Dose response characteristics and basic dose ... - BIR Publications

The British Journal of Radiology, 73 (2000), 58±65

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2000 The British Institute of Radiology

Dose response characteristics and basic dose distribution data for a polymerization-based dosemeter gel evaluated using MR Ê J BAÈCK, PhD, P MAGNUSSON, MSc and L E OLSSON, PhD P HARALDSSON, MSc, S A Department of Radiation Physics, Lund University, MalmoÈ University Hospital, SE-205 02 MalmoÈ, Sweden

Abstract. A safe and reproducible mixing procedure for the manufacture of a polymerizationbased dosemeter gel evaluated using MRI (PoMRI) is presented. The dose response, obtained by irradiating gel-®lled vials with absorbed doses in the interval 0±20 Gy and evaluated with respect to 1/T2, was found to be linear in the interval 0±8 Gy, with a sensitivity of 0.211 s21Gy21 (r250.998) at 1.5 T. Evaluation of the same set of vials with respect to 1/T1 gave a sensitivity of 0.018 s21Gy21 (r250.960). PoMRI and diode data were compared for standard photon and electron treatment beams. A deviation of less than 3% was found between the two methods for central depth dose curves as well as dose pro®les (2 mm for electrons in the steep dose gradient regions). The importance of the method used for background correction for the reliability of the results was also evaluated. BarexH (with a wall thickness of 1.5 mm) was investigated for use as phantom material and found to be favourable compared with glass. The results obtained in this study show that PoMRI has excellent potential as a 3D detector. Recent progress in radiation therapy is characterized by an increasing complexity in treatment techniques (e.g. dynamic wedge, use of multileaf collimators and stereotactic treatment). Accordingly, there is a great need for a system that is able to measure dose distributions in three dimensions, as this is dif®cult using conventional methods. Gel dosimetry, in combination with MRI, is a system with this potential [1]. The method was ®rst suggested in 1984 [2] when the NMR relaxation rate, by means of 1/T1, was shown to be linearly correlated with the amount of ferric (Fe3+) ions produced by irradiation of a ferrous (Fe2+) solution. The ferrous-based method (FeMRI) has since been developed into a useful tool for clinical dosimetry in radiation therapy [3± 5]. However, diffusion of ions tends to alter the dose distribution over time [3], which may be a limitation for this kind of gel. A new type of gel has been suggested [6±8], in which localized polymerization of monomers is initiated by irradiation. The NMR relaxation rate of the neighbouring water protons, measured preferably by means of 1/T2, is increased in proportion to the absorbed dose. This polymer gel can, in analogy with FeMRI, be evaluated using MRI (PoMRI). PoMRI has certain advantages over FeMRI, e.g. there is no diffusion leading to deterioration of the localized polymer structure formed by Received 11 December 1998 and in revised form 8 July 1999, accepted 23 July 1999. 58

irradiation and there is a higher sensitivity [7]. In addition, the gel becomes increasingly opaque with increasing absorbed dose, enabling optical evaluation as well as visual inspection [7, 9]. The drawbacks of this otherwise promising PoMRI gel include the complicated mixing procedure and the toxicity of the chemicals. Photopolymerization of the monomers must be prevented and oxygen must not be present in the ®nal gel since it works as a ``desensitiser'' for the polymerization procedure, leading to dose responses that are not linear from 0 Gy [7, 8]. At present, only Maryanski et al [7] and Oldham et al [10] have presented dose responses that are linear from 0 Gy. It has been shown for FeMRI that when complex dose distributions are compared with other detectors and dose planning systems, the actual source of an obtained deviation is hard to identify [5, 11]. Accordingly, to use PoMRI for complex radiotherapy schemes, it is necessary to ®rst investigate the performance in basic geometries. So far, interest for investigations of basic radiation beam data has not been large. Only three central depth dose curves have been presented in the literature (one for the type of polymer gel used in this work [7] and two for another composition of polymer gel [12]) and no dose pro®les at all. In addition, it is not clear how to perform optimal MRI measurements for PoMRI, for example the background subtraction technique used for FeMRI [13, 14] must be evaluated. The British Journal of Radiology, January 2000

