D. Plyku

Recombinant human thyroid-stimulating hormone versus thyroid hormone withdrawal in 124I PET/CT-based dosimetry for 131I therapy of metastatic differentiated thyroid cancer

Patients with metastatic differentiated thyroid cancer (DTC) may be prepared using either thyroid-stimulating hormone withdrawal (THW) or recombinant human thyroid-stimulating hormone (rhTSH) injections before 131I administration for treatment. The objective of this study was to compare the absorbed dose to the critical organs and tumors determined by 124I PET/CT–based dosimetry for 131I therapy of metastatic DTC when the same patient was prepared with and imaged after both THW and rhTSH injections. Methods: Four DTC patients at MedStar Washington Hospital Center were first prepared using the rhTSH method and imaged by 124I PET/CT at 2, 24, 48, 72, and 96 h after administration of approximately 30–63 MBq of 124I. After 5–8 wk, the same patients were prepared using the THW method and imaged as before. The 124I PET/CT images acquired as part of a prospective study were used to perform retrospective dosimetric calculations for 131I therapy for the normal organs with the dosimetry package 3D-RD. The absorbed doses from 131I for the lungs, liver, heart, kidneys, and bone marrow were obtained for each study (rhTSH and THW). Twenty-two lesions in 3 patients were identified. The contours were drawn on each PET image of each study. Time-integrated activity coefficients were calculated and used as input in OLINDA/EXM sphere dose calculator to obtain the absorbed dose to tumors. Results: The THW-to-rhTSH organ absorbed dose ratio averaged over 5 organs for the first 3 patients was 1.5, 2.5, and 0.64, respectively, and averaged over 3 organs for the fourth patient was 1.1. The absorbed dose per unit administered activity to the bone marrow was 0.13, 0.086, 0.33, and 0.068 mGy/MBq after rhTSH and 0.11, 0.14, 0.22, and 0.080 mGy/MBq after THW for each patient, respectively. With the exception of 3 lesions of 1 patient, the absorbed dose per unit administered activity of 131I was higher in the THW study than in the rhTSH study. The ratio of the average tumor absorbed dose after stimulation by THW compared with stimulation by rhTSH injections was 3.9, 27, and 1.4 for patient 1, patient 2, and patient 3, respectively. The ratio of mean tumor to bone marrow absorbed dose per unit administered activity of 131I, after THW and rhTSH, was 232 and 62 (patient 1), 12 and 0.78 (patient 2), and 22 and 11 (patient 3), respectively. Conclusion: The results suggest a high patient variability in the overall absorbed dose to the normal organs per MBq of 131I administered, between the 2 TSH stimulation methods. The tumor–to–dose-limiting-organ (bone marrow) absorbed dose ratio, that is, the therapeutic index, was higher in the THW-aided than rhTSH-aided administrations. Additional comparison for tumor and normal organ absorbed dose in patients prepared using both methods is needed before definitive conclusions may be drawn regarding rhTSH versus THW patient preparation methods for 131I therapy of metastatic DTC.

Dose Estimation in Pediatric Nuclear Medicine

The practice of nuclear medicine in children is well established for imaging practically all physiologic systems but particularly in the fields of oncology, neurology, urology, and orthopedics. Pediatric nuclear medicine yields images of physiologic and molecular processes that can provide essential diagnostic information to the clinician. However, nuclear medicine involves the administration of radiopharmaceuticals that expose the patient to ionizing radiation and children are thought to be at a higher risk for adverse effects from radiation exposure than adults. Therefore it may be considered prudent to take extra care to optimize the radiation dose associated with pediatric nuclear medicine. This requires a solid understanding of the dosimetry associated with the administration of radiopharmaceuticals in children. Models for estimating the internal radiation dose from radiopharmaceuticals have been developed by the Medical Internal Radiation Dosimetry Committee of the Society of Nuclear Medicine and Molecular Imaging and other groups. But to use these models accurately in children, better pharmacokinetic data for the radiopharmaceuticals and anatomical models specifically for children need to be developed. The use of CT in the context of hybrid imaging has also increased significantly in the past 15 years, and thus CT dosimetry as it applies to children needs to be better understood. The concept of effective dose has been used to compare different practices involving radiation on a dosimetric level, but this approach may not be appropriate when applied to a population of children of different ages as the radiosensitivity weights utilized in the calculation of effective dose are not specific to children and may vary as a function of age on an organ-by-organ bias. As these gaps in knowledge of dosimetry and radiation risk as they apply to children are filled, more accurate models can be developed that allow for better approaches to dose optimization. In turn, this will lead to an overall improvement in the practice of pediatric nuclear medicine by providing excellent diagnostic image quality at the lowest radiation dose possible.

