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Purpose: Radioembolization with yttrium-90 microspheres may be optimized with patient-specific pretherapy treatment planning. Dose verification and validation of treatment planning methods require quantitative imaging of the post-therapy distribution of yttrium-90 (Y-90). Methods for quantitative imaging of Y-90 using both bremsstrahlung SPECT and PET have previously been described. The purpose of this study was to compare the two modalities quantitatively in humans. Methods: Calibration correction factors for both quantitative Y-90 bremsstrahlung SPECT and a non-time-of-flight PET system without compensation for prompt coincidences were developed by imaging three phantoms. The consistency of these calibration correction factors for the different phantoms was evaluated. Post-therapy images from both modalities were obtained from 15 patients with hepatocellular carcinoma who underwent hepatic radioembolization using Y-90 glass microspheres. Quantitative SPECT and PET images were rigidly registered and the total liver activities and activity distributions estimated for each modality were compared. The activity distributions were compared using profiles, voxel-by-voxel correlation and Bland–Altman analyses, and activity-volume histograms. Results: The mean ± standard deviation of difference in the total activity in the liver between the two modalities was 0% ± 9% (range −21%–18%). Voxel-by-voxel comparisons showed a good agreement in regions corresponding roughly to treated tumor and treated normal liver; the agreement was poorer in regions with low or no expected activity, where PET appeared to overestimate the activity. The correlation coefficients between intrahepatic voxel pairs for the two modalities ranged from 0.86 to 0.94. Cumulative activity volume histograms were in good agreement. Conclusions: These data indicate that, with appropriate reconstruction methods and measured calibration correction factors, either Y-90 SPECT/CT or Y-90 PET/CT can be used for quantitative post-therapy monitoring of Y-90 activity distribution following hepatic radioembolization.

The dosimetric assessment of novel radiotracers represents a legal requirement in most countries. While the techniques for the computation of internal absorbed dose in a therapeutic context have made huge progresses in recent years, in a diagnostic scenario the absorbed dose is usually extracted from model-based lookup tables, most often derived from International Commission on Radiological Protection (ICRP) or Medical Internal Radiation Dose (MIRD) Committee models. The level of approximation introduced by these models may impact the resulting dosimetry. The aim of this work is to establish whether a more refined approach to dosimetry can be implemented in nuclear medicine diagnostics, by analyzing a specific case.

Radioembolization with yttrium-90 microspheres may be optimized with patient-specific pretherapy treatment planning. Dose verification and validation of treatment planning methods require quantitative imaging of the post-therapy distribution of yttrium-90 (Y-90). Methods for quantitative imaging of Y-90 using both bremsstrahlung SPECT and PET have previously been described. The purpose of this study was to compare the two modalities quantitatively in humans.Calibration correction factors for both quantitative Y-90 bremsstrahlung SPECT and a non-time-of-flight PET system without compensation for prompt coincidences were developed by imaging three phantoms. The consistency of these calibration correction factors for the different phantoms was evaluated. Post-therapy images from both modalities were obtained from 15 patients with hepatocellular carcinoma who underwent hepatic radioembolization using Y-90 glass microspheres. Quantitative SPECT and PET images were rigidly registered and the total liver activities and activity distributions estimated for each modality were compared. The activity distributions were compared using profiles, voxel-by-voxel correlation and Bland-Altman analyses, and activity-volume histograms.The mean ± standard deviation of difference in the total activity in the liver between the two modalities was 0% ± 9% (range -21%-18%). Voxel-by-voxel comparisons showed a good agreement in regions corresponding roughly to treated tumor and treated normal liver; the agreement was poorer in regions with low or no expected activity, where PET appeared to overestimate the activity. The correlation coefficients between intrahepatic voxel pairs for the two modalities ranged from 0.86 to 0.94. Cumulative activity volume histograms were in good agreement.These data indicate that, with appropriate reconstruction methods and measured calibration correction factors, either Y-90 SPECT/CT or Y-90 PET/CT can be used for quantitative post-therapy monitoring of Y-90 activity distribution following hepatic radioembolization.

