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Patient-specific dosimetry of 99mTc-HYNIC-Tyr3-Octreotide in children Hou, Xinchi; Birkenfeld, Bozena; Piwowarska-Bilska, Hanna; Celler, Anna Oct 13, 2017

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ORIGINAL RESEARCH Open AccessPatient-specific dosimetry of 99mTc-HYNIC-Tyr3-Octreotide in childrenXinchi Hou1, Bozena Birkenfeld2, Hanna Piwowarska-Bilska2 and Anna Celler1** Correspondence:aceller@phas.ubc.ca1Medical Imaging Research Group,Department of Radiology, Universityof British Columbia, 828 West 10thAvenue, Rm 366, Vancouver, BCV5Z1L8, CanadaFull list of author information isavailable at the end of the articleAbstractBackground: Technetium-99m-hydrazinonicotinamide-Tyr3-octreotide (99mTc-HYNIC-TOC)is recognized as a promising radiopharmaceutical for diagnosing neuroendocrinetumors (NETs). However, 99mTc-HYNIC-TOC dosimetry has been investigated only foradults. As pediatric radionuclide therapies become increasingly common, similardosimetric studies for children are urgently needed. The aim of this study is to reportpersonalized image-based biodistributions and dosimetry evaluations for childrenstudies performed using 99mTc-HYNIC-TOC and to compare them with those fromadult subjects.Eleven children/teenage patients with suspected or diagnosed NETs were enrolled.Patient imaging included a series of 2–3 whole-body planar scans and SPECT/CTperformed over 2–24 h after the 99mTc-HYNIC-TOC injections. The time-integratedactivity coefficients (TIACs) were obtained from the hybrid planar/SPECT technique.Patient-specific doses were calculated using both the voxel-level and the organ-levelapproaches. Estimated children doses were compared with adults’ dosimetry.Results: Pathologic uptake was observed in five patients. TIACs for normal organswith significant uptakes, i.e., kidneys, spleen, and liver, were similar to adults’ TIACs.Using the voxel-level approach, the average organ doses for children were 0.024 ± 0.009, 0.032 ± 0.017, and 0.017 ± 0.007 mGy/MBq for the kidneys, spleen, and liver,respectively, which were 30% larger than adults’ doses. Similar values were obtainedfrom the organ-level dosimetry when using OLINDA with adapted organ masses.Tumor doses were 0.010–0.024 mGy/MBq. However, cross-organ contributions weremuch larger in children than in adults, comprising about 15–40% of the total organ/tumor doses. No statistical differences were found between mean doses and dosedistributions in patients with and without pathologic uptakes.Conclusion: Although the children TIACs were similar to those in adults, their doseswere about 30% higher. No significant correlation was found between the children’sdoses and their ages. However, substantial inter-patient variability in radiotracer uptake,indicating disparity in expression of somatostatin receptor between different patients,emphasizes the importance and necessity of patient-specific dosimetry for clinicalstudies.Keywords: Pediatric patient-specific dosimetry, 99mTc-HYNIC-Tyr3-octreotide, SPECT/CT,Neuroendocrine tumorsEJNMMI Physics© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 InternationalLicense (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, andindicate if changes were made.Hou et al. EJNMMI Physics  (2017) 4:24 DOI 10.1186/s40658-017-0191-6BackgroundSomatostatin receptor scintigraphy (SSRS) has been identified as an efficient diagnostictechnique for localizing and staging neuroendocrine tumors (NETs) which overexpresssomatostatin receptors [1, 2]. The benefits of using SPECT and PET for diagnostic im-aging of NETs are already well recognized. Currently, the most popular tracers used forNETs diagnosis are 99mTc-hydrazinonicotinamide-Tyr3-octreotide (99mTc-HYNIC-TOC)and 111In-diethylenetriaminepentaacetic acid (DTPA)-octreotide for SPECT [1, 3, 4]and 68Ga-DOTA-conjugated peptides for PET [5–9]. Although PET/CT imaging using68Ga-DOTA-conjugated peptides has been shown to have high diagnostic accuracy andlow radiation exposure [10, 11], limited availability of PET cameras worldwide mayrestrict its clinical use. On the other hand, SPECT, and also planar scintigraphy, remainthe most popular nuclear medicine imaging techniques. Considering the SPECT tracersmentioned above, 99mTc-HYNIC-TOC results in better image quality and lower radi-ation dose than 111In-labeled pharmaceuticals [10, 12, 13]. Additionally, 99mTc-HYNIC-TOC can be obtained using a simple, single-vial kit formulation [14] which makes itespecially advantageous for use in centers with limited resources [15]. Finally, labelingwith technetium makes this tracer more readily available and less expensive thantracers labeled with 68Ga.The incidence of NETs is rather low in the adult population and even lower inchildren. Recently, however, its rate is steadily increasing [16–18]. The SSRS studies areoften used not only for the initial diagnosis and localization of the disease, but also forthe therapy follow-up or diagnosis of the disease recurrence. Hence, information aboutradiation exposure, be it due to single administration or to repeated procedures, is veryimportant, especially in children.Since 99mTc-HYNIC-TOC diagnostic studies provide information about this radio-tracer uptake and biodistribution, evaluation of its uptake in organs at risk (OAR) canpredict potential toxicities. At the same time, this information may be used in radio-nuclide therapy planning, because its uptake in tumors is proportional to the intensityof somatostatin receptor expression in tumor cells, thus it may indicate potential effect-iveness of the treatment.Additionally, using the theranostic approach, the dose calculated for diagnosticisotope can be used to predict that which will be delivered when the diagnostic agent isreplaced by the therapeutic one, (labeled with a beta-emitting radioisotope). Theseconsiderations will apply to the 99mTc-HYNIC-TOC imaging studies. Quantification ofits uptake and biodistribution in tumors and OARs can be used in 99mTc-HYNIC-TOCdosimetry calculations and at the next stage to predict doses which will be delivered bypeptide receptor therapy agents such as DOTA-TATE or DOTA-TOC labeled with177Lu or 90Y. Although this procedure involves pharmaceuticals which are not identical,recent studies comparing pre-therapy biodistributions of 99mTc-HYNIC-TOC and68Ge-DOTA-TATE with that of post-therapy of 177Lu-DOTA-octreotate support thevalidity of this approach [15].Currently, only limited radiation dosimetry information is available for 99mTc-HYNIC-TOC. The earliest dosimetry study, published in 2006 by Gonzalez-Vazquez etal., determined absorbed radiation doses for eight patients using a two-dimensionaldosimetry protocol based on five whole-body scans [19]. In 2011, our group reportedpatient-specific dosimetry calculations for 99mTc-HYNIC-TOC based on a larger studyHou et al. EJNMMI Physics  (2017) 4:24 Page 2 of 13of 28 subjects [20]. A hybrid imaging protocol, including single SPECT/CT combinedwith a series of whole-body planar scans was used. Additionally, a 3D Monte Carlodose estimation has been published by Momennezhad et al. in 2016 [21].All of these dosimetry studies were done only for adults. However, the absorbed doseestimates are especially important for children [18, 22]. This is because children havean increased risk of potential adverse health effects due to their higher sensitivity toradiation and longer life expectancy resulting in increased opportunity for experiencingradiation-related cancers or cardiovascular and other non-cancer diseases [23].Additionally, due to their smaller body sizes and potential differences in radiotraceruptakes, dosimetry calculations performed for adult subjects may not be appropriatefor children. Finally, when considering the adult population, multiple studies haveshown significant dose differences between individual subjects [20]. Thus, similarpatient-specific dosimetry studies are needed for children.For these reasons, the importance of dosimetry for pediatric radionuclide diagnosticand therapeutic procedures [24, 25] and also for CT imaging [26] cannot beunderestimated. Currently, however, pediatric dosimetry calculations are limited to onlya few child models (OLINDA software allows only for dosimetry calculation fornewborn, 5, 10, and 15 years old) [27, 28].The objective of the present study is to improve this situation. To this end, we appliedthe same methods as were used in our personalized image-based dosimetry determinationfor 99mTc-HYNIC-TOC imaging studies in adult subjects, to process and analyze 12 data-sets from children’s studies. A hybrid planar/SPECT technique was employed to estimatethe cumulated activities and biodistributions [20]. Both voxel-level (voxel-S) and organ-level dosimetry approaches were used to evaluate tumors’ and normal organs’ doses.Comparison between children doses and those estimated for adults [20] was performed.MethodsPatient