A risk index for pediatric patients undergoing diagnostic imaging with 99mTc-dimercaptosuccinic acid that accounts for body habitus*

Published guidelines for administered activity to pediatric patients undergoing diagnostic nuclear medicine imaging are currently obtained through expert consensus of the minimum values as a function of body weight as required to yield diagnostic quality images. We have previously shown that consideration of body habitus is also important in obtaining diagnostic quality images at the lowest administered activity. The objective of this study was to create a series of computational phantoms that realistically portray the anatomy of the pediatric patient population which can be used to develop and validate techniques to minimize radiation dose while maintaining adequate image quality. To achieve this objective, we have defined an imaging risk index that may be used in future studies to develop pediatric patient dosing guidelines. A population of 48 hybrid phantoms consisting of non-uniform B-spline surfaces and polygon meshes was generated. The representative ages included the newborn, 1 year, 5 year, 10 year and 15 year male and female. For each age, the phantoms were modeled at their 10th, 50th, and 90th height percentile each at a constant 50th weight percentile. To test the impact of kidney size, the newborn phantoms were modeled with the following three kidney volumes: -15%, average, and +15%. To illustrate the impact of different morphologies on dose optimization, we calculated the effective dose for each phantom using weight-based (99m)Tc-DMSA activity administration. For a given patient weight, body habitus had a considerable effect on effective dose. Substantial variations were observed in the risk index between the 10th and 90th percentile height phantoms from the 50th percentile phantoms for a given age, with the greatest difference being 18%. There was a dependence found between kidney size and risk of radiation induced kidney cancer, with the highest risk indices observed in newborns with the smallest kidneys. Overall, the phantoms and techniques in this study can be used to provide data to refine dosing guidelines for pediatric nuclear imaging studies while taking into account the effects on both radiation dose and image quality.

Pharmacokinetic modeling of [18F]fluorodeoxyglucose (FDG) for premature infants, and newborns through 5-year-olds

BackgroundAbsorbed dose estimates for pediatric patients require pharmacokinetics that are, to the extent possible, age-specific. Such age-specific pharmacokinetic data are lacking for many of the diagnostic agents typically used in pediatric imaging. We have developed a pharmacokinetic model of [18F]fluorodeoxyglucose (FDG) applicable to premature infants and to 0- (newborns) to 5-year-old patients, which may be used to generate model-derived time-integrated activity coefficients and absorbed dose calculations for these patients.MethodsThe FDG compartmental model developed by Hays and Segall for adults was fitted to published data from infants and also to a retrospective data set collected at the Boston Children’s Hospital (BCH). The BCH data set was also used to examine the relationship between uptake of FDG in different organs and patient weight or age.ResultsSubstantial changes in the structure of the FDG model were required to fit the pediatric data. Fitted rate constants and fractional blood volumes were reduced relative to the adult values.ConclusionsThe pharmacokinetic models developed differ substantially from adult pharmacokinetic (PK) models which can have considerable impact on the dosimetric models for pediatric patients. This approach may be used as a model for estimating dosimetry in children from other radiopharmaceuticals.

Strengths and Weaknesses of a Planar Whole-Body Method of 153Sm Dosimetry for Patients with Metastatic Osteosarcoma and Comparison with Three-Dimensional Dosimetry