Purpose To evaluate whether technetium-99 ( 99m Tc)-labeled macroaggregated albumin (MAA) can predict subsequent yttrium-90 ( 90 Y) distribution and imaging response in patients with hepatocellular carcinoma (HCC). Materials Retrospective review was performed of records of 83 patients with HCC who underwent 90 Y glass microsphere radioembolization with 99m Tc-MAA single photon emission computed tomography (SPECT) and 90 Y positron emission tomography (PET)/CT between January 2013 and December 2014. Images were fused to segment the whole liver normal tissue (WLNT) and the largest tumors. Fused images were reviewed and analyzed for comparison of absorbed dose (AD) to tumors and WLNT as calculated from 99m Tc-MAA SPECT and from 90 Y PET/CT, subjective imaging comparison of 99m Tc-MAA SPECT and 90 Y PET for tumors and WLNT, and correlation of tumoral AD with response on follow-up CT. Results Final analysis included 73 and 63 patients for WLNT and tumor 99m Tc-MAA/ 90 Y correlation, respectively, and 62 patients for AD vs response. 99m Tc-MAA/ 90 Y limit of agreement for each reviewer was viewed as clinically acceptable only for WLNT (–15 to 15 Gy). AD interreviewer variability was clinically acceptable for WLNT but was too broad for tumor. Mean tumor AD for objective response (78%) was 313 Gy vs 234 Gy for nonresponders. No threshold was found between tumor AD and response ( P > .1). Catheter mismatch between 99m Tc-MAA and 90 Y had a direct impact on AD mismatch between the 2 image sets. Conclusions 99m Tc-MAA was found to be a poor surrogate to quantitatively predict subsequent 90 Y AD to hepatocellular tumors. 99m Tc-MAA distribution correlated with 90 Y distribution in the normal hepatic parenchyma.

Low-energy Auger and conversion electrons deposit their energy in a very small volume (a few nm3) around the site of emission. From a radiotoxicological point of view the effects of low-energy electrons on normal tissues are largely unknown, understudied, and generally assumed to be negligible. In this context, the discovery that the low-energy electron emitter, 99mTc, can induce stunning on primary thyrocytes in vitro, at low absorbed doses, is intriguing. Extrapolated in vivo, this observation suggests that a radioisotope as commonly used in nuclear medicine as 99mTc may significantly influence thyroid physiology. The aims of this study were to determine whether 99mTc pertechnetate (99mTcO4 −) is capable of inducing thyroid stunning in vivo, to evaluate the absorbed dose of 99mTcO4 − required to induce this stunning, and to analyze the biological events associated/concomitant with this effect. Our results show that 99mTcO4 −–mediated thyroid stunning can be observed in vivo in mouse thyroid. The threshold of the absorbed dose in the thyroid required to obtain a significant stunning effect is in the range of 20 Gy. This effect is associated with a reduced level of functional Na/I symporter (NIS) protein, with no significant cell death. It is reversible within a few days. At the cellular and molecular levels, a decrease in NIS mRNA, the generation of double-strand DNA breaks, and the activation of the p53 pathway are observed. Low-energy electrons emitted by 99mTc can, therefore, induce thyroid stunning in vivo in mice, if it is exposed to an absorbed dose of at least 20 Gy, a level unlikely to be encountered in clinical practice. Nevertheless this report presents an unexpected effect of low-energy electrons on a normal tissue in vivo, and provides a unique experimental setup to understand the fine molecular mechanisms involved in their biological effects.

In targeted radionuclide therapy, patient-specific dosimetry based on voxel S values (VSVs) is preferable to dosimetry based on mathematical phantoms. Monte-Carlo (MC) simulations are necessary to deduce VSVs for those voxel sizes required by quantitative imaging. The aim of this study is, starting from a single set of high-resolution VSVs obtained by MC simulations for a small voxel size along one single axis perpendicular to the source voxel, to present a suitable method to accurately calculate VSVs for larger voxel sizes.Accurate sets of VSVs for target voxel to source voxel distances up to 10 cm were obtained for high-resolution voxel sizes (0.5 mm for electrons and 1.0 mm for photons) from MC simulations for Y-90, Lu-177, and I-131 using the radiation transport code MCNPX v.2.7a. To make these values suitable to any larger voxel size, different analytical methods (based on resamplings, interpolations, and fits) were tested and compared to values obtained by direct MC simulations. As a result, an optimal calculation procedure is proposed. This procedure consisted of: (1) MC simulation for obtaining of a starting set of VSVs along a single line of voxels for a small voxel size for each radionuclide and type of radiation; (2) interpolation within the values obtained in point (1) for obtaining the VSVs for voxels within a spherical volume; (3) resampling of the data obtained in (1) and (2) for obtaining VSVs for voxels sizes larger than the one used for the MC calculation for integer voxel ratios (voxel ratio=new voxel size∕voxel size MC simulation); (4) interpolation on within the data obtained in (3) for integer voxel ratios. The results were also compared to results from other authors.The results obtained with the method proposed in this work show deviations relative to the source voxel below 1% for I-131 and Lu-177 and below 1.5% for Y-90 as compared with values obtained by direct MC simulations for voxel sizes ranging between 1.0 and 10.0 cm. The results obtained in this work show differences between the scored deposited energy and the emitted energy lower than 2% for electron radiation. Higher differences, attributable to the short considered radius of 10 cm in comparison with their penetration, can be found for photons. The authors' results agree well with previously published data obtained by other authors using different methods.A reliable and fast approach for obtaining accurate VSVs for voxel sizes larger than the voxel size used for the MC calculation of the starting set of high-resolution VSVs was developed and successfully tested for three different radionuclides of interest for targeted radiotherapy: one pure beta (Y-90) and 2 beta-gamma emitters (Lu-177 und I-131). Applying the method of this work allows any interested reader to repeat the calculations for arbitrary radionuclides of interest and∕or smaller high-resolution voxel sizes, provided the means for running MC simulations are available.

