Objective.The skeleton contains the red bone marrow (RBM) and the endosteum, tissues linked to radiation-induced leukemia and bone cancer, making their consideration essential in radiation dosimetry. Although adult skeletal dosimetry has advanced with 3D images such asμCT images, the scarcity of comparable pediatric images prevents pediatric skeletal dosimetry from achieving a similar level. This study aims to develop 3D image-based detailed pediatric skeletal models that, while grounded in adultμCT images, incorporate the anatomical features of the developing pediatric skeleton.Approach.Target skeletal values were established from extensive anatomical literature and International Commission on Radiological Protection publications, including skeletal tissue mass, cellularity factor, trabecular bone volume fraction, and trabecular number. Guided by these values, trabecular bone models converted from adultμCT images were refined, a 50μm endosteal layer was defined, yellow bone marrow (YBM) was incorporated as adipocytes, and remaining regions were assigned as RBM. All modeling steps were performed automatically using our C++-based bone modeling program.Main results.A total of 246 pediatric skeletal models were developed in a high-quality mesh format across six age and sex groups (sex-averaged newborn, 1 year-old, 5 year-old, and 10 year-old, and sex-specific 15 year-old male and female), with each group comprising 41 models. These models represent trabecular bone and RBM/YBM in both the shallow and deep marrow, and all matched their target values within 2%. For selected cases, PHITS Monte Carlo simulations were used to calculate specific absorbed fractions, which increased with decreasing age due to differences in target mass and the combined effects of the anatomical factors incorporated in this study.Significance.This study provides the first comprehensive set of 3D image-based pediatric skeletal models for skeletal dosimetry. These models, together with the dosimetric datasets derived from them, are expected to provide an anatomically robust foundation for improving the accuracy and reliability of pediatric skeletal dosimetry.

In the VISION trial, [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus protocol-permitted standard of care significantly improved overall survival and radiographic progression-free survival compared with standard of care alone in patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer. This VISION dosimetry substudy quantified absorbed doses of 177Lu-PSMA-617 in the kidneys and other organs. Methods: Participants were a separate cohort of 30 nonrandomized patients receiving standard of care plus 177Lu-PSMA-617 at 7.4 GBq per cycle for up to 6 cycles. Blood samples, whole-body conjugate planar image scintigraphy, and abdominal SPECT/CT images were collected. SPECT/CT images were collected at 2, 24, 48, and 168 h after administration in cycle 1 and at a single time point 48 h after administration in cycles 2-6. Outcomes were absorbed dose per unit activity per cycle and cumulative absorbed dose over all cycles. Cumulative absorbed doses were predicted by extrapolation from cycle 1, and calculation of observed values was based on measurements of cycle 1 and cycles 2-6. Safety was also assessed. Results: Mean (±SD) absorbed doses per cycle in the kidneys were 0.43 ± 0.16 Gy/GBq in cycle 1 and 0.44 ± 0.21 Gy/GBq in cycles 2-6. The observed and predicted 6-cycle cumulative absorbed doses in the kidneys were 15 ± 6 and 19 ± 7 Gy, respectively. Observed and predicted cumulative absorbed doses were similar in other at-risk organs. Safety findings were consistent with those in the VISION study; no patients experienced renal treatment-emergent adverse events of a grade higher than 3. Conclusion: The renal cumulative absorbed 177Lu-PSMA-617 dose was below the established limit. 177Lu-PSMA-617 had a good overall safety profile, and low renal radiotoxicity was not a safety concern. Cumulative absorbed doses in at-risk organs over multiple cycles can be predicted by extrapolation from cycle 1 data in patients with metastatic castration-resistant prostate cancer receiving 177Lu-PSMA-617.