PURPOSE Dosimetric accuracy depends directly upon the accuracy of the activity measurements in tumors and organs. The authors present the methods and results of a retrospective tumor dosimetry analysis in 14 patients with a total of 28 tumors treated with high activities of (153)Sm-ethylenediaminetetramethylenephosphonate ((153)Sm-EDTMP) for therapy of metastatic osteosarcoma using planar images and compare the results with three-dimensional dosimetry. MATERIALS AND METHODS Analysis of phantom data provided a complete set of parameters for dosimetric calculations, including buildup factor, attenuation coefficient, and camera dead-time compensation. The latter was obtained using a previously developed methodology that accounts for the relative motion of the camera and patient during whole-body (WB) imaging. Tumor activity values calculated from the anterior and posterior views of WB planar images of patients treated with (153)Sm-EDTMP for pediatric osteosarcoma were compared with the geometric mean value. The mean activities were integrated over time and tumor-absorbed doses were calculated using the software package OLINDA/EXM. RESULTS The authors found that it was necessary to employ the dead-time correction algorithm to prevent measured tumor activity half-lives from often exceeding the physical decay half-life of (153)Sm. Measured half-lives so long are unquestionably in error. Tumor-absorbed doses varied between 0.0022 and 0.27 cGy/MBq with an average of 0.065 cGy/MBq; however, a comparison with absorbed dose values derived from a three-dimensional analysis for the same tumors showed no correlation; moreover, the ratio of three-dimensional absorbed dose value to planar absorbed dose value was 2.19. From the anterior and posterior activity comparisons, the order of clinical uncertainty for activity and dose calculations from WB planar images, with the present methodology, is hypothesized to be about 70%. CONCLUSION The dosimetric results from clinical patient data indicate that absolute planar dosimetry is unreliable and dosimetry using three-dimensional imaging is preferable, particularly for tumors, except perhaps for the most sophisticated planar methods. The relative activity and patient kinetics derived from planar imaging show a greater level of reliability than the dosimetry.

Biodistribution and Radiation Dosimetry of 124I-iodo-DPA-713, a PET Radiotracer for Macrophage-Associated Inflammation

Whole-body PET/CT was performed using 124I-DPA-713, a radioligand for the 18-kDa translocator protein (TSPO), to determine biodistribution and radiation dosimetry. Methods: Healthy subjects aged 18–65 y underwent whole-body PET/CT either at 4, 24, and 48 h or at 24, 48, and 72 h after intravenous injection of 124I-DPA-713. Time–activity curves were generated and used to calculate organ time-integrated activity coefficients for each subject. The resulting time-integrated activity coefficients provided input data for calculation of organ absorbed doses and effective dose for each subject using OLINDA. Subjects were genotyped for the TSPO polymorphism rs6971, and plasma protein binding of 124I-DPA-713 was measured. Results: Three male and 3 female adults with a mean age of 40 ± 19 y were imaged. The mean administered activity and mass were 70.5 ± 5.1 MBq (range, 62.4–78.1 MBq) and 469 ± 34 ng (range, 416–520 ng), respectively. There were no adverse or clinically detectable pharmacologic effects in any of the 6 subjects. No changes in vital signs, laboratory values, or electrocardiograms were observed. 124I-DPA-713 cleared rapidly (4 h after injection) from the lungs, with hepatic elimination and localization to the gastrointestinal tract. The mean effective dose over the 6 subjects was 0.459 ± 0.127 mSv/MBq, with the liver being the dose-limiting organ (0.924 ± 0.501 mGy/MBq). The percentage of free radiotracer in blood was approximately 30% at 30 and 60 min after injection. Conclusion: 124I-DPA-713 clears rapidly from the lungs, with predominantly hepatic elimination, and is safe and well tolerated in healthy adults.

Comparative Dosimetry for 68Ga-DOTATATE: Impact of using Updated ICRP phantoms, S values and Tissue Weighting Factors

