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Values for CA 125 were correlated with severity of PID, but not with CRP in serum. We have now studied the correla- tion between CRP and another marker for ...

References 1. Whelton A. Therapeutic initiatives for the avoidance of aminoglycoside toxicity. J Clin Pharmacol 1985;25:67-81. 2. Rudy JL, Rutledge JC, Lewis SL. Phenylalanine and tyrosine in serum and eluates from dried blood spots as determined by reversed-phase liquid chromatography. Clin Chem 1987;33:1152-4. 3. Bassett F, Gross BA, Eastman CJ. Radioimmunoassay of prolactin in blood spotted on filter paper. Clin Chem 1986;32:854-6. 4. Albani M, Toseland PA. A simple rapid gas chromatographic method for the determination of theophylline in dried whole blood on filter paper cards. Neuropaediatrie 1987;9:97-9.

dIN.

CHEM.

35/5,

869-871

5. Coombes EJ, Garnien TR, Batstone GF, Holgate ST. The validation of a fluoroimmunoassay for the determination of theophylline concentration in dried blood spots suitable fordomiciliary therapeutic drug monitoring. Clin Chim Acts 1984;136:187-95. 6. Li PK, Lee JT, Conboy KA, EllisEF. Fluorescence polarization immunoassay for theophylline modified for use with dried blood spots on filter paper. Clin Chem 1987;32:552-5. 7. Fujimoto T, Tawa R, Hirose S. Fluorometric determination of sisomicin, an aminoglycoside antibiotic, in dried blood spots on filter paper by reversed-phase high-performance liquid chromatog-

raphy with pre-column

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Chem Pharm Bull

1988;36:1571-4.

(1989)

Concentrations of Tumor-Associated Trypsin Inhibitor and C-Reactive Protein in Serum in Acute Pelvic Inflammatory Disease Jorma Paavonen,’ Mattl Lehtlnen,2 Malll Lehto,3 Seppo Lame,4 Risto Alne,3Lllsa R#{224}s#{225}nen,2 and Ult-H#{226}kan Stenman1 tumor-associated trypsin inhibitor (TATI) and C-reactive protein (CAP) in serum of 29 patients with proven pelvic inflammatory disease (PlO). TATI values were increased in seven (24%), paralleling increases in CAP. TATI was increased by about 3.5-fold in seven of eight patients with CAP concentrations >90 mg/L, but in none of 21 patients with CAP concentrations 90 mg/L, but in none of 21 patients with a CRP concentration 24 /L) are marked (0) TATI (pg/L)

CRP

(mg/L)

Fig. 2. Correlationbetween values for TATI and CRP in serum of 29 womenwithacute pelvicinflammatorydisease 870

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CHEMISTRY,

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TATI-positive patients had fever (>37.5 #{176}C) vs only one of the TATI-negative patients (P = 0.05, Fisher’s exact test). All seven patients with increased TAT! concentrations in the acute phase had normal concentrations in the convalescent phase (range 10 to 16 zg/L). A second laparoscopy, performed approximately four months after the index episode, showed tubo-ovarian adhesions in three of six TAT!positive patients vs only two of 17 TATI-negative patients. Discussion Several tumor-associated proteins are used as biochemical markers for ovarian carcinoma and other malignancies. One of the markers mainly used for gynecological cancer, CA 125, may become increased in benign gynecological conditions as well (13-15). We now show that another marker for gynecological cancer, TAT!, may also become increased in severe gynecological infections. However, the mechanisms behind the increases in these two markers may differ. The increase in TAT!, but not CA 125 (2), was associated with an increased concentration of CRP. This supports the idea that TAT! in some respects resembles acute-phase proteins. This may also be related to the fact that CA 125 and TAT! are preferentially associated with different types of ovarian tumors, TAT! with mucinous tumors (4, 16) and CA 125 with nonmucinous tumors (17). We found increased TAT! in serum of 24% of patients with P11), and increased TAT! concentrations were invariably associated with high values for CRP. Several studies have demonstrated that the CRP assay is a sensitive and specific augmentary testforthe diagnosisof P11) (1, 18-20). The ability of microbial substances to stimulate the synthesis of hepatic acute-phase proteins such as CRP appears to be a prominent pathophysiological mechanism in Pm. Production of interleukin-1 (IL-i) by cells of monocyte-macrophage origin is a part of the pathological mechanism in many infections, leading to dramatic increases in the synthesis of CRP (21). In our patients, TAT! was never increased in connection with moderate increases in CRP. Evidently some additional factor, such as tumor necrosis factor (TNF), is required beforethe expressionof TAT! is increased. Induction of one protease inhibitor, a1antichymotrypsin, in TNF-treated hepatocytes has been described (22). We have recently described a significant correlation between the concentrations in serum of another physiological protease inhibitor, a1-antitrypsin, and TAT! in pm patients (23). However, the role of both IL-i and TNF as the primary inducers of the acute-phase response is still controversial (24). In P11) it is likely that: various lymphokines take part in the acute-phase response, their action is not synergistic, and there are complex interactions and feedback mechanisms. Although theTAT! concentrations were clearlyincreased in pm during the acutephase, they normalized in allcases after the antimicrobial treatment.This was alsothecasefor CA 125 (2). Although there was no correlation between TAT! and the severityof Pifi,increased concentrationof TAT! seemed to predict tubal damage observed at second laparoscopy. This suggeststhat acute-phaseTAT! reflects tissue damage caused by severe inflammation, presumably associated with disruption of the basement membrane. Thus, healing of the inflammation by fibrosis might be more common in TATI-positive than in TATI-negative cases. However, larger prospective studies are needed to find out whether an increase in TAT! during the acute episode is a marker ofpermanent tubaldamage.