This is a dosimetry analysis of the prospective randomized phase 2 trial RESIST-PC which evaluated the efficacy and safety of 2 injected activity regimens of [177Lu]Lu-PSMA-617 in patients with progressive metastatic castration-resistant prostate cancer. Methods: This biinstitutional study randomized patients with metastatic castration-resistant prostate cancer to receive either 6.0 or 7.4 GBq of [177Lu]Lu-PSMA-617 per cycle for up to 4 cycles (1:1 randomization). The γ-images were obtained at the first cycle using a hybrid protocol (planar + SPECT). Whole-body planar scintigraphy images were acquired at 4, 24, 48, and 72 h (optionally at 168 h), and a quantitative SPECT/CT was performed at 24 h postinjection. Absorbed doses (ADs) were calculated for the kidneys, salivary glands, liver, and tumors. Planar time-activity curves were derived on a per-region basis from counts in the serial scans, with exponential curve fit selection based on Akaike information criterion. Quantitative SPECT data per region were scaled by the planar time-activity data and then convolved with a voxel-S value dose kernel to yield AD estimates. No partial volume corrections were applied. Adverse events and efficacy data were correlated to the calculated AD. Results: A total of 48 of 64 patients (16 treated with 6.0 GBq vs. 32 in the 7.4-GBq arm) had complete imaging datasets and were analyzed. The mean kidney, submandibular, parotid, and liver ADs were 0.29 ± 0.11, 0.23 ± 0.18, 0.26 ± 0.15, and 0.11 ± 0.09 Gy/GBq, respectively. There was no significant difference in organ or tumor ADs between arms. In total, 358 lesions were included in the analysis (median, 7/patient [range, 0-18/patient]). The mean AD to bone lesions (n = 304) was 1.90 ± 1.83 and 1.64 ± 1.77 Gy/GBq for the 6.0-GBq (n = 121) and 7.4-GBq (n = 183) groups, respectively. For lymph node lesions (n = 35), mean ADs were 5.61 ± 3.93 Gy/GBq (n = 22) and 1.79 ± 1.96 Gy/GBq (n = 13) for the 6.0- and 7.4-GBq groups, respectively. Only the 7.4-GBq cohort presented liver lesions; mean AD was 1.59 ± 1.45 Gy/GBq (n = 19). A statistically significant inverse correlation was observed between prostate-specific antigen response and tumor AD (ρ = -0.404, P = 0.006). Conclusion: In the RESIST-PC prospective phase 2 trial, dosimetry analyses using a hybrid imaging protocol revealed organ ADs within tolerable ranges, and tumor ADs varied widely on the inter- and intrapatient level regardless of injected activity.

Radiological or nuclear incidents can release radionuclide mixtures that contaminate populations in fallout areas. Medical management may involve biodosimetry assays to identify individuals who need care. The γ-H2AX + 53BP1 double-strand break (DSB) focus assay is a rapid triage tool for detecting irradiated individuals, but its specificity is limited by physiological background foci and individual variability. In this study, we characterized baseline γ-H2AX + 53BP1 DSB foci levels in peripheral blood mononuclear cells from 60 healthy volunteers (31 men, 29 women), aged 20-64 years, to assess the influence of age and sex. The detection threshold was set at the 95th percentile of baseline foci values. This threshold was tested against data based on blood samples from 10 donors irradiated ex vivo with [223Ra]RaCl2 and [177Lu]LuCl3 mixtures at absorbed doses to the blood of 25-75 mGy (β-contribution only), measured at 0, 4, and 24 h postirradiation. The median baseline foci value was 0.51 foci/cell (IQR: 0.41-0.63). Older individuals showed significantly higher baseline levels (P = 0.03), with greater variability, while no sex differences were observed. Setting the threshold at 0.86 foci/cell enabled reliable detection of irradiated samples shortly after exposure (sensitivity: 96.7%; specificity: 95.0%). However, sensitivity decreased at 4 h (63.3%) and 24 h (36.7%) postirradiation due to DNA repair. These findings suggest that individuals irradiated with low doses can be identified soon after exposure using the DSB focus assay. Age-related variability and DNA repair kinetics should be considered in emergency biodosimetry planning.

Purpose: Aim of the study was to investigate DNA damage induction and repair in peripheral blood mononuclear cells (PBMCs) after internal ex vivo irradiation with short-lived radionuclides with varying emission properties.Methods: Blood samples from healthy volunteers were irradiated with different activity concentrations for 1 h, resulting in absorbed doses to the blood from nominally 3 to 100 mGy. DNA double-strand breaks (DSBs) in PBMCs were assessed by quantifying radiation-induced γ-H2AX+53BP1-positive foci (RIF). In part A of the study, four different radionuclides (177Lu, 90Y, 99mTc and 68Ga) were used to test for radionuclide dependence. In part B, blood samples were exposed to 177Lu and cells were fixed at three different time points (directly, 4 h and 24 h after irradiation) to investigate DSB repair and its dependence on the absorbed dose.Results: The number of RIF increases linearly with the absorbed dose to the blood, independent of the radionuclide used for irradiation. The decline in RIF after irradiation can be described by an exponential function, with a trend towards higher repair rates at higher absorbed doses to the blood, i.e. (0.20±0.12) h⁻1 for 25 mGy, (0.22±0.04) h⁻1 for 50 mGy, and (0.37±0.06) h⁻1 for 100 mGy.Conclusion: Our results show a clear relationship between absorbed dose and DSB foci induced by internal irradiation in blood cells, independent of the emission properties of the particular radionuclide used. A better understanding of DNA damage repair dynamics after internal irradiation can improve future nuclear medicine therapies.