Recent developments of hybrid realistic models, such as Moby (mouse) and Roby (rat) developed by Segars et al. ["Development of a 4-D digital mouse phantom for molecular imaging research," Mol. Imaging Biol. 6, 149-159 (2004)] have found several applications in preclinical experiments. Indeed, their improved realism and flexibility in terms of mass scaling represent an attractive option for absorbed dose calculations based on "representative" models. However, the range of radiations involved in small animal molecular imaging and radiotherapy is of the same order of magnitude as organs of interest dimensions. As a consequence, minor geometric variations between rodents may lead to major differences in absorbed dose calculations. This study aims at validating a voxel-based model for use in absorbed dose estimates with two Monte Carlo codes and at assessing the dosimetric impact of Moby-based models definition.The authors generated a 30 g-mouse phantom based on realistic hybrid model Moby (version 1). Dosimetric calculations (S-values, specific absorbed fraction) were performed with two Monte Carlo codes (MCNPX v2.7a and GATE v6.1) for (18)F, and a comparison with values published for Radiation Dose Assessment Resource realistic animal series was made. Several parameters such as material definition∕densities, fine suborgan segmentation for airways (trachea, lungs, remaining body), bones (ribs, spine, skull, remaining bones), heart (blood pool and myocardium), and stomach (wall and gastrointestinal content) were further studied, as well as nuclear data and spatial sampling.Most organ masses matched the reference model (Moby v1) within ± 6%, except lungs, thyroid, and bones for which differences could reach 29%. Comparison of S-values (especially self-S-values) was consistent with mass differences observed between the two models. The reciprocity theorem for source∕target pairs was satisfied within few percents for specific absorbed fractions (g(-1)). However, significant discrepancies, reaching 160%, were observed for mutual liver∕stomach∕spleen S-values and could not be directly related to mass variations. Nonetheless, differences between S-values calculated with MCNPX and GATE for our model remained in the order of a few percents, i.e., within statistical uncertainties. Besides, modifications of organ densities increased S-values up to a factor 50 for the lungs∕thyroid pair when upper airway was properly segmented out of the body. Specific material composition and densities for several bone types led to a 10% decrease of S-values from the bone source to several target organs. Moreover, relative differences up to 100% were observed for S(stomach wall⇐spleen) when improving spatial-sampling by a factor 3.This study demonstrated that comparison between two "similar" realistic digital mouse whole-body phantoms generated from the same software still led to very different S-values, even when total body and organ mass scaling were performed. Moreover, parameters such as organ segmentation, tissue material∕density, or spatial sampling should be defined and reported with great care to perform accurate small animal absorbed dose calculation based on "reference" models.