Basic investigations of PoMRI for dose measurements

Glass is the material most often used for phantoms, since the majority of plastic materials dissolve oxygen and slowly release it into hypoxic media [7]. A problem with glass is that its wall thickness is usually too thick for the dose build-up region to be studied in applications with external beams. The aim of this study was to investigate the dose response characteristics for PoMRI with respect to oxygen contamination, chemical purity of the ingredients used and magnetic ®eld strength. A reproducible and safe mixing procedure for PoMRI was also developed. In order to investigate detailed depth dose data of PoMRI, measurements were performed in standard treatment beams for photons and electrons and compared with corresponding diode data. The properties of BarexH as phantom material were investigated and a method for background subtraction was also evaluated.

Materials and methods Mixing procedure During the entire mixing procedure care must be taken to ensure that no oxygen is present in the ®nal gel, as oxygen inhibits polymerization [7, 8]. Special care must also be taken because of the highly toxic monomers used. The method used for the manufacture of PoMRI gel was a slightly modi®ed form (with respect to temperature and the amount of ingredients used) of the ones suggested by Maryanski et al [7] and Baldock et al [8]. Redistilled water (88.5%) was purged with nitrogen gas (N2) to remove oxygen before addition of gelatine (5.5%), which was melted by heating the water to 55 ÊC. The thermostat was then turned down to 45 ÊC and when that temperature was reached the co-monomers (acrylamide 3%, and BIS-acrylamide 3%) were added. Equipment for the gel preparation consisted of a Pyrex ¯ange ¯ask with openings in which a thermometer, a steam condenser and a Pyrex tube with a ®tted glass ending for a continuous ¯ow of N2 into the ¯ange ¯ask were placed. There was also an opening through which ingredients were added. The ¯ange ¯ask was placed in a heat basket whose power supply was controlled by a thermostat. A magnetic stirrer with an independent power supply was incorporated into the bottom plate. During the whole mixing procedure, N2 was allowed to ¯ow into the ¯ange ¯ask. Before addition of the co-monomers, the ¯ange ¯ask was wrapped in a light-proof cover to prevent photopolymerization. When the co-monomers were completely dissolved, N2-®lled glass vials, The British Journal of Radiology, January 2000

2 cm in diameter and 5 cm in height (Amersham, Sweden), or a cylindrical glass container, 11 cm in diameter and 15 cm in height, were ®lled with the gel. The container was ®lled via a short tube connecting the ¯ange ¯ask to the container. It was ¯ushed with N2 10 min before, during and up to 1 h after ®lling, to ensure that no oxygen was present in the ®nal gel. To examine the signi®cance of the method of ®lling the vials with gel, different procedures were evaluated. The method that proved most reliable for preventing oxygen contamination was to ®ll the N2-®lled vials with a syringe (inserted through the rubber stopper) in a N2-®lled glove box, into which the whole ¯ange ¯ask was placed when the mixing procedure was complete. After ®lling, the vials and container were left to cool overnight in a light-proof box, stored in a refrigerator. To investigate which gelatine powder and comonomers to use, different brands and purities were studied: gelatine: Sigma±Aldrich, MalmoÈ, Sweden, and Merck, Dramstedet, Germany; comonomers: purity .99.9%, ICN, Biomedicals, Inc., OH, USA, and purity .98%, KEBO lab, SpaÊnga, Sweden.

Dose response evaluation Irradiation Dose response was investigated by irradiating the vials with absorbed doses ranging from 0 to 20 Gy. The vials were irradiated from the side (270 Ê) using a 10 MV photon beam produced by a linear accelerator (Elekta SLi, Sweden). During irradiation the samples were placed at the depth of dose maximum in a water-®lled phantom, the ®eld size was rectangular (10 cm620 cm) and the source-to-surface distance (SSD) was 100 cm. After irradiation the vials were placed in the light-proof box again and stored for at least 12 h at room temperature (22 ÊC) to ensure that all chemical reactions within the gel were completed before MR evaluation. MR evaluation The dose response has been shown to be affected by temperature during MR evaluation [7, 15]. All vials and containers were therefore placed in the MR room at least 8 h prior to evaluation to ensure a uniform temperature throughout the gel volume. Irradiated vials were evaluated using a Praxis II Analyser (Praxis Corp., USA), a pulsed nuclear magnetic resonance (PNMR) analyser with a permanent magnet of 0.25 T (10.6 MHz). This evaluation was carried out with respect to 1/T2 as well as 1/T1. T2 was measured using a 90 Ê±180 Ê sequence (Hahn echo) and T1 using a 90 Ê±90 Ê 59