Radiopharmaceutical therapy (RPT) delivers protracted, low absorbed dose rate radiation over time, with cellular DNA repair capacity potentially limiting its efficacy. This article explores how lessons from radiobiology-particularly regarding DNA damage response (DDR)-inform the rational design of 177Lu-labeled RPT (177Lu-RPT)-based clinical trials, with emphasis on combinations with DDR inhibitors and replication stress response (RSR) inhibitors. Methods: We integrate preclinical and clinical data on both the induction and repair of DNA damage in the context of 177Lu-RPT and on their combination with inhibitors of DDR/RSR pathways. Results: At the low absorbed dose rates typical of 177Lu-RPT (<0.1 Gy/h), sublethal DNA damage is largely repaired during exposure, minimizing the quadratic component (β) of the linear quadratic model and making intrinsic radiosensitivity (α) the main determinant of cell killing. This raises questions regarding the biologic factors underlying intrinsic radiation sensitivity, as well as the influence of the activity administered per cycle and the number of treatment cycles. Conclusion: Despite the attenuated β-component, the efficacy of 177Lu-RPT could be improved by combining it with DDR and RSR inhibitors to disrupt the DNA repair processes that occur simultaneously with irradiation, provided that such combinations are rationally designed and sequenced. Optimal combinations will require integration of tumor- and patient-specific radiosensitivity profiles and incorporation of dosimetry and biomarker endpoints into trial designs.

Objective. The skeleton is critical in radiation dosimetry. It is the tissue that houses both the red bone marrow (RBM) and the endosteum which are respectively linked to radiation-induced leukemia and bone cancer. The complex microstructure of these tissues provides challenges to dose assessment. Although detailed skeletal models have been developed, even the latest series of models remain voxel-based, thus limiting their anatomical and geometrical fidelity. The present study aims to develop the first mesh-based skeletal models aligned with the International Commission on Radiological Protection (ICRP) Reference Adult Male and Reference Adult Female to address these limitations. Approach. A target skeletal dataset was first established through an extensive literature review to align with the ICRP Reference Adults while achieving anatomical realism. Primitive trabecular bone models were then generated from micro-computed tomography images using Fiji/ImageJ and Blender. These models were subsequently processed through an in-house automated C++/Python program, which adjusted their trabecular bone volumes, defined their endosteal layers, and partitioned the marrow into RBM and yellow bone marrow (YBM) to generate a final series of mesh-based skeletal models consistent with the target mass dataset. Main Results. A total of 35 male and 38 female models of trabecular spongiosa were developed in a high-quality mesh format. Each model represents five distinct skeletal tissue regions: trabecular bone, and RBM and YBM within both the shallow (endosteal) and deep (non-endosteal) marrow. The models were designed to match the total skeletal tissue masses of the ICRP Reference Adults to within 0.5%. For selected cases, Monte Carlo simulations were performed by inputting them to the Particle and Heavy Ion Transport code System code together with the ICRP mesh-type reference phantoms, which showed that the improved model format enhanced specific absorbed fractions by up to 2.0-fold, while their anatomical refinement showed improvement by up to 1.6-fold. Significance. The automated modeling techniques established here show strong potential for improvements in radiological protection as well as optimization of patient-specific marrow dosimetry in radiopharmaceutical therapy.

This study aimed to determine a mathematical model for accurately calculating time-integrated activities (TIAs) of target tissue in 131I therapy for benign thyroid disease using the population-based model selection and non-linear mixed-effects (PBMS-NLME) method. Biokinetic data of 131I in target tissue were collected from seventy-three patients at 2, 6, 24, 48, and 96 (N = 53) or 120 (N = 20) h after oral capsule administration with 1 MBq 131I. Based on the Akaike weight, the best sum-of-exponential function (SOEF) describing the biokinetic data was selected using PBMS-NLME modelling. Nine SOEF with three to six parameters (including the function from the European Association of Nuclear Medicine Standard Operational Procedure (EANM SOP)) were used. The fittings were repeated 1000 times with different starting values of the SOE parameters to find the optimal fit. Akaike weight was used to identify the performance of the best model from PBMS-NLME and the EANM SOP SOE function with individual fitting. Based on the PBMS-NLME analysis, the SOEF λ_1/λ_2 + λ_1 - λ_3( e^ - ( λ_3 + λ_phys)t - e^ - ( λ_1 + λ_2 + λ_phys)t) + a_1 e^ - ( λ_1 + λ_2 + λ_phys)t was selected as the function most supported by the data. The Akaike weight of the best function was approximately 100

