Modelling the In Vivo and Ex Vivo DNA Damage Response after Internal Irradiation of Blood from Patients with Thyroid Cancer.

This work reports on a model that describes patient-specific absorbed dose-dependent DNA damage response in peripheral blood mononuclear cells of thyroid cancer patients during radioiodine therapy and compares the results with the ex vivo DNA damage response in these patients. Blood samples of 18 patients (nine time points up to 168 h post-administration) were analyzed for radiation-induced γ-H2AX + 53BP1 DNA double-strand break foci (RIF). A linear one-compartment model described the absorbed dose-dependent time course of RIF (Parameters: c characterizes DSB damage induction; k1 and k2 are rate constants describing fast and slow repair). The rate constants were compared to ex vivo repair rates. A total of 14 patient datasets could be analyzed; c ranged from 0.012 to 0.109 mGy-1, k2 from 0 to 0.04 h-1. On average, 96% of the damage is repaired quickly with k1 (range: 0.19-3.03 h-1). Two patient subgroups were distinguished by k1-values (n = 6, k1 > 1.1 h-1; n = 8, k1 < 0.6 h-1). A weak correlation with patient age was observed. While induction of RIF was similar among ex vivo and in vivo, the respective repair rates failed to correlate. The lack of correlation between in vivo and ex vivo repair rates and the applicability of the model to other therapies will be addressed in further studies.

Dosimetry and pharmacokinetics of [177Lu]Lu-satoreotide tetraxetan in patients with progressive neuroendocrine tumours.

PURPOSE: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [177Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs). METHODS: This study was part of a phase I/II trial of [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients. RESULTS: In all evaluated organs, maximum [177Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57-66% within 48 h following the first treatment cycle. At the first treatment cycle, [177Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [177Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles. CONCLUSION: [177Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy. TRIAL REGISTRATION: NCT02592707. Registered October 30, 2015.

Renal and Multiorgan Safety of 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer in the VISION Dosimetry Substudy.

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.

Analysis of image data from the EuroNet PHL-C2 trial indicates a potential reduction in injected F-18 FDG activities in children: a proposal to update the EANM Paediatric Dosage Card.

BACKGROUND: The aim of this work is to provide the currently missing evidence that may allow an update of the Paediatric Dosage Card provided by the European Association of Nuclear Medicine (EANM) for conventional PET/CT systems. METHODS: In a total of 2082 consecutive [18F]FDG-PET scans performed within the EuroNet-PHL-C2 trial, the administered [18F]FDG activity was compared to the activity recommended by the EANM Paediatric Dosage Card. None of these scans had been rejected beforehand by the reference nuclear medicine panel of the trial because of poor image quality. For detailed quality assessment, a subset of 91 [18F]FDG-PET scans, all performed in different patients at staging, was selected according to pre-defined criteria, which (a) included only patients who had received substantially lower activities than those recommended by the EANM Paediatric Dosage Card, and (b) included as wide a range of different PET systems and imaging parameters as possible to ensure that the conclusions drawn in this work are as generally valid as possible. The image quality of the subset was evaluated visually by two independent readers using a quality scoring system as well as analytically based on a volume-of-interest analysis in 244 lesions and the healthy liver. Finally, recommendations for an update of the EANM Paediatric Dosage Card were derived based on the available data. RESULTS: The activity recommended by the EANM Paediatric Dosage Card was undercut by a median of 99.4 MBq in 1960 [18F]FDG-PET scans and exceeded by a median of 15.1 MBq in 119 scans. In the subset analysis (n = 91), all image data were visually classified as clinically useful. In addition, only a very weak correlation (r = 0.06) between activity reduction and tumour-to-background ratio was found. Due to the intended heterogeneity of the dataset, the noise could not be analysed statistically sound as the high range of different imaging variables resulted in very small subsets. Finally, a suggestion for an update of the EANM Paediatric Dosage Card was developed, based on the analysis presented, resulting in a mean activity reduction by 39%. CONCLUSION: The results of this work allow for a conservative update of the EANM Paediatric Dosage Card for [18F]FDG-PET/CT scans performed with conventional PET/CT systems.

On the use of solid 133Ba sources as surrogate for liquid 131I in SPECT/CT calibration: a European multi-centre evaluation.