P Haraldsson, S AÊ J BaÈck, P Magnusson and L E Olsson

sequence (saturation recovery) [16]. The relaxation curve was obtained by varying the time between two radiofrequency pulses. The total number of acquisitions was 32, with a time interval between acquisitions denoted as step time, and for all measurements the number of excitations was four. For the T2 measurements, a repetition time (TR) of 12 s and a step time of 0.6 ms was used. The corresponding values for the T1 measurements were 6 s and 20 ms. For the purpose of investigating the effect of different magnetic ®eld strengths on 1/T1 and 1/T2, the same set of vials was evaluated using an MRI system (Magnetom Vision, Siemens, Erlangen, Germany, 1.5 T, 63.6 MHz). T1 weighted images were obtained with an inversion±recovery turbo spin echo sequence (tir7229b130.ykc) with the following parameters: repetition time, 5000 ms; echo time, 29 ms; inversion times, 100±3000 ms. The ®eld of view was chosen to be 300 mm6300 mm for a 2566256 matrix, resulting in a pixel size of 1.17 mm61.17 mm. The T1 values of the samples were calculated from regions of interest by an iterative least-squares ®t using MicrosoftH ExcelTM. T2 weighted images were obtained as when evaluating the phantoms (see section on MRI evaluation below). The dose response of the gel (1/T2 and 1/T1 vs absorbed dose, (s21Gy21)) was obtained as the slope given by a linear ®t to the data in the linear region.

Depth dose and pro®le evaluation Irradiation To obtain depth dose and pro®le data, the containers were irradiated through the bottom using a single square beam of photons (4 cm64 cm, 10 MV) or electrons (6 cm66 cm, 15 MeV), both produced by a linear accelerator (Elekta SLi, Sweden). The SSD was 100 cm and the delivered absorbed dose 8 Gy at dose maximum. As for the vials, the phantoms were placed in a light-proof box after irradiation and stored for at least 12 h before MR evaluation. The central depth dose curves and dose pro®les obtained were compared with corresponding diode data (p-Si ®eld semiconductor, Scanditronix, Uppsala, Sweden) measured using a three-dimensional radiation ®eld analyser (RFA-300, Scanditronix, Uppsala, Sweden). In photon beams, depth doses obtained from a semiconductor tend to be overestimated. The diodes from Scanditronix are shielded with a tungsten/epoxy mixture to capture low energy back-scattered photons, which results in an energy-compensated photon detector, giving 60

readings that agree with those obtained from the Nordic Association of Clinical Physics (NACP) ionization chamber within ¡1% [17]. The 5 mm entrance window of the gel container was scaled to an equivalent thickness of water using the linear attenuation coef®cient for the photon applications [18] and the continuous slowing down range for the electron applications [19]. Phantom material The vials and containers were made of glass as most plastic materials dissolve oxygen and release it slowly into hypoxic media [7], which is undesirable. In containers made of glass, the wall is often too thick for the dose build-up region to be studied. Therefore, for one application we used a box (10 cm64 cm610 cm) made of BarexH (with a wall thickness of 1.5 mm, BP chemicals, UK) to investigate its properties as a phantom material. The BarexH box was ®lled with gel in the same manner as the glass phantoms. It was irradiated with a single square beam of electrons (6 cm66 cm, 10 MeV). The SSD was 100 cm and the delivered absorbed dose 8 Gy at dose maximum. Owing to the small size of the box, it was placed in a water tank to ensure lateral electron equilibrium. The depth dose curve was compared with corresponding diode data. The 1.5 mm thick bottom of the gel phantom was scaled to an equivalent thickness of water using the mass density of BarexH (r51150 kg m23), as no continuous slowing down range is available for this material. MRI evaluation The phantoms were evaluated in the head coil using an MRI system (Magnetom Vision, Siemens, Erlangen, Germany, 1.5 T, 63.6 MHz). A T2 multi-echo sequence (se_16_360b130.wkc) modi®ed from 16 to 32 echoes was used. TR was always >3000 ms, TE522.5±720 ms and the interecho time 22.5 ms. The ®eld of view chosen was 256 mm6256 mm for a 2566256 matrix, resulting in a pixel size of 1 mm61 mm. A slice width of 5 mm was chosen in order to ensure a high signal-to-noise ratio (SNR). T2 calculations were carried out using the in-house developed software PMRelax v3.0 (Dept of Radiation Physics, MAS, MalmoÈ, Sweden). The 1/T2 image obtained was background corrected (see next section) and normalized to 100% at the depth of dose maximum. Non-uniformity To study the non-uniformity of the 1/T2 images, and on the basis of this decide whether background subtraction was necessary, one gel®lled container was evaluated in the transverse, The British Journal of Radiology, January 2000