studiesEleven children/teenage patients (ages 2–17 years, 4 males and 7 females) withsuspected or diagnosed NETs were enrolled into this investigation, and a total of twelveimaging studies were performed. Table 1 lists these patients’ demographic information.All the patient imaging studies were performed at the Nuclear Medicine Department,Pomeranian Medical University, Szczecin, Poland.The injected activities ranged from 320 to 940 MBq. For each patient, a series of twoor three whole-body planar scans and a single SPECT/CT scan were performed withinthe 24-h time period after the injection. The majority of studies used a dual-headInfinia Hawkeye4 camera (GE Healthcare), while three whole-body planar scans wereperformed using a Nucline X-Ring/R camera (Mediso Medical Imaging Systems). Forthe SPECT/CT scans, 60 projections with 20 s/projection acquisition time werecollected over the 360° non-circular orbit. The projection matrices of SPECT scanswere 128 × 128 with 4.418-mm pixel size, while the matrices used for planar scans were256 × 1024 with 2.21-mm pixel size or 512 × 1024 with 2.88-mm pixel size. A low-dose CT was used to generate attenuation maps. Additionally, for one patient, a 30-min dynamic scan was performed to study pharmacokinetics of the radiopharmaceuti-cal uptake phase.Hou et al. EJNMMI Physics  (2017) 4:24 Page 3 of 13SPECT image reconstruction and quantificationSPECT images were reconstructed using the camera software with iterative ordered-subsets expectation maximization algorithm (OSEM) with 2 iterations and 10 subsets.The CT-based attenuation correction and Hann filter were included in the reconstruc-tion. Although no scatter correction was applied, the attenuation map was rescaled tothe broad beam values which indirectly corrected for scatter.In order to achieve accurate image quantification, camera calibration, necessary toconvert counts in the reconstructed image to activity, was performed using a pointsource and a planar acquisition. A 3-mL vial filled with 4.82 MBq of 99mTc was placedin air centrally between the two detectors. The camera sensitivity factor was deter-mined by averaging the value from the two detectors.Pharmacokinetics calculationsFor use in dosimetry calculations based on the hybrid planar/SPECT approach,first, the time-activity curves (TACs) for all organs with significant uptakes(kidneys, liver, spleen) and tumors were determined from a series of whole-body(WB) planar scans. The following segmentation method was used. For each ofthese organs/tumors, an oversized region of interest (ROI) was manually drawnin the first WB image (acquired < 3 h after injection). A threshold set at 50% ofa maximum pixel count in this ROI was then used to create a smaller 2D ROI50.Subsequently, this 2D ROI50 was registered to the entire sequence of the WBscans. Additionally, in order to perform geometrically based background subtrac-tion [20, 29], a small ROI in the background region adjacent to each investigatedorgan was drawn. For each ROI50, the TAC was generated by plotting the back-ground corrected mean-counts in this 2D ROI50 versus scan-time (hours afterinjection) and then fitting a mono-exponential curve to this data. From this pro-cedure, the organ and tumor TACs, expressed in relative units of counts perTable 1 Demographic information of children patients involved in this study, sorted by agePatient#Sex Age(year) Injected activity(MBq)Diagnosis1 M 2 320 Mediastinum 7-cm diameter NET2 F 7 4503 M 11 490 Right adrenal pheochromocytoma (only shown inSPECT/CT image)4-Aa F 12 5005 F 12 6004-Ba F 13 4506 F 13 480 Appendix NET, area of accumulation above the uterus7 F 14 600 MEN-1, head of the pancreas NET and lymph node accumulationon the left side8 M 14 9409 F 16 50010 F 16 60011 M 17 720 MEN-1, head of the pancreas insulinomaaPatient #4 had two scans done in the interval of one year, i.e., 4-A and 4-BHou et al. EJNMMI Physics  (2017) 4:24 Page 4 of 13hour, were obtained. Then, the effective and biological half-lives for each organwere determined.At the next stage, the time-integrated activity coefficients (TIACs) were generated byrescaling these TACs using absolute organ activities obtained from the quantitativelyreconstructed SPECT/CT images. For each organ and tumor, our dual iterative adap-tive thresholding method [20, 30] was used to determine this organ/tumor volume andactivity. This method uses a series of phantom experiments to generate two calibrationcurves. They provide