagido, M. Machado, R. Tavieira da Silva, M. Einicker-Lamas, W.A. Zin, V. Correa da Costa Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Thyroid hormones play an important role on lung development and maturation through neonatal and perinatal periods of life, nevertheless, its effect on respiratory system along adulthood remains unclear: there are several reports of respiratory symptoms during severe and transient hypothyroidism, but the causes and mechanisms involved are still unknown. In order to investigate alterations on adult pulmonary function due to hypothyroidism, young adult Wistar rats (n = 87) received 0,03% methimazole (MMI) in drinking water for 21 days followed by daily saline injections on the last 10 days of protocol (H group); only water followed daily saline injections on the last 10 days of protocol (C group) or MMI 0,03% followed daily T4 (1lg/100g bw) injections on the last 10 days of protocol (HR group). At the end of the protocol lung function parameters and lung mechanics, lung histology, functional residual capacity (FRC), gas exchange, total lipid content of bronchial alveolar fluid (BALF), surfactant protein (SPB and SPD) and lung TTF1 (thyroid transcription factor 1) expression, as well as thyroid hormones (TH) levels (T3 and T4) and lung type 1 deiodinase activity (D1) were evaluated. Hypothyroidism (T3: p = 0,0150) (T4: p < 0,0001) impairs lung mechanics, ventilatory pattern of spontaneous breathing (p < 0,0002), respiratory muscles behavior and breathing control of H group. D1 lung activity decreases in H group (p = 0,0212). Besides, evidence of possible TTF-1, SPB and SPD modulation by TH were detected. Hypothyroidism was also able to cause lung parenchyma remodeling marked by elastosis, fibrosis, alveolar hyperinsuflation and as a result increase of alveolar diameter and FRC (p < 0,001). These results lead, for the first time, to possible explanations for some unexplained respiratory symptoms found on hypothyroid patients. HT appears to protect the respiratory system also during adulthood as T4 reposition was able to reverse the majority of main functional and structural lung alterations found through hypothyroidism, demonstrating new possibilities for further studies to investigate the importance of TH also as a possible adjuvant therapeutic strategy on respiratory system diseases treatment.

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015

Poster 785 Thyroid Hormone Metabolism & Regulation Wednesday & Thursday Poster 9:00 AM HYPOPARATHYROIDISM FOLLOWING TOTAL THYROIDECTOMY IN A PATIENT PREVIOUSLY OPERATED ON WITH GASTRIC BYPASS A THERAPEUTIC CHALLENGE O. Gimm1,2, C. Zsigmond Sjo¨stedt2 1 Linko¨ping University, Linko¨ping, Sweden; 2University Hospital, Linko¨ping, Sweden It is known that patients who underwent gastric bypass surgery are prone to develop secondary hyperparathyroidism due to impaired intestinal calcium uptake. Surprisingly, only a few cases regarding hypoparathyroidism following total thyroidectomy complicated by previous gastric bypass have been reported. We present one of the youngest patients with this condition. A 28year-old female patient who previously had undergone gastric bypass surgery was operated on with total thyroidectomy due to Graves disease. Her preoperative vitamins-D level was just below the normal range. Despite an early parathyroid hormone level just below the normal range, she developed symptomatic hypocalcemia requiring intravenous calcium treatment. In addition, the patient was treated with oral vitamin-D-analogue and calcium. While the vitamin-Danalogue treatment was increased, the intravenous calcium substitution could subsequently be decreased. She could be discharged on post-op day 12 with normal to low-normal calcium levels. Hypoparathyroidism following total thyroidectomy in this patient previously operated on with gastric bypass increased the post-op hospital-stay time from regularly 1-2 days to 12 days. Surgeons dealing with patients that can develop post-op hypoparathyroidism must be aware of this potential risk in patients previously operated on with gastric bypass. Individual treatment is mandatory and the patient should be well informed preoperatively.

Poster 786 Thyroid Hormone Metabolism & Regulation Wednesday & Thursday Poster 9:00 AM WHEN THYROID TESTS LIE: A CASE OF HETEROPHILE ANTIBODY INTERFERENCE M.A. Szkudlinska2, M. Holman1, T.S. Tylee2 1 Pathology, University of Washington, Seattle, WA; 2Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA When discordant thyroid function tests occur, a systematic approach with appropriate investigations and management is needed, including reassessment of the patient’s clinical status. A 56 year-old female with presumed Hashimoto’s hypothyroidism presented for a second opinion regarding management. She was initially diagnosed with hypothyroidism 6 years ago at an outside hospital (OSH) with symptoms including weight gain, constipation, lethargy, and difficulty with balance. Her initial TSH was highnormal at 4.93 mIU/L (0.35–4.94 mIU/L) and she was started on levothyroxine treatment. She was repeatedly found to have a discrepancy between her TSH (high-normal) and free T4 (high-normal to high), managed with frequent changes in medication doses, resulting in constipation on lower doses and tremor on higher doses of levothyroxine. After several years of medication adjustments without normalization of her labs, she sought a second opinion at our institution. Repeat thyroid function tests performed at our institution (Beckman Coulter, Access HYPERsensitive hTSH immunoassay) were consistent with iatrogenic hyperthyroidism. Given the dis-

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crepancy with her prior thyroid tests, we arranged for additional testing comparing the two assays. This revealed the presence of lowtiter, high-avidity, cross-linking antibody on the OSH assay (Abbott immunoenzymatic two-site assay) causing a falsely elevated TSH. Subsequently, the patient’s levothyroxine was titrated down with plan to eventually discontinue treatment. This case demonstrates an often overlooked issue in the interpretation of thyroid function tests: the confounding effects of heterophile antibodies, which, by interfering with the TSH assay, can cause a falsely elevated TSH. This can result in iatrogenic hyperthyroidism due to inappropriate use of levothyroxine in these cases. The prevalence of heterophile antibodies in the general population has been reported to be up to 15%, with the range depending on the detection method used and the specific panel of patients selected. Health professionals should be aware of clinical situations in which heterophile antibody interference may result in misleading thyroid function test results, potentially compromising patient care.

Poster 787 Thyroid Hormone Metabolism & Regulation Wednesday & Thursday Poster Clinical 9:00 AM POSSIBLE ROLE OF LOW MAGNESIUM SERUM LEVELS IN THE ONSET OF POSTOPERATIVE HYPOCALCAEMIA IN PATIENTS UNDERGOING THYROID SURGERY M.N. Minuto1,2, G. Santori1, M. Mascherini2, M. Puglisi2,3, F. Cafiero3, G. Ansaldo2,3, E. Varaldo1,2 1 Department of Surgery (DISC), University of Genoa, Genoa, Italy; 2 U.O.S. Chirurgia Endocrina (U.O. Chirurgia 1), IRCCS A.O.U. San Martino-IST, Genoa, Italy; 3U.O. Chirurgia 1, IRCCS A.O.U. San Martino-IST, Genoa, Italy A positive correlation between calcium and magnesium serum levels is well known and depends upon different factors. We hypothesized that hypomagnesaemia might play a role in the onset of hypocalcaemia after thyroid surgery. This study aims at verifying the existence of this association in a retrospective series of patients who underwent thyroid surgery in a tertiary care referral center for the treatment of thyroid diseases. 285 consecutive patients (202F, 83M, mean age 57 years) who underwent at least a total thyroidectomy (TT) and had a complete clinical and biochemical pre- and postoperative evaluation were included in the study. Patients underwent surgery for a hyperthyroid disease in 65 cases (23%); in all other cases the hormonal profile was normal. 223 patients underwent a TT (78%), 54 underwent TT and central neck dissection (19%), 8 underwent bilateral completion surgery (3%). Patients were evaluated with regard to: sex, age, indications for surgery, number of parathyroids intraoperatively identified, extent and time of surgery, presence of thyroiditis, final histology, pre- and postoperative levels of calcium, magnesium, and creatinine, presence of symptoms of hypocalcaemia. The statistical analysis has been performed using the ‘‘R’’ software. At surgery, less than 4 parathyroids were identified in 12 cases (4%). In the postoperative period, hypocalcaemia was evident in 126 patients (44%), 68 of whom displayed symptoms (24%). When analyzing the patients with and without postoperative hypocalcaemia, the factors affecting postoperative hypocalcaemia were: older age (p = 0.019), longer operative time (p = 0.039), lower magnesium levels (p < 0.001). All these factors were confirmed when analyzing symptomatic hypocalcaemia, also adding the intraoperative identification of < 4 parathyroids (p = 0.041). Many well-known factors can significantly affect the onset of postoperative hypocalcaemia after thyroid surgery. This retrospective study confirms that low magnesium levels in the postoperative

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period might favor the onset of hypocalcaemia. A prospective randomized study with a group of patients undergoing magnesium replacement in the postoperative period can clarify the possible role of magnesium repletion on hypocalcaemia.

Poster 788 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM THE CLINICAL IMPACT OF MAGNESIUM INTEGRATION ON POSTOPERATIVE HYPOPARATHYROIDISM: RESULTS OF A PROSPECTIVE STUDY E. Varaldo1,2, G. Ansaldo1, G. Santori2, F. Cafiero3, M. Puglisi1, M. Mascherini3, M.N. Minuto1,2 1 U.O.S. Chirurgia Endocrina (U.O. Chirurgia 1), IRCCS A.O.U. San Martino-IST, Genoa, Italy; 2Department of Surgery, University of Genoa, Genoa, Italy; 3U.O. Chirurgia 1, IRCCS A.O.U. San MartinoIST, Genoa, Italy It is well known that magnesium and calcium levels are strictly associated in physiologic conditions. The aim of this prospective study was to evaluate if prophylactic and/or postoperative magnesium administration in patients undergoing thyroid surgery have an impact on postoperative hypocalcemia and hospitalization length. One hundred and 20 consenting patients undergoing at least a total thyroidectomy accepted to enter this prospective study. Seventythree patients were included in the Study Group (SG), and 47 in the Control Group (CG). Before surgery, patients in the SG were given magnesium orally, at a daily dose of 3 g for 5 days. Postoperatively, magnesium was always administered in all patients from both groups displaying hypomagnesaemia. The statistical analysis was performed using the R software. The two groups were similar in terms of demographics, preoperative parameters, and indications for surgery. A postoperative biochemical hypocalcemia was recorded in 60 patients (50%) in the first postoperative day, and in 58 (48.3%) in the second postoperative day. Magnesium was given to 68 patients postoperatively because of hypomagnesaemia. One hundred and 5 patients were regularly discharged on the second postoperative day (87.5%), while 15 (12.5%) prolonged the hospitalization. The SG showed a significantly higher magnesium level (1.95 + / - 0.21 mg/dL) than CG (1.88 + / - 0.19) on the first postoperative day (P = 0.03). An increase in the postoperative calcium level was observed in the SG, however without reaching statistical significance. Recursive partitioning and logistic regression showed that the increase of calcium ( > 7.5 mg/dL; P = 0.0001) at the first postoperative day and magnesium ( > 1.4 mg/dL; P = 0.0004) at the second postoperative day significantly decreased the probability of an hospitalization length exceeding 2 days. Even though magnesium is involved in the chain of events leading to postoperative hypocalcemia, its role in either favoring/maintaining it is still unclear. Although the magnesium administration seemed to have only a marginal effect on the postoperative calcium levels, specific postoperative cut-off values of calcium and magnesium were significantly associated with hospitalization length.

Poster 789 Thyroid Hormone Metabolism & Regulation Wednesday & Thursday Poster Clinical 9:00 AM SERUM TSH LEVELS NORMALIZATION IN PATIENTS TREATED WITH BARIATRIC SURGERY AFTER THE SWITCH FROM LEVO-THYROXINE IN TABLET FORM TO AN ORAL LIQUID FORMULATION P. Fallahi1, S. Ferrari1, U. Politti1, I. Ruffilli1, R. Vita2, S. Camastra1, S. Benvenga2, A. Antonelli1

1

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 2Department of Clinical and Experimental Medicine, Section of Endocrinology, University of Messina, Messina, Italy Drug malabsorption is one of the potential troubles after bariatric surgery. This study reports 15 cases of hypothyroid patients (9 females, 6 males; age 31–59 years) who were well replaced with thyroxine tablets (for > 1 year) to euthyroid thyrotropin (TSH) levels before surgery (7 Roux-en-Y gastric bypass; 3 biliary pancreatic diversions). From 2 to 7 months after surgery, these patients had elevated TSH levels. Patients were then switched from oral tablets to a liquid formulation of Levo-thyroxine (with the same dosage, 30 minutes before breakfast). After 1–3 months after the switch, TSH was significantly reduced: 1) gastric bypass, from 5.6 – 4.1 to 2.7 – 2.3 mIU/mL, p < 0.05; 2) biliary pancreatic diversion, from 8.1 – 2.4 to 3.9 – 1.7 mIU/mL, p < 0.05). The abovementioned data suggest that the Levo-thyroxine oral liquid formulation could prevent the problem of the malabsorption after bariatric surgery.

Poster 790 Thyroid Hormone Metabolism & Regulation Wednesday & Thursday Poster Clinical 9:00 AM HYPOTHYROIDSIM AFTER THYROID LOBECTOMY: NOT ALL PATIENTS NEED TREATMENT E.L. Rudolf, S. Schaefer, R.S. Sippel, H. Chen, D.F. Schneider, D.M. Elfenbein Endocrine Surgery, University of Wisconsin-Madison, Madison, WI Thyroid function after thyroid lobectomy is assessed by measuring thyroid stimulating hormone (TSH) two months after surgery. Most patients undergoing lobectomy have normal TSH postoperatively. Some patients with elevated TSH are clinically asymptomatic. The aim of this study was to evaluate and describe patients with high TSH after lobectomy, and identify predictive variables for asymptomatic patients who did not require levothyroxine (LT4). We identified patients who underwent primary thyroid lobectomy for benign disease between 1/2003 - 8/2014 from our endocrine surgery database. If patients had elevated TSH and hypothyroid symptoms, or if their TSH was above 10 mIU/L, they were prescribed LT4. If they had no symptoms and mild TSH elevation, they were monitored closely with TSH drawn at regular intervals. Patient demographics, laboratory studies, and time to euthyroidism were recorded. Of 188 patients, 62 (33%) patients had TSH above the normal range 2 months after lobectomy. These patients had higher preoperative TSH (2.3 vs 1.3, p < 0.001) than euthyroid patients. Twenty (32%) of these patients reported no clinical symptoms of hypothyroidism, had only mild elevation of TSH (5.6 vs 11.3, p < 0.001), and were not prescribed LT4. Sixteen (80%) of these patients ultimately normalized their TSH without LT4. Mean time to euthyroidism for these patients was 208 – 166 days. Compared to patients who had a high TSH and were started on LT4, these asymptomatic patients had a lower pre-operative TSH (1.4 vs 2.7, p = 0.02) and higher BMI (33 vs. 28, p = 0.048). On a multivariate model, no factors independently predicted the need for LT4. Patients with mild elevation of TSH after lobectomy who have a higher BMI may not require LT4. Physicians may consider careful surveillance of patients with mild elevations in TSH without symptoms up to full year after surgery as we have seen these labs ultimately normalize, avoiding the need for long term hormone replacement.

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Poster 791 Thyroid Hormone Metabolism & Regulation Wednesday & Thursday Poster Clinical 9:00 AM THYROID FUNCTIONS AND SERUM LIPID PROFILE IN METABOLIC SYNDROME M. Mittal1, M. Gutch2 1 Medical Endocrinology, King George’s Medical University, Meerut, India; 2King George’s Medical University, Lucknow, India Thyroid hormones are known to affect energy metabolism. Many patients of metabolic syndrome have subclinical or clinical hypothyroidism and vice versa. Aim and Objective: To study the correlation of thyroid profile and serum lipid profile with metabolic syndrome. Material and Method: It is a hospital based cross sectional casecontrol study carried out in tertiary care health center, we studied thyroid functions test and serum lipid profile in 100 metabolic syndrome patients according to IDF criteria and a similar number of age, gender and ethnicity matched healthy controls. We found that Serum HDL was significantly lower (p < 0.001) in Cases (41.28 – 8.81) as compared to Controls (54.00 – 6.31). It was also found that Serum LDL, VLDL, Triglyceride levels and total cholesterol were found to be significantly higher (p < 0.001) in Cases than Controls. Serum TSH levels of subjects in Cases group (3.33 – 0.78) were significantly higher (p < 0.001) than that of controls (2.30 – 0.91) and significantly lower levels of T4 (p < 0.001) in the patients of metabolic syndrome (117.45) than in controls (134.64) while higher levels of T3, although statistically insignificant in the patients of metabolic syndrome. Thyroid hormones up-regulate metabolic pathways relevant to resting energy expenditure, hence, obesity and thyroid functions are often correlated.

Poster 792 Thyroid Hormone Metabolism & Regulation Wednesday & Thursday Poster Translational 9:00 AM INCREASED CYTOKINE TRANSCRIPTIONAL RESPONSE TO LIPOPOLYSACCHARIDE STIMULATION IN MACROPHAGES FROM A PATIENT WITH A THYROID HORMONE RECEPTOR a MUTATION A.H. van der Spek1, S. Aan1, O.V. Surovtseva1, A.V. Gucht2, P. van Trotsenburg3, E. Fliers1, A. Boelen1 1 Laboratory of Endocrinology, AMC, Amsterdam, Netherlands; 2 Dept. of Endocrinology, Erasmus Medisch Centrum, Rotterdam, Netherlands; 3Dept. of Pediatric Endocrinology, AMC, Amsterdam, Netherlands Recently, the first patients with resistance to thyroid hormone due to a mutation in thyroid hormone receptor alpha (TRa) were described. TRa is the primary thyroid hormone receptor in macrophages and other bone marrow derived cells. It has been shown to play an anti-inflammatory role in murine macrophages. In the present study, we assessed neutrophil and macrophage function in a patient with a newly diagnosed TRa mutation (p.D211G) prior to the initiation of levothyroxine treatment. Neutrophils and monocytes were isolated from venous blood. Monocytes were differentiated into macrophages in vitro. We determined neutrophil apoptosis by incubating the cells at 37 C and assessing Annexin V/Propidium Iodide staining using flow cytometry at 0, 4, 8 and 24 hours. We assessed phagocytosis by incubating macrophages with zymosan conjugated to pHrodo, a pH sensitive fluorescent dye, for 2 hours after which fluorescence was quantified using a spectrophotometer. Finally, macrophages were incubated with 100 nM of bacterial endotoxin (lipopolysaccharide (LPS)) for 3 hours, after which RNA was

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extracted. Cytokine mRNA expression was determined using qPCR. The response of the patient was compared to a reference interval established by the response of healthy controls (n = 5). Preliminary results showed increased apoptosis in neutrophils from the patient with the TRa mutation. Phagocytosis in macrophages was not different from controls. However, the increase in mRNA expression of the pro-inflammatory cytokines TNFa and IL-6 in response to LPS stimulation was markedly higher in macrophages derived from the patient compared to controls. LPS stimulation resulted in a 44-fold increase in TNFa expression in the patient’s macrophages versus a 27-fold increase in controls (95% CI 17.835.4), while IL-6 expression increased 420-fold in the patient versus 120-fold in controls (95% CI 65.3-175.5). We observed increased transcriptional cytokine response to LPS stimulation in macrophages derived from a patient with a TRa mutation, suggesting an anti-inflammatory role for TRa. These results are in accordance with previous studies in mice.