INTRODUCTION: Commissioning, calibration, and quality control procedures for nuclear medicine imaging systems are typically performed using hollow containers filled with radionuclide solutions. This leads to multiple sources of uncertainty, many of which can be overcome by using traceable, sealed, long-lived surrogate sources containing a radionuclide of comparable energies and emission probabilities. This study presents the results of a quantitative SPECT/CT imaging comparison exercise performed within the MRTDosimetry consortium to assess the feasibility of using 133Ba as a surrogate for 131I imaging. MATERIALS AND METHODS: Two sets of four traceable 133Ba sources were produced at two National Metrology Institutes and encapsulated in 3D-printed cylinders (volume range 1.68-107.4 mL). Corresponding hollow cylinders to be filled with liquid 131I and a mounting baseplate for repeatable positioning within a Jaszczak phantom were also produced. A quantitative SPECT/CT imaging comparison exercise was conducted between seven members of the consortium (eight SPECT/CT systems from two major vendors) based on a standardised protocol. Each site had to perform three measurements with the two sets of 133Ba sources and liquid 131I. RESULTS: As anticipated, the 131I pseudo-image calibration factors (cps/MBq) were higher than those for 133Ba for all reconstructions and systems. A site-specific cross-calibration reduced the performance differences between both radionuclides with respect to a cross-calibration based on the ratio of emission probabilities from a median of 12-1.5%. The site-specific cross-calibration method also showed agreement between 133Ba and 131I for all cylinder volumes, which highlights the potential use of 133Ba sources to calculate recovery coefficients for partial volume correction. CONCLUSION: This comparison exercise demonstrated that traceable solid 133Ba sources can be used as surrogate for liquid 131I imaging. The use of solid surrogate sources could solve the radiation protection problem inherent in the preparation of phantoms with 131I liquid activity solutions as well as reduce the measurement uncertainties in the activity. This is particularly relevant for stability measurements, which have to be carried out at regular intervals.

PSMA-PET improves deep learning-based automated CT kidney segmentation.

For dosimetry of radiopharmaceutical therapies, it is essential to determine the volume of relevant structures exposed to therapeutic radiation. For many radiopharmaceuticals, the kidneys represent an important organ-at-risk. To reduce the time required for kidney segmentation, which is often still performed manually, numerous approaches have been presented in recent years to apply deep learning-based methods for CT-based automated segmentation. While the automatic segmentation methods presented so far have been based solely on CT information, the aim of this work is to examine the added value of incorporating PSMA-PET data in the automatic kidney segmentation. METHODS: A total of 108 PET/CT examinations (53 [68Ga]Ga-PSMA-I&T and 55 [18F]F-PSMA-1007 examinations) were grouped to create a reference data set of manual segmentations of the kidney. These segmentations were performed by a human examiner. For each subject, two segmentations were carried out: one CT-based (detailed) segmentation and one PET-based (coarser) segmentation. Five different u-net based approaches were applied to the data set to perform an automated segmentation of the kidney: CT images only, PET images only (coarse segmentation), a combination of CT and PET images, a combination of CT images and a PET-based coarse mask, and a CT image, which had been pre-segmented using a PET-based coarse mask. A quantitative assessment of these approaches was performed based on a test data set of 20 patients, including Dice score, volume deviation and average Hausdorff distance between automated and manual segmentations. Additionally, a visual evaluation of automated segmentations for 100 additional (i.e., exclusively automatically segmented) patients was performed by a nuclear physician. RESULTS: Out of all approaches, the best results were achieved by using CT images which had been pre-segmented using a PET-based coarse mask as input. In addition, this method performed significantly better than the segmentation based solely on CT, which was supported by the visual examination of the additional segmentations. In 80% of the cases, the segmentations created by exploiting the PET-based pre-segmentation were preferred by the nuclear physician. CONCLUSION: This study shows that deep-learning based kidney segmentation can be significantly improved through the addition of a PET-based pre-segmentation. The presented method was shown to be especially beneficial for kidneys with cysts or kidneys that are closely adjacent to other organs such as the spleen, liver or pancreas. In the future, this could lead to a considerable reduction in the time required for dosimetry calculations as well as an improvement in the results.