the optimal thresholds, one for determining the true volume andthe other for determining the true activity of the hot object placed in a warm back-ground, as a function of the observed signal-to-background ratio of this object. Thevalue of the threshold depends on the image reconstruction method, thus it indirectlyaccounts for partial volume effects and, for objects larger than 12 mL, has been shownto not depend on the object size [30]. An example of kidney segmentation using thedual iterative adaptive thresholding method is shown in Fig. 1.Dosimetry calculationsFor each investigated organ and tumor, its mean dose and dose distribution (repre-sented by the cumulated dose-volume histograms—DVHs) were estimated using thevoxel-S approach. Similar to our previous dosimetry study of adult patients, the analysisof images and the dose calculations were performed using our in-house developed dos-imetry software JADA [31]. The matrices of voxel-S value were pre-calculated with theEGSnr DOSXYZnrc Monte Carlo program. The voxel array corresponded to a215 × 215 × 215 grid with voxel size of 4.418 mm, which was large enough for estima-tion of the cross-organ dose exchange between all the ROIs. More details about thisapproach can be found in [32]. Using this method, both self- and cross-organ doseswere studied.In parallel, the OLINDA 1.1 [28] dosimetry software was employed for organ-leveldosimetry. The TIACs for the main organs, i.e., kidneys, liver, and spleen, were deter-mined using the JADA software, whereas TIACs for the urinary bladder contents wereFig. 1 An example of the right kidney segmentation based on dual iterative thresholding method in SPECT(a) and CT (b). The activity threshold was set to 25% (yellow line), and the volume threshold was equal to36% (red line)Hou et al. EJNMMI Physics  (2017) 4:24 Page 5 of 13calculated using the voiding bladder model provided by OLINDA. Additionally, theTIACs for the remainder of the body were estimated by subtracting all TIACs of the in-vestigated organs from those corresponding to the whole body. Since OLINDA 1.1 pro-vides only models for children 1, 5, 10, and 15 years old, for each of our patients, thecalculations were performed using the model which was closest to his/her age. Organ-level dosimetry obtained from OLINDA with and without adjusted organ masses frompatients’ SPECT/CT images were studied. The doses for tumors were estimated basedon the OLINDA spherical model.Finally, the dose estimated using the two methods described above were comparedwith each other and with the adult doses derived from our previous study [20]. Further-more, the relationship between the children’s doses and their ages was analyzed.ResultsTIAC and effective half-lifeIn patient imaging studies, six tumors were discovered in five of the patients, as shownin Table 1. Fig. 2 displays examples of the whole-body images acquired within 3 h afterinjection from three of the patients who had visible tumors. The locations of tumorsare indicated by arrows in this figure. The main uptake organs were the kidneys, liver,and spleen.The time-activity data for the left and right kidneys, the liver, and the spleen are dis-played in Fig. 3 together with the curves corresponding to the mono-exponential fit tothis data. The mean effective and biological half-lives determined from these time-activity curves are summarized in Table 2 for normal organs and tumors. Furthermore,the relationship between these TIACs and the ages of the patients are depicted in Fig. 4.The mean values of the children’s TIACs for the analyzed organs and tumors, togetherwith the adults’ TIACs, are summarized in Table 3. Please note that all the data shownin Tables 2, 3, and 4 correspond to the average value ± standard deviation; the rangesof these average values are shown in parentheses.In order to investigate the uptake phase of 99mTc-HYNIC-TOC pharmacokinetics, a 30-min dynamic planar scan with a total of 60 time frames was performed for one patient.Fig. 2 Whole-body planar images acquired at approximately 1.5–2.5 h after injection, with pathologicuptake indicated by arrows. Patient #1: a large tumor with low uptake located in the mediastinum; patient#7: two tumors, one located in the pancreatic head and the other in the lymph node on the left side;patient #11: a single tumor located at the center of the patient’s body (insulinoma head of pancreas)Hou et al. EJNMMI Physics  (2017) 4:24 Page 6 of 13For the plotting of the changes