Poster 793 Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM COMPLICATIONS FOLLOWING US-GUIDED CORE-NEEDLE BIOPSY FOR THYROID LESIONS: A RETROSPECTIVE STUDY OF 6175 CONSECUTIVE PATIENTS AND SYSTEMATIC REVIEW E. Ha2, J. Baek1 1 Asan Medical Center, Seoul, Korea (the Republic of); 2Radiology, Ajou University Medical Center, Suwon, Korea (the Republic of) To present the spectrum of clinical adverse events of core needle biopsy (CNB) for thyroid lesions and to make performers aware of the potential complications with preventive measures. Between January 2008 and March 2013, US-guided CNB was performed in 6175 patients with 6406 thyroid nodules in a single institution by the clinicians’ requests. CNB was performed by experienced staff or fellow radiologists with 5–17 years of clinical experience using a 18-gauge double action spring-activated needle. We assessed the numbers and types of major and minor complications using the definition adopted by the Society of Interventional Radiology. The authors observed 64 complications (1.04%), 7 major and 57 minor. The major complications were massive hematoma (n = 2), pseudoaneurysm (n = 1), CCA injury (n = 1), voice change (n = 2), and tracheal puncture (n = 1). The minor complications were small hematoma (n = 41), edema (n = 11), vertebral puncture (n = 3), vasovagal reaction (n = 1), and dysphagia (n = 1). All patients recovered spontaneously except for two with massive hematoma who required hospitalization. Although the complication rate of CNB for thyroid lesions is low, various complications may occur; comprehension of complications and suggested technical tips may prevent complications or properly manage those that occur.

Poster 794 Thyroid Imaging Wednesday & Thursday Poster 9:00 AM DIAGNOSTIC VALUE OF CONTRAST-ENHANCED ULTRASONOGRAPHY IN SOLID THYROID NODULES WITH BOTH ENHANCEMENT AND NO-ENHANCEMENT W. Yan, Q. Wu Department of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Institute of Ultrasound in Medicine, Shanghai, China Thyroid nodules are a common and frequently encountered thyroid disease at present. Although only 5% of these are malignant, it is still

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of great importance to distinguish malignant lesions from all. Actually, using a microbubble contrast agent (average diameter at 2.5lm), contrast-enhanced ultrasonography (CEUS) could provide a better vascularity representation and dynamic enhancing pattern of thyroid nodules. A total of 196 patients scheduled for surgery or fine needle aspiration (FNA) for 229 solid thyroid nodules underwent conventional ultrasound and CEUS. According to the presence of microbubble echoes in the lesion, all were divided into enhancement group, no-enhancement group. The contrast-enhancement patterns in the enhancement group were evaluated with five observed indicators including arrival time, mode of entrance, echo intensity, homogeneity of enhancement and washout time. In the no-enhancement group, thyroid nodules were evaluated according to different sonographic features. Then sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of corresponding indicators and sonographic features for the diagnosis of thyroid cancer were determined. Among the enhancement group, the differences of three CEUS indicators including arrival time, mode of entrance and washout time between malignant and benign thyroid nodules were statistically significant in < 10mm subgroup (P < 0.05), while all CEUS indicators showed statistically significant difference in ‡ 10mm subgroup (P < 0.05). Earlier washout in ‡ 10mm group had a high sensitivity at 84.78%, while both the specificity and accuracy of hypo-enhancement in ‡ 10mm group ranked first with 92.86% and 78.38%. Among the no-enhancement group, only nodular border obscurity showed significant difference between benign and malignant nodules (p < 0.05, sensitivity 75.0%, specificity 84.8%, accuracy 84.4%). While none of other sonographic features was significantly different (p > 0.05). On the basis of conventional ultrasound and clinical data, our study indicated that CEUS has important diagnostic value in benign and malignant thyroid nodules with both enhancement and noenhancement.

Poster 795 Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM VARIATIONS OF ORBIT UPTAKE, ON 99MTC-ANTI-TNF-a SCINTIGRAPHY: RELATIONSHIP TO RESPONSE TO CORTICOSTEROID THERAPY A.M. Lacerda, S. de Souza, M. Vaisman, B. Gutfilen, L. da Fonseca, P.D. Teixeira UFRJ, Rio de Janeiro, Brazil

Recently, it was suggested that 99mTc-anti-TNF-a scintigraphy (SCI) could be promising in the approach of active Graves’ ophthalmopathy (GO). This study aimed to evaluate, in a longitudinal design, the variations of the uptake on SCI, during corticosteroid therapy (CorT) for active GO. Also aimed to determine if such uptake could be a predictor of response in those patients. All patients underwent SCI at baseline and 2 months after conclusion of CorT (methylprednisolone, 0.5g/week [6 consecutive weeks] and 0.25g/week [more 6 weeks]). Planar images were obtained in a 256 · 256 matrix (each lasting 5 min) and single photon emission computed tomography (SPECT) scan lasting 13 min. Regions of interest (ROI) were drawn on the orbit and cerebral hemispheres, and each average (AVG) of ROI calculated. All patients had clinical evaluation of Clinical Activity Score (CAS) and measurements of serum concentrations of TSH, FT4 and TRAb at the inclusion and at the end of the study. Magnetic resonance was also performed to confirm active eye disease. From sixteen patients, 31 orbits were evaluated (25 with active CAS), since one patient have only one eye. There were positive correlations between absolute and relative variations on CAS throughout the time and variations on AVG of regions of interest (ROI) drawn on orbit ((rs = 0.381 [p = 0.017]) and rs = 344 [p = 0.029], respectively). Evaluating the relative variations of AVG throughout the time, according to activity and response to therapy, it was detected a mean average reduction of 7.5% in orbits that became inactive (p = 0.07 [Wilcoxon]). These results were different (p = 0.04) from the positive variation of + 11.9% (p = 0.49 [Wilcoxon]) detected in orbits that were still active at the end of the study (n = 7). The medium baseline AVG of ROI didn’t differ between adequately responders to glucocorticoid and those that maintained active eye disease despite treatment (43.8 vs 22.8 p = 0.270). The uptake variations, throughout the time, on SCI were significantly different between responders and non-responders patients to therapy. However, the preliminary results suggest that baseline AVG of ROI drawn on orbit, by this method, didn’t showed to be a good predictor of response to CorT.

Poster 796 Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM DIFFUSE MICROCALCIFICATIONS IN THE THYROID GLAND: CLINICAL SIGNIFICANCE AND MANAGEMENT H. Park1, J. Baek1, H. Yoo2, D. Choi3, J. Sung4 1 Radiology, Asan Medical Center, Seoul, Korea (the Republic of); 2 pathology, Daerim St. Mary’s Hospital, Seoul, Korea (the Republic of); 3Surgery, Daerim St. Mary’s Hospital, Seoul, Korea (the Republic of); 4Radiology, Daerim St. Mary’s Hospital, Seoul, Korea (the Republic of) The aim of this study is to evaluate the clinical significance of diffuse microcalcifications in the thyroid gland on ultrasound (US) which may help determine the best management strategy, and compare the diagnostic performances of fine-needle aspiration (FNA) and core needle biopsy (CNB). We assessed 66 patients with diffuse microcalcifications in the thyroid gland. The histopathologic characteristics of the surgical specimens were considered the standard reference for malignancy. Patients with surgically proven malignancy, multifocal cancer, intrathyroid lymphatic spread in the opposite lobe, and cervical lymph node metastasis were evaluated. Among the 66 confirmed patients, 53 had malignant lesions (80.3%) and 13 had benign lesions (19.7%). CNB was performed on 41 patients, and FNA was performed on 54 patients. Both CNB and FNA were performed on 29 patients. There were no statistical differences in terms of diagnostic accuracy, specificity, or positive

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a. US image shows diffuse microcalcifications in the right thyroid gland and isthmus. b. Clusters of psammomma bodies (arrows) were present in the lymphatics, which indicate intrathyroid lymphatic spread of tumor. It was confirmed as the sclerosing variant of PTC. c. Diffuse microcalcifications were noted throughout the right thyroid gland (arroheads). d. Tumor emboli (arrows) with psammoma bodies (arrowheads) were noted in the lymphatics. predictive value between CNB and FNA ( p = 0.086, > 0.99, and > 0.99). The sensitivity and negative predictive value were significantly higher for CNB ( p = 0.044 and 0.001) Diffuse microcalcifications in the thyroid gland show high prevalence of malignancy. Considering that thyroid cancer with diffuse microcalcifications commonly has multifocal tumor foci, intrathyroid lymphatic spread and cervical lymph node metastasis, total thyroidectomy may be the preferred for the management. Although both CNB and FNA demonstrate acceptable diagnostic accuracies, CNB may be preferred because it demonstrates a significantly higher sensitivity and NPV.

Poster 797

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Example of intensely FDG-avid benign degenerate nodule with dystrophic calcification (inferiorly) and mildly avid papillary thyroid cancer (superiorly). to impairment of mitochondrial respiratory chain complex I and consequent upregulation of glycolytic metabolism. Retrospective audit of 33009 scans between 2007 and 2013 identified 416 patients with FDG-avid TI (1.3%). Further evaluation was performed when clinically appropriate in the context of comorbid malignancy in 116 patients (38 cases of presumed FDG-avid malignancy). Of these, available surgical pathology (hemi or total thyroidectomy) for 24 FDG-avid lesions (18 women, aged 28–80) underwent a detailed histopathologic (location, size, diagnosis, percentage oncocyte density [POD]) and PET/CT imaging (location, size, SUVmax) review performed by a head & neck oncologic pathologist and nuclear medicine physician. 3 of 15 (20%) presumed malignant FDG-avid TI were not malignant on histopathologic-imaging review. In 2 cases, benign TI were identified as the cause of FDG uptake whilst in 1 case the original pathologic diagnosis was revised. Final diagnosis in this surgical population was 13 malignant (oncocytic 6, PTC 6, MTC 1) and 11 benign (oncocytic 8, parathyroid adenoma, degenerate nodule & thyroiditis) lesions. 14 of 22 FDG-avid lesions demonstrated significant ( > 60%) oncocyte density. Median/range SUVmax of benign (11.3/[3.7–37]), malignant (5.5/[3.4–54]), oncocytic (12.1/[3.6–54]) and non-oncocytic (5.4/[3.4–42]) lesions were estimated. There was no correlation (r2 = 0.11) between POD and SUVmax. 5 patients in this cohort died after median follow-up of 56 months from index FDG PET/CT; there were no thyroid cancer related deaths. Oncocytic lesions may have very intense FDG uptake and are a common cause of FDG-avid TI. The incidence of FDG-avid malignancy may be overestimated without careful histopathologic-imaging correlation. It is also critical to consider the prognosis of underlying malignancy when evaluating FDG-avid TI.

Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM ONCOCYTIC THYROID NODULES ARE A COMMON AETIOLOGY FOR INTENSELY 18 F-FLUORODEOXYGLUCOSE-AVID THYROID INCIDENTALOMAS D.A. Pattison1,2, C.A. Angel3, M. Bozin4, M.S. Hofman1,5, R.J. Hicks1,5 1 Centre for Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; 2Department of Endocrinology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; 3 Department of Anatomical Pathology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; 4Department of Surgical Oncology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; 5 Department of Medicine, University of Melbourne, Parkville, VIC, Australia

Poster 798

Thyroid cancer is variably reported in 8–55% of thyroid incidentaloma (TI) detected by FDG positron emission tomography/ computed tomography (PET/CT). Pathologic misclassification (identification of incidental non-avid thyroid cancer and not attributing FDG-avidity to benign thyroid uptake) potentially explains this heterogeneity. Intense FDG uptake occurs in oncocytic tumours due

Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM IS THE REPRODUCIBILITY OF SHEAR WAVE ELASTOGRAPHY OF THYROID NODULES HIGH ENOUGH FOR CLINICAL USE? A METHODOLOGICAL STUDY K.Z. Rubeck1,2, S.J. Bonnema3, M. Jespersen4, P. Christiansen6, B. Bibby5, V.E. Nielsen1

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1

Department of oto rhino laryngology and head & neck surgery, Aarhus Universityhospital, Aarhus C, Denmark; 2Clinical Medicine, Aarhus University, Aarhus C, Denmark; 3Department of Endocrinology, Odense Universityhospital, Odense, Denmark; 4 Department of Pathology, Aarhus Universityhospital, Aarhus, Denmark; 5Department of Biostatistics, Aarhus University, Aarhus, Denmark; 6Surgical Department P, Section of Breastand Endocrine Surgery, Aarhus Universityhospital, Aarhus, Denmark Shear Wave Elastography (SWE) assesses tissue elasticity quantitatively (Elasticity Index, EI). A higher EI in malignant thyroid nodules has been reported, suggesting SWE as a potential tool for diagnosing thyroid malignancy. However, thyroid SWE needs to be further evaluated before clinical application is legitimate. Our aim was therefore to systematically assess the reproducibility of SWE, when applied to patients undergoing surgery for thyroid nodular disease. SWE examinations were performed pre-operatively in 52 patients [male/female: 13/39; mean age: 53 years (range 21–81); malignant/benign 13/39] referred to a tertiary thyroid center. Guided by at color-coded map, repeat registrations of EI in predefined regions of interest (ROIs) were performed for the index nodule by two independent investigators on the same day, and by one investigator on a different day. We assessed thyroid SWE reliability by calculating the inter- and intraobserver variation along with the day-to-day variation. Results are presented as 95% limits of agreement, by which a variation of 0% indicates perfect concordance between observations. Independent measurements for mean EI of 10mm ROI showed an inter-observer variation of 95%, whereas the intra-observer variation was 92% and 85% for the two observers, respectively. The day-today variation (n = 40) was 176%. Using mean EI for a 3mm ROI, measurements showed an inter-observer variation of 164%, while the intra-observer variation was 131% and 126% for the two observers, respectively. The day-to-day variation (n = 40) was 243%. When comparing EI measurements of 10mm ROI, a systematic interobserver difference of 18% (95%-CI: 9–29%, p = 0.0002) was registered, whereas no systematic difference was found for 3mm ROI (p = 0.38). In this methodological study of thyroid SWE, we found a suboptimal observer agreement, as measured by the 10mm ROI, and the variation was even higher by a 3mm ROI. In addition, a high day-today variation of EI raises concern, and may invalidate this method as a reliable tool for discriminating malignant from benign thyroid nodules.

Poster 799 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM A NOVEL ROBOTIC SURGICAL TECHNIC FOR THYROID SURGERY - BILATERAL AXILLAR APPROACH (BAA J. Woo, S. Kim, I. Park, J. Choe, J. Kim, J. Kim Department of Surgery, Samsung Medical Center, Seoul, Korea (the Republic of) Robot assisted thyroidectomy (RT) is proven as a feasible method for the treatment of well differentiated thyroid cancers in terms of oncology as well as cosmesis. Two approaching methods have been widely performing in Korea; Axillary approach (AA) and Bilateral Axillo-Breast Approach (BABA). Although each approach has its own merits, several limitations still exist. We suggest here a novel robotic surgical technic for thyroid surgery free from breast incision, bilateral axillar approach (BAA).

Since October 2014, we have recruited patients willing to undergo the novel BAA robotic thyroid surgery after informed consents. The clinical data and quetionares were collected prospectively after approval of institutional review board. Total 36 patients underwent BAA robotic thyroid surgery. Mean age of the patients was 34.0 years. Thirty two patients were female, and 4 patients were male. Thirteen patients underwent total thyroidectomy, while 23 patients underwent ipsilateral thyroid lobectomy, and 35 patients underwent concomitant central lymph node dissection. Mean flap dissection time was 33.0 minutes, and mean ipsilateral console time was 64.1 minutes. Mean number of ipsilateral dissected lymph nodes were 2.7 lymph nodes. There were 2 cases of postoperative radioactive iodine ablation, and their stimulated thyroglobulin were both 0.1 ng/mL. There were 1 case of transient vocal cord paresis (1 event/nerves at risk), and 2 cases of transient hypoparathyroidism (postOP 1 day PTH £ 5.0 cases/13 total thyroidectomy cases). There was no case of postoperative bleeding or chyle leak. Of 36 patents who had undergone BAA procedure, 12 patients answered the questionnaire. The scale, range from 0 to 10, at postoperative 1 day/2weeks are as follows: voice change score, 2.4/1.0; swallowing difficulty score, 4.2/0.7; anterior neck pain score, 5.5/4.0; anterior neck numbness score, 5.1/4.5; right chest pain score, 4.1/3.0; left chest pain score, 4.0/2/3; right chest numbness score, 2.9/1.0; and left chest numbness score, 2.6/ 2.3 respectively. BAA robotic thyroid surgery is a novel, safe and feasible oncoplastic method especially for patients who fear for breast nipple areolar incision.

Poster 800 Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM A NOVEL GEL PAD LARYNGEAL ULTRASOUND (LUS) FOR VOCAL CORD EVALUATION J. Woo, S. Kim, I. Park, J. Choe, J. Kim, J. Kim Department of Surgery, Samsung Medical Center, Seoul, Korea (the Republic of) Laryngeal ultrasound (LUS) is a recently developed method of vocal cord (VC) evaluation in patients with risk of vocal cord palsy (VCP). However, the LUS reportedly has high failure rate of VC visualization in male patients. We devised a novel gel pad LUS to improve the limitations. A total of 14 (5 male, 9 female) consecutive LUS and direct laryngoscopy (DL) exams were performed for thyroidectomy and other neck surgery patients. The conventional LUS, lateral-approach LUS, and gel pad LUS were used for all patients. Findings were independently cross-validated with DL. The conventional LUS, lateral-approach LUS, and gel pad LUS methods had 78.6%, 92.9%, and 100% visualization rate, respectively with an overall sensitivity of 100% and specificity of 100% for VCP. Among the 14 patients, 2 patients had VCP, and 5 patients had diffuse thyroid cartilage calcification interrupting LUS. With

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(25%), fibrosis or calcification only (75%). All nodules with nondiagnostic results of normal thyroid tissue only were micronodules. The nondiagnostic rate of CNB was very low and CNB could effectively reduce nondiagnostic results. The major US features of nondiagnostic nodules were solid, hypoechogenicity, and macrocalcifications, which were correlated with major pathology features revealed as fibrosis and calcifications.

Poster 802

gel pad LUS, bilateral simultaneous visualizations of VC were possible in 3 male patients (21.4%) which was not feasible in conventional LUS. Compared to conventional LUS, new gel pad LUS method significantly enhances the visualization of VC in patients with diffuse thyroid cartilage calcification and enables the simultaneous bilateral VC evaluation in male patients, heightening the overall efficacy of LUS as a perioperative diagnostic tool for VCP. Normal vocal cord (VC) and laryngeal ultrasound (LUS) view. (a) Normal VC. (b) Normal LUS view. All 3 VC landmarks (TC; true cord, FC; false cord, AR; arytenoid) are visible. (c) Diffuse calcification of thyroid cartilage. (d) Gel pad LUS view for calcified thyroid cartilage.