A phase I/II study of the safety and efficacy of [177Lu]Lu-satoreotide tetraxetan in advanced somatostatin receptor-positive neuroendocrine tumours.

PURPOSE: We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [177Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity. METHODS: This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [177Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [177Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 µg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow. RESULTS: Median cumulative administered activity of [177Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment­related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3-99.4), and overall response rate was 21.1% (95% CI: 9.6-37.3). CONCLUSION: [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02592707. Registered October 30, 2015.

Radiation-induced double-strand breaks by internal ex vivo irradiation of lymphocytes: Validation of a Monte Carlo simulation model using GATE and Geant4-DNA.

This study describes a method to validate a radiation transport model that quantifies the number of DNA double-strand breaks (DSB) produced in the lymphocyte nucleus by internal ex vivo irradiation of whole blood with the radionuclides 90Y, 99mTc, 123I, 131I, 177Lu, 223Ra, and 225Ac in a test vial using the GATE/Geant4 code at the macroscopic level and the Geant4-DNA code at the microscopic level. METHODS: The simulation at the macroscopic level reproduces an 8 mL cylindrical water-equivalent medium contained in a vial that mimics the geometry for internal ex vivo blood irradiation. The lymphocytes were simulated as spheres of 3.75 µm radius randomly distributed, with a concentration of 125 spheres/mL. A phase-space actor was attached to each sphere to register all the entering particles. The simulation at the microscopic level for each radionuclide was performed using the Geant4-DNA tool kit, which includes the clustering example centered on a density-based spatial clustering of applications with noise (DBSCAN) algorithm. The irradiation source was constructed by generating a single phase space from the sum of all phase spaces. The lymphocyte nucleus was defined as a water sphere of a 3.1 µm radius. The absorbed dose coefficients for lymphocyte nuclei (dLymph) were calculated and compared with macroscopic whole blood absorbed dose coefficients (dBlood). The DBSCAN algorithm was used to calculate the number of DSBs. Lastly, the number of DSB∙cell-1∙mGy-1 (simulation) was compared with the number of radiation-induced foci per cell and absorbed dose (RIF∙cell-1∙mGy-1) provided by experimental data for gamma and beta emitting radionuclides. For alpha emitters, dLymph and the number of α-tracks∙100 cell-1∙mGy-1 and DBSs∙µm-1 were calculated using experiment-based thresholds for the α-track lengths and DBSs/track values. The results were compared with the results of an ex vivo study with 223Ra. RESULTS: The dLymph values differed from the dBlood values by -1.0% (90Y), -5.2% (99mTc), -22.3% (123I), 0.35% (131I), 2.4% (177Lu), -5.6% (223Ra) and -6.1% (225Ac). The number of DSB∙cell-1∙mGy-1 for each radionuclide was 0.015 DSB∙cell-1∙mGy-1 (90Y), 0.012 DSB∙cell-1∙mGy-1 (99mTc), 0.014DSB∙cell-1∙mGy-1 (123I), 0.012 DSB∙cell-1∙mGy-1 (131I), and 0.016 DSB∙cell-1∙mGy-1 (177Lu). These values agree very well with experimental data. The number of α-tracks∙100 cells-1∙mGy-1 for 223Ra and 225Ac where 0.144 α-tracks∙100 cells-1∙mGy-1 and 0.151 α-tracks∙100 cells-1∙mGy-1, respectively. These values agree very well with experimental data. Moreover, the linear density of DSBs per micrometer α-track length were 11.13 ±â€¯0.04 DSB/µm and 10.86 ±â€¯0.06 DSB/µm for 223Ra and 225Ac, respectively. CONCLUSION: This study describes a model to simulate the DNA DSB damage in lymphocyte nuclei validated by experimental data obtained from internal ex vivo blood irradiation with radionuclides frequently used in diagnostic and therapeutic procedures in nuclear medicine.

Normal organ dosimetry for thyroid cancer patients treated with radioiodine as part of the multi-centre multi-national Horizon 2020 MEDIRAD project.