We investigated influences of pretargeting variables, tumor location, and radionuclides in pretargeted radioimmunotherapy (PRIT) as well as estimated tumor absorbed doses.LS-174T human colonic carcinoma cells expressing carcinoembryonic antigen (CEA) were inoculated in nude mice. Biodistribution of a bispecific anti-CEA x anti-hapten antibody, TF2, and of a TF2-pretargeted peptide was assessed and a multi-compartment pharmacokinetic model was devised. Tissue absorbed doses were calculated for (131)I, (177)Lu, (90)Y, (211)At, and (213)Bi using realistic specific activities.Under conditions optimized for tumor imaging (10:1 TF2 to peptide molar ratio, interval time 15-24 h), tumor uptake reached ∼9 ID/g in subcutaneous tumors at 2 h with very low accretion in normal tissues (tumor to blood ratio20:1 after 2 h). For a low dose of peptide (0.04 nmol), (211)At is predicted to deliver a high absorbed dose to tumors [41.5 Gy considering a relative biologic effect (RBE) of 5], kidneys being dose-limiting. (90)Y and (213)Bi would also deliver high absorbed doses to tumor (18.6 for (90)Y and 26.5 Gy for (213)Bi, taking RBE into account, for 0.1 nmol) and acceptable absorbed doses to kidneys. With hepatic metastases, a twofold higher tumor absorbed dose is expected. Owing to the low activities measured in blood, the bone marrow absorbed dose is expected to be without significant toxicity.Pretargeting achieves high tumor uptake and higher tumor to background ratios compared to direct RIT. Short-lived radionuclides are predicted to deliver high tumor absorbed doses especially (211)At, with kidneys being the dose-limiting organ. (177)Lu and (131)I should be considered for repeated injections.

In this paper, the authors' review the applicability of the open-source GATE Monte Carlo simulation platform based on the GEANT4 toolkit for radiation therapy and dosimetry applications. The many applications of GATE for state-of-the-art radiotherapy simulations are described including external beam radiotherapy, brachytherapy, intraoperative radiotherapy, hadrontherapy, molecular radiotherapy, and in vivo dose monitoring. Investigations that have been performed using GEANT4 only are also mentioned to illustrate the potential of GATE. The very practical feature of GATE making it easy to model both a treatment and an imaging acquisition within the same frameworkis emphasized. The computational times associated with several applications are provided to illustrate the practical feasibility of the simulations using current computing facilities.

Low-energy Auger and conversion electrons deposit their energy in a very small volume (a few nm3) around the site of emission. From a radiotoxicological point of view the effects of low-energy electrons on normal tissues are largely unknown, understudied, and generally assumed to be negligible. In this context, the discovery that the low-energy electron emitter, 99mTc, can induce stunning on primary thyrocytes in vitro, at low absorbed doses, is intriguing. Extrapolated in vivo, this observation suggests that a radioisotope as commonly used in nuclear medicine as 99mTc may significantly influence thyroid physiology. The aims of this study were to determine whether 99mTc pertechnetate (99mTcO4−) is capable of inducing thyroid stunning in vivo, to evaluate the absorbed dose of 99mTcO4− required to induce this stunning, and to analyze the biological events associated/concomitant with this effect. Our results show that 99mTcO4−–mediated thyroid stunning can be observed in vivo in mouse thyroid. The threshold of the absorbed dose in the thyroid required to obtain a significant stunning effect is in the range of 20 Gy. This effect is associated with a reduced level of functional Na/I symporter (NIS) protein, with no significant cell death. It is reversible within a few days. At the cellular and molecular levels, a decrease in NIS mRNA, the generation of double-strand DNA breaks, and the activation of the p53 pathway are observed. Low-energy electrons emitted by 99mTc can, therefore, induce thyroid stunning in vivo in mice, if it is exposed to an absorbed dose of at least 20 Gy, a level unlikely to be encountered in clinical practice. Nevertheless this report presents an unexpected effect of low-energy electrons on a normal tissue in vivo, and provides a unique experimental setup to understand the fine molecular mechanisms involved in their biological effects.