Poster 801 Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM NONDIAGNOSTIC RATE OF CORE-NEEDLE BIOPSY AND ULTRASOUND-PATHOLOGY FEATURES OF THYROID NODULES WITH NONDIAGNOSTIC RESULTS S. Kim, D. Na Radiology, Human Medical Imaging & Intervention Center, Seoul, Korea (the Republic of) The purpose of this study was to determine the nondiagnostic rate of core-needle biopsy (CNB) in thyroid nodules and to assess US and pathology features of nodules with nondiagnostic CNB results. From January 2010 to June 2014, we included 1302 consecutive data of CNB on thyroid nodules in a single institution. We calculated the nondiagnostic rate and analyzed US features and pathologic features of nodules with nondiagnostic CNB results. The pathology criteria for the ‘‘nondiagnostic’’ included normal thyroid tissue only, extra-thyroidal issue only, blood clots or fibrotic tissue only, and virtually acellular tissue. Sixteen (1.2%) of 1302 nodule were read as nondiagnostic CNB results, in which micronodules ( 30%) (P < 0.001), severe microfollicle formations ( > 90%) (P = 0.008), uniform follicular pattern (P = 0.014), and severe hypercellularity by univariable analysis (P = .026), and the presence of fibrosis was independently associated with hypoechogenicity (P = 0.014) by multivariable analysis. At least one of these 4 histologic features were present in 68 (95.8%) of 72 hypoechoic nodules. There was a significant correlation between nodule echogenicity and the severity of fibrosis and uniformity of follicles (r = 0.520, P < 0.001 and r = 0.240, p = 0.014, respectively). The hypoechogenicity of thyroid nodules is associated with histopathologic features of fibrosis, severe microfollicle formation, uniform follicular pattern, and severe hypercellularity, and the nodule echogenicity correlates with the degree of fibrosis and follicular uniformity.

Poster 804 Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM THYROID INCIDENTALOMAS ON FDG-PET/CT: CORRELATION WITH CYTOLOGY, HISTOPATHOLOGICAL RESULTS AND ONCOLOGIC OUTCOMES FROM A SINGLE INSTITUTION IN SHERBROOKE, QUe´BEC N. Hagenimana1, J. Dallaire2, M. Belzile1 1 Oto-rhino-laryngology & Head and Neck Surgery, Universite de Sherbrooke, Sherbrooke, QC, Canada; 2Universite de Sherbrooke, Sherbrooke, QC, Canada Thyroid incidentaloma is defined as an unsuspected thyroid lesion found on imaging study or when performing a surgery unrelated to thyroid gland. Most recent scientific litterature tend to demonstrate a detection rate of 2–3% for incidental findings of thyroid lesions identified by 18F-fluorodeoxyglugose Positron Emission Tomography with computed tomography (FDG-PET/CT) initially prescribed for

nonthyroid disease. In between 25–50% of the patients who undergo further evaluation are diagnosed with malignant lesions, which is not negligeable. Objective : To determine the proportion of patients, treated in our tertiary care center (Centre hospitalier universitaire de Sherbrooke CHUS), with thyroid incidentalomas on FDG-PET/CT in whom a cancer was diagnosed and if predictive criterion can be outlined to help in their management. Methods : We retrospectively reviewed 53000 charts of patients who had a FDG-PET/CT done for the evaluation of nonthyroid disease from 2004 to 2014. From these, we extracted 1369 patients with a thyroid incidentaloma reported by the nucleist. The standardized uptake value (SUV), thyroid function, other imagery results, cytology and histopathological results as well as oncologic outcomes were analysed. On preliminary results, it seems that the proportion of malignancy diagnosed in our series of thyroid incidentalomas seen on the FDGPET/CT corresponds to those of the literature. We also noticed that an enormous proportion (29.6%) of patients did not get an adequate follow-up concerning their thyroid incidentaloma. An algorithm will be drawn from the final results in order to propose a simple orientation for clinical management derived from the SUV. As a pioneer in Que´bec and as one of the first center in Canada to use PET/CT routinely for diagnosis of cancer, we hope to use Sherbrooke’s significant experience to help define accurately proper management for this more common clinical situation.

Poster 805 Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM CORRELATION BETWEEN BRAF V600E MUTATION AND EARLY WASHOUT OF I-131 OF REMNANT THYROID UPTAKE IN PAPILLARY THYROID CANCER; COMPARISON OF IMAGING AT MULTIPLE TIMES AFTER HIGH DOSE I-131 RADIOIODINE ABLATION K. Kim2, I. Kim1, S. Kim1, K. Pak1, B. Kim1 1 Pusan National University Hospital, Pusan, Korea (the Republic of); 2 Yangsan Pusan National University Hospital, Yangsan, Korea (the Republic of) The object of the present study was to investigate the relationship between the BRAF V600E mutation and therapeutic radioiodine avidity. From November 2012 to April 2013, 46 patients with pathologically documented papillary thyroid cancer who had total thyroidectomy were included in a prospective cohort study. Among these patients, the BRAF V600E mutation was analyzed in 28 patients. Whole body scan (WBS) was performed at 48hr, 216hrs and 240hrs after high dose I-131 radioiodine administration. The grades of the remnant thyroid activity in each WBS were classified from 0 to 3 by visual assessment. The changes of intensity of the remnant thyroid tissue at different times were calculated. BRAF V600E mutation was found in 17 of 28 patients (60.7%). The intensity of thyroid bed uptake at 48hr was not associated with BRAF V600E mutation. The activities of thyroid bed in WBS at 216hr and at 240hr were significantly lower in BRAF V600E positive patients than in BRAF V600E negative patients (p = 0.01). The intensity of remnant thyroid was significantly decreased in WBS at 216hr and at 240hr compared with WBS at 48hr in patients with BRAF V600E mutation (p = 0.01). BRAF V600E negative patients showed that the activity of the thyroid bed was more frequently persisted or increased in delayed WBS at 216hr and at 240hr. The BRAF V600E mutation was significantly associated with rapid clearance of I-131 in thyroid bed after therapeutic high dose I-131 radioiodine administration. Therefore, patients with BRAF V600E mutation may have decreased radioiodine retention in remnant thyroid tissue and lead failure of treatment.

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015

Poster 806 Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM FRACTAL DIMENSION OF THYROID NODULE IMAGES: FIELD OF APPLICATION IN CLINICAL PRACTICE P. Lothaire1, P. Uzureau2, K. Zouaoui2, N. Nagy3, L. Bissen4, D. Dequanter1, C. Michiels5, T. Carletti6 1 Head and Neck Surgery, CHU Ve´sale, Montigny Le Tilleul, Belgium; 2Laboratory of experimental medicine, CHU Ve´sale, Montigny Le Tilleul, Belgium; 3Pathology, CHU Ve´sale, Montigny Le Tilleul, Belgium; 4Radiology, CHU Ve´sale, Montigny Le Tilleul, Belgium; 5Biology, University of Namur, Namur, Belgium; 6 Mathematics, University of Namur, Namur, Belgium Ultrasound-guided fine-needle aspiration is the most sensitive investigation procedure in the evaluation of patients with thyroid nodules; however, despite the level of achieved precision, it is still impossible to preoperatively discriminate between follicular adenomas and carcinomas. Thus, no current detection tool of thyroid nodule has both high sensitivity and high positive predictive value for the diagnosis of thyroid cancer. Ultrasound images could provide some important information that would help to distinguish benign from malignant nodules but that are currently missed due to visual interpretation. For example, the roughness of the echotexture of US images cannot be quantified using standard image analysis tools. However, such information can be retrieved using the measurement of the fractal dimension (FD). In a previous study, we observed on a small sampling (13 benign and 14 malignant nodules) that the difference of the FD value between malignant nodules and normal tissues was significant while the FD value of the benign nodules and normal tissues could not be distinguished. A larger sampling of nodules (>100) issued from the database of radiology department of CHU Charleroi (Belgium) are evaluated using the previously described method for fractal dimension evaluation. Our first results stressed the importance of the size of the nodule image for the accuracy of the algorithm we developed for FD calculation. Therefore, the analysis was restricted to the adequate US nodules: surface > 10 000 pixels2 and height > 80 pixels. Running data seemed to confirm the results of the preliminary study. However, final conclusions will only be drawn in light of the analysis of the remaining images. Our preliminary work supported the hypothesis that FD could be an additional feature to discriminate benign from malignant nodules. This larger sampling will challenge the possible utilization of FD in the thyroid cancer diagnosis in clinical practice.

Poster 807 Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM A PREOPERATIVE PET/MR IMAGING FOR ASSESSING PAPILLARY THYROID CARCINOMA J. Choi1,2, S. Lee1, J. Moon3, E. Kong2, Y. Byeon1, S. Kang1, J. Park1, K. Yeu1 1 Department of Surgery, Yeungnam University College of Medicine, Daegu, Korea (the Republic of); 2Nuclear medicine, Yeungnam University College of Medicine, Daegu, Korea (the Republic of); 3 internal medicine, Yeungnam University College of Medicine, Daegu, Korea (the Republic of) For preoperative evaluation of neck node status in papillary thyroid carcinoma (PTC), ultrasound and neck CT has been generally used. This study evaluated the accuracy of a preoperative positron emission tomography/magnetic resonance (PET/MR) imaging for main mass and neck node status of PTC. Among 300 PTC patients who received preoperative PET/MR within 3 months prior to surgery from Aug 2012 to Oct 2013, 285

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patients who underwent open thyroidectomy due to primary PTC were included. Through PET/MR, visual FDG uptake and morphologic abnormality including nodal shape, cortical thickness and loss of fat hilum of neck nodes were analyzed. All data were collected and analyzed retrospectively. Mean age of patients was 48.5 – 11.4 year and mean tumor size was 0.9 – 0.6 cm. Total thyroidectomy and lobectomy was conducted in 78.2% (223/285) and 21.8% (62/285), respectively. All patients were underwent the evaluation for status of central neck node during surgery and additional evaluation for status of lateral neck node were conducted in 11.9% (34/285) of patients through selective sampling or modified radical neck dissection. In total, 36.1% (103/285) of patients had pathologic neck lymph node metastasis. PET/MR showed a high detection rate for main tumor of PTC (98.2%, 280/285). For detection of central neck nodes metastasis, PET/MR showed 68.8% accuracy (positive predictive value (PPV) = 61.1%, negative predictive value (NPV) = 70.6%) and for lateral neck nodes, 69.6% (PPV = 72.2 and NPV = 62.5%). PET/MR showed a higher accuracy for detecting neck node metastasis in 164 patients who were not suspected of clinical thyroiditis with positive thyroid antibodies or history of medical thyroid disease than total patients. For central neck nodes and lateral neck node, PET/MR had 75.0% and 73.2% accuracy, respectively. PET/MR imaging technique as preoperative evaluation of PTC seems to show a high accuracy in detecting main tumor. In detecting neck node metastasis, PET/MR imaging seems to show a higher accuracy in the patients without clinical thyroiditis than those with thyroiditis.

Poster 808 Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM COEXISTING METASTATIC HURTHLE CELL THYROID CANCER AND LUNG CANCER WITH MARKEDLY DIFFERENT METABOLIC ACTIVITIES ON FDG PET/CT M.A. Muhleman, Z. Al-faham, D. Wu Nuclear Medicine, William Beuamont Health Systems, Royal Oak, MI FDG PET/CT has been increasingly utilized for restaging of metastatic thyroid cancers. Interpretation of PET/CT images could be challenging due to a wide range of FDG activities seen in different malignancies, and there is no cut-off standard uptake value (SUV) that could reliably separate benign versus malignant. The patient was a 70-year-old male with subtotal thyroidectomy on 10/15/2007 (left lobectomy and subtotal right lobectomy). Pathology revealed a 7 cm minimal invasive follicular thyroid cancer in the left lobe, Hurthle cell type, with capsular/vascular invasion, no extrathyroid extension, and no lymph node metastasis. On 11/26/ 2007, I-131 scan showed uptake in the right thyroid bed, for which he received 30 mCi of I-131 for ablation. We started to see this patient in 2013 due to rising thyroglobulin (Tg) and non-conclusive imaging studies. FDG PET/CT was performed on 07/09/2013, which revealed a known right upper lung nodule with minimal FDG activity (max SUV 0.7), stable since the prior PET/CT dated 10/10/2011 (max SUV 0.7). In contrast, there was a new 1-cm node in the left upper paratracheal region, with intense FDG activity, max SUV 39.7. On 07/26/2013, CT guided biopsy of the RUL nodule was positive for well-differentiated bronchogenic adenocarcinoma, while biopsy of multiple mediastinal nodes on 08/08/2013 was all negative. On 08/ 15/2013, right upper lung lobectomy was performed, and revealed a 2.7 cm primary pulmonary invasive moderately differentiated adenocarcinoma. Due to continue rising Tg, and positive repeat PET/CT, mediastinolomy was performed on 02/20/2014, which revealed a 1.6 cm left upper paratracheal node, positive for metastatic Hurthle cell carcinoma of thyroid origin. Since then, the patient had two followup CTs, both were unremarkable.

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WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015

Poster 810 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM CAVERNOUS SINUS METASTASIS FROM CRIBRIFORM PAPILLARY THYROID CARCINOMA A. Lowenstein1, A. Reyes1, L. Fernando1, A. Colobraro1, M. Monteros Alvi2, A. De los Rios2, V. Concilio1, A. Rogozinski1 1 Hospital JM Ramos Mejia, Buenos Aires, Argentina; 2Hospital Dr A. On˜ativia, Salta, Argentina

Representative PET/CT image showing a RUL nodule with minimal FDG activity (right lower panel) and intense FDG-avid left mediastinal node (right upper panel). Results from this case illustrate a huge different metabolic activity seen in primary lung cancer (max SUV 0.7) and metastatic Hurthle cell cancer of thyroid (max SUV 39.7). Results from this case illustrate a huge different metabolic activity seen in primary lung cancer (max SUV 0.7) and metastatic Hurthle cell cancer of thyroid (max SUV 39.7).

Poster 809 Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM ULTRASONOGRAPHIC FEATURES OF WELL DIFFERENITED THYROID CARCINOMA (WDTC) AND PATHOLOGICAL CORRELATION: A STUDY OF 46 CASES FROM FARWANIYA HOSPITAL, KUWAIT N. Al-Brahim1, N. Taher1, S. Hebbar2 1 Pathology, Farwaniya Hospital, Kuwait, Kuwait; 2Diagnostic Radiology, Farwaniya Hospital, Kuwait, Kuwait Ultrasound (US) imaging is a very useful, cost-effective diagnostic test for evaluating thyroid nodules. Despite the fact that there is no single ultrasongraphic feature that can predict malignant nodules, a collection of characteristics can help in achieving this. Therefore, ultrasonographers should be aware of these features and include them in the report. This study was conducted to assess completeness of thyroid ultrasound reports, common sonographic features in WDTC and correlation of these features with pathological characteristics of the nodules. Cases of thyroid cancer more than 1.0 cm in size and diagnosed between 2006 and 2013 were retrieved from the electronic files of the Department of Pathology, Farwaniya Hospital. Pathology reports and histological slides were reviewed to confirm the diagnosis and to identify prognostic factors. Cases with preoperative (US) performed in the hospital and reports available for review were included in the study. Nine features that were included in ATA guidelines that help predicting in malignancy were identified. Fourty-six cases had US performed in the hospital and included in the study, 33 cases were female (71.7%) and patients’ age ranged 2365. Ten reports out of 46 (21.7%) included ‡ 6 features, 25 reports (54.3%) included 4-5 features and 11 (24%) reports included £ 3 features in the report. The most common features commented on were lymph nodes (46/46), increased nodular vascularity (41/46) and solid vs cystic nodule (32/46). The least features commented on were halo sign (4/46) and hypoechogenecity (15/46). Increase intranodular vascularity and calcification are the most common features seen in WDTC and seen in (53.6%) and (45.4%) reported cases respectively. Papillary carcinoma was seen in all cases. Analysis of sonographic reports of WDTC revealed high percentage of uncompleted reports. There was no correlation between sonographic features and pathological features in our series.

Distant metastases from papillary thyroid carcinoma (PC) is rare and usually occur synchronously. There are few reports of cavernous sinus (CS) metastasis. The cribriform variant from PC may be sporadic or associated to familial colonic polyposis. We present a clinical case, with a history of differentiated thyroid carcinoma (DTC), and a methacronous metastasis to cavernous sinus. A 61 year old male, who lives in an endemic area (Salta), complains of headache and bilateral ptosis. Four years before (2008), he had had a history of thyroidectomy and left lateral cervical dissection. Histology: Left lobe: 2 cm PC cribriform variant with extrathyroid invasion. Right lobe: 5 cm follicular thyroid carcinoma 2/ 4 nodes metastasis tall cell PC. Ablation: 150 mci 131I. WBS neck positive. E IVa (AJCC 7th ed). Two years later (2010) with THW:TSH 41 uUI/ml, Tg < 1 ng/ml, TgAb 1756 UI/ml, US negative WBS negative After one year without control (2011), he attends with neurological compromise. He is sent to our center for diagnosis and treatment. MNR : solid mass, on right selar and paraselar topography 24 · 26 · 17 mm, it englobes intracavernous carotid artery. Neck US negative. Under LT4 treatment: TSH 0,02 uUI/ml Tg 9,3 ng/ml Tg Ab 1473 UI/ml, PRL 13 ng/ ml, cortisol 23 ug/dl, LH 5,6 mUI/ml FSH 7,3 mUI/ ml To 1,1 ng/ml, IGF1 158ng/ml. Colonoscopy could not be performed. Transnasal endoscopic biopsy: Cribriform PC metastasis. FDG-PET : cervical recurrence, lymph nodes, lung and brain secondarism. Hipermetabolic focus on CS. The patient was hospitalized and treated with recombinant human TSH (rhTSH Thyrogen) followed by 300 mCi 131I. WBS-131I uptake on skull base, thyroid bed and upper mediastinum. The dose was well tolerated without adverse effects. The patient died 2 years after radioactive iodine therapy. a) We report an unusual site of distant metastasis in cavernous sinus, in a patient with concurrent follicular thyroid carcinoma and cribriform, tall cell variants from PC. b) Radioactive iodine dose after rhTSH was administrated, without complications. c) FDG-PET was positive and had had an unexpected 131I uptake in CS . d) The patient would have been a good candidate for tyrosine kinase inhibitor therapy.