PURPOSE: Dosimetry is rarely performed for the treatment of differentiated thyroid cancer patients with Na[131I]I (radioiodine), and information regarding absorbed doses delivered is limited. Collection of dosimetry data in a multi-centre setting requires standardised quantitative imaging and dosimetry. A multi-national, multi-centre clinical study was performed to assess absorbed doses delivered to normal organs for differentiated thyroid cancer patients treated with Na[131I]I. METHODS: Patients were enrolled in four centres and administered fixed activities of 1.1 or 3.7 GBq of Na[131I]I using rhTSH stimulation or under thyroid hormone withdrawal according to local protocols. Patients were imaged using SPECT(/CT) at variable imaging time-points following standardised acquisition and reconstruction protocols. Whole-body retention data were collected. Dosimetry for normal organs was performed at two dosimetry centres and results collated. RESULTS: One hundred and five patients were recruited. Median absorbed doses per unit administered activity of 0.44, 0.14, 0.05 and 0.16 mGy/MBq were determined for the salivary glands of patients treated at centre 1, 2, 3 and 4, respectively. Median whole-body absorbed doses for 1.1 and 3.7 GBq were 0.05 Gy and 0.16 Gy, respectively. Median whole-body absorbed doses per unit administered activity of 0.04, 0.05, 0.04 and 0.04 mGy/MBq were calculated for centre 1, 2, 3 and 4, respectively. CONCLUSIONS: A wide range of normal organ doses were observed for differentiated thyroid cancer patients treated with Na[131I]I, highlighting the necessity for individualised dosimetry. The results show that data may be collated from multiple centres if minimum standards for the acquisition and dosimetry protocols can be achieved.

Joint EANM/SNMMI procedure guideline for the use of 177Lu-labeled PSMA-targeted radioligand-therapy (177Lu-PSMA-RLT).

Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [177Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that 177Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from 177Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [177Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis.

Development of a validation imaging dataset for Molecular Radiotherapy dosimetry multicenter intercomparison exercises based on anthropomorphic phantoms.

Validation of a Molecular Radiotherapy (MRT) dosimetry system requires imaging data for which an accompanying "ground truth" pharmacokinetic model and absorbed dose calculation are known. METHODS: We present a methodology for production of a validation dataset for image based 177Lu dotatate dosimetry calculations. A pharmacokinetic model is presented with activity concentrations corresponding to common imaging timepoints. Anthropomorphic 3D printed phantoms, corresponding to the organs at risk, have been developed to provide SPECT/CT and Whole Body imaging with known organ activities corresponding to common clinical timepoints. RESULTS: Results for the accuracy of phantom filling reproduce the activity concentrations from the pharmacokinetic model for all timepoints and organs within measurement uncertainties, with a mean deviation of 0.6(8)%. The imaging dataset, ancillary data and phantoms designs are provided as a source of well characterized input data for the validation of clinical MRT dosimetry systems. CONCLUSIONS: The combination of pharmacokinetic modelling with the use of anthropomorphic 3D printed phantoms are a promising procedure to provide data for the validation of Molecular Radiotherapy Dosimetry systems, allowing multicentre comparisons.

Application of artificial intelligence in nuclear medicine and molecular imaging: a review of current status and future perspectives for clinical translation.

Artificial intelligence (AI) will change the face of nuclear medicine and molecular imaging as it will in everyday life. In this review, we focus on the potential applications of AI in the field, both from a physical (radiomics, underlying statistics, image reconstruction and data analysis) and a clinical (neurology, cardiology, oncology) perspective. Challenges for transferability from research to clinical practice are being discussed as is the concept of explainable AI. Finally, we focus on the fields where challenges should be set out to introduce AI in the field of nuclear medicine and molecular imaging in a reliable manner.

Modelling SPECT auto-contouring acquisitions for 177Lu & 131I molecular radiotherapy using new developments in Geant4/GATE.