of tracer uptake versus time, a threshold of 50% of themaximum pixel counts in each region was applied to each time frame and the countswere summed in the segmented regions. The resulting curves are shown in Fig. 5.Absorbed dosesFigure 6 displays the absorbed doses in children’s organs and tumors estimated usingthe voxel-S approach (by convolving voxel-S matrices with the activity distributions)and the organ-level method (from OLINDA software with/without adapted organTable 2 Effective and biological half-lives determined from the mono-exponential fits to the dataof radiotracer uptakes in organs and lesions in children patientsOrgan Effective half-life (hour) Biological half-life (hour)LKidney 4.72 ± 1.08 (2.44–5.93) 69.5 ± 117.1 (4.1–431.4)RKidney 4.94 ± 1.32 (1.57–5.99) 308.5 ± 534.2 (2.1–1873.3)Liver 5.07 ± 0.76 (3.04–5.99) 182.4 ± 429.6 (6.1–1521.6)Spleena 5.83 ± 1.33 (4.26–8.22) 15.0 ± 42.8 (− 54.8–90.5)Tumors 4.18 ± 1.21 (2.86–5.71) 35.0 ± 45.7 (5.4–112.9)aThe effective half-life of spleens in four of the patients were higher than 99mTc physical half-lifeFig. 3 Organ time-activity curves based on mono-exponential fittings for all of the patients. Differentsymbols correspond to different patientsHou et al. EJNMMI Physics  (2017) 4:24 Page 7 of 13masses). The mean doses are summarized and compared with the adults’ dosimetry inTable 4. Fig. 7 displays the percent contributions of self- and cross-organ doses to thetotal organ and tumor doses for children patients, calculated using the voxel-Sapproach. Additionally, dose distributions, in terms of the cumulated DVHs, arepresented in Fig. 8.DiscussionIn this study, the investigation of the biodistribution of 99mTc-HYNIC-TOC in childrenpatients and the corresponding dosimetry calculations were performed and comparedwith those of adults. The study employed the hybrid planar/SPECT imaging technique.The main radiopharmaceutical uptake occurred in the kidneys, liver, and spleen.Although in our previous adult study some thyroid uptake was observed [20], no sig-nificant uptake was found in the children (shown in Fig. 2).The TACs and TIACs determined for the kidneys, liver, and spleen are shown in Fig. 3and Table 3. The average values of organ TIACs were 0.37 ± 0.08, 0.56 ± 0.21, and0.43 ± 0.15 for the kidneys, liver, and spleen, respectively. The children’s TIACs for thekidneys and spleens were very similar to those obtained in the adult’s study, whileTIACs for the livers in children patients were smaller than those in adults [20].Dynamics of the radiotracer uptake was investigated in one of the patients. The ana-lysis of this temporal behavior, displayed in Fig. 5, showed maximum uptake for thekidneys at about 7–10 min, while faster maximum uptake happened, at about 1–3 min,Fig. 4 Organ and tumor TIACs displayed versus patient age. Symbols represent different organs andtumors, including the left and right kidneys, liver, spleen, and tumorTable 3 Comparison of organ TIAC for children to those for adultsOrgan TIAC (Bq.h/Bq)Children Adults [20]Kidneysa 0.37 ± 0.08 (0.22–0.52) 0.35 ± 0.10 (0.19–0.54)Liver 0.56 ± 0.21 (0.19–0.85) 0.75 ± 0.31 (0.20–1.72)Spleen 0.43 ± 0.15 (0.19–0.75) 0.43 ± 0.20 (0.04–0.89)Urinary bladderb 0.17 ± 0.19 (0.05–0.28) 0.23 ± 0.09 (0.12–0.53)Remainder of bodyc 5.01 ± 2.15 (2.52–8.92) 4.34 ± 0.74 (3.00–6.10)Tumors 0.07 ± 0.10 (0.02–0.26) –aThe TIAC of the kidneys were obtained by performing the time-activity curve fitting for both the left and right kidneysbThe TIAC values of urinary bladder contents were calculated using the voiding bladder model provided by OLINDAcThe TIACs for the remainder of the body were estimated by subtracting the organs’ TIACs from the whole-body TIACsHou et al. EJNMMI Physics  (2017) 4:24 Page 8 of 13for both the liver and spleen. After reaching their maximum uptake, a washout phasewas observed for both the kidneys and livers. However, for the spleen, after a rapiddecrease following the peak uptake, a gradually increasing uptake seemed to continuebeyond the time covered by this 30-min dynamic scan. This could explain the negativebiological half-lives found in four of the patients, as indicated in Table 2.Considering dosimetry for normal organs, as shown in Table 4 and Fig. 6, no signifi-cant differences were found between voxel-level dosimetry and organ-level dosimetrywhen using adapted organ masses in OLINDA for the kidneys and livers. On the otherhand, the voxel-level doses for the spleen were slightly