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015

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Poster 811

Poster 812

Thyroid Cancer Wednesday & Thursday Poster Basic 9:00 AM MICRORNA (MIR)-221, MIR-222, AND MIR-146B EXPRESSION IN IN PAPILLARY THYROID CARCINOMA WITH BRAFV600E MUTATION S. Yang1, K. Park2, Y. Choi3, J. Kim1 1 Surgery, Kosin University College of medicine, Busan, Korea (the Republic of); 2Surgery, Hub-hu hospital, Busan, Korea (the Republic of); 3Internal maedicine, Kosin University College of Medicins, Busan, Korea (the Republic of)

Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM WHAT IS THE MOST IDEAL CORE NUMBER FOR ULTRASONOGRAPHY-GUIDED THYROID BIOPSY OF CYTOLOGICALLY INCONCLUSIVE NODULE? S. Hahn1, J. Shin1, Y. Oh2 1 Radiology, Samsung Medical Center, Sungkyunkwang University, School of Medicine, Seoul, Korea (the Republic of); 2Pathology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea (the Republic of)

Aberrant microRNA (miRNA) expression, particularly miR-221, miR-222, and miR-146b, is increased in papillary thyroid carcinoma (PTC). BRAFV600E is the most frequently identified genetic alteration in papillary thyroid carcinoma. The purpose of this study was to identify the link between BRAFV600E status and the expression of miRNAs in PTC and analyzed the associations of miRNAs with clinicopathological characteristics. The author used total RNA of 51 formalin-fixed paraffin-embedded tissues of 42 PTCs (36 classic PTC, 6 follicular variants PTC) and 9 benign tumor to analyse the miRNA expression pattern of five selected miRNAs (miR-221, miR-222, and miR-146b) using RTPCR TaqMan miRNA assay to explore the diagnostic utility of this method and the presence of the BRAFV600E mutation was determined by polymerase chain reaction amplification of exon 15 followed by direct sequencing. The expression levels of all three miRNAs were significantly increased in PTC when compared to benign tumor. miRNAs expression was significantly high in patients with cervical lymph node metastasis and advanced TNM stage. In addition, miR-146b expression levels were significantly higher in papillary thyroid carcinoma patients with BRAFV600E mutation. The relative quantification (2 -66Ct) of miR146b was also high among the miRNAs. To evaluate the diagnostic value of these three miRNAs for PTCs, Receiver operating characteristic (ROC) curve analysis was performed. Individually, the AUCs for miRNA-146b was 0.923 (cutoff value - 1.97, sensitivity 88.9%, specificity 85.7%). In this study expression of miR-221, miR-222, and miR-146b was associated with a poorer clinicopathological outcome. Especially, expression of miR-146b increased higher in PTC patients with BRAFV600E mutation. These findings showed a role of miR146b as potential biomarkers in differentiating PTC from benign tumor and as a prognostic indicator of PTCs. Further investigation will need for the roles of miRNAs in the pathogenesis of papillary thyroid carcinomas.

Ultrasonography (US)-guided core needle biopsy (CNB) provides reliable diagnostic accuracy, reducing the need for repetitive find needle aspiration biopsy or diagnostic surgery. To our knowledge, however, there is no consensus about the ideal number of core specimen to be obtained. The purpose of this study was to compare the diagnostic ability based on the specimen numbers and to decide the most ideal core number for US-guided thyroid biopsy of cytologically inconclusive nodule. Sixty consecutive biopsies of inconclusive thyroid nodules were performed by using an 18-gauge biopsy device. Total three biopsy cores were obtained for each thyroid nodule. The first and third biopsy specimens were taken to contain capsule of the thyroid nodule and surrounding parenchyma, and the second biopsy specimens were done in the nodule (intranodular sampling). The diagnostic ability were achieved in 41 nodules (68.3%) using the protocol A, 60 nodules (100%) using the protocol B, and 46 nodules (76.7%) using the protocol C. There were no significant differences in the diagnostic ability between the protocols A and C (p = 0.063). However, the diagnostic ability of protocol B showed significantly higher than that of protocol A (p < 0.001) or protocol C (p < 0.001). The diagnostic ability was not significantly different between the first and third specimens (68.3% vs. 58.3%, p = 0.210). For 24 malignancies, diagnostic ability was established in 18 cases (75.0%) in the first specimen and 6 cases (25%) in the second specimen. In cases of cytologically inconclusive thyroid nodules, a minimum of two core specimens, one is containing nodular tissue, capsule of the thyroid nodule, and surrounding parenchyma, and the other is corresponding to the intranodular sampling, could be enough to decide whether surgery would be necessary.

Poster 813 Thyroid Imaging Wednesday & Thursday Poster Clinical 9:00 AM THYROID BIOPSY TECHNIQUE TO ENHANCE DIAGNOSTIC YIELD FOR CYTOLOGICALLY INCONCLUSIVE NODULES S. Han1, J. Shin1, S. Hahn1, Y. Oh2 1 Radiology, Samsung Medical Center, Sungkyunkwang University, School of Medicine, Seoul, Korea (the Republic of); 2Pathology, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Korea (the Republic of) Core-needle biopsy (CNB) helps clarify non-diagnostic or atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS) in fine-needle aspiration (FNA) readings. But it is difficult to differentiate nodular hyperplasia from follicular neoplasm even after CNB. The aim of this study was to evaluate whether ultrasonography-guided core needle biopsy (US-CNB) technique containing capsule of the thyroid nodule and surrounding parenchyma may enhance diagnostic yield for cytologically inconclusive nodules.

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WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015

This was a retrospective comparative study of 26 consecutive patients who had 26 thyroid nodules biopsied by US-CNB with conventional method between 2006 and 2010 and 60 patients with 61 nodules who underwent US-CNB with new technique in 2013. These nodules showed well-defined solid nodules lack of malignant features at US with nondiagnostic or AUS/FLUS at previous cytology. CNB results of two groups were compared. The mean size of 26 thyroid nodules with conventional US-CNB was 1.6 cm (range, 0.4*6 cm). The mean size of 61 thyroid nodules with new technique of CNB was 2.0 cm (range 0.7*6 cm) (P = 0.098). The inconclusive rate of US-CNB results was 34.6% (10/26) in conventional method and 11.4% (7/61) in new technique of CNB (P = 0.004). Malignant rate was 33% (3/9) in conventional group and 52% (27/52) in new technique group (P = 0.473). Final malignant pathologies in 30 nodules showed follicular variant of papillary thyroid carcinoma (PTC) in 13, classic PTC in 10, Warthin-like variant of PTC in 1, follicular thyroid carcinoma in 5 and medullary thyroid carcinoma in 1. US-CNB technique containing capsule of the thyroid nodule and surrounding parenchyma for differentiating nodular hyperplasia from follicular neoplasm can reduce the frequency of inconclusive diagnostic results and indicate surgical candidates.

Poster 814 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM DIAGNOSTIC CHALLENGES OF AN ACUTELY ENLARGING THYROID Y. Khan1, D. Irizarry1, C. Edwards1, V. Patel2, E. Stoll2 1 Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL; 2Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL Thyroiditis is often associated with thyroid gland enlargement in its acute phase. Similarly, rapid thyroid growth can occur in anaplastic thyroid carcinoma. We present two challenging cases of enlarging neck mass. A 55 year old female presented with pain and rapid growth of a neck mass, preceded by influenza a month prior. She was afebrile with WBC 15500/mm3 and normal TFTs. A firm, irregular left thyroid mass was noted on exam. CT and MRI showed a left thyroid necrotic 3.1 · 3.3 · 4.2cm mass with extension into surrounding tissues and suspicious left-sided lymph nodes. FNA and core biopsy showed inflammatory changes. Open biopsy was performed and Riedel’s thyroiditis was diagnosed after histochemical evaluation. Prednisone was started with improvement. A 61 year old female presented with neck pain two weeks after a sinus infection. She was febrile with WBC 14800/mm3 and normal TSH. Left thyroid lobe was enlarged and nontender. CT scan confirmed a 5.7 · 3.7 · 6.5cm mass with pulmonary nodules and mediastinal adenopathy. FNA was unsatisfactory due to inflammation and subsequent biopsy was indeterminate. Within two weeks, she had worsened neck pain with interval thyroid gland enlargement and new pulmonary nodules on CT. Surgical neck exploration confirmed an abscess and open biopsy was performed. Meanwhile, post-operative course was complicated by tachycardia and TSH was 0.02mIU/L (ref 0.27–4.2) and FT4 3.75ng/dL (ref 0.93–1.7). Acute thyroiditis was suspected and dexamethasone, ibuprofen and propanolol were started. FT4 gradually normalized. Final pathology, however, showed anaplastic thyroid carcinoma. Both cases were diagnostically challenging due to inflammatory changes obscuring cytologic analysis and increased risk of sampling error with large nodules. Concomitant thyroiditis described in the second case was suspected due to acute change in TSH. Lastly, in part

due to rarity, there is no consensus on steroid doses for medical treatment of Riedel’s thyroiditis. These cases emphasize the need to keep a wide differential during the evaluation of an enlarging neck mass and thyroiditis, and anticipate possible significant inflammatory changes that can make a diagnosis of anaplastic thyroid cancer challenging.

Poster 815 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM ISOLATED ACROPACHY PRECEDING HYPERTHYROIDISM: A CASE REPORT H. Amer, A. Aggarwal, V. Mohan, J. Cabral, P. DeSantis, S. Williams, C. Polanco, T. Jose, N. Das, C. Villabona Endocrinology, Cleveland Clinic Florida, Weston, FL Thyroid Acropachy (TA) is an uncommon manifestation of autoimmune thyroid disease. It occurs in about 1% of patients with Grave’s Disease and is almost always associated with ophthalmopathy and frequently with dermopathy (myxedema). TA is typically the last manifestation to appear in the chronology of the pathognomonic physical findings of Graves’ disease. A 33 year old male presented with thyromegaly noted in context of upper respiratory tract infection. He had a positive family history of hyperthyroidism. He was totally asymptomatic without any eye or skin findings. He was noted to have clubbing in his hands which had been present since childhood and for which he had previously undergone a series of investigations where no etiology was uncovered. Thyroid function tests after presentation showed positive thyroid peroxidase antibodies (TPO Ab), low Thyroid Stimulating Hormone (TSH), and a high free T3. Thyroid ultrasound showed a diffuse goiter with heterogeneous echotexture. Radioactive Iodine uptake was elevated with diffuse distribution by scintigraphy confirming Graves’ disease. Acropachy is characterized by sub-periosteal new bone formation and pathognomonic radiographic features including subperiosteal spiculated, frothy or lacy appearance. It is the least common presentation in cases of hyperthyroidism. Previous reports have indicated that 7% of patients with pretibial myxedema have TA. We report a rare case with isolated acropachy preceding the development of asymptomatic hyperthyroidism in a patient with Graves’ disease and no clinically-evident skin or eye findings. No treatment is available for asymptomatic TA and the management plan is to restore euthyroidism. We report the first case with isolated TA preceding the diagnosis of hyperthyroidism and not associated with exophthalmos or pretibial myxedema. Long term follow up is crucial in anticipation of the potential development of the full blown picture of ophthalmopathy and dermopathy.

Isolated Acropachy without exophthalmos and Myxedema

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015

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Poster 816

Poster 817

Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM A RARE CASE OF BILATERAL HURTHLE CELL ADENOMA IN AN ADOLESCENT E.B. Kochummen1, S. Tong2, J. Montecalvo3, R. Gupta3, C. Shao3, C. Yudis3, V. Umpaichitra1, V.L. Chin1 1 Division of Pediatric Endocrinology, SUNY Downstate Medical Center, Brooklyn, NY; 2College of Medicine, SUNY Downstate Medical Center, Brooklyn, NY; 3Division of Pathology, SUNY Downstate Medical Center, Brooklyn, NY

Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM RETROCARDIAC GOITER. A CASE REPORT T. Koraitim General Surgery, Faculty of Medicine, University of Alexandria, Alexandria, Egypt

Hurthle cell neoplasms are rare among pediatric thyroid cancers. Hurthle cell adenoma (HCA) rarely present bilaterally while Hurthle cell carcinoma (HCC) can be bilateral and invasive, necessitating total thyroidectomy. We report a case of an adolescent with bilateral HCA. 14 year old healthy female presented with painless, non-progressive neck swelling and no other symptoms for 1 month. Her thyroid measured 4.5 cm and 6 cm on the right and left lobes respectively. TSH was low (0.20 uIU/mL) and free T4 normal; thyroid antibodies were normal. Ultrasound (US) revealed three small nodules in the right lobe; a large nodule occupied the majority of the left lobe with solid and cystic areas with hypervascular flow and no microcalcifications. Fine Needle Aspiration Biopsy (FNAB) was negative for malignancy. One month later, she had worse neck swelling and dysphagia. Exam showed a nontender nodule measuring 2x3 cm on the left. Labs and US were unchanged. 14 months later, the patient returned with worse neck swelling, dysphagia, and hyperthyroid symptoms but was euthyroid. CT scan revealed an oval heterogeneously enhancing mass in the left lobe with mild tracheal deviation to the right. Left hemithyroidectomy confirmed a diagnosis of HCA. By one year postop, a nodule in the right lower pole doubled in size and increased in vascularity. FNAB was nondiagnostic. Right hemithyroidectomy revealed HCA. HCA represent benign localized growth, unilateral involvement and non-recurrent behavior. Distinction between HCA and HCC is important due to the highly aggressive nature of HCC. Diagnosis relies upon surgical histopathology because FNAB fails to differentiate between the two. Vascular/capsular invasion or metastasis supports a diagnosis of HCC.The 2009 ATA guidelines suggest total thyroidectomy for HCA size > 4 cm, marked atypia seen on biopsy, presence of positive family history of thyroid cancer or history of radiation exposure. Our patient did not have factors that would necessitate a total thyroidectomy. To our knowledge, this is the first case of bilateral HCA in an adolescent. This case highlights the importance of histopathology in the assessment of thyroid nodules and the variability in biological behavior of HCA.

Retro sternal goiter is a well known entity in thyroid clinical practice. However, retrocardiac goiter is uncommon. Even in the presence of retrosternal extention, the gland has its lower border plunging with deglutition because the part of the gland in the chest is usually not so large. It has been reported in literature that the gland may be hugely enlarged, so that that it does not only occupy the superior mediastinum, but also extends more inferiorly to be retrocardiac. The challenge in such cases is mainly the safe delivery through a formal sternotomy. A 55 year old woman presented to our hospital by moderate dysphagia five years ago. Neck & chest CT scans were done to reveal an ovoid huge mediastinal mass continous with a neck seated goiter. The patient was prepared and operated through a neck collar incision and a formal sternotomy. The gland was totally excised but the patient had suffered from right vocal cord paralysis that did not recover till now. On postoperative laryngoscopic examination, a tongue mass was discovered which was clinically diagnosed as an ectopic thyroid tissue. The patient presented with a goiter that was impossible to deliver through the neck incision alone. Sternotomy is a wise & safe option in case imaging shows huge retrosternal extention and it is a must in case goiter sinks so inferiorly in the chest as in case of a retrocardiac goiter. The association between such huge retrocardiac goiter and ectopic thyroid tissue in the tongue is to be clarified. Whether the incidence of recurrent laryngeal nerve injury is higher with sternotomy is a question to be answered. Retrocardiac goiter is less common than retrosternal goiter. Retrocardiac goiter necessitates formal sternotomy which is a well known and safe practice.

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Poster 818 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM RENAL CELL CARCINOMA METASTASIS TO THE THYROID 14 YEARS AFTER NEPHRECTOMY J. Figueroa Flores, S. Shetty, Y. Oo, A. Tessnow UT Southwestern, Dallas, TX The most common primary neoplasm originating in the kidney is renal cell carcinoma (RCC). Although 85% of metastases occur within three years after the first surgical intervention, RCC is known for its late metastases. We describe a patient presenting with RCC metastasis to the thyroid 14 years following nephrectomy. A 54 year-old man with a past medical history of renal cell carcinoma status post right nephrectomy in 2000, was referred for evaluation of bilateral thyroid nodules. A chest CT performed for evaluation of interstitial lung disease incidentally revealed bilateral thyroid nodules. Physical evaluation revealed no findings suggestive of abnormal thyroid function and laboratory evaluation revealed a normal TSH of 2.94uIU/mL. An ultrasound of the neck was performed confirming the presence of a solid, heterogeneous, hypoechoic, taller than wider nodule with microcalcifications measuring 2.5 cm CC · 2.0 cm AP · 1.8 cm transverse in the right lobe and a solid, heterogeneous, hypervascular, hypoechoic nodule with irregular margins measuring 1.3 cm CC solid · 1.0 cm AP · 1.1 cm transverse in the left lobe. FNA of the right nodule demonstrated clear cells (singles and clusters), with immunohistologic staining positive for RCC marker and focally positive for epithelial membrane antigen but negative for thyroid transcription factor-1and thyroglobulin. PET/CT and Brain MRI showed no evidence of other metastases. Near-total thyroidectomy was performed with pathology confirming metastatic renal cell carcinoma (clear cell type). The surrounding background thyroid parenchyma was unremarkable. This is a case of a metachronous thyroid metastasis from RCC, demonstrating the importance of long-term follow up of these patients even in the presence of a nephrectomy. It illustrates that the latency period between initial surgical resection of RCC and the detection of thyroid metastases can be many years. Metastases to the thyroid gland represent 1.4% to 3% of all thyroid malignancies though based on autopsy studies, the prevalence may be higher. Although metastasis to thyroid is uncommon, this should be considered in the differential when a patient with a prior history of RCC presents with a thyroid nodule.

Poster 819 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM IMPLICATION OF ATYPIA/FOLLICULAR LESION OF UNDETERMINED SIGNIFICANCE IN FINE NEEDLE ASPIRATION OF THYROID NODULES D. Guelho1, C. Ribeiro1, S. Paiva1, M. Melo1, I. Paiva1, C. Moreno1, N. Vicente1, L. Cardoso1, D. Martins1, D. Oliveira1, M. Balsa2, G. Fernandes3, F. Carrilho1 1 Endocrinology, Diabetes and Metabolism Department of Coimbra Hospital and University Centre, Coimbra, Portugal; 2Endocrinology, Diabetes and Nutrition Department of Baixo Vouga Hospital Centre, Aveiro, Portugal; 3Pathological Anatomy Department of Coimbra Hospital and Universiy Centre, Coimbra, Portugal Bethesda System is used in risk stratification for malignancy in fine needle aspiration (FNA) of thyroid nodules. The category III, atypia/ follicular lesion of undetermined significance (FLUS), encompasses heterogeneous results with a malignancy risk of 5–15%. However, recently published studies have demonstrated a significantly greater risk. This work aimed to evaluate the frequency and risk of malignancy of FLUS results in FNA performed at our institution.

Review of all FNA performed at our department between October 2009 and August 2014. Selection and analysis of the nodules with FLUS result. The correlation between clinical and echographic features/pathologic findings of patients undergoing surgery was performed. Statistical analysis: SPSS(21). Of 11810 FNA, 534 (4.5%) presented FLUS. Of these, 94 (17.6%) patients were proposed for surgery, 224 (41.9%) repeated FNA and 216 (40.5%) maintained surveillance/lost follow-up. The nodes with ‡ 2cm (OR = 4.71, p < 0.01) or suggestive of malignancy (OR = 43.4; p < 0.01) were more likely to be immediately proposed to surgery. Of those who repeated FNA, 140 (62.5%) had benign lesions, 8 (3.6%) nondiagnostic 48 (21.4%) FLUS, 18 (8%) suspicious for malignancy and 10 (4.5%) were malignant. In total, only 118 (22.1%) of the nodes with initial diagnosis of FLUS were resected. Malignancy was confirmed in 34, which corresponds to 6.4% of all nodules with initial FLUS result and 28.8% of those undergoing surgery. The presence of microcalcifications (OR = 20.4; p < 0.01), irregularity of the margins (OR = 16.9; p < 0.01), positive anti-peroxidase antibodies (OR = 3.2, p < 0.05) or higher TSH values (4.5 – 2.2mUI/ml vs.1.2 – 1.1; p < 0.01) were associated with a higher risk of malignancy. This study presents preliminary results, with some patients waiting for histopathological analysis. Although the risk of malignancy could be overestimated for the selection of the most suspicious lesions, there was a high rate of malignancy (28.8%) in the nodes with initial FLUS, in opposite to the 6.4%, considering all the nodules. The cytological result FLUS may imply a more aggressive approach. Ultrasound and analytical data can contribute to this decision.