sagittal and coronal direction prior to irradiation. MRI parameters were the same as for the other evaluations, T2 calculations were carried out using PMRelax v3.0. The non-uniformity test in the 1/T2 images obtained was also carried out using PMRelax, where the non-uniformity is given as the mean deviation in per cent from a reference point at the origin of the MRI scanner's coordinate system. Stability To investigate the stability of the radiationinduced changes in the gel, one phantom was evaluated at repeated occasions (within a week after irradiation) using the same MRI conditions.

Results Mixing procedure The dose response was found to be linear from 0 Gy and reproducible when the vials were ®lled in a N2-®lled glove box and co-monomers of ultra pure grade .99.9% (ICN, Biomedicals, Inc., OH, USA) were used (Figure 1). Typical results with oxygen contamination or chemical impurities showed a dose response that was not linear from 0 Gy (Figure 2). The gelatine chosen was acid-derived (300 Bloom, Sigma±Aldrich, MalmoÈ, Sweden) as the gel was then completely transparent before irradiation.

Dose response evaluation The gel became visually more opaque with increasing absorbed dose, up to a saturation level of about 10 Gy. The dose response in the interval 0±8 Gy was found to be 0.232 s21Gy21 for 1/T2 (with a correlation coef®cient r250.993) and

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Figure 2. Typical results of 1/T1 (u) and 1/T2 ( ) vs absorbed dose for gel preparations with oxygen contamination or chemical impurities. Evaluation was performed using a PRAXIS analyser.

0.045 s21Gy21 for 1/T1 (r250.997) (Figure 1), evaluated using the PRAXIS analyser (0.25 T). Evaluation of the same set of vials using MRI (1.5 T) gave a dose response of 0.211 s21Gy21 for 1/T2 (r250.998) (Figure 1) and 0.018 s21Gy21 for 1/T1 (r250.960). Subsequent MR evaluations were carried out with respect to 1/T2 as this parameter was more sensitive to the absorbed dose than 1/T1.

Depth dose and pro®le evaluation For the photon beam (10 MV), both the central depth dose curve and the dose pro®le obtained with PoMRI were compared with diode measurements (Figures 3 and 4), after normalization to 100% at the depth of dose maximum. PoMRI data were obtained using an averaged spatial resolution of three pixel rows or columns (i.e. 3 mm) in the absorbed dose image (rows for the depth doses and columns for the dose pro®les). PoMRI measurements were found to be in good agreement with diode measurements, with a deviation of less than 3% for the central depth

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Figure 1. 1/T1 (u) and 1/T2 ( , m) vs absorbed dose for gel preparations using co-monomers with a purity of .99.9%. The vials were ®lled in a N2-®lled glove box and the evaluation performed using two different MR systems: PRAXIS analyser (u, ) and MRI (m). The slope of the linear region (0±8 Gy) for 1/T2 is 0.232 s21Gy21 (r250.993) using the PRAXIS analyser and 0.211 s21Gy21 (r250.998) using MRI.

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The British Journal of Radiology, January 2000

Figure 3. Central depth dose curve for a 10 MV photon beam (4 cm64 cm, SSD5100 cm) measured with PoMRI ( ) and diode (2). The curves were normalized at the depth of dose maximum. An MRI evaluation, prior to irradiation, was used for the background subtraction.