lower than organ-based doses.However, for all the normal organs, large discrepancies could be observed betweenvoxel-level doses and those calculated using OLINDA without adapting organ masses.This indicates that dosimetry using OLINDA with default organ masses, especially forchildren models, may not reflect their true absorbed doses.The tumor doses (shown in Table 4, Fig. 6, and Fig. 7) from the spherical modelobtained using OLINDA were approximately equal to only half of the voxel-level tumordoses. This discrepancy is related to the fact that the spherical model only allows forcalculation of the self-tumor doses; however, for tumors located close to the organswith large uptakes (like the kidneys, liver, or spleen), the cross-organ contributions maybe substantial. This effect can be especially pronounced in small children, where dis-tances between organs are smaller than in adults. It is more important in dose esti-mates for photons, because they deposit their energy at distances larger than, forexample, beta particles, whose dose depositions are more localized.When comparing children dosimetry to that for adults (listed in Table 4), organ dosesfor children were found to be up to 30% higher than those for adults, due to smallerTable 4 Comparison of absorbed doses in organs and tumors in children and adultsOrgan Mean dose (mGy/MBq)Children (Voxel-S approach) Children (OLINDA withadapted organ masses)Adults (OLINDA withadapted organ masses) [20]Kidneys 0.024 ± 0.009 (0.011–0.047) 0.026 ± 0.009 (0.009–0.046) 0.021 ± 0.007 (0.011–0.039)Spleen 0.032 ± 0.017 (0.019–0.081) 0.038 ± 0.021 (0.017–0.092) 0.030 ± 0.012 (0.005–0.057)Liver 0.017 ± 0.007 (0.009–0.032) 0.016 ± 0.007 (0.007–0.029) 0.012 ± 0.005 (0.005–0.028)Tumora 0.017 ± 0.006 (0.010–0.024) 0.010 ± 0.003 (0.007–0.015) 0.024 ± 0.016 (0.003–0.047)aTumor masses are 14–546 g for children, while 8–855 g from adultsFig. 5 Time-activity curves showing radiotracer uptake in the kidneys, liver, and spleen. The data wereobtained from a 30-min dynamic planar scanHou et al. EJNMMI Physics  (2017) 4:24 Page 9 of 13organ sizes. This effect is related to the fact that, as already noted, the children’s andadults’ TIACs were similar, while the absorbed doses are inversely proportional to theorgan masses. However, the tumor doses for children were lower than those for adults.Additionally, as shown in Fig. 7, children’s cross-organ contributions were equal toabout 15–40% of the total organ and tumor doses, while for adults, the cross-organdoses were less than 15% of the total doses (see Fig. 3a in [32]).Fig. 6 Absorbed doses in the organs and tumors calculated using the voxel-S approach, the OLINDA withadapted organ masses and OLINDA with default organ masses displayed versus patient ageFig. 7 Average percent contributions of self- and cross-organ doses to the total organ and tumor doses forchildren patients, calculated using voxel-S approach. Error bars represent standard deviations estimatedfrom all patients’ dataHou et al. EJNMMI Physics  (2017) 4:24 Page 10 of 13Furthermore, no statistical correlation was noted between TIACs (Fig. 4), theabsorbed doses (Fig. 6), and the age of children (please note, however, this statement isbased on the analysis of a small sample of only 11 patients). Similarly, no statistical dif-ferences were found between mean doses and dose distributions (represented byDVHs) in patients with and without pathologic uptakes. However, large inter-patientvariability was clearly observed (Fig. 6 and Fig. 8), which emphasizes the importance ofperforming patient-specific dosimetry in clinical studies.ConclusionsIn this study, we report the results of biodistribution analysis and dosimetry calculationsfor children who had 99mTc-HYNIC-TOC injections for the diagnosis of neuroendocrinetumors. The absorbed doses in children were slightly higher than those in adults. No sig-nificant correlation was found between the children’s doses and their ages. However, sub-stantial inter-patient variability in radiotracer uptake, potentially indicating disparity inexpression of somatostatin receptors between different patients, emphasizes the import-ance and necessity of patient-specific dosimetry in future clinical studies.Abbreviations99mTc-HYNIC-TOC: Technetium-99m-hydrazinonicotinamide-Tyr3-octreotide; DVH: Dose-volume histogram;NET: Neuroendocrine tumor; OAR: Organs at risk; OSEM: Ordered-subsets expectation maximization; ROI: Region ofinterest; SSRS: Somatostatin