Poster 820 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM PAPILLARY THYROID CARCINOMA AND BRAIN METASTASIS - CLINICAL CASE D. Guelho1, C. Ribeiro1, I. Paiva1, M. Melo1, G. Costa2, M. Martins3, J. Saraiva1, C. Moreno1, L. Cardoso1, N. Vicente1, F. Carrilho1 1 Endocrinology, Diabetes and Metabolism Department of Coimbra Hospital and University Centre, Coimbra, Portugal; 2Nuclear Medicine Department of Coimbra Hospital and University Centre, Coimbra, Portugal; 3Pathological Anatomy Department of Coimbra Hospital and University Centre, Coimbra, Portugal Papillary carcinoma is the most common malignant thyroid tumor and generally has a good prognosis. Brain metastases constitute an extremely rare event, affecting only 0.4–1.2% of patients, and, according to recently published series, implies a median survival of only 7.1months. Female, 43 years-old, underwent total thyroidectomy with bilateral cervical lymph node dissection (28/04/2000). Histological study revealed papillary carcinoma, solid variant (T4bN1bMx). The molecular study showed V600E mutation of the BRAF without changes in NRAS and TERT. After ablative therapy with 170mCi of 131I (06/10/2000) presented undetectable Tg levels with negative anti-Tg antibodies. During follow-up anti-Tg antibodies progressively increased. Radioiodine imaging identified nodal involvement and lung metastasis. Excisional biopsy of lung lesions (15/01/2010) and four treatments with I131 (last one at 19/04/2010) were performed. Post-treatment whole-body scintigraphy showed not only diffuse pulmonary metastasis, but also cerebral frontoparietal and cerebellar lesions, confirmed through MRI. The patient remained asymptomatic and underwent radiosurgery (24/06/2010). The brain MRI and pulmonary CT control showed persistence of metastases but 18F-FDG-PET scan did not identify hypermetabolic lesions (15/12/ 2011). She was subjected to further treatment with I131, under corticosteroids (16/12/2011). Currently has a cumulative 131I activity of 1255mCi. Post-treatment whole-body scintigraphy showed slight pulmonary uptake, without cerebral uptake. The last brain MRI (10/02/2013) showed no lesions, pulmonary CT (12/12/2013) showed stable lung micronodules and there was a reduction in titer of anti-Tg antibodies.

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 Initial histological and molecular study (BRAF V600E) could point to a more aggressive clinical behavior, which came to take place. Cerebral metastasis, a rare event in differentiated carcinomas, showed a good response to treatment with complete imagiological regression of the lesions and higher survival than reported for these cases. It’s a peculiar case of differentiated thyroid carcinoma with recurrent lung and brain metastatic lesions detected through anti-Tg antibodies.

Poster 821 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM LONG-INTERVAL VERSUS SHORT-INTERVAL FOLLOW-UP OF CYTOLOGICALLY BENIGN THYROID NODULES: A PROSPECTIVE COHORT STUDY M. Medici1,2, X. Liu1,3, N. Kwong1, T.E. Angell1, E. Marqusee1, M.I. Kim1, E.K. Alexander1 1 Brigham and Women’s Hospital, Boston, MA; 2Erasmus Medical Center, Rotterdam, Netherlands; 3First Affiliated Hospital of Nanjing Medical University, Nanjing, China Thyroid nodules are common, and most are benign. Given the risk of false-negative cytology (i.e., malignancy), follow-up is recommended after 1-2 years, though this recommendation is based solely on expert opinion. Sonographic appearance may assist with planning, but is limited by large inter-observer variability. We therefore compared the safety and efficacy of long- versus short-interval follow-up after a benign initial aspiration, regardless of sonographic appearance. This study evaluated all patients referred to the BWH Thyroid Nodule Clinic, between 1999–2010 who had a cytologically benign nodule > 1 cm, and returned for follow-up sonographic evaluation. Despite standard clinical recommendations, variation in patient compliance resulted in variable follow-up intervals from time of initial aspiration to the first repeat evaluation. Main outcome measures included nodule growth, repeat fine needle aspiration (FNA), thyroidectomy, malignancy, and disease-specific mortality. We evaluated 1254 patients with 1819 cytologically benign nodules, with a mean time to first follow-up of 2.1 years, but a range of 0.5-14.1 years. The longer the follow-up interval, the more nodules grew and the more repeat FNAs were performed (P < 0.001). The most clinical meaningful endpoints of malignancy or mortality, however, did not differ between various follow-up intervals. The risk of a thyroidectomy (usually because of compressive symptoms) increased when time to first follow-up exceeded > 3 years (4.9 vs 1.2%, P = 0.0001), though no difference in malignancy risk was identified (0.2-0.8%, P = 0.77). No (0%) thyroid cancer specific deaths were identified in either cohort. While expert opinion currently recommends repeat evaluation of a cytologically benign nodule at 1–2 years, these data demonstrate that this interval can be safely extended to 3 years without increased mortality or patient harm. Nodule growth can be expected, though detection of malignancies is unchanged. This extension in follow-up interval will reduce unnecessary visits and medical interventions for millions of affected patients worldwide, leading to healthcare savings.

Poster 822 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM IMPACT OF AFIRMA GEC ON CYTOPATHOLOGY DIAGNOSIS AND THYROIDECTOMY INCIDENCE W.L. Sacks2, S. Bose3, R. Wong2, G.D. Braunstein2, A.S. Ho1 1 Surgery, Cedars-Sinai Medical Center, Culver City, CA; 2Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA; 3 Pathology, Cedars-Sinai Medical Center, Los Angeles, CA

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The Afirma Gene Expression Classifier (GEC) is a molecular assay that assesses malignancy risk in indeterminate thyroid nodules (Bethesda III-IV). Afirma putatively improves outcomes and reduces costs by classifying certain nodules as benign and avoiding unnecessary surgery. Our objective was to analyze the effect of Afirma on (1) cytopathology diagnosis and (2) rate of surgery at a high-volume tertiary thyroid center. Retrospective cohort analysis of Bethesda III/IV thyroid nodules at a single institution from 2012–2014. As Afirma was first made routinely available at our center in July 2013, cases were evaluated from January 2012 to July 2013 (pre-Afirma), and from July 2013 to Dec 2014 (post-Afirma). Collectively, 4,292 FNAs were performed with 14.4% classified as indeterminate (Bethesda III: 12.0%, Bethesda IV: 2.4%). Median age was 55.3 years, 74.0% of patients were female, and median nodule size was 2.4 cm. The Afirma GEC was employed in 38.9% of post-Afirma cases. In comparing pre-Afirma and post-Afirma cohorts, significant escalation in the incidence of Bethesda III diagnoses (10.7% vs. 13.4%, p < 0.005) and Bethesda IV diagnoses (1.8% vs. 2.9%, p < 0.01) was observed. Conversely, a decrease in the incidence of Bethesda II diagnoses was noted (74.6% vs. 68.8%, p < 0.001). No significant changes in Bethesda I, V, or VI diagnoses were seen. The rate of surgeries for indeterminate nodules did not significantly change between pre-Afirma and post-Afirma cohorts (Bethesda III: 26.7% vs. 24.5%, p = 0.48) (Bethesda IV: 64.1% vs. 61.8%, p = 0.54). The incidence of thyroid nodules classified as indeterminate significantly increased in the period after Afirma became routinely available, while the incidence of benign nodules significantly decreased. In the absence of other notable factors, this data suggest that Afirma affects the distribution of Bethesda diagnoses: it may cluster FNA interpretation to Bethesda III/IV, where molecular testing can be used. Moreover, the incidence of surgery between the periods was not substantially different, raising uncertainty about one of Afirma’s main intended benefits. The presence of Afirma itself may ultimately escalate usage and cost, while not reducing unnecessary thyroidectomies.

Poster 823 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM COMPARISON OF THYROID NODULE FNA—CYTOLOGY VERSUS GENE EXPRESSION CLASSIFIER TESTING: THE IDEC EXPERIENCE K. McAnally1, T. Khoo1,2 1 Internal Medicine Residency Program, Mercy Medical Center, Des Moines, IA; 2Iowa Diabetes and Endocrinology Center, Des Moines, IA Thyroid nodules are common, with a prevalence of up to 67% in some populations. The gold-standard for evaluation is FNA for cytology, which has limitations-especially with indeterminate (ID) nodules (suspicious for follicular neoplasm, atypia) in which surgery is often necessary to rule out malignancy. To minimize unnecessary surgery, Afirma Gene Expression Classifier (GEC) was introduced to reclassify these as ‘benign’ or ‘suspicious’. We present comparative data describing our experience with conventional cytology and GEC, since our practice adopted it in December 2013. From 2008–2013, we used conventional cytology utilizing the Mercy Clinical Laboratory pathology services (MCL). From 2013– 2015, samples were sent for Afirma. All biopsies were performed by a single operator utilizing US. Four to five passes were performed per nodule and, when sent for Afirma, passes were divided equally between cytology and potential GEC testing.

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From 2008–2013, 226 samples were sent to MCL, and from 2013–2015, 59 were sent for Afirma. Average nodule size was 2.8 cm. For MCL, 81.4% were benign (B), 4.0% malignant (M), 1.8% suspicious for malignancy (3/4 subsequently found to be cancerous on surgical pathology), 4.9% nondiagnostic (ND) and 8.0% ID. In contrast, with Afirma, the rates were 52.5% B, 5.1% M, 11.9% ND and 30.5% ID-which prompted GEC testing. GEC reclassified 72.2% of the nodules as suspicious-of which malignancy was found in 5/13 patients (38.5%). Overall, there were 12/226 cases of cancer (5.3%) with MCL, and 8/59 (13.6%) with Afirma. The ND rate was higher with Afirma, which is to be expected as fewer samples were available for cytology. This could be reduced by increasing the number of biopsy passes. Unexpectedly, there was a large difference in ID rates between MCL and Afirma, suggesting interpretive variability between pathologists. Indeed, the MCL rate of ID was much lower than published national data. The incidence of malignancy was higher overall with Afirma than MCL, suggesting false negatives with the latter. The availability of GEC improves our ability to evaluate and riskstratify thyroid nodules, while minimizing surgery for ID nodules. This modality, however, is associated with a higher ND rate.

Poster 824 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM LONG TERM FOLLOW UP OF AN OFFICE BASED GENE EXPRESSION CLASSIFIER TO MANAGE THYROID NODULES OVER FOUR AND ONE HALF YEARS B.E. Michael Endocrinology, Wellspan Health, Gettysburg, PA Genetic testing of atypical FNA specimens may offer the option of reducing thyroid surgery. A gene expression classifier (Afirma) designed to have a high negative predictive value of malignancy has been available in the United States since early 2011. Biopsy material from indeterminate FNA specimens is subjected to molecular analysis and results are reported as benign or suspicious. Suspicious specimens are referred for surgery and benign specimens are generally observed per ATA guidelines. Scant long term follow up information is available regarding the outcomes of patients evaluated in this manner, and there is no published data regarding actual cost savings to the system to date. I report the 4.5 year follow up on data available from a single practice. UGFNA material was collected from January 2011 through May 2015 on 587 patients. 54 GEC were successfully run on 54 patients with indeterminate cytology. (10.9%) 32 specimens were reported as suspicious and were referred for surgery. (5.5%) These results have been reported elsewhere. 22 GEC benign patients were evaluated for long term follow up (4% )This is the subject group of the study.

Three of the benign GEC group have undergone surgery (13%). Two had nodule enlargement after biopsy. One had two nodules evaluated, one suspicious and one benign. GEC was correct on final histopathology in each case. The remaining 19 patients have been followed since original biopsy with serial physical exam and periodic ultrasound. Six patients have been followed for 4–4.5 years, 4 patients for 2.5–4 years, 3 patients for 1–2.5 years, and 6 for 0.5–1 year. All have shown no change in nodules by serial exam or sonography. Follow up of cytologically indeterminate, GEC benign thyroid nodules for a time period of up to 4.5 years by physical exam and serial ultrasound appears to be a viable option in many cases. In this relatively small sample, from a single location, 19 patients who would have originally been referred for surgery (35%) have shown stable physical and ultrasound findings for a follow up period of up to 4.5 years. In addition to avoiding the morbidity of unnecessary surgery, potential savings to the medical system in this group are estimated at $162,000.

Poster 825 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM MALIGNANCY PREDICTION POTENTIAL OF SUSPICIOUS ULTRASONOGRAPHIC FEATURES IN THYROID NODULES WITH INDETERMINATE CYTOLOGY T. Scullen, Z. Al-Qurayshi, A. Deniwar, H. Mohamed, E. Kandil Tulane University, New Orleans, LA Inconclusive data exists for predictive factors for malignancy in indeterminate thyroid nodules. The objective of this study is to determine if suspicious ultrasound (US) features either alone could be of benefit in medical decision-making. This is a retrospective study of patients who had undergone fine needle aspiration by a single surgeon over a five-year period in a tertiary academic hospital. We included only patients with indeterminate thyroid nodules as defined by a Bethesda cytopathology category of III (AUS or FLUS), IV (FN/SHN), or V (SM). Suspicious US features included the presence of internal vascularity, irregular margins, hypoechogenicity, or calcifications. Of the 298 patients who met the inclusion criteria, 77.5% underwent surgery, with a malignancy rate of 35.23%. Both internal vascularity [OR:3.31,95%CI:(1.77–6.20), p < 0.001] and an increasing number of US suspicious features [OR:1.57,95%CI:(1.07– 2.31), p = 0.020] were significant predictors of malignancy. In AUS, internal vascularity was an independent predictor of malignancy [OR:14.30,95%CI:(2.70,75.65), p = 0.002]. Intra-categorical analysis demonstrated significant differences in malignancy rates between cytology subcategories (34.85%AUSvs.42.86%FLUSvs. 44.12%FN/SHNvs.88.88%SM,p = 0.026). The presence of both irregular margins and internal vascularity was associated with higher malignancy in AUS and FLUS nodules with positive likelihood ratios ( + LRs) of 6.67 and 3.90 respectively. Presence of microcalcifications was associated with higher rate of malignancy in FN ( + LR of 4.76). Having a family history of papillary thyroid carcinoma in addition to the higher risk of internal vascularity was associated with higher risk of malignancy ( + LR of 9.04). The absence of suspicious ultrasonographic features was associated with a negative likelihood ratio (-LR) of 0.26 in all indeterminate nodules and 0.18 in FN/SHN. Specific suspicious ultrasonographic features might provide significant predictive potential for malignancy in indeterminate thyroid nodules.

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015

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Poster 826 Withdrawn

Poster 827 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM GAUGING THE EXTENT OF THYROIDECTOMY FOR INDETERMINATE THYROID NODULES D.F. Schneider, L.M. Cherney Stafford, C.C. Greenberg, C.J. Balentine, D.M. Elfenbein, S.C. Pitt Surgery, University of Wisconsin, Madison, WI Increasing emphasis is being placed on appropriateness of care and avoidance of over- and under-treatment. Indeterminate thyroid nodules (ITN), present a particular risk for this problem because cancer found via diagnostic lobectomy (DL) constitutes under-treatment since the patient requires a completion thyroidectomy (CT). However, initial total thyroidectomy (TT) for benign ITN (over-treatment) results in lifelong thyroid hormone replacement. We sought to measure the accuracy and factors associated with the extent of initial thyroidectomy for ITN. We queried a single institution thyroid surgery database for all adult patients undergoing an initial operation for ITN. Multivariate logistic regression identified factors associated with either oncologic under- or over-treatment at initial operation. There were 639 patients with ITN. The median age was 52 (range 18–93), 78.4% were female, and final pathology revealed a cancer ‡ 1 cm in 24.7%. The most common cytology was follicular neoplasm (45.1%) followed by Hurthle cell neoplasm (20.2%). CT or initial oncologic under-treatment was required in 58 patients (9.3%). Excluding those with goiters, 19.0% were oncologically over-treated. Multivariate analysis failed to identify any factor that independently predicted the need for CT. Female gender was associated with over-treatment (OR 2.1, 95% C.I. 1.0–4.5, p = 0.05). Age > 45 predicted correct initial use of DL (OR 2.6, 95% C.I. 1.2–5.7, p = 0.02). Suspicious for PTC (OR 5.7, 95% C.I. 2.1–15.3, p < 0.01) and frozen section (OR 9.7, 95% C.I. 2.5–38.6, p < 0.01) were associated with oncologically correct initial TT. The highest frequency of CT occurred in patients with follicular lesion of undetermined significance (11.6%). Over-treatment occurred most frequently in patients with a Hurthle cell neoplasm (24.8%). The most common reasons cited for performing an initial TT were the cancer risk (54.2%) and presence of bilateral nodules (23.0%). In patients with ITN, nearly 30% are either under- or overtreated with over-treatment being more frequent. Tools to preoperatively identify both benign and malignant disease can assist in the complex decision-making to gauge the proper extent of initial surgery for ITN.

Poster 828 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM DOES THE HEALTHY THYROID (HT) EXIST? THE TRUE STORY OF THYROID ULTRASOUND (TUS) A. De Remigis, V. Falzano, M. D’Angelo, A. Quirino, R. Pepe, D. Rapino, L. Vianale University of Chieti, Chieti, Italy On the occasion of world thyroid (T) day TUS screening was done. We performed many epidemiologic investigations with TUS looking for goiters, thyroid nodules (TN) and autoimmune thyroiditis (the 1th in 1986 in Abruzzo), showing morphologic T alterations (MTA) were widespread, much more than we thought on the physical exam only. Over time the diffusion of US confirmed the exceptional spread of

MTA. Therefore, we set as primary aim to seek HT arising the question: does HT exist? This was a provocative title, almost a paradox. Controversies rise also on US used as a screening tool. The getting accustomed to TUS is likely to lead us into the temptation of giving up the physical exam and lets us to find a too high number of micronodules (MN) having no clinical, but only psychological impact. Similar debate exists about T dysfunction screening. The 1st aim of TUS screening is to detect HT, the 2nd is to consider MTA. 561 US exams were done, subjects were recruited randomly and recorded in database and then underwent TUS. Three sonographers specialized were engaged and used 3 high-resolution ESAOTE US machines, high-frequency probes with piezoelectric material resonate across wider bandwidths, 4-13MHZ. Results demonstrate: A- HT is very young (80% HT below 20 years). B- MTA increase with age, showing higher prevalence in the decade between 60-70 years (84%). C- A large number of MTA were incidentally discovered: 55% of the sub-population,never performed any thyroid test, resulted positive for MTA on US screening. A growing number of MTA are expected in the future with people aging. The problem is the abuse of TUS in the first diagnosis and follow-up of MTA, in particular of TN. As first line diagnosis clinical observation may be enough in most cases to detect TN, sparing many US exams. These can be useful for defining TN nature. Incidentally MN and benign nodule may be followed-up with less TUS and a new digital TN App, we are going to present. TUS story is changing over the time, turning from a routine exam to discover TN into a tool to explain TN nature.