This study was supported by grants from the Emil Aaltonen Foundation (M.L.), from the Sigrid Juselius Foundation and the Finnish Cancer Society (U.-HS.), and from the Medical Research Council, Academy of Finland (J.P. and U.-H.S.).

References 1. Lehtinen M, Lame S, HeinonenPK, et al.Serum C-reactive protein determination in acute pelvic inflammatory disease. Am J Obstet Gynecol 1986;154:158-9. 2. Paavonen J, Miettinen A, Heinonen PK, et al. Serum CA 125 in acute pelvicinflammatory disease.Br J Obstet Gynecol 1988;57:304-7.

3. Stenman U-H, Huhtala M-L, Koistinen R, et al. Immunochemical demonstration of an ovarian cancer-associated urinary peptide. hit J Cancer 1982;30:53-7. 4. Huhtala M-L,PesonenK, KalkkinenN, et a!. Purification and characterization ofa tumor-associated trypsin inhibitor from the urine of a patient with ovarian cancer. J Biol Chem 1982;257:13713-6. 5. Halila H, Huhtala M-L, Schroder T, et al. Pancreatic secretory trypain inhibitor-like immunoreactivity in pancreatectomized patients. Clin Chim Acts 1985;153:209-16. 6. Halila H, Huhtala M-L, Haglund C, et al. Tumor-associated trypsin inhibitor (TAT!) in human ovarian cyst fluid. Comparison with CA 125 and CEA. Br J Cancer 1987;56:153-6. 7. Haglund C, Huhtala M-L, Halila H, et al. Tumor-associated trypsin inhibitor, TAT!, in patients with pancreatic cancer, pancreatitis and benign biliary disease. Br J Cancer 1986;54:297-303. 8. Huhtala M-L, Kahanpaa K, Seppala M, et a!. Excretion of tumor associated trypsin inhibitor (TAT!) in urine of patients with gynecological malignancy. hit J Cancer 1983;31:711-4. 9. Paavonen J, Teisala K, Heinonen PK, et al. Microbiological and histopathological findings in acute pelvic inflammatory disease. Br J Obstet Gynecol 1987;94:454-60. 10. Paavonen J, Aine R, Teisala K, et al. Chlamydial endometritis.

J Clin Pathol 1985;38:726-32. 11. Jacobson L, Westr#{233}m L Objectivized diagnosis ofacutepelvic inflammatory disease. Am J Obstet Gynecol 1969;105:1088-95.