BACKGROUND:Single Photon Emission Computed Tomography (SPECT) is increasingly used as a quantitative modality, especially in the context of Molecular Radiotherapy, where the measurements are used as input to absorbed dose calculations for patient-specific dosimetry. Establishing measurement traceability is an essential step in providing confidence in quantitative measurements. This requires an unbroken chain of calibrations where uncertainties must be reported in all stages of calibration and for the final measurement result. Traceability ensures that a measurement result can be related to an underlying standard, allowing harmonisation of data, and facilitating comparison of results between sites. METHODS:The process of establishing measurement traceability for quantitative SPECT is demonstrated for the therapeutic radionuclide 177Lu using a common, phantom based, calibration method. Phantoms with activities of 177Lu, measured using a traceably calibrated radionuclide calibrator, were used to perform the calibration. The calibration was validated using 3D-printed anthropomorphic organ phantom inserts mimicking clinically relevant geometries. For all measurements, traceability to primary standards for radioactivity is demonstrated along with an accompanying calibration chain and statement of uncertainty. RESULTS:For all activity measurements the dominant component in the activity uncertainty budget was the uncertainty on the radionuclide calibrator calibration factor, resulting in an average combined standard uncertainty of 1.57%. The resulting uncertainty on the SPECT Image Calibration Factor was 1.6%. An optional additional correction was included in the calibration to provide volume-based partial volume correction (PVC). Measurement traceability was extended for measurands using this additional correction. The activity recovery in the organ phantoms with PVC applied was 96(7)% for both the kidney and spleen. CONCLUSIONS:A manufacturer independent methodology for establishing measurement traceability for quantitative SPECT is demonstrated for 177Lu, using a radionuclide calibrator previously calibrated against national standards. The ability to establish measurement traceability for quantitative SPECT using standard clinical equipment, and the limitations of traceability are presented.

Radiopharmaceutical therapy (RPT) is entering a new era of personalization, driven by advances in molecular imaging, radiopharmaceutical development, and a growing body of clinical evidence linking absorbed dose to treatment outcomes. Although external-beam radiotherapy has long integrated dosimetry into standard practice, RPT historically relied on fixed radiopharmaceutical activities and absorbed dose-effect relationships adapted from external-beam radiotherapy, often without accounting for the unique pharmacokinetics, absorbed dose rate dynamics, and biologic responses of systemically administered radiopharmaceuticals. As RPT expands into earlier disease stages, at which patients have longer life expectancies and better performance status, the role of dosimetry in optimizing treatment is becoming increasingly evident. However, despite growing recognition of its benefits, the implementation of dosimetry in clinical practice remains limited, partly because of a self-reinforcing cycle in which the lack of routine dosimetry limits clinical evidence, which in turn hinders its broader adoption. Breaking this cycle is essential to advancing RPT and ensuring that evaluation of dosimetry is based on clinical merit rather than logistic constraints. This article examines the current landscape of RPT dosimetry, highlighting key challenges and opportunities from a European perspective and aiming to foster a more factual and constructive discussion on the topic. We discuss the fundamental differences between dosimetry-driven treatment planning and posttherapy absorbed dose verification, emphasizing the latter as a practical entry point for clinical adoption. We underscore the need for harmonized standards, improved imaging resolution, and tailored absorbed dose-effect relationships that reflect the heterogeneity of RPT delivery and the complexity of tumor and organ responses. The paper also addresses regulatory, infrastructural, and resource barriers to RPT dosimetry implementation and highlights ongoing European initiatives to strengthen frameworks, enhance stakeholder collaboration, and integrate absorbed dose biomarkers into authorization processes and clinical decision-making. By rethinking dosimetry and promoting standardized, evidence-based approaches, the field can advance beyond fixed-activity protocols toward truly individualized RPT. However, achieving clinically feasible integration of dosimetry into routine practice requires structured efforts to generate high-quality clinical evidence and improve accessibility. Ultimately, reliable, patient-centered dosimetry has the potential to enhance therapeutic efficacy, manage toxicity more effectively, and support the long-term evolution of RPT as a cornerstone of precision oncology.

Dosimetry is integral to informed implementation of radiopharmaceutical therapies, enabling personalized treatment planning and ensuring patient safety by calculating absorbed doses to organs and tumors. As the therapeutic radiopharmaceutical field continues to expand, dosimetry software has emerged as a crucial tool for optimization of treatment efficacy. This review discusses key features and capabilities that current dosimetry software solutions have or should have in the future. We highlight the need for standardization across platforms to support consistent and accurate dose calculations. Furthermore, we explore opportunities for advancing software, such as incorporating biologically effective dose modeling and improving uncertainty quantification. Looking ahead, we advocate for expanding infrastructure for open data sets and fostering ongoing collaboration between vendors and end users to guide the field toward greater integration and efficacy.