Poster 829 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM IMPACT OF MALIGNANCY PREVALENCE RATES ON ACCURACY OF GENE EXPRESSION CLASSIFIER TESTING FOR INDETERMINATE THYROID NODULES A. Deniwar, T. Mallik, T. Thethi, P. Bhatia, A. Sholl, Z. Al-Qurayshi, K. Moroz, E. Kandil Tulane University School of Medicine, New Orleans, LA Afirma gene express classifier (GEC) has been increasingly used as an adjunct to improve the diagnostic accuracy of fine needle aspiration (FNA) in indeterminate nodules. The main value of GEC testing lies in its reported high negative predictive value (NPV) to avoid unnecessary diagnostic surgery. Our study aims to examine the effect of high prevalence of thyroid malignancy in a surgical practice on the accuracy of GEC testing. This is a retrospective study on patients with indeterminate thyroid nodules (Bethesda Category 3 and 4) who had GEC testing done over a 2-year period in an academic institution. Postoperative surgical pathology was used to evaluate the efficacy of Afirma GEC. We examined the effect of malignancy prevalence on the accuracy of GEC testing compared to prior published studies.

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A total of 101 patients with 109 indeterminate FNA results and Afirma GEC testing were included. Sixty four of our patients underwent surgery with 70 nodules excised. The prevalence of malignancy in the excised nodules was 42.86%. Fourteen (12.84%) samples had insufficient RNA for GEC testing; ten of them decided not to repeat the biopsy and underwent surgery, where 3 (30%) found to be malignant. Thirty-nine nodules (35.78%) had benign GEC; seventeen of them underwent surgical intervention for various indications, and 10 were confirmed to have benign final pathology (NPV = 58.8%). Fifty six nodules (51.38%) were suspicious by GEC Afirma testing. Twenty nodules out of 43 with suspicious GEC that underwent surgery had confirmed malignancy on final pathology (PPV = 46.5%). The high malignancy prevalence in our practice was associated with a significantly lower NPV of GEC in our practice compared to what was previously reported. These results show that physicians should be careful in using GEC testing in guiding surgical decisionmaking. Future further prospective multi-institutional studies are needed.

Poster 830 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM CELEBRATION OF THE WORLD THYROID DAY IN THESSALONIKI, GREECE: ULTRASOUND SCREENING OF GENERAL POPULATION G. Panagiotou1, D. Komninou1, G. Linardos1, P. Anagnostis2, M. Somali1, E. Karoglou1, E. Margaritidou1, Y. Feodoridis1, Y. Kita2, K. Pazaitou-Panayiotou1 1 Department of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, Greece; 2Department of Endocrinology, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece; 3 Department of Endocrinology, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece Celebrating the World Thyroid Day in May 2014, two collaborating Endocrinology Departments offered free ultrasound screening to general population, for the diagnosis of thyroid nodules. In every subject that participated on its free will, medical history, demographic and anthropometric characteristics (i.e. gender, age, height, weight and waist, hip and neck circumference) were recorded. We also evaluated total body fat and omental fat, as well as metabolic age, using Bioelectrical Impedance. All participants underwent a thorough thyroid ultrasound examination, and data on thyroid nodules (i.e. number, size) were recorded. Three hundred and thirteen subjects [mean age 49 – 15 years, 95 males (30.4%)] were included. More than half of them (54%) were harbouring ‡ 1 nodules and had higher body mass index (BMI) (p = 0.025), waist circumference (p = 0.019), total body fat (p = 0.018), metabolic age (p = 0.001), visceral fat racing (p = 0.056) and waist-tohip ratio (p = 0,048) compared with individuals without nodules. Regarding gender, the majority of men with nodular thyroid disease (NTD) had more than one nodule (56.1%). The respective percentage in women was 47.7%. The mean diameter of the largest nodule was 7.7 mm in men and 9.0 mm in women (p = 0.189). Women with nodule(s) > 1 cm were at older physical and metabolic age and had greater waist circumference, waist-to-hip ratio and visceral fat compared with those harbouring nodules £ 1 cm. The prevalence of NTD in overweight or obese subjects was higher than in normal-weight participants (65.1% vs. 34.9%, respectively, p < 0.001). Diabetes mellitus (DM) was diagnosed in 33 participants, 69.7% of which had NTD. These individuals had significantly higher body weight (p = 0.028), BMI (p = 0.042) and total body fat (p = 0.045), compared with diabetic individuals without NTD.

More than half of the participants had one or more thyroid nodules. Obesity and visceral adiposity, both in diabetic and nondiabetic states, were positively associated with the prevalence of NTD.

Poster 831 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM EVALUATION OF CYTOLOGICALLY INDETERMINATE NODULES USING AFIRMA GENE EXPRESSION CLASSIFIER (GEC) AT AN ACADEMIC MEDICAL CENTER A.P. Kuker1, D. Hamele-Bena2, T. Wood2, P. Tiscornia-Wasserman2, S.A. Ebner1 1 Division of Endocrinology, Columbia University College of Physicians and Surgeons, New York, NY; 2Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY Although fine-needle aspiration (FNA) cytology provides sufficient information to classify most thyroid nodules as benign or malignant, some laboratories report up to 1/3 of nodules as having ‘‘indeterminate’’ cytology. The Afirma diagnostic test is a gene expression classifier (GEC) that can classify these indeterminate nodules as either benign or suspicious. Retrospective study of indeterminate cytology samples that were sent for Afirma Gene Expression Classifier (GEC) analysis in our institution over a 15-month period. From January 2014 thru March 2015, 1088 FNA cytology samples were analyzed: 110 samples (10%) were classified as Bethesda Category III (Atypia of Undetermined Significance), and 46 (4%) were classified as Bethesda Category IV (Suspicious for a Follicular Neoplasm). 32 samples from these two categories were sent for Afirma GEC (Table 1). 50% of the samples were classified as GEC-Suspicious and 50% as GEC-Benign. Sixteen cases had histopathological follow-up. Of the 5 cases with malignant histology, 4 had been classified as GEC-Suspicious (true positive GEC) and 1 as GEC-Benign (false negative GEC). Of the 11 cases with benign histology, 3 had been reported as GEC-Benign (true negative GEC) and 8 had been reported as GEC-Suspicious (false positive GEC). The single GEC false negative case was diagnosed as Bethesda Category IV on cytology and showed follicular variant of papillary thyroid carcinoma on histology. In our institution, Afirma GEC has shown 80% sensitivity and 27% specificity for diagnosis of thyroid malignancy, with a positive predictive value of GEC-Suspicious of 33% and a negative predictive value of GEC-Benign of 75%.

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 Although the high false positive rate is a limitation of the Afirma GEC test, its apparent high negative predictive value suggests valuable clinical utility in the evaluation of cytologically indeterminate thyroid nodules.

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With the exception of one of the supplements, the content of active thyroid hormone in these dietary supplements was undetectable. Nonetheless, lack of regulation and safety monitoring of these supplements is dangerous, and can interfere with adequate treatment of true thyroid disease.

Poster 832 Disorders of Thyroid Function Wednesday & Thursday Poster Clinical 9:00 AM THYROID HORMONE CONTENT IN OVER-THECOUNTER DIETARY SUPPLEMENTS A.P. Kuker1, S.V. Pollack2, S. Cremers2, S.A. Ebner1, R. McConnell1 1 Division of Endocrinology, Columbia University College of Physicians and Surgeons, New York, NY; 2Irving Institute for Clinical and Translational Research, Columbia University College of Physicians and Surgeons, New York, NY We present four patients seen in our Thyroid Clinic who were taking over-the-counter dietary supplements, as well as the results of the analysis of these supplements to assess the content of thyroid hormone in each of them. Patient 1 was a 60 year-old man with post-operative hypothyroidism, who had been prescribed levothyroxine 50 mcg daily but instead took Iodomere and Thyrotrophin PMG supplements. Patient 2 was a 58 year-old woman who presented with clinical and biochemical evidence of hyperthyroidism in the setting of taking EcoThyro 125 supplements, and whose thyroid function tests normalized after stopping the supplements. Patient 3 was a 70 year-old woman with h/o toxic goiter who presented with congestive heart failure and atrial fibrillation, was found to have evidence of biochemical hyperthyroidism, and admitted to taking Raw Thyroid supplements for a ‘‘slugging thyroid.’’ Patient 4 was a 62 year-old man with h/o hyperthyroidism due to Graves’ disease who self-treated with HTHY Thyroid Drops, and presented with clinical and biochemical of hyperthyroidism. Each tablet was dissolved in 10 mL distilled water. Tablets were completely crushed, spun for 10 minutes at 850 g and the supernatant for each was recovered. The supernatant and the drops were analyzed for T3 and T4 using an Immulite 1000 Immunoassay System, Siemens Medical Solutions, Malvern, PA. Table 1 details the content per unit of thyroid tissue and/or iodine reported by the manufacturers (a), and the content of T3 and T4 in the supplements as per our analysis (b). It also shows the calculated total daily dose of T3 and T4 based on our analysis and according to the manufacturers’ recommended daily dose (c). Only one of the formulations (EcoThyro 125) had enough thyroid hormone (8.78 ug/tab of T4) that could result in adverse clinical effects, and was likely responsible for Patient’s 2 presentation. The other four formulations had undetectable amounts of T3 and T4.

Poster 833 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM USING A THYRABLATOR BIPOLAR HEADPIECE IN RADIOFREQUENCY ABLATION FOR NODULAR THYROID DISEASE: GROSS VS MICROSCOPIC SIZE OF NECROTIC AREA EVALUATION D. Branovan1, M. Fridman2, V. Drozd1,2, L. Danilova2, M. Lushchyk2, N. Shiglik1, Y. Demidchik2 1 Project Chernobyl, New York, Brooklyn, NY; 2Belarusian Medical Academy of Post-Graduate Education, Minsk, Belarus Minimally invasive modalities, such as ethanol, laser, radiofrequency, and high intensity focused ultrasound ablation of benign thyroid nodules were reported to be an effective option to threat the nodular goiter and may be prevent the thyroid cancer. Our study aimed to compare gross and microscopic size of thermo-lesions in surgically removed thyroid nodules that were pre-treated with radiofrequency electro-coagulation. Bipolar radiofrequency system was used for ablation of 21 thyroid parenchymatous nodules sized 5-10 mm removed surgically in patients with goiter. Thermal energy was delivered during 10 seconds through an applicator with a diameter of 1.3 mm (18gauge), a shaft length of 102 mm, and an active tip length of 10 mm. The size of thermo-lesion was evaluated with a standard ruler and with TTF-1 antibody (DAKO, clone 8G7G3/1) to visualize foci of necrosis. The extension of visible lesions in thyroid nodules sized up to 1 cm was 0.08 ml (SD 0.08) which means 56.6% (SD 42.2%) of total nodule volume. Loss of nuclear stain that corresponded to necrotic foci or severe dystrophy involved about 70% (SD 16%) of nodule. Other parts were the transition region (20%, SD 12%) with a faint nuclear staining in more than 10% of cells and small inclusions of unchanged tissue. Therefore, the boundary of ablation zone quite accurately determined by the macroscopic evaluation (no significant difference between gross and microscopic dimensions of the necrotic area was detected, p = 0.15). Radiofrequency ablation for thyroid nodules sized up to 10 mm yields excellent result. This method is promising for elimination of bigger nodules because of histological polymorphism in the ablation area that implies the progressive expansion of necrotic area (owing to the transition zone). Questions about the multisession approach and call for pre-treatment to increase the electrical conductivity and radio-frequency influence need further consideration.

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Table 1. Results of analyzed dietary supplements.

Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM BENEFIT OF REPEAT FNA IN INDETERMINATE THYROID NODULES: AN INSTITUTIONAL REVIEW I. Ahmad1, M. Itani3, G. Deftereos2, E.E. Waner4, M. Dighe3, M.Y. Roth1, T.S. Tylee1 1 Metabolism, Endocrinology, and Diabetes, University of Washington, Seattle, WA; 2Pathology, University of Washington, Seattle, WA; 3Radiology, University of Washington, Seattle, WA; 4 Medicine, University of Washington, Seattle, WA

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Fine needle aspiration (FNA) is the primary method for histologic evaluation of thyroid nodules. The Bethesda system for thyroid cytopathology classifies FNA results along a spectrum from benign (Bethesda I) to malignant (Bethesda VI) to stratify risk of malignancy in these nodules. However, approximately10-20% of nodules are indeterminate, including atypia of undetermined significance (AUS) and follicular lesion of undetermined significance (FLUS), classified as Bethesda III (B-III). As the risk of malignancy for AUS and FLUS nodules combined can be up to 30%, current guidelines recommend repeat FNA for B-III nodules. While the literature suggests repeat FNA will yield a definitive diagnosis 50% of the time, this varies widely among institutions. We sought to evaluate the rate of B-III nodules and the utility of repeat FNA at our institution. We performed an IRB-approved retrospective chart review of FNAs performed at the University of Washington between 1/1/ 2010 to 6/30/2014. We identified all nodules classified as B- III. We reviewed these charts for subsequent follow up: repeat FNA, surgery, or monitoring with serial ultrasound. For those patients who had repeat FNA, we reviewed outcomes of the FNA and the patient’s ultimate disposition. Of the 1008 FNAs performed, 125 (15%) were classified at B-III. Repeat FNA was performed for 14% (n = 18), surgery for 25% (n = 32) and clinical follow up for 42% (n = 53). The remaining 18% were lost to follow up (n = 23). For the FLUS nodules (n = 79), 11 underwent repeat FNA: 6 were benign, 3 B-III and 2 non-diagnostic. For the AUS nodules (n = 47), 7 had repeat FNA: 3 were benign, 1 malignant and 3 B-III. Overall for B-III nodules that underwent repeat FNA, 50% were benign, 6% malignant and 33% B-III. Of the 6 B-III nodules on repeat FNA, only 2 underwent surgery. Both nodules were malignant. At our institution, repeat FNA for B-III nodules is useful for identifying benign nodules approximately 50% of the time. However, we are still left with a significant portion of nodules indeterminate after 2nd FNA. The optimal evaluation for these patients is limited by lack of long term outcomes. Further research is needed to identify the best means of follow up for these patients.

Poster 835 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM INSTITUTIONAL EXPERIENCE FOR THE THYROID NODULE DIAGNOSED AS ATYPIA/FOLLICULAR LESION OF UNDETERMINED SIGNIFICANCE (AUS/FLUS) J. Choi1,2, J. Kim2 1 Surgery, Jeju National University, School of medicine, Jeju Self-Governing Province, Korea (the Republic of); 2Surgery, Jeju National University Hospital, Jeju-si, Korea (the Republic of) We present our institutional experience of thyroid nodule with atypia/follicular Lesion of Undetermined Significance(AUS/FLUS) and evaluate the malignancy risk and characteristics of AUS/FLUS nodules. Retrospective review was performed about the results of thyroid FNA diagnosed as AUS/FLUS(n = 280) from March 2011 to May 2015 retrospectively. We investigated their FNA results, ultrasound findings and surgical histologic results. Thyroid nodules were categorized into three groups (benign, indeterminate or suspicious malignant) according to the sonographic findings, and tumor size was measured.

Thyroidectomy was performed in 35.4%(n = 99) of AUS/FLUS thyroid nodules and 76.7%(n = 69) of them were diagnosed as malignancy after surgery. Tumor size of malignant nodule was smaller than benign (1.0 – 0.9cm vs 1.9 – 1.3cm). In US findings, suspicious malignant feature were found in 73.9% of malignant nodule, and 80% of benign nodule showed benign or indeterminate findings. The most common histologic type was papillary carcinonoma (89.9%, 62/69) in malignant nodule and follicular adenoma in benign (43.3%, 13/30). At least, 24.6%(69/280) of thyroid nodules with AUS/FLUS are diagnosed as malignancy after surgery and most of them(79.9%) already showed suspicious malignant feature by US before surgery. Surgery should be considered if malignant features are suspicious in ultrasound rather than repeated FNA.

Poster 836 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM LONG TERM FOLLOW UP OF BENIGN THYROID NODULES: A POPULATION BASED STUDY N. Singh Ospina1,2, S. Maraka1,2, A. Espinosa De Ycaza1, J. Brito Campana1,2, M. Castro1, J. Morris1, V. Montori1,2 1 Endocrinology, Mayo Clinic, Rochester, MN; 2Knowledge and Evaluation Research Unit, Mayo Clinic, Rochster, MN The number of patients with biopsy proven benign thyroid nodules (BTN) has increased with the widespread use of imaging technology. The long term outcomes of these patients are not well defined. We sought to determine the prognosis of BTN and identify predictors of adverse outcomes. Population based study using the Rochester Epidemiology Project database to identify patients with BTN diagnosed via ultrasoundguided fine needle aspiration (USFNA) followed by detailed medical record review. Between January 2003 and December 2006, 520 USFNA were performed on residents of Olmsted County, MN and 363 (70%) were BTN. The mean age was 56 (SD 16) years and 80% were women. The median nodule size was 1.3 cm, 79% had multiple nodules, and 27% had one or more suspicious ultrasound features. During a median follow up time of 8.1 years no patient died from thyroid cancer and 61 (17%) underwent thyroidectomy, most (43%) for compressive symptoms. Follicular thyroid cancer was found in the index nodule in 2 of 61 cases (2 of 363 total - 5 in 1000 new diagnosis of thyroid cancer), and incidental papillary thyroid cancer was detected in another 6 of 61 (6 of 363 total). Repeat USFNA during follow up was conducted in 12% of the patients and follow up ultrasound in 44%. Patients in whom repeat US was performed were generally younger (49 vs 56 years, P = 0.0001). There were no differences in terms of sex, TSH, nodule size, suspicious ultrasound features and rate of thyroidectomy between those receiving or not receiving follow up ultrasound. Younger age at the time of USFNA and larger nodule size were significant predictors of thyroidectomy during follow up in a univariate and multivariate model. (Hazard Ratio for age 0.98 (95% CI: 0.96-0.99) and 1.3 (95% CI: 1.13–1.45) for nodule size). The frequency of patient important adverse outcomes during the follow up of BTN is low (5 in 1000 for new diagnosis of thyroid cancer, 0% for mortality due to thyroid cancer and 17% for thyroidectomy). Younger age and larger nodule size at the time of initial USFNA are clinical predictors for thyroidectomy during follow up. Further studies should evaluate the optimal follow up strategy (what tests for whom) of patients with BTN.