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Figure 4. Dose pro®les at the depth of dose maximum (top) and at 5 cm (below) for a 10 MV photon beam (4 cm64 cm, SSD5100 cm) measured with PoMRI ( ) and diode (2). The curves were normalized at the depth of dose maximum. An MRI evaluation prior to irradiation was used for the background subtraction.

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Figure 6. Dose pro®les at the depth of dose maximum for a 15 MeV photon beam (6 cm66 cm, SSD5100 cm) measured with PoMRI ( ) and diode (2). The curves were normalized at the depth of dose maximum. The phantom material was glass.

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Non-uniformity The non-uniformity in the three different planes differed slightly. The transverse plane had the lowest non-uniformity level, with a mean

deviation from the reference point of 1.6% (maximum of 8%, positioned near the corners). For both the sagittal and coronal planes the corresponding value was 2% (maximum 8%). As the non-uniformity level was lowest (i.e. the best) in the transverse direction, all evaluations in this study were done in this plane. For the phantom irradiated with photons, an MR evaluation prior to irradiation was used for the background subtraction. This was performed by a pixel by pixel subtraction of the 1/T2 image of the background phantom from the 1/T2 image of the irradiated phantom. When, in the case of photons, a background offset value in the image after irradiation was used rather than pixel by pixel subtraction from an MR evaluation prior to irradiation, it was found that the absorbed dose was overestimated at larger depths (Figure 8). For the phantoms irradiated with electrons, the dose distribution was in the area with the lowest non-uniformity level (¡1%). A pixel by pixel subtraction was therefore not needed, and a background offset value measured in the nonirradiated area of the 1/T2 image was subtracted from the 1/T2 image instead.

Figure 5. Central depth dose curve for a 15 MeV electron beam (6 cm66 cm, SSD5100 cm) measured with PoMRI ( ) and diode (2). The curves were normalized at the depth of dose maximum. The phantom material was glass.

Figure 7. Central depth dose curve for a 10 MeV electron beam (6 cm66 cm, SSD5100 cm) measured with PoMRI ( ) and diode (2). The curves were normalized at the depth of dose maximum. The phantom material was BarexH.

dose curve as well as the dose pro®le (2 mm in the steep dose gradient regions). Data for the electron beams (10 and 15 MeV) were compared with diode data in the same way as for the photons (Figures 5±7), also with a spatial resolution of three pixel rows or columns. For the application with the BarexH phantom, no dose pro®le was obtained owing to the large ®eld used in comparison with the size of the box. Normalization to 100% was carried out at the depth of dose maximum. For both energy levels a deviation of less than 3% was found between PoMRI and diode. In the steep dose gradient regions, the PoMRI data were within 2 mm of the diode data. The properties of BarexH as phantom material seem to be good, since no tendency towards inhibited polymerization was observed (Figure 7).

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Figure 8. Central depth dose curve for a 10 MV photon beam (4 cm64 cm, SSD5100 cm) measured with PoMRI ( , u) and diode (2). Comparison between a background offset value subtracted from the 1/T2 image (u), and when an MR evaluation prior to irradiation was used for a subsequent pixel by pixel subtraction ( ). The difference in relative absorbed dose between PoMRI and diode in the case of the background offset value method (n) and the pixel by pixel subtraction method (m) is given on the right hand y-axis.

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Stability The container repeatedly evaluated with MRI (within a week) after irradiation showed that the radiation-induced changes were stable. The maximum deviation in relative absorbed dose in each point between the measurements was less than 3% (standard deviation51.0%). After a couple of weeks, however, crystals formed in some of the containers.