The aim of this study is to evaluate the induction of DNA damage by 45 radionuclides, including those used in medical applications and others relevant to radiation protection. The research focuses on understanding the differential effects of irradiating lymphocytes with beta/gamma- and alpha-emitting radionuclides using Monte Carlo simulations. A validated Monte Carlo simulation model was used to assess radiation-induced DNA damage in lymphocytes. The model integrates GATE for macroscopic radiation transport and Geant4-DNA for microscopic simulations at the cellular level. For the study, 45 radionuclides were selected and their S-values and DNA double-strand break (DSB) induction were investigated. For beta- and gamma-emitting radionuclides, DSBs per cell per mGy were quantified, while for alpha-emitters, alpha tracks per cell per mGy, DSBs per cell per mGy, and DSBs per micrometer of alpha track were calculated. For beta/gamma emitters, the lowest number of DSBs was observed with 125I at 0.006 ± 0.003 DSBs·cell⁻¹·mGy⁻¹, while 99mTc had the highest at approximately 0.015 ± 0.005 DSBs·cell⁻¹·mGy⁻¹. The S-value for lymphocyte nuclei ranked from 0.91 ± 0.14 mGy∙h⁻¹∙MBq⁻¹ (63Ni) and 1.06 ± 0.15 mGy∙h⁻¹∙MBq⁻¹ (125I) to 61.83 ± 1.17 mGy∙h⁻¹∙MBq⁻¹ (90Sr). For alpha-emitting radionuclides, 213Bi produced 0.0677 ± 0.0005 DSB·cell⁻¹·mGy⁻¹ while 232Th yielded 0.0914 ± 0.0004 DSB·cell⁻¹·mGy⁻¹. The DSB linear density for alpha tracks ranged from 7.4 ± 0.1 DSBs/µm for 252Cf to 16.8 ± 0.1 DSBs/µm for 232Th. The S-values for lymphocyte nuclei for alpha emitters varied, from 232Th (0.29 ± 0.21 Gy∙h⁻¹∙MBq⁻¹) to 227Th having the highest at 2.22 ± 0.16 Gy∙h⁻¹∙MBq⁻¹, due to cumulative energy deposition. Differences were observed in DNA damage induced by beta/gamma- and alpha-emitting radionuclides. High-energy beta emitters induced DSBs similarly to gamma emitters, but with greater fluctuations in low-energy beta and gamma emitters due to heterogeneous energy deposition and varying interaction probabilities at the cellular level. This study highlights that long half-life alpha-emitting radionuclides may cause more extensive DNA damage due to their higher LET. This work provides a comprehensive S-values database for future experimental studies on radiation-induced DNA damage in lymphocytes.

Objective: Serum thyroglobulin measurements are used in the long-term management of patients with differentiated thyroid cancer following thyroidectomy and radioiodine therapy. The use of predictive biomarkers, such as post-operative stimulated thyroglobulin levels and absorbed dose, may help to identify patients at risk of disease recurrence or an unsuccessful initial treatment. Methods: Differentiated thyroid cancer patients treated with 1.1 or 3.7 GBq of radioiodine using recombinant human thyrotropin stimulation or thyroid hormone withdrawal were recruited into observational clinical studies in France, Germany and the UK with aligned study endpoints (MEDIRAD). The maximum absorbed dose to the thyroid remnant was determined and compared to post-operative stimulated thyroglobulin with respect to its ability to predict ablation success. Radioiodine therapy success was defined as unstimulated or stimulated thyroglobulin level of <0.2 or <1.0 ng/mL 9–12 months post-radioiodine. Results: Ninety-four patients had follow-up data and negative antithyroglobulin antibody tests. Seventy-eight patients (83%) were deemed excellent biochemical responders. Post-operative thyroglobulin and maximum absorbed dose predicted ablation success with receiver operating characteristic area under the curves of 0.83 ± 0.05 (P < 0.001) and 0.64 ± 0.08 (P = 0.12). A dose–response relationship between maximum absorbed dose and ablation success was found for patients with a post-operative stimulated thyroglobulin of ≥1 ng/mL. Conclusions: Predictions of ablation success using post-operative stimulated thyroglobulin or the absorbed dose to the thyroid remnant could inform personalisation of management of differentiated thyroid cancer and identify patients where further treatments or more intensive follow-up are required. Patients with a post-operative stimulated Tg of <1 ng/mL likely do not benefit from radioiodine.