Purpose: In targeted radionuclide therapy, patient-specific dosimetry based on voxel S values (VSVs) is preferable to dosimetry based on mathematical phantoms. Monte-Carlo (MC) simulations are necessary to deduce VSVs for those voxel sizes required by quantitative imaging. The aim of this study is, starting from a single set of high-resolution VSVs obtained by MC simulations for a small voxel size along one single axis perpendicular to the source voxel, to present a suitable method to accurately calculate VSVs for larger voxel sizes. Methods: Accurate sets of VSVs for target voxel to source voxel distances up to 10 cm were obtained for high-resolution voxel sizes (0.5 mm for electrons and 1.0 mm for photons) from MC simulations for Y-90, Lu-177, and I-131 using the radiation transport code MCNPX v.2.7a. To make these values suitable to any larger voxel size, different analytical methods (based on resamplings, interpolations, and fits) were tested and compared to values obtained by direct MC simulations. As a result, an optimal calculation procedure is proposed. This procedure consisted of: (1) MC simulation for obtaining of a starting set of VSVs along a single line of voxels for a small voxel size for each radionuclide and type of radiation; (2) interpolation within the values obtained in point (1) for obtaining the VSVs for voxels within a spherical volume; (3) resampling of the data obtained in (1) and (2) for obtaining VSVs for voxels sizes larger than the one used for the MC calculation for integer voxel ratios (voxel ratio = new voxel size/voxel size MC simulation); (4) interpolation on within the data obtained in (3) for integer voxel ratios. The results were also compared to results from other authors. Results: The results obtained with the method proposed in this work show deviations relative to the source voxel below 1% for I-131 and Lu-177 and below 1.5% for Y-90 as compared with values obtained by direct MC simulations for voxel sizes ranging between 1.0 and 10.0 cm. The results obtained in this work show differences between the scored deposited energy and the emitted energy lower than 2% for electron radiation. Higher differences, attributable to the short considered radius of 10 cm in comparison with their penetration, can be found for photons. The authors’ results agree well with previously published data obtained by other authors using different methods. Conclusions: A reliable and fast approach for obtaining accurate VSVs for voxel sizes larger than the voxel size used for the MC calculation of the starting set of high-resolution VSVs was developed and successfully tested for three different radionuclides of interest for targeted radiotherapy: one pure beta (Y-90) and 2 beta-gamma emitters (Lu-177 und I-131). Applying the method of this work allows any interested reader to repeat the calculations for arbitrary radionuclides of interest and/or smaller high-resolution voxel sizes, provided the means for running MC simulations are available.

Purpose: Recent developments of hybrid realistic models, such as Moby (mouse) and Roby (rat) developed bySegars et al. [“Development of a 4-D digital mouse phantom for molecular imaging research,” Mol. Imaging Biol.6, 149–159 (Year: 2004)10.1016/j.mibio.2004.03.002] have found several applications in preclinical experiments. Indeed, their improved realism and flexibility in terms of mass scaling represent an attractive option for absorbed dose calculations based on “representative” models. However, the range of radiations involved in small animal molecular imaging and radiotherapy is of the same order of magnitude as organs of interest dimensions. As a consequence, minor geometric variations between rodents may lead to major differences in absorbed dose calculations. This study aims at validating a voxel-based model for use in absorbed dose estimates with two Monte Carlo codes and at assessing the dosimetric impact of Moby-based models definition. Methods: The authors generated a 30 g-mouse phantom based on realistic hybrid model Moby (version 1). Dosimetric calculations (S-values, specific absorbed fraction) were performed with two Monte Carlo codes (MCNPX v2.7a and GATE v6.1) for18F, and a comparison with values published for Radiation Dose Assessment Resource realistic animal series was made. Several parameters such as material definition/densities, fine suborgan segmentation for airways (trachea, lungs, remaining body), bones (ribs, spine, skull, remaining bones), heart (blood pool and myocardium), and stomach (wall and gastrointestinal content) were further studied, as well as nuclear data and spatial sampling. Results: Most organ masses matched the reference model (Moby v1) within ±6%, except lungs, thyroid, and bones for which differences could reach 29%. Comparison of S-values (especially self-S-values) was consistent with mass differences observed between the two models. The reciprocity theorem for source/target pairs was satisfied within few percents for specific absorbed fractions (g−1). However, significant discrepancies, reaching 160%, were observed for mutual liver/stomach/spleen S-values and could not be directly related to mass variations. Nonetheless, differences between S-values calculated with MCNPX and GATE for our model remained in the order of a few percents, i.e., within statistical uncertainties. Besides, modifications of organ densities increased S-values up to a factor 50 for the lungs/thyroid pair when upper airway was properly segmented out of the body. Specific material composition and densities for several bone types led to a 10% decrease of S-values from the bone source to several target organs. Moreover, relative differences up to 100% were observed for S(stomach wall⇐spleen) when improving spatial-sampling by a factor 3. Conclusions: This study demonstrated that comparison between two “similar” realistic digital mouse whole-body phantoms generated from the same software still led to very different S-values, even when total body and organ mass scaling were performed. Moreover, parameters such as organ segmentation, tissue material/density, or spatial sampling should be defined and reported with great care to perform accurate small animal absorbed dose calculation based on “reference” models.