Discussion A linear dose response from 0 Gy was obtained when the vials were ®lled in a N2-®lled glove box and co-monomers of ultra pure grade were used. If there was oxygen contamination during vial ®lling and co-monomers of lower purity were used, the dose response was linear from approximately 1 Gy instead of 0 Gy. The method of ®lling the gel into vials or phantoms seems to be a very critical step concerning oxygen, which works as a ``desensitiser'' for the polymerization if present in the gel [20]. Some oxygen may get in when ingredients are added, but should be removed by the N2 supplied during the whole mixing procedure. Since areas of inhibited polymerization were not observed in the phantoms, it was assumed that the method of ®lling phantoms with gel via a short tube connecting the container with the ¯ange ¯ask was successful. In the case of the vials, ®lling in a N2-®lled glove box is recommended, as it is the safest method considering both oxygen contamination and gel sprinkling. It is obvious that the purity of the ingredients is important. It has been noted earlier that small amounts of impurities may cause effects such as a The British Journal of Radiology, January 2000

dose response that is not linear from 0 Gy (C Baldock, personal communication, 1997). It is assumed that the impurities are consumed by the irradiation-initiated reactions before polymerization can start. The gelatine chosen was acidderived as the gel was then found to be completely transparent before irradiation, and the visual aspects therefore most outstanding. A dose response of 0.21 s21Gy21 in the interval 0±8 Gy was found, when evaluated with respect to 1/T2 (1.5 T), for the polymer gel described in this study. A similar relationship was presented by Maryanski et al [7] (0.25 s21Gy21 when evaluated with respect to 1/T2, 1.5 T). The dose response presented by Oldham et al [10] is not comparable, as the composition of their polymer gel was not the same as the one used in this work. Baldock et al [8] obtained a dose response of 0.0285 s21Gy21 in the interval 2±10 Gy, when evaluated with respect to 1/T1 (0.5 T). Our value for 1/T1 was 0.045 s21Gy21, which was for the interval 0±8 Gy and evaluated at 0.25 T. Both the slope (slightly) and intercept decrease with increasing magnetic ®eld strength (Figure 1). Maryanski et al [6] have found the opposite relationship between 1/T2 and magnetic ®eld strength for polymer gel. Factors that may explain the difference between our results and those of Maryanski et al are different gel types and temperatures during evaluation [7, 15, 22]. For the central depth dose curves as well as the dose pro®les, there was close agreement between PoMRI and diode measurements for both photons and electrons (less than 3%). In the steep dose gradient regions there was a discrepancy between PoMRI and diode data of up to 2 mm. Similar studies carried out by Maryanski et al [7] showed discrepancies of the same order of magnitude. No areas of inhibited polymerization were observed when using BarexH as a phantom material. This makes BarexH (available in a thickness of f1.5 mm) preferable as phantom material when studying dose build-up regions and dose distributions near the entrance window compared to the glass phantoms used today, which have thicker walls and higher mass density. In addition, BarexH may be moulded into any shape. To obtain accurate dose maps, the nonuniformity of the MRI system is an important factor [14]. The preliminary non-uniformity test performed in this study showed that for certain applications the absorbed dose was overestimated at larger depths when a background offset value was subtracted from the T2 image. When the dose distribution covers a larger area, exceeding the 63


boundaries of the lowest non-uniformity level (¡1%), it may therefore be of importance to perform a pixel by pixel background subtraction to get reliable results. Our result showed that the ®nal polymer formed by irradiation is stable and does not diffuse over time, which makes it possible to carry out the evaluation on a later occasion. The same observations have been made by other authors [7, 10, 12]. However, since we observed that crystals were formed in some containers a couple of weeks after irradiation, we recommend that the MR evaluation is carried out within a week after irradiation.

Conclusion In this study we describe a safe mixing procedure regarding the toxic ingredients used, and a dose response that is reproducible and linear from 0±8 Gy. For central depth dose curves as well as for dose pro®les, a deviation of less than 3% (2 mm in the steep dose gradient regions) was found between PoMRI and corresponding diode data. A simple background subtraction technique for correction of the non-uniformity of the MRI system was evaluated. Background subtraction was found to be necessary to obtain reliable dose distribution data for applications where the dose distribution covers an area large enough to exceed the boundaries of the lowest non-uniformity level (¡1%).

Acknowledgments This work was supported by the Swedish Cancer Foundation (project number 2349-B9709XAB), the Cancer Foundation of MalmoÈ University Hospital and the Crafoord Foundation (project number 980809). The valuable discussions about gel preparation with Dr C Baldock are also acknowledged.

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