PURPOSE: Monte Carlo modelling of SPECT imaging in Molecular Radiotherapy can improve activity quantification. Until now, SPECT modelling with GATE only considered circular orbit (CO) acquisitions. This cannot reproduce auto-contour acquisitions, where the detector head moves close to the patient to improve image resolution. The aim of this work is to develop and validate an auto-contouring step-and-shoot acquisition mode for GATE SPECT modelling. METHODS: 177Lu and 131I SPECT experimental acquisitions performed on a Siemens Symbia T2 and GE Discovery 670 gamma camera, respectively, were modelled. SPECT projections were obtained for a cylindrical Jaszczak phantom and a lung and spine phantom. Detector head parameters (radial positions and acquisition angles) were extracted from the experimental projections to model the non-circular orbit (NCO) detector motion. The gamma camera model was validated against the experimental projections obtained with the cylindrical Jaszczak (177Lu) and lung and spine phantom (131I). Then, 177Lu and 131I CO and NCO SPECT projections were simulated to validate the impact of explicit NCO modelling on simulated projections. RESULTS: Experimental and simulated SPECT images were compared using the gamma index, and were in good agreement with gamma index passing rate (GIPR) and gammaavg of 96.27%, 0.242 (177Lu) and 92.89%, 0.36 (131I). Then, simulated 177Lu and 131I CO and NCO SPECT projections were compared. The GIPR, gammaavg between the two gamma camera motions was 99.85%, 0.108 for 177Lu and 75.58%, 0.6 for 131I. CONCLUSION: This work thereby justifies the need for auto-contouring modelling for isotopes with high septal penetration.

Quantification of the volume fraction of fat, water and bone mineral in spongiosa for red marrow dosimetry in molecular radiotherapy by using a dual-energy (SPECT/)CT.

A patient-specific absorbed dose calculation for red marrow dosimetry requires quantifying patient-specific volume fractions of the red marrow, yellow marrow, and trabecular bone in the spongiosa of several skeletal sites. This quantification allows selecting appropriate S values calculated from the parameterized radiation transport models for bone and bone marrow dosimetry. Currently, no comprehensive, individualized, and non-invasive procedure is available for quantifying the volume fractions of red marrow, yellow marrow, and trabecular bone in the spongiosa. This study aims to provide a new quantitative method based on dual-energy computed tomography to fill this gap in red marrow dosimetry using a (SPECT/)CT system. METHODS: First, a method for parametrizing the photon attenuation coefficients relative to water was implemented. Next, a method to calculate the effective atomic number (Zeff) and effective mass density (ρeff) using dual-energy CT (DECT) was employed. Lastly, two- and three-material decomposition using a dual-energy quantitative CT method (DEQCT) was performed in an anthropomorphic spine phantom and two bone samples of a boar, respectively. The measurements of Zeff and ρeff were compared with the syngo.CT DE Rho/Z tool (Siemens Healthineers). Furthermore, the DEQCT method implemented in this study (DEQCT-I) was compared with a second DEQCT method based on the use of external material standards (DEQCT-II). DEQCT-II was used as reference method for calculating relative errors. RESULTS: The two-material decomposition in the anthropomorphic spine phantom presented a maximum relative error of -10% for the bone mineral density quantification. Furthermore, Zeff and ρeff calculated by DEQCT-I differed from syngo.CT DE Rho/Z tool by less than 4.4% and 1.9%, respectively. The three-material decomposition in the two bone samples showed a maximum relative error of 21%, -17%, and 15% for the quantification of the volume fractions of fat, water, and bone mineral equivalent materials. Lastly, Zeff and ρeff calculated by DEQCT-I differed from syngo.CT DE Rho/Z tool by less than 8.2% and 7.0%, respectively. CONCLUSION: This study shows that quantifying the volume fraction of fat, water, and bone mineral using a phantom-independent and post-reconstruction DEQCT method is feasible. DEQCT-I has the advantage of not requiring prior information about the X-ray spectra or the detector sensitivity function, as is the case with spectral-based DEQCT methods. Instead, DEQCT-I, similar to other DEQCT methods depends on the chemical description of reference materials and a beam hardening correction function. DEQCT-I method provides an individualized and non-invasive procedure using a (SPECT/)CT system to apply S values based on the patient-specific volume fractions of yellow marrow, red marrow, and bone mineral in red marrow dosimetry.

Biokinetics and Dosimetry of 177Lu-Pentixather.