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Poster 837 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM REPEAT FNA OF CYTOLOGICALLY INDETERMINATE MUTATION-NEGATIVE THYROID NODULES HAS LIMITED CLINICAL VALUE K. Lovig1, Y. Nikiforov5, S. Carty2, M. Tublin3, L. Yip2, R. Ferris4, J. Borrebach6, C. Coyne1, S. Dixit1, N.P. Ohori5, S. LeBeau1 1 Endocrinology, University of PIttsburgh, Pittsburgh, PA; 2Endocrine Surgery, University of Pittsburgh, Pittsburgh, PA; 3Radiology, University of Pittsburgh, Pittsburgh, PA; 4Otolaryngology, University of Pittsburgh, Pittsburgh, PA; 5Pathology, University of Pittsburgh, Pittsburgh, PA; 6University of Pittsburgh Medical Center, Pittsburgh, PA Thyroid nodules are common in adults, but only a small fraction of them are malignant. Fine-needle aspiration (FNA) cytology provides a definite diagnosis in most nodules, however about 25% are indeterminate. Recently it was shown that nodules with the cytologic result Atypia/follicular lesion of undetermined significance (AUS/ FLUS/Bethesda III), with negative 7-gene mutation panel (MP) results, possess only a 6% risk of cancer. Notably, nodules with benign cytology still carry up to a 3% chance of malignancy. We sought to determine if performing a second FNA on AUS/FLUS MP negative nodules was warranted. Additionally, we assessed if MP negative AUS/FLUS nodules were less likely to undergo diagnostic resection in 2013 vs. 2009 given the low risk of malignancy. We reviewed the data for 570 nodules (293 from 2009, 277 from 2013) with a diagnosis of AUS/FLUS, examining MP results, subsequent FNA cytology, nodule size, whether these nodules were resected, and if so final pathology. 546 AUS/FLUS nodules were MP negative on the first FNA. Of these 134 (47.7%) in 2009 and 119 (44.9%) in 2013 underwent a second FNA (P = 0.548). Of the 253 MP negative AUS/FLUS nodules that underwent a second FNA, 61 (45.5%) had a different diagnosis in 2009 and 51 (42.9%) in 2013 (P = 0.628). However, only 5 (2.0%) nodules had a subsequent FNA yielding a more advanced diagnosis. Among nodules which were MP negative AUS/FLUS after one FNA, 56 (50.9%) underwent surgery in 2009 vs. 64 (59.3%) in 2013 (p = 0.224) with final pathology revealing a malignant process in 4 (7.1%) in 2009 and 3 (4.7%) in 2013(p = 0.704). Among AUS/FLUS nodules with negative 7-gene mutation panel, a second FNA has only a 2% chance of rendering a more advanced cytologic diagnosis. Among resected AUS/FLUS MP negative nodules, the incidences of thyroid cancer in 2009 and 2013 were 7.1% and 4.7%, respectively, which is in accordance with our previous reported risk. Given the low risk of malignancy in MP negative AUS/FLUS nodules and the limited utility of a second FNA, active surveillance in lieu of definitive surgical management is reasonable.

Poster 838 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM LONG-TERM NONOPERATIVE RATE OF THYROID NODULES WITH BENIGN RESULTS ON THE AFIRMA GENE EXPRESSION CLASSIFIER J.A. Sipos1, T. Blevins2, H. Chamberlain Shea3, D. Duick4, S. Lakhian3, B.E. Michael5, M.J. Thomas6, J.A. Sosa7 1 Endocrinology, Ohio State University, Columbus, OH; 2Texas Diabetes and Endocrinology, Austin, TX; 3Endocrine Associates of Dallas, Dallas, TX; 4Endocrinology Associates, Scottsdale, AZ; 5 Wellspan Health, Gettysburg, PA; 6Carolina Endocrine, Raleigh, NC; 7Surgery, Duke University, Durham, NC

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The primary objective was to assess the operative rate in patients with a ‘benign’ result from the Afirma Gene Expression Classifier (GEC) during long-term follow-up at non-academic medical facilities. The secondary endpoint of this study was the treating physician’s opinion regarding the safety of GEC use compared to the hypothetical situation of providing thyroid nodule management without the GEC. This is a retrospective study of non-academic medical practices utilizing the GEC. Those clinicians utilizing the GEC testing who had three or more ‘benign’ results during the data collection period (Sept 2010 through June 2014) were invited to participate. Operative status and patient demographics were documented for patients with GEC testing at least 36 months ( + / - 3 months) prior. A survey also was administered to the treating physicians to assess their perceived safety of using the GEC in patient care. During 36 months ( + / - 3 months) of follow up, 17 of 98 patients (17.3%) with a ‘benign’ GEC result underwent surgery. Within the first two years after a ‘benign’ GEC, 88% of surgeries were performed. Regarding the safety of the GEC, the treating physicians reported that patient safety was improved by using the GEC compared to not using the GEC in 78 of 91 (86%) cases. It appears that a ‘benign’ result on the GEC is associated with a reduction in the rate of thyroid surgeries compared to published data when patients are followed for 36 months after testing. A non-operative approach to follow-up was felt to be a safe alternative to diagnostic surgery by the majority of responsible physicians in the study.

Poster 839 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM EARLY DETECTION OF HYPOPARATHYROIDISM AFTER TOTAL THYROIDECTOMY R.S. Tunes2, G.G. Yogolare2, E.C. Castilho2, C.R. Padovani3, G.M. Mazeto1, J. Tagliarini2 1 Internal Medicine, Botucatu Medical School - Unesp, Botucatu, Brazil; 2Botucatu Medical School - Unesp, Botucatu, Brazil; 3 Sao Paulo State University, Botucatu, Brazil The postoperative serum levels of calcium (Ca) or parathyroid hormone (PTH) have been pointed out as predictors of the post total thyroidectomy (TT) hypoparathyroidism. However, it has not yet been established standards for such purpose. This study aimed to identify beforehand the postoperative hypoparathyroidism, in patients submited to TT, through the Ca and PTH measures in the first 24 hours after surgery. 76 patients operated between 2013 and 2014 were studied prospectively. The Ca measures were performed the day before, during the TT, and with 1, 8, 14 and 24 hours (hs) postoperative (PO), while PTH measures occurred before, during and with 1 and 8 hs of PO. The patients were re-evaluated after 7, 30 days and 6 months of PO, and classified as: without hypoparathyroidism (G1), with transient hypoparathyroidism (G2) or with definitive hypoparathyroidism (DH, G3). 40 patients (52.6%) were classified as G1, 24 (31.6%) as G2 and 12 (15.8%) as G3. Females were more prevalent in the three groups [G1: 85%; G2: 91.7%; G3:100%; p < 0.05], and presented a higher risk for DH [relative risk (RR) = 1.14 (IC 95%:1.04–1.25)]. The Ca curves showed downward pattern in all groups, sharpest in group G3 (p < 0.05), with significant drop in the groups after 8hs (p < 0.05). For a drop of Ca > 20% in 24hs, there was higher risk of DH [RR = 1.21 (IC 95%:1.21–23.35)]. The PTH presented a drop of its absolute values already during the TT (G3 > G2 > G1; p < 0.05). With 8hs, the average percentage of PTH drop was 100% for the cases with DH (p < 0.01). The drop of PTH > 90% was associated with higher risk of

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DH [RR = 2.96 (IC 95%:1.20–7.30), during the TT; RR = 4.19 (IC 95%:2.55-6.86), with 1h; and RR = 5.33 (IC 95%:2.86–9.94), with 8hs]. The absolute values and, mainly, the negative percentage variation of Ca > 20% and PTH > 90% in the first 24hs, when compared to the baseline, predict DH.

Poster 840 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM HYPOPARATHYROIDISM POST-THYROIDECTOMY: HOW TO REPLACE WITH CALCIUM CARBONATE? L. Gollino2, M.G. Biagioni1, N.R. Sabatini1, J. Corrente3, S.A. Paiva1, G.M. Mazeto1 1 Internal Medicine, Botucatu Medical School - Unesp, Botucatu, Brazil; 2Botucatu Medical School - Unesp, Botucatu, Brazil; 3 Sao Paulo State University - Unesp, Botucatu, Brazil In hypoparathyroidism, calcium (Ca) replacement is needed in order to control the hypocalcemia, and is performed, mainly, using calcium carbonate (CaCO3). There are doubts about the best way to ingest the CaCO3, either on empty stomach or after the meals. This study aimed to evaluate, in women with hypoparathyroidism post-total thyroidectomy, the evolution of Ca and phosphorus (P) levels, and product Ca.P, after the supplementation with CaCO3, ingested in three different ways. It has been made a cross over study with 12 adult women (aged 18 to 50 years old) with hypoparathyroidism post-total thyroidectomy due to thyroid cancer, evaluated in three different situations [fasting, with water (W); fasting, with orange juice ( J); with breakfast (B), with water], with a week break. Ca and P levels were dosed before and each 30 minutes (min), during 5 hours, after the ingestion of CaCO3 (500 mg of elemental Ca). The evolution of both was evaluated, besides the product Ca.P, as well as the maximum peak, the time-topeak and the area under the curve (AUC) related to these parameters. The evolution and the average values of Ca, P and the product Ca.P for the maximum peak (8.63 mg/dL for W, 8,77 mg/dL for J and 8,95 mg/dL for B; 4,04 mg/dL for W, 4.03 mg/dL for J and 4.12 mg/dL for B; 34.3 mg2/dL2 for W, 35.8 mg2/dL2 for J and 34.5 mg2/dL2 for B, respectively), time-to-peak (202.5 min for W, 182.5 min for J and 152.5 min for B; 142 min for W, 135 min for J and 167 min for B; 180 min for W, 187 min for J and 192 min for B, respectively); and AUC (2433 mg/dL.min for W, 2506 mg/dL.min for J and 2577 mg/ dL.min for B; 105 mg/dL.min for W, 105 mg/dL.min for J and 106 mg/ dL.min for B, respectively) weren’t different between the three different forms of ingesting CaCO3 ( p > 0.05). Ca and P blood levels, and product Ca.P evolved in a similar way, in the three forms of taking CaCO3.

Poster 841 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM BIOCHEMICAL FOLLOW UP OF NON-FUNCTIONING THYROID NODULES: INCIDENCE OF DEVELOPING THYROID DYSFUNCTION OVER TIME Y. Mohtasebi, S.R. Salgado Nunez del Prado, C. Overby, S. Stein, E. Lamos, K. Munir Endocrinology, University of Maryland Medical Center, Baltimore, MD Thyroid nodules are a common clinical problem; with an estimated prevalence of 19–68% by ultrasound(US). In case of a benign nodule, periodic long life measurement of TSH has been recommended by some authors to rule out the development of toxic nodule over time. The purpose of this retrospective study was to assess the incidence of

thyroid dysfunction over time in patients with thyroid nodule/s who had normal TSH at diagnosis. Medical records of the patients with diagnosis of thyroid nodule/s between 1/1/2011-8/8/2014 were reviewed. Patients with abnormal TSH at diagnosis, on anti-thyroid or levothyroxine therapy, malignancy, history of head/neck radiation, any exposure to interferon-a, lithium or amiodarone, glucocorticoid exposure > 3 months, age > 89 and those with incomplete data were excluded. Patients who had TSH measurement within 1 year of initial US were included. Follow-up was the time period from initial/first available TSH and last recorded TSH in the chart. 564 patients with thyroid nodule/s were identified. 403 were excluded. 94 patients met inclusion criteria. Another 67 patients without TSH at diagnosis who had normal first available TSH were also included as a separate group. Mean follow-up was 4.1 – 1.7 yrs. 7/161 (4.3%) developed thyroid dysfunction. 2/7 developed hypothyroidism and 5/7 developed subclinical hyperthyroidism (SH). Of these 7 patients, only 1 patient had TSH measurement at diagnosis. Mean initial TSH level in patients who developed SH was 0.6 mcIU/mL and it eventually normalized in 3/5 patients with no intervention. Time to thyroid dysfunction in 5 patients with SH was 3.3 – 2.3 yrs. None of the 94 patients with initial TSH > 1mcIU/mL developed abnormal TSH at F/U. Almost all patients with thyroid nodule/s who were biochemically euthyroid did not develop thyroid dysfunction after 4.1 years of average follow-up. Therefore, frequent TSH measurement in these patients is most likely unnecessary, particularly if initial TSH level is >1mcIU/mL.

Poster 842 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM ELASTOGRAPHY FOR THE EVALUATION OF THYROID NODULES IN CHILDREN A.N. Cury1, L.I. Marino2, C. Kochi2, O. Monte2, C.A. Longui2, E.C. Fleury3 1 Medicine - Endocrinology, Santa Casa Medical Faculty, Sao Paulo, Brazil; 2Pediatric Endocrinology Unit, Santa Casa of Sa˜o Paulo, Sa˜o Paulo, Brazil; 3Radiology Departament, Santa Casa of Sa˜o Paulo, Sa˜o Paulo, Brazil Thyroid nodules (TNs) are rare in children, with an incidence rate of only 1.5%. However, the risk of malignancy among children with TNs is high, reaching a quarter. Elastography is a new technique that uses ultrasound to provide an estimation of tissue stiffness by measuring the degree of distortion under the application of an external force. Stiffness is usually correlated with malignancy because benign lesions are supposed to be softer. We found no studies in the literature on elastography in the diagnosis of thyroid cancer in childhood. We enrolled 32 patients with a total of 38 thyroid nodules in our study. We collected TSH, free T4 and calcitonin; performed USG, elastography

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 and FNA cytology by the same operator, when necessary. Thyroidectomy was recommended for patients who had possible non-benign cytology, TNs classified as Bethesda (Bt) IV, V, or VI. In this study, elastography was evaluated using 2 scores, namely E1 and E2. Every TN was given a score of E1 or E2. If the TNs had a red coloring of < 50% then it was classified as E1 (elastic TNs); when red was present in > 50% of the thyroid nodule then it was classified as E2 (hard TNs). The mean age of patients was 12.9 years (range, 6–18 years) and the female: male ratio was 2.5. FNAB was done for all nodules (0.5– 4.3cm). In the FNAB, 24 of the 38 TNs (63%) were classified as Bt II, 6 (16%) as Bt IV, 7 (18%) as Bt V, and 1 (3%) as Bt VI. Twelve of the 32 patients with cytological abnormalities concerning for cancer were referred for surgery. Overall, 7 patients were diagnosed with thyroid cancer, corresponding to a 22% cancer rate. High elasticity of a nodule on was associated with a low risk of thyroid cancer, if we consider that 24 TNs classified as benign after FNAB, 92% were classified E1. Only one malignant thyroid nodule was classified as elastography E1, and it was a particularly case of a boy with elevated calcitonin and final diagnosis of medullary thyroid carcinoma. In summary, it is easy to incorporate elastography in routine ultrasound examination and it can be used as a complementary screening test for children who present with TNs. Larger studies are needed to obtain the diagnostic accuracy of elastography in children.

Poster 843 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM CORRELATION OF CLINICAL AND ULTRASONOGRAPHIC FEATURES TO MALIGNANT DISEASE IN PATIENTS WITH INDETERMINATE THYROID NODULES F. Murad, M. Anwar, M. Alshehri, R. Kholmatov, Z. Al-Qurayshi, E. Kandil Surgery, Tulane University School of Medicine, New Orleans, LA The management of thyroid nodules differ based on various clinicopathologic features. Various researchers have attempted to identify the preoperative risk factors which may indicate a malignancy. The aim of this study is to evaluate whether clinical symptoms, physical examination findings, and ultrasonographic features correlate with a malignant outcome in patients with indeterminate thyroid nodules. This is a retrospective review of our patients over a three years period, who were found to have atypia of undetermined significance (AUS), follicular lesion of undetermined significance (FLUS), or follicular neoplasm (or suspicious for follicular neoplasm) in a fine needle aspiration of a thyroid nodule, according to the Bethesda classification system. The age, gender, clinicopathologic features, and ultrasonography reports were reviewed and correlated with the final diagnosis in the surgical pathology report. Student’s t test was used for the continuous variables, and Fisher’s exact test was used for the categorical variables. Significance level was set as (a = 0.05). Out of 307 nodules included in this study (67 in males, 240 in females) (age: 55.6 – 14.7), surgical pathology showed a malignant outcome in 100 cases (32.9%), a benign nodule in 141 (46.4%) and was not done in 63(20.8%). Asymptomatic patients with Internal vascularity and irregular margins on ultrasonography were more likely to have a malignant nodule (P < 0.001, 0.015 respectively). There was no correlation between thyroid cancer and compressive symptoms, tracheal deviation or substernal extension (P = 0.99, 0.6, and 0.64 respectively). Compressive symptoms, tracheal deviation, and substernal extension did not correlate with malignancy in patients with indeterminate thyroid nodules. Patients with suspicious ultrasonographic features were more likely to have a malignant pathology.

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Poster 844 Thyroid Cancer Wednesday & Thursday Poster Clinical 9:00 AM INCREASING USE OF CHEMOTHERAPY FOR THYROID CANCER, FACT OR FICTION? S. Fedewa2, A.Y. Chen1 1 Otolaryngology Head and Neck Surgery, Emory, Atlanta, GA; 2 American Cancer Society, Atlanta, GA Chemotherapy has been used traditionally for anaplastic thyroid cancer. However, with the FDA approval of tyrosine kinase inhibitors (TKI) for medullary and well-differentiated thyroid cancer, increasing use of chemotherapy (including TKI) is expected. The National Cancer Database was used to analyze the use of chemotherapy (traditional and TKI) in thyroid cancer cases from 2004–2012. Univariate and multivariate analyses were performed to identify factors associated with receipt of chemotherapy. 198,360 cases of thyroid cancer from 2004–2012 were eligible for analysis. Those cases with missing sex, chemotherapy data, metastasis information and tumor size were previously excluded. Demographic and clinical factors were abstracted. 1417 received chemotherapy. Univariate analysis demonstrated that the following factors were associated with receipt of chemotherapy: male sex, increasing age up to age 70 years, Medicare or private insurance, receiving care at teaching research centers or NCI designated cancer centers, having anaplastic or medullary histology, having > 3cm primary size, having metastatic disease, and receiving radiation. Multivariate analysis demonstrated that male race (OR = 1.6; 95% CI 1.4–1.8), age 61–70 (OR = 2.47, 95% CI 1.7–3.6), Medullary histology (OR = 9.5, 95% CI 7.56–12.01), anaplastic histology (OR = 94.1, 95% CI 77.2–114.7), metastatic disease (OR = 2.93, 95% CI 2.45–3.50), and greater than 4 cm primary (OR = 7.99, 95% CI 6.0–10.6). 51% of the patients receiving chemotherapy were treated at teaching research hospitals; 67% of the patients had primaries In spite of increasing number of indications for use of chemotherapy in the treatment of thyroid cancer, we did not find a significant trend from 2004–2012. We did demonstrate that clinical factors (size, histology, extent of disease) and non-clinical factors (sex and age) were associated with receipt of chemotherapy.

Poster 845 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM INTEREST OF FINE NEEDLE ASPIRATION IN THYROID NODULES OVER THREE CENTIMETERS T. Raguin1, O. Schneegans3, J. Rodier2, E. Sauleau4, C. Debry1, J. Ghnassia6, A. Dupret-Bories5 1 Service ORL et chirurgie cervico-facial, CHU Strasbourg, Strasbourg, France; 2Service de chirurgie, Groupe Saint Vincent, Strasbourg, France; 3Service d’endocrinologie et de me´decine nucle´aire, Centre Paul Strauss, Strasbourg, France; 4sante´ publique, CHU Strasbourg, Strasbourg, France; 5Service d’otorhinolaryngologie et chirurgie cervico-faciale., Institut Universitaire du Cancer, Toulouse, France; 6Service d’anatomopathologie, Centre Paul Strauss, Strasbourg, France In over half of the world population aged 60 years or older, thyroid nodules are detected either clinically or by imagery. The American Thyroid Association recommends a diagnostic examination with an ultrasound in association with a fine needle aspiration in case of a potential subcentimeter thyroid nodule. The risk of a mistake in the diagnosis by fine needle aspiration combined with the increase in the

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prevalence of malignancy with nodules over three centimeters may compromise the interest of fine needle aspiration before surgery. This is a retrospective, monocentric study based on patients operated for a thyroid nodule over 3 centimeters between June 2004 and June 2014. The inclusion criteria were the size of the nodule, a fine needle aspiration coupled with an ultrasound measurement prior to surgery and a final postoperative histopathology. Of the 6393 patients who had thyroid surgery, 843 were included in this study. The average size of the nodules was 42.2 mm. The fine needle aspiration was informative in 42.6% of the cases (type II, V et VI of the Bethesda classification). The correlation between fine needle aspiration and the final postoperative histopathology analysis was 94.82% for benign nodules and 70.97% for malignant nodules. (Table 1) In our study, fine needle aspiration had a positive predictive value of 71%, a negative predictive value of 95%, a specificity of 97% and a sensitivity of 56% (with an error rate of 0.07). The risk of having a thyroid cancer is 44.72 times more important in case of malignancy fine needle aspiration rather than benign (Odds Ratio 44,72)(IC : 0.14–0.39). These results indicate that fine needle aspiration improves the diagnosis for nodules over 3 cm in only 42.6% of the cases, with a sensitivity of 56%. The fine needle aspiration should not delay surgical indication for thyroid nodules with a size greater than 3 centimeters.