receptor scintigraphy; TAC: Time-activity curve; TIAC: Time-integrated activity coefficient;WB: Whole-bodyAcknowledgementsThis study was partly supported by the NSERC grant (194512-12).FundingThis study was partly supported by funds from the Natural Sciences and Engineering Research Council of Canada(NSERC) Discovery Grant (194512-12).Availability of data and materialsPatient imaging was done in the scope of the routine clinical diagnostic studies, and the data are stored (followingthe standard protocol) at the Nuclear Medicine Department, Pomeranian Medical University, Szczecin, Poland.Fig. 8 Dose-volume histograms (DVHs) for normal organs and tumors. Each line represents a differentpatient; the lines with symbols represents the patients with pathologic uptakesHou et al. EJNMMI Physics  (2017) 4:24 Page 11 of 13Authors’ contributionsAll authors, XH, BB, HP-B, and AC, contributed to the design of this work. Drs. BB and HP-B were responsible for patientrecruitment, imaging studies, and interpretation of images. Drs. XH and AC analyzed the data, performed dosimetrycalculations, and wrote the manuscript. None of the authors have any competing interests in the manuscript. Allauthors read and approved the final manuscript.Ethics approval and consent to participateFor all patients, this 99mTc-HYNIC-TOC study was part of their diagnostic routine for primary and metastatic lesionlocalization, staging, or follow-up, with the final diagnosis based on the histopathologic examination. Subsequently,these patients’ data were anonymized and used to perform dosimetry calculations, with no impact on their treatment.Ethics approval for such use of anonymized patient data has been obtained.Consent for publicationAll authors read the manuscript and consented for its publication.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Author details1Medical Imaging Research Group, Department of Radiology, University of British Columbia, 828 West 10th Avenue,Rm 366, Vancouver, BC V5Z1L8, Canada. 2Nuclear Medicine Department, Pomeranian Medical University, Szczecin,Poland.Received: 5 July 2017 Accepted: 4 October 2017References1. Gabriel M, Decristoforo C, Donnemiller E, Ulmer H, Rychlinski CW, Mather SJ, et al. An intrapatient comparison of99mTc-EDDA/diagnosis of somatostatin receptor—expressing tumors. J Nucl Med. 2003;44:708–16.2. Reubi JC, Waser B, Schaer JC, Laissue JA. Somatostatin receptor sst1-sst5 expression in normal and neoplastichuman tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med. 2001;28:836–46.3. Czepczyński R, Parisella MG, Kosowicz J, Mikołajczak R, Ziemnicka K, Gryczyńska M, et al. Somatostatin receptorscintigraphy using 99mTc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma. Eur J Nucl Med MolImaging. 2007;34:1635–45.4. Rodrigues M, Traub-Weidinger T, Li S, Ibi B, Virgolini I. Comparison of 111In-DOTA-DPhe1-Tyr3-octreotide and111In-DOTA-lanreotide scintigraphy and dosimetry in patients with neuroendocrine tumours. Eur J Nucl Med MolImaging. 2006;33:532–40.5. Deppen SA, Liu E, Blume JD, Clanton J, Shi C, Jones-Jackson LB, et al. Safety and efficacy of 68Ga-DOTATATE PET/CT for diagnosis, staging and treatment management of neuroendocrine tumors. J Nucl Med. 2016;57:708–15.6. Herrmann K, Czernin J, Wolin EM, Gupta P, Barrio M, Gutierrez A, et al. Impact of 68Ga-DOTATATE PET/CT on themanagement of neuroendocrine tumors: the referring physician’s perspective. J Nucl Med. 2015;56:70–5.7. Hope TA, Pampaloni MH, Flavell RR, Nakakura EK, Bergsland EK. Somatostatin receptor PET/MRI for the evaluationof neuroendocrine tumors. Clin Transl Imaging Springer Milan. 2017;5:63–9.8. Kaewput C, Vinjamuri S. Comparison of renal uptake of 68Ga-DOTANOC PET/CT and estimated glomerularfiltration rate before and after peptide receptor radionuclide therapy in patients with metastatic neuroendocrinetumours. Nucl Med Commun. 2016;37:1325–32.9. Putzer D, Kroiss A, Waitz D, Gabriel M, Traub-Weidinger T, Uprimny C, et al. Somatostatin receptor PET inneuroendocrine tumours: 68Ga- DOTA0, Tyr3-octreotide versus 68Ga-DOTA 0-lanreotide. Eur J Nucl Med MolImaging. 2013;40:364–72.10. Etchebehere ECSDC, de Oliveira SA, Gumz B, Vicente A, Hoff PG, Corradi G, et al. 68Ga-DOTATATE PET/CT, 99mTc-HYNIC-octreotide SPECT/CT, and whole-body MR imaging in detection of neuroendocrine tumors: a prospectivetrial. J Nucl Med. 2014;55:1598–604.11. Kalsy N, Vinjamuri S. Should we stop offering indium-111 octreotide scans in favour of gallium-68 PET-CT scans inthe UK? Nucl Med Commun. 