The data that have been used in almost all calculations of MIRD S value absorbed dose and effective dose are based on stylized anatomic computational phantoms and tissue-weighting factors adopted by the International Commission on Radiological Protection (ICRP) in its publication 60. The more anatomically realistic phantoms that have recently become available are likely to provide more accurate effective doses for diagnostic agents. 68Ga-DOTATATE is a radiolabeled somatostatin analog that binds with high affinity to somatostatin receptors, which are overexpressed in neuroendocrine tumors and can be used for diagnostic PET/CT-based imaging. Several studies have reported effective doses for 68Ga-DOTATATE using the stylized Cristy–Eckerman (CE) phantoms from 1987; here, we present effective dose calculations using both the ICRP 60 and more updated formalisms. Methods: Whole-body PET/CT scans were acquired for 16 patients after 68Ga-DOTATATE administration. Contours were drawn on the CT images for spleen, liver, kidneys, adrenal glands, brain, heart, lungs, thyroid gland, salivary glands, testes, red marrow (L1–L5), muscle (right thigh), and whole body. Dosimetric calculations were based on the CE phantoms and the more recent ICRP 110 reference-voxel phantoms. Tissue-weighting factors from ICRP 60 and ICRP 103 were used in effective dose calculations for the CE phantoms and ICRP 110 phantoms, respectively. Results: The highest absorbed dose coefficients (absorbed dose per unit activity) were, in descending order, in the spleen, pituitary gland, kidneys, adrenal glands, and liver. For ICRP 110 phantoms with tissue-weighting factors from ICRP 103, the effective dose coefficient was 0.023 ± 0.003 mSv/MBq, which was significantly lower than the 0.027 ± 0.005 mSv/MBq calculated for CE phantoms with tissue-weighting factors from ICRP 60. One of the largest differences in estimated absorbed dose coefficients was for the urinary bladder wall, at 0.040 ± 0.011 mGy/MBq for ICRP 110 phantoms compared with 0.090 ± 0.032 mGy/MBq for CE phantoms. Conclusion: This study showed that the effective dose coefficient was slightly overestimated for CE phantoms, compared with ICRP 110 phantoms using the latest tissue-weighting factors from ICRP 103. The more detailed handling of electron transport in the latest phantom calculations gives significant differences in estimates of the absorbed dose to stem cells in the walled organs of the alimentary tract.

Evaluation of 111In-DOTA-5D3, a Surrogate SPECT Imaging Agent for Radioimmunotherapy of Prostate-Specific Membrane Antigen

5D3 is a new high-affinity murine monoclonal antibody specific for prostate-specific membrane antigen (PSMA). PSMA is a target for the imaging and therapy of prostate cancer. 111In-labeled antibodies have been used as surrogates for 177Lu/90Y-labeled therapeutics. We characterized 111In-DOTA-5D3 by SPECT/CT imaging, tissue biodistribution studies, and dosimetry. Methods: Radiolabeling, stability, cell uptake, and internalization of 111In-DOTA-5D3 were performed by established techniques. Biodistribution and SPECT imaging were done on male nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice bearing human PSMA(+) PC3 PIP and PSMA(−) PC3 flu prostate cancer xenografts on the upper right and left flanks, respectively, at 2, 24, 48, 72, and 192 h after injection. Biodistribution was also evaluated in tumor-free, healthy male CD-1 mice. Blocking studies were performed by coinjection of a 10-fold and 50-fold excess of 5D3 followed by biodistribution at 24 h to determine PSMA binding specificity. The absorbed radiation doses were calculated on the basis of murine biodistribution data, which were translated to a human adult man using organ weights as implemented in OLINDA/EXM. Results: 111In-DOTA-5D3 was synthesized with specific activity of approximately 2.24 ± 0.74 MBq/μg (60.54 ± 20 μCi/μg). Distribution of 111In-DOTA-5D3 in PSMA(+) PC3 PIP tumor peaked at 24 h after injection and remained high until 72 h. Uptake in normal tissues, including the blood, spleen, liver, heart, and lungs, was highest at 2 h after injection. Coinjection of 111In-DOTA-5D3 with a 10- and 50-fold excess of nonradiolabeled antibody significantly reduced PSMA(+) PC3 PIP tumor and salivary gland uptake at 24 h but did not reduce uptake in kidneys and lacrimal glands. Significant clearance of 111In-DOTA-5D3 from all organs occurred at 192 h. The highest radiation dose was received by the liver (0.5 mGy/MBq), followed by the spleen and kidneys. Absorbed radiation doses to the salivary and lacrimal glands and bone marrow were low. Conclusion: 111In-DOTA-5D3 is a new radiolabeled antibody for imaging and a surrogate for therapy of malignant tissues expressing PSMA.