Poster 846 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM LONG-TERM OUTCOME FOLLOWING LASER THERAPY OF BENIGN CYSTIC THYROID NODULES H. Døssing1, L. Hegedu¨s2, F.N. Bennedbæk3 1 Oto-Rhin-Lanyngology and Neck Surgery, Odense University Hospital, Odense C, Denmark; 2Endocrinology, Odense University Hospital, Odense, Denmark; 3Endocrinology, Herlev Hospital, Herlev, Denmark Laser therapy (LT) is a safe and effective procedure for inducing thyroid nodule necrosis and shrinkage. Here, our aim was to evaluate long-term efficacy of LT in patients with a predominantly cystic benign recurrent thyroid nodule. Eighty-seven euthyroid outpatients (21 men and 46 women; mean age: 48 years; range; 17–82) with a recurrent cytologically benign cystic ( ‡ 2ml cyst-volume) thyroid nodule causing local discomfort were assigned to LT. LT, using one laser fibre, was performed after complete cyst aspiration and under continuous ultrasound (US) guidance. The output power was 2.0–3.0 W, and mean delivered energy was 1305 J (range; 94–4392 J). Mean treatment duration was 569 sec. (range; 47–1545). 16 patients (14 within 6 months) had surgery after LT. All had benign histology. The mean follow- up for the remaining 71 patients was 50 months (range; 12–134). Pressure symptoms and cosmetic complaints were evaluated on a visual analogue scale (0–10 cm). The overall mean nodule volume in the 71 patients decreased from 12.2 ml (range; 2.3–45.0) to 1.5 ml (range; 0.7-11.0) (p < 0.001) at the final evaluation, corresponding to a mean reduction of 82% (range; 14% - 100%). Remission of the cystic part (cyst volume £ 1 ml) was

obtained in 66 of 71 (93%) patients after LT. The mean cyst volume decreased from 9.8 ml (range; 2.0–45.0) to 0.3 ml (range; 0–4.0) (P < 000.1), corresponding to a reduction of 95% (range; 43%100%). The mean volume of the solid part of the nodule was reduced from 2.6 ml (range; 1.8–15.1) to 1.1 ml (range; 0.5–6.1) (P < 0.001). These results correlated with a significant decrease in pressure as well as cosmetic complaints. Thyroid function was unaltered throughout and side effects were restricted to mild local pain. US-guided aspiration and subsequent LT of benign recurrent predominantly cystic thyroid nodules results in a satisfactory longterm clinical response in the majority of patients. It is a safe and welltolerated procedure and significantly reduces long-term recurrence rate, size of the solid portion of the nodule, and nodule related symptoms. LT constitutes a clinically relevant alternative to surgery in such patients.

Poster 847 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM THYROID FUNCTION AND STRUCTURE IN PATIENTS WITH POLYCYSTIC OVARIAN SYNDROME AND INSULIN RESISTANCE E.N. Herna´ndez, L.R. Figueroa, R. Pizzi, L. Fung Endocrinology, Hospital Universitario de Caracas, Chile, Chile Introduction: Thyroid structure and function was determined in patients with Polycystic Ovarian Syndrome (PCOS) and insulin resistance (IR). This study is an observational, cross-sectional analytical study. Thyroid function and thyroid structure by ultrasonography was determined in 64 patients that were newly diagnosed with PCOS, and had not yet undergone treatment. The patients were divided in two groups of 32 patients according to the presence of IR, Group 1 (G1) with HOMA-IR > 2.5 and Group 2 (G2) with HOMA-IR < 2.5. Thyroid stimulating hormone (TSH) > 2.5 was observed in 15/32 (46.9%) patients in G1,while > 2.5 in 7/32 (21.9%) patients in G2 (p = 0.035). The presence of positive antibodies against thyroid peroxidase (anti-TPO) was identified in 11/32 (34.4%) patients in G1 and 6/32 (18.8%) in G2 (p = 0.15). Ultrasound evaluation of the thyroid gland, revealed the presence of nodules in 12/32 (37.6%) of patients in the G1 and 4/32 of G2 (p = 0.025). Overweight and Obesity was observed in 74.99% of patients in G1 and 37.49% in G2 (p = 0.001). Other parameters were assessed, including hirsutism, which was identified in 96.9% in the G1 and 62.5% of G2 patients (p = 0.002). The free androgen index (FAI) was 3.8 in 20/32 (62.5%) patients in G1 and in 14/32 (43.8%) in G2 (p = 0.13). The effects of insulin resistance in PCOS are not limited to ovarian function. There is relationship between IR, TSH and ultrasound changes of the thyroid gland, as well as the increased presence of Thyroid Autoimmune Disease. This justifies the thyroid gland evaluation to optimize a correct therapeutic approach.

Poster 848 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM LARGE THYROID NODULE CAUSING RECURRENT CHYLOUS EFFUSIONS J. Zwiener Endocrinology, UT Houston, Houston, TX Thyroid nodules are well-known to cause mass effect. Here we describe an uncommon presentation of a large nodule goiter.

WEDNESDAY, OCTOBER 21–THURSDAY, OCTOBER 22, 2015 A 66 year old man with hypertension, diabetes, and diastolic heart failure presented to the emergency department complaining of dyspnea and orthopnea. Chest x-ray showed a large pleural effusion; thoracentesis produced > 1 L cloudy fluid with elevated triglyceride count. CT of the chest noted an 8 cm thyroid nodule with tracheal deviation. The patient improved with diuresis and inhaled steroids and was discharged home. He was readmitted four days later with dyspnea and peripheral edema. He was initially diuresed with some improvement, but three days later became hypoxic; 1.4 L chylous pleural fluid was removed via thoracentesis with improvement in his oxygenation. Ultrasound of the thyroid showed an 11 · 6.2 · 6.3 cm solid thyroid mass replacing much of the left lobe, with central vascularity and microcalcifications, and a smaller right-sided 1.8 · 1.6 · 1.9 cm thyroid nodule. Lymphangiogram showed opacification of the thoracic duct with abrupt cutoff in the upper mediastinum likely secondary to extrinsic mass effect from the large substernal goiter. He underwent left lobectomy with resolution of his chylous effusions. Pathology of the thyroid nodule was benign. On review of outside records, he was noted to have had a 6.1 cm thyroid nodule on CT chest performed in 2003, but never sought further evaluation due to financial issues. Typically, large thyroid masses cause compressive symptoms such as dysphagia, orthopnea, and hoarseness. It is important to remember that other local structures, such as the thoracic duct, may also be affected. Chylous effusions have been associated with both hyper- and hypothyroidism, and are more commonly seen as a complication of mediastinal lymph node dissection for thyroid cancer.

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Bulky thyroid masses should be considered when evaluating the etiology of a recurrent chylous effusion.

Poster 849 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM J-131 THERAPY IN PATIENTS WITH AUTONOMOUSLY FUNCTIONING THYROID NODULES WITH A NORMAL TSH LEVEL M. Lacic Polyclinic Lacic, Zagreb, Croatia In this study we evaluate the effect of J-131 therapy in patients (pts) with autonomously functioning thyroid nodules (AFTNs) and a normal thyroid stimulating hormone (TSH) value. Up to our knowledge, this is the first study which has scintigraphically evaluated the effect of J-131 therapy in patients with AFTNs and normal TSH level. During the last five years 43 cytological benign AFTNs in 40 pts (36 female and 4 male) with normal TSH level have been treated with a fixed J-131 doses (370 MBq). Clinical exam, ultrasonography with color Doppler (US), fine needle aspiration biopsy (FNAB), TSH, FT4, FT3, anti-TPO, anti-Tg and thyroid scan (scintigraphy) have been performed in all pts before J-131 therapy. After the J-131 therapy a careful clinical follow up of the patients has been done including: US, TSH, FT4, FT3, anti-TPO and anti-Tg measurements. A 6 month post J-131 therapy a thyroid scan has been performed in 27 pts with 30 AFTNs. The median age of the pts was 57 (range 37–83) years. AFTNs were located more frequently in the right thyroid lobe (25 nodules) than in the left lobe (18 nodules). In 10 pts a solitary AFTN has been found on ultrasonography and the other 30 patients had AFTNs in multinodular goiter. On post J-131 therapy thyroid scan in 25 AFTNs complete therapy effect has been observed, but in 5 AFTNs a scintigraphycally partial effect has been noted. Statistical analysis showed a significant reduction in the thyroid (p = 1,8827E-12) and AFTNs (p = 1,60185E-06) volume after J-131 therapy. TSH value significantly increased (p < 0,001) and FT4 value significantly decreased (p < 0,001) after J-131 therapy. FT3, anti-TPO and anti-Tg values did not change significantly. J-131 therapy in pts with AFTN is a simple and very effective modality. The effect of the therapy can be exactly evaluated only with a post J-131 therapy thyroid scan.

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Poster 850 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM THE EFFICACY OF ORAL IODINE FOR THE TREATMENT OF AUTONOMOUSLY FUNCTIONING THYROID NODULES (AFTNS) F. Shigiyama, N. Kumashiro, Y. Andou, H. Uchino, K. Tsuboi, T. Hirose Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan Toxic multinodular goiter (TMNG) or autonomously functioning thyroid nodules (AFTNs) produce thyroid hormones independently from thyroid stimulating hormone (TSH) regulation. Although clinical symptom is similar to Grave’s disease, it has been uncommon to use antithyroid-drugs for AFTNs. We experienced the 10 cases of AFTNs, 4 patients were treated with oral iodine administration. 10 patients with AFTNs, age 64 median, were evaluated in this study. 4 of 10 with thyrotoxicosis were treated by oral iodine administration and 6 cases who were with subclinical hyperthyroidism were observed with no medication. We assessed serum FT3, FT4, TSH and thyroglobulin before and after treatment or without treatment. Three months of oral iodine administration for 4 cases decreased serum FT3 and FT4 levels (FT3: 9.77 – 7.62 pg/ml to 2.88 – 0.7 pg/ml, FT4: 3.62 – 2.44 ng/dl to 1.36 – 0.32 ng/dl). 6 cases with subclinical hyperthyroidism had no further thyrotoxicosis without any medication. Surgery or Radioactive iodine (RI) therapy is the choice of treatments for AFTNs. For multiple and bilateral nodules, surgical treatment is recommended. However, it is more invasive than other treatments because of secondary hypoparathyroidism and some cases are accompanied with laryngeal nerve palsy. RI is effective for thyrotoxicosis and reducing nodule size. However, in RI, 131I is absorbed in both the normal region and nodule tissues, which might lead to an increasing ratio of hypothyroidism. Due to the strict legal regulations and the fear of radioactive substances, radioactive treatment has not been preferable in Japan. While iodine administration may induce thyrotoxicosis in patients living in iodine deficient area, it may improve thyrotoxicosis in patients living in iodine sufficient or abundant area, such as Japan. Control of thyrotoxicosis is important for elderly patients to prevent atrial fibrillation. Oral iodine therapy could be a potential therapeutic alternative for cases who are apprehensive surgery or RI, for patients who require treatment with internal medications, and for elderly patients.

Poster 851 Thyroid Cancer Wednesday & Thursday Poster 9:00 AM SPORADIC MEDULLARY THYROID CARCINOMA WITH SYMPTOMATIC PITUITARY METASTASIS DURING VANDETINIB A. Roman-Gonzalez1, C. Jimenez2, M.A. Habra2 1 Endocrinology, Hospital Universitario San Vicente Fundacio´n, Medelin, Colombia; 2Department of Endocrine Neoplasia and Hormonal Disorders, he University of Texas MD Anderson Cancer Center, Houston, TX Medullary thyroid carcinoma (MTC) constitutes less than 4% of all thyroid carcinomas. Only 4 cases of MTC with pituitary metastases are reported. We present the first case of sporadic MTC that developed symptomatic pituitary metastasis during vandetinib therapy A 35 year-old man presented with 6-months history of diarrhea and cervical lymphadenopathy. Further testing identified bilateral lung

metastases that proved to be metastatic MTC. The thyroid gland contained small nodules without mass effect. There was no evidence of metastases in the brain, liver or the bone. Vandetanib 300 mg daily was initiated with excellent tolerance and remarkable improvement in lung and cervical lymph node metastases. 11 months after starting vandetinib, he had sudden growth of a right upper jugular lymph node required resection. Pathological exam showed a multifocal medullary thyroid carcinoma with the largest focus measuring 0.7 cm with extrathyroidal extension and lymphovascular invasion and multiple involved lymph nodes in levels 2, 3, 4 and 5 (T3,N1b,M1). Germ line RET testing was negative, he had a somatic RET mutation (M918T). 16 months during vandetinib therapy, he developed polyuria and polydipisia with extreme fatigue. Laboratory evaluation showed urine osmolality of 130 mOsm/Kg H2O, serum osmolality of 309mOsm/Kg H2O, serum sodium of 148, serum cortisol 16.1 mcg/dl, TSH 1.4 uIU/ mL (0.27–4.20), free T4 0.42 L ng/dL (0.93–1.70), LH undetectable, FSH 0.6 mIU/ml, and serum testosterone of 20 ng/dL. MRI confirmed new pituitary mass that was not present at the beginning of the treatment. Surgical resection was performed and pathological examination showed nests of atypical cells, consistent with medullary thyroid carcinoma with positive calcitonin staining. Pituitary metastases in the context of metastatic MTC are very rare. This is the first reported case of MTC with pituitary metastasis developing during anti-angiogenic therapy (vandetinib). The clinical association of diabetes insipidus and anterior pituitary hormone deficiency highly suggests metastatic disease and requires prompt medical evaluation. This is the first reported case of MTC with pituitary metastasis developing during anti-angiogenic therapy (vandetinib).

Poster 852 Thyroid Nodules & Goiter Wednesday & Thursday Poster 9:00 AM THYROID PARAGANGLIOMA A. Roman-Gonzalez1, C.A. Builes-Barrera1,5, A. Velez2,3, C. Jimenez4 1 Endocrinology, Hospital Universitario San Vicente Fundacio´n, Medelin, Colombia; 2Pathology, Hospital Pablo Tobon Uribe, Medellin, Colombia; 3Pathology, Dinamica IPS, Medellin, Colombia; 4 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas - MD Anderson Cancer Center, Houston, TX; 5 Endocrinology, Universidad de Antioquia, Medellin, Colombia Paragangliomas are rare neuroendocrine tumors arising from chromaffin + cells located outside the adrenal medulla. Head and neck paragangliomas can originate in the thyroid gland as the inferior laryngeal paraganglia could be contained within the thyroid capsule. A differential diagnosis is given by medullary thyroid carcinoma as this the most common thyroid primary neuroendocrine tumor. A 54 year-old woman with no relevant medical history presents with an anterior neck mass. This mass was noted two years ago and was associated with rapid growth over the last two months. The patient did not have other symptoms. Ultrasound demonstrated a 17 · 20 mm carotid body paraganglioma. A CT angiography showed a 31 · 22 · 16mm vascular mass in the posterior space of the carotids (Figure 1). Surgery was performed. The pathological examination showed a thyroid neuroendocrine tumor with S100, synaptophysin and chromogranin expression; TTF1, thyroglobulin, calcitonin and cytokeratin were negative. Head and neck paragangliomas are non-functional tumors. They can be sporadic or associated with familial paraganglioma syndromes secondary to germline inactivating mutations of the genes encoding for the different subunits of the mitochondrial enzymatic complex 2. Thyroid paraganglioma are rare. Only 0.5% of the head and neck paragangliomas are located in the thyroid. 60 cases have been reported in the English

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Fine needle aspiration of the thyroid. Hematoxylin-eosin stain with cartilaginous tissue

scientific literature. The most common neuroendocrine tumor of the thyroid is medullary carcinoma and the difference with thyroid paraganglioma is based on immunohistochemistry stain. As both tumors are positive for classic neuroendocrine markers (chromogranin and synaptophysin), calcitonin and cytokeratin panel are always necessary to establish an appropriate diagnosis. Our patient had negative calcitonin and cytokeratin supporting the diagnosis of paraganglioma. Eighty percent of the thyroid paraganglioma are associated with germline mutations. In this case a genetic evaluation has not been done yet. Head and neck paragangliomas can be located in the thyroid. Usually are non-functioning tumors. The main differential diagnosis is medullary thyroid carcinoma.

Poster 853 Thyroid Nodules & Goiter Wednesday & Thursday Poster Clinical 9:00 AM BENIGN THYROID TERATOMA. FIRST REPORT FROM COLOMBIA A. Roman-Gonzalez1, A. Velez2,3, A. Jaller3, C. Rua-Marin1 1 Endocrinology, Hospital Universitario San Vicente Fundacio´n, Medelin, Colombia; 2Pathology, Hospital Pablo Tobo Uribe, Medellin, Colombia; 3Pathology, Dinamica IPS, Medellin, Colombia Teratomas are infrequent tumors arising from ectodermic, mesodermic and endodermic embryonic tissue. These tumors are usually located in the gonadal tissue but can be found in extra-gonadal sites, especially in the middle line. Thyroid teratomas are quite rare tu-

mors, almost benign in the majority of cases, and the diagnosis is done predominantly during the childhood. Their importance subsides in the malignant potential especially if the diagnosis is made in middle age women and the necessity of establishing the origin of the tumor to provide an appropriate diagnosis and management. A 3 years-old boy presents with a slowly growing neck mass. The physical exam discloses a 2 centimeters (cms) thyroid nodule without associated lymph nodes. Thyroid function test were normal. Ultrasound evaluation found a left thyroid lobe solid lesion of 2 · 2 cms, with heterogeneous aspect and gross calcifications. Neck computed tomography also showed a solid lesion of the left thyroid lobe with gross calcification without abnormal lymph nodes. A fine needle aspiration was performed. The presence of cartilaginous tissue of mature aspect in the aspiration was compatible with a benign teratoma (Figure 1). The nodule was surgically resected. A 3 · 2 cm lesion was resected. The tumoral size was 2 · 1.8 cm. Microscopic findings showed a benign neoplastic proliferation with presence of condroid cartilaginous elements compatible with teratoma. After 6 six years of follow-up there is no recurrence and the patient is completely normal. Thyroid teratomas are an infrequent lesion. This diagnosis must be in the mind of the physician when young patients presents with neck mass. The treatment in the benign cases is usually surgical resection without needing other therapies such as chemotherapy or radiotherapy. To our knowledge this is the first case report in our country. In Latin America there are reports from Costa Rica (LoboSanahuja F et al 1986), Brazil (Simao N et al 2011) and Venezuela (Paz F et al, 2007). Thyroid teratoma are infrequent tumors. They are usually diagnosed during childhood. Malignant thyroid teratomas usually present in women of reproductive age.