2016;37:1221–2.12. Płachcińska A, Mikołajczak R, Maecke HR, Młodkowska E, Kunert-Radek J, Michalski A, et al. Clinical usefulness of99mTc-EDDA/HYNIC-TOC scintigraphy in oncological diagnostics: a preliminary communication. Eur J Nucl MedMol Imaging. 2003;30:1402–6.13. Sager S, Kabasakal L, Ocak M, Maecke H, Uslu L, Halac M, et al. Clinical value of technetium-99m-labeledoctreotide scintigraphy in local recurrent or metastatic medullary thyroid cancers: a comparison of lesions with18F-FDG-PET and MIBI images. Nucl Med Commun. 2013;34:1190–5.14. Von Guggenberg E, Mikolajczak R, Janota B, Riccabona G, Decristoforo C. Radiopharmaceutical development of afreeze-dried kit formulation for the preparation of [99mTc-EDDA-HYNIC-D-Phe1, Tyr 3]-octreotide, a somatostatinanalog for tumor diagnosis. J Pharm Sci. 2004;93:2497–506.15. Basu S, Kand P, Mallia M, Korde A, Shimpi H. Gratifying clinical experience with an indigenously formulated single-vial lyophilized HYNIC-TOC kit at the radiopharmaceutical division of BARC: a pivotal boost for building up apeptide receptor radionuclide therapy programme in an Indian setting. Eur J Nucl Med Mol Imaging. 2013;40:1622–4.Hou et al. EJNMMI Physics  (2017) 4:24 Page 12 of 1316. Öberg K, Knigge U, Kwekkeboom D, Perren A. Neuroendocrine gastro-entero-pancreatic tumors: ESMO clinicalpractice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;2317. Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the incidence, prevalence, and survivaloutcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;26:2124–30.18. Pérez-Albert P, Rojas T De, Lendínez MÁ, Illade L, Andión M, Madero L. Management and outcome of childrenwith neuroendocrine tumors of the appendix in Spain: is there room for improvement? Clin Transl Oncol. 2017;19:1168–72.19. González-Vázquez A, Ferro-Flores G, Arteaga de Murphy C, Gutiérrez-García Z. Biokinetics and dosimetry inpatients of 99mTc-EDDA/HYNIC-Tyr3-octreotide prepared from lyophilized kits. Appl Radiat Isot. 2006;64:792–7.20. Grimes J, Celler A, Birkenfeld B, Shcherbinin S, Listewnik MH, Piwowarska-Bilska H, et al. Patient-specific radiationdosimetry of 99mTc-HYNIC-Tyr3-Octreotide in neuroendocrine tumors. J Nucl Med. 2011;52:1474–81.21. Momennezhad M, Nasseri S, Zakavi S, Parach A, Ghorbani M, Asl R. A 3D Monte Carlo method for estimation ofpatient-specific internal organs absorbed dose for 99mTc-hynic-Tyr3 -octreotide imaging. World J Nucl Med. 2016;15:114.22. Allan B, Davis J, Perez E, Lew J, Sola J. Malignant neuroendocrine tumors: incidence and outcomes in pediatricpatients. Eur J Pediatr Surg. 2013;23:394–9.23. Kamiya K, Ozasa K, Akiba S, Niwa O, Kodama K, Takamura N, et al. Long-term effects of radiation exposure onhealth. Lancet Elsevier Ltd. 2015;386:469–78.24. Jacobs F, Thierens H, Piepsz A, Bacher K, Van De Wiele C, Ham H, et al. Optimised tracer-dependent dosage cardsto obtain weight-independent effective doses. Eur J Nucl Med Mol Imaging. 2005;32:581–8.25. Johnson TN. Modelling approaches to dose estimation in children. Br J Clin Pharmacol. 2005;59:663–9.26. Gao Y, Quinn B, Mahmood U, Long D, Erdi Y, St. Germain J, et al. A comparison of pediatric and adult CT organdose estimation methods. BMC Med. Imaging. BMC Med Imaging; 2017;17:28.27. Cristy M, Eckerman K. Specific absorbed fractions of energy at various ages from internal photons sources.Oak Ridge: Oak Ridge National Laboratory; 1987. p. V1–V7. ORNL/TM-8381.28. Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internaldose assessment in nuclear medicine. J Nucl Med. 2005;46:1023–7.29. Siegel JA, Thomas SR, Stubbs JB, Stabin MG, Hays MT, Koral KF, et al. MIRD pamphlet no. 16: techniques forquantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation doseestimates. J Nucl Med. 1999;40:37S–61S.30. Grimes J, Celler A, Shcherbinin S, Piwowarska-bilska H, Birkenfeld B. The accuracy and reproducibility of SPECTtarget volumes and activities estimated using an iterative adaptive thresholding technique. Nucl Medi Commun.2012;33:1254–66.31. Grimes J, Uribe C, Celler A. JADA: a graphical user interface for comprehensive internal dose assessment innuclear medicine. Med Phys. 2013;40:72501.32. Grimes J, Celler A. Comparison of internal dose estimates obtained using organ-level, voxel S value, and MonteCarlo techniques. Med Phys. 2014;41:92501.Hou et al. EJNMMI Physics  (2017) 4:24 Page 13 of 13


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