The chemokine receptor 4 (CXCR4), which is overexpressed in many solid and hematologic malignancies, can be targeted for radiopeptide therapy via the antagonist pentixather. The biokinetics and dosimetry of 177Lu-pentixather and 90Y-pentixather were analyzed in this study. Methods: This retrospective study was a standardized reevaluation of data collected for treatment planning. Nineteen patients with complete sets of planar whole-body scans over at least 4 d and a single SPECT/CT scan after administration of 200 MBq of 177Lu-pentixather were included. Kinetics were measured in the whole body, in tissues with activity retention, and in 10 individuals in the blood. Time-integrated activity coefficients and tissue-absorbed doses were derived. Results: Increased uptake of pentixather was observed in the kidneys, liver, spleen, and bone marrow, inducing respective median absorbed doses of 0.91 Gy (range, 0.38-3.47 Gy), 0.71 Gy (range, 0.39-1.17 Gy), 0.58 Gy (range, 0.34-2.26 Gy), and 0.47 Gy (range, 0.14-2.33 Gy) per GBq of 177Lu-pentixather and 3.75 Gy (range, 1.48-12.2 Gy), 1.61 Gy (range, 1.14-2.97 Gy), 1.66 Gy (range, 0.97-6.69 Gy), and 1.06 Gy (range, 0.27-4.45 Gy) per GBq of 90Y-pentixather. In most tissues, activity increased during the first day after the administration of 177Lu-pentixather and afterward decayed with mean effective half-lives of 41 ± 10 h (range, 24-64 h) in the kidneys and median half-lives of 109, 86, and 92 h in the liver, spleen, and bone marrow, respectively. Maximum uptake per kidney was 2.2% ± 1.0% (range, 0.6%-5.1%). In organs showing no specific uptake, absorbed doses exceeding 0.3 Gy/GBq of 90Y-pentixather were estimated for the urinary bladder and for tissues adjacent to accumulating organs such as the adrenal glands, bone surface, and gallbladder. Dose estimates for tumors and extramedullary lesions ranged from 1.5 to 18.2 Gy/GBq of 90Y-pentixather. Conclusion: In patients with hematologic neoplasms, absorbed doses calculated for bone marrow and extramedullary lesions are sufficient to be effective as an adjunct to high-dose chemotherapies before stem cell transplantation.

Toward a Patient-Specific Traceable Quantification of SPECT/CT-Based Radiopharmaceutical Distributions.

Quantitative SPECT/CT imaging is currently the state of the art for peritherapeutic monitoring of radiopharmaceutical distributions. Because of poor resolution, however, the verification of SPECT/CT-based activity distributions is of particular importance. Because of the lack of a ground truth in patient measurements, phantoms are commonly used as a substitute for clinical validation of quantitative SPECT/CT. Because of the time-consuming and erroneous preparation of multicompartment phantoms, such as for the kidney, the usually very complex internal activity distributions are typically replaced by 1- or 2-compartment models. To provide a simplified solution for generating inhomogeneous activity distributions, this work presents a methodology for designing single-compartment phantoms that mimic inhomogeneous spatial activity distributions by using internal filling structures of different volume fractions. Methods: A series of phantoms with different filling structures was designed, 3-dimensionally printed, and measured. After assessing the feasibility of the presented approach in a simple geometry, a set of three patient-specific kidney phantoms was designed on the basis of the contrast-enhanced CT scan of a patient with metastatic castration-resistant prostate cancer. Internal gyroid structures of different wall thicknesses were used in the renal medulla and cortex to reproduce the inhomogeneous activity distribution observed in a peritherapeutic SPECT/CT acquisition 24 h after injection of 177Lu-labeled prostate-specific membrane antigen (apparent activity concentration ratios of 1:1, 1:3.5, and 1:7.5). After 3-dimensional printing, SPECT/CT experiments were performed and the results were compared with the patient data for different reconstruction settings (iterations, subsets, and postfiltering). Results: Good agreement was found between phantom designs and fabricated phantoms (based on high-resolution CT). No internal filling structures were visible in any of the SPECT images, indicating a sufficiently small feature size. Although good visual and quantitative agreement was achieved for certain combinations of filling structure and reconstruction, a histogram analysis indicated an even more complex activity distribution in the patient than represented by the two compartments assumed in our model. Conclusion: The proposed methodology provides patient-specific phantoms mimicking inhomogeneous activity distributions while using a single stock solution, thus simplifying the filling process and reducing uncertainties in the activity determination. This method enables an unprecedented possibility for patient-specific evaluation of radiopharmaceutical uptake, reducing uncertainties in internal dosimetry and individualized treatments.

mRNA and small RNA gene expression changes in peripheral blood to detect internal Ra-223 exposure.