Re-evaluation of pediatric 18F-FDG dosimetry: Cristy–Eckerman versus UF/NCI hybrid computational phantoms

Because of the concerns associated with radiation exposure at a young age, there is an increased interest in pediatric absorbed dose estimates for imaging agents. Almost all reported pediatric absorbed dose estimates, however, have been determined using adult pharmacokinetic data with radionuclide S values that take into account the anatomical differences between adults and children based upon the older Cristy-Eckerman (C-E) stylized phantoms. In this work, we use pediatric model-derived pharmacokinetics to compare absorbed dose and effective dose estimates for 18F-FDG in pediatric patients using S values generated from two different geometries of computational phantoms. Time-integrated activity coefficients of 18F-FDG in brain, lungs, heart wall, kidneys and liver, retrospectively, calculated from 35 pediatric patients at the Bostons Children Hospital were used. The absorbed dose calculation was performed in accordance with the Medical Internal Radiation Dose method using S values generated from the University of Florida/National Cancer Institute (UF/NCI) hybrid phantoms, as well as those from C-E stylized computational phantoms. The effective dose was computed using tissue-weighting factors from ICRP Publication 60 and ICRP Publication 103 for the C-E and UF/NCI, respectively. Substantial differences in the absorbed dose estimates between UF/NCI hybrid pediatric phantoms and the C-E stylized phantoms were found for the lungs, ovaries, red bone marrow and urinary bladder wall. Large discrepancies in the calculated dose values were observed in the bone marrow; ranging between  -26% to  +199%. The effective doses computed by the UF/NCI hybrid phantom S values were slightly different than those seen using the C-E stylized phantoms with percent differences of  -0.7%, 2.9% and  2.5% for a newborn, 1 year old and 5 year old, respectively. Differences in anatomical modeling features among computational phantoms used to perform Monte Carlo-based photon and electron transport simulations for 18F, and very likely for other radionuclides, impact internal organ dosimetry computations for pediatric nuclear medicine studies.

A projection image database to investigate factors affecting image quality in weight-based dosing: Application to pediatric renal SPECT

Balancing the tradeoff between radiation dose, acquisition duration and diagnostic image quality is essential for medical imaging modalities involving ionizing radiation. Lower administered activities to the patient can reduce absorbed dose, but can result in reduced diagnostic image quality or require longer acquisition durations. In pediatric nuclear medicine, it is desirable to use the lowest amount of administered radiopharmaceutical activity and the shortest acquisition duration that gives sufficient image quality for clinical diagnosis. However, diagnostic image quality is a complex function of patient factors including body morphometry. In this study, we present a digital population of 90 computational anatomic phantoms that model realistic variations in body morphometry and internal anatomy. These phantoms were used to generate a large database of projection images modeling pediatric SPECT imaging using a 99mTc-DMSA tracer. We used an analytic projection code that models attenuation, spatially varying collimator-detector response, and object-dependent scatter to generate the projections. The projections for each organ were generated separately and can be subsequently scaled by parameters extracted from a pharmacokinetics model to simulate realistic tracer biodistribution, including variations in uptake, inside each relevant organ or tissue structure for a given tracer. Noise-free projection images can be obtained by summing these individual organ projections and scaling by the system sensitivity and acquisition duration. We applied this database in the context of 99mTc-DMSA renal SPECT, the most common nuclear medicine imaging procedure in pediatric patients. Organ uptake fractions based on literature values and patient studies were used. Patient SPECT images were used to verify that the sum of counts in the simulated projection images was clinically realistic. For each phantom, 384 uptake realizations, modeling random variations in the uptakes of organs of interest, were generated, producing 34 560 noise-free projection datasets (384 uptake realizations times 90 phantoms). Noisy images modeling various count levels (corresponding to different products of acquisition duration and administered activity) were generated by appropriately scaling these images and simulating Poisson noise. Acquisition duration was fixed; six count levels were simulated corresponding to projection images acquired using 25%, 50%, 75%, 100%, 125%, and 150% of the original weight-based administrated activity as computed using the North American Guidelines (Gelfand et al 2011 J. Nucl. Med. 52 318-22). Combined, a total number of 207 360 noisy projection images were generated, creating a realistic projection database for use in renal pediatric SPECT imaging research. The phantoms and projection datasets were used to calculate three surrogate indices for factors affecting image quality: renal count density, average radius of rotation, and scatter-to-primary ratio. Differences in these indices were seen across the phantoms for dosing based on current guidelines, and especially for the phantom modeling the newborn. We also performed an image quality study using an anthropomorphic model observer that demonstrates that the weight-based dose scaling does not equalize image quality as measured by the area under the receiver-operating characteristics curve. These studies suggest that a dosing procedure beyond weight-based scaling of administered activities is required to equalize image quality in pediatric renal SPECT.