12. Harmoinen A, Perko M, GrOnroos P. Rapid quantitative determination of C-reactive protein using LKB 8600 reaction rate analyzer. Clin Chim Acts 1981;111:117-20. 13. NiloffJM, Knapp RC, Schaetzl E, et al. CA 125 antigen levels in obstetric and gynecologic patients. ObstetGynecol 1984;84:703-7. 14. Barbieri RL, Niloff JM, Bast Jr RC, et al. Elevated serum concentrations of CA 125 in patients with advanced endometriosis. Fertil Steril 1986;45:630-4. 15. Halila H, Stemnan

U-H, Seppala M. Ovarian antigen CA 125

levels in pelvic inflammatory disease and pregnancy. Cancer 1986;57:1327-9. 16. Halila H, Lehtovirta P, Stenman U-H. Tumor-associated trypsin inhibitor (TAT!) in ovarian cancer. Br J Cancer (in press). 17. Canney PA, Moore M, Wilkinson PM, et al. Ovarian cancer antigen CA 125. A prospective clinical assessment of its role as a tumor marker. Br J Cancer 1986;50:765-9. 18. Wasserheit J, Bell T, Kiviat N, et a!. Microbial causes of proven pelvic inflammatory disease and efficacy of clindamycin and tobramycin. Ann Intern Med 1986;104:187-93. 19. Jacobson L, Laurell C-B, Gennser G, et a!. Plasma protein changes induced by acute inflammation of the fallopian tubes. hit J Gynecol Obstet 1975;13:249-56. 20. Hemila M, Henriksson L, Ylikorkala 0. Serum CRP in the diagnosis and treatment of pelvic inflammatory disease. Arch Gynecol Obstet 1987;241:1977-82. 21. Dinarello CA. Interleukin-1 and the pathogenesis of the acutephase response. N Eng! J Med 1984;311:1413-8. 22. Perlmutter DH, Dinarello CA, Punsai P1, Colten HR. Cachectin/tumor necrosisfactor regulates hepatic acute phase gene expres-

sion. J Clin hivest 1986;78:1349-54. 23. Paavonen J, Lame S, Aaran R-K, et al. Comparison of serum CA 125 and CRP determinations in predicting the severity of acute pelvic inflammatory disease. hi: Montorri M, Granelli P, eds. Proc. XXVIII World Congress of hit. College of Surgeons, Bologna: Monduzzi Ed., 1988:493-6. 24. KojA, Kurdowska A, Magielska-Zero D, eta!. Limited effects of recombinant human and murme interleukin 1 and tumor necrosis factor of production of acute phase proteins by cultured rat hepatocytes. Biochem hit 1987;14:553-60.

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Lactate Dehydrogenase Isoenzyme Patterns in Serum of Patients with Metastatic Liver Disease Z.

I.Welnberger, E. Davidson, J. Fuchs, D. HarelI,1 and J. Agmon2

ROtenberg,

Total lactate dehydrogenase (LD, EC 1.1.1.27) and LD isoenzymes were determined in serum of 170 patients with metastatic liver disease, 35 of whom had multiple metastatic sites. Overall, values of LD were above normal for 78% of the 170 patients. Half of the patients had an isomorphic pattern of LD isoenzymes (i.e., relative increase in all five isoenzymes); the other half had an increased LD-4,5 pattern, mostly a solitary increase in LD-5 only. Of those patients with normal LD values, 92% had the increased LD-4,5 pattern, whereas 70% of patients with LD values >350 U/L had an isomorphic pattern of LD isoenzymes. All 35 patients with

ofMedicine “A” and theIsrael and loneMassada CenterforHeartDisease, and ‘Clinical Biochemistry Laboratory, Beilinson Medical Center, Petah Tikva, and the Tel Aviv University Sackler School ofMedicine, TelAviv,Israe!. 2Address correspondence to this author at: Massada Center for Department

Heart

Diseases,

Beilinson

Medical

Center, Petah Tikva 49100,

Israel. Received

December

5, 1988; accepted February

6, 1989.

multiple metastatic sites had LD activity >350 U/L; in the majority of them (74%) it was >500 U/L; in 31(89%), the increase was isomorphic. The diagnostic efficiency of the combined LD >225 U/L (upper limit of normal) and increased LD-4,5 test results was much better than that of LD >225 U/L alone (93% vs 74%). We conclude that serum LD and LD isoenzymes should be determined in every patient with suspected liver metastatic disease. The isomorphic pattern of LD isoenzymes is apparently associated with higher values for total LD and was common among the patients with multiple metastatic sites. Additional Keyphrases: cancer nostic efficiency

multiple metastases

.

diag-

Lactate dehydrogenase (LD, EC 1.1.1.27), one of the glycolytic enzymes, catalyzesthe reversiblereductionof pyruvate to lactate in the glycolytic cycle(1). The observation(2-4) that many tumors utilize glucose through the anaerobicpathway and generatea considerable amount of

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