PURPOSE: Excretion analysis is the established method for detection of incorporated alpha-emitting radionuclides, but it is laborious and time consuming. We sought a simplified method in which changes in gene expression might be measured in human peripheral blood to detect incorporated radionuclides. Such an approach could be used to quickly determine internal exposure in instances of a radiological dispersal device or a radiation accident. MATERIALS AND METHODS: We evaluated whole blood samples from five patients with castration-resistant prostate cancer and multiple bone metastases (without visceral or nodal involvement), who underwent treatment with the alpha emitting isotope Radium-223 dichloride (Ra-223, Xofigo®). Patients received about 4 MBq per cycle and, depending on survival and treatment tolerance, were followed for six months. We collected 24 blood samples approximately monthly corresponding to treatment cycle. RESULTS: Firstly, we conducted whole genome screening of mRNAs (mRNA seq) and small RNAs (small RNA seq) using next generation sequencing in one patient at eight different time points during all six cycles of Ra-223-therapy. We identified 1900 mRNAs and 972 small RNAs (222 miRNAs) that were differentially up- or down-regulated during follow-up after the first treatment with Ra-223. Overall candidate RNA species inclusion criteria were a general (≥|2|-fold) change or with peaking profiles (≥|5|-fold) at specific points in time. Next we chose 72 candidate mRNAs and 101 small RNAs (comprising 29 miRNAs) for methodologic (n = 8 samples, one patient) and independent (n = 16 samples, four patients) validation by qRT-PCR. In total, 15 mRNAs (but no small RNAs) were validated by methodologic and independent testing. However, the deregulation occurred at different time points, showing a large inter-individual variability in response among patients. CONCLUSIONS: This proof of concept provides support for the applicability of gene expression measurements to detect internalized alpha-emitting radionuclides, but further work is needed with a larger sample size. While our approach has merit for internal deposition monitoring, it was complicated by the severe clinical condition of the patients we studied.

Comparing absorbed doses and radiation risk of the α-emitting bone-seekers [223Ra]RaCl2 and [224Ra]RaCl2.

[223Ra]RaCl2 and [224Ra]RaCl2 are bone seekers, emitting high LET, and short range (< 100 µm) alpha-particles. Both radionuclides show similar decay properties; the total alpha energies are comparable (223Ra: ≈28 MeV, 224Ra: ≈26 MeV). [224Ra]RaCl2 has been used from the mid-1940s until 1990 for treating different bone and joint diseases with activities of up to approximately 50 MBq [224Ra]RaCl2. In 2013 [223Ra]RaCl2 obtained marketing authorization by the FDA and by the European Union for the treatment of metastatic prostate cancer with an activity to administer of 0.055 MBq per kg body weight for six cycles. For intravenous injections in humans a model calculation using the biokinetic model of ICRP67 shows a ratio of organ absorbed dose coefficients (224Ra:223Ra) between 0.37 (liver) and 0.97 except for the kidneys (2.27) and blood (1.57). For the red marrow as primary organ-at-risk, the ratio is 0.57. The differences are mainly caused be the differing half-lives of the decay products of both radium isotopes. Both radionuclides show comparable DNA damage patterns in peripheral blood mononuclear cells after internal ex-vivo irradiation. Data on the long-term radiation-associated side effects are only available for treatment with [224Ra]RaCl2. Two epidemiological studies followed two patient groups treated with [224Ra]RaCl2 for more than 25 years. One of them was the "Spiess study", a cohort of 899 juvenile patients who received several injections of [224Ra]RaCl2 with a mean specific activity of 0.66 MBq/kg. Another patient group of ankylosing spondylitis patients was treated with 10 repeated intravenous injections of [224Ra]RaCl2, 1 MBq each, 1 week apart. In total 1,471 of these patients were followed-up in the "Wick study". In both studies, an increased cancer mortality by leukemia and solid cancers was observed. Similar considerations on long-term effects likely apply to [223Ra]RaCl2 as well since the biokinetics are similar and the absorbed doses in the same range. However, this increased risk will most likely not be observed due to the much shorter life expectancy of prostate cancer patients treated with [223Ra]RaCl2.

Dosimetry for Radiopharmaceutical Therapy: The European Perspective.

This review presents efforts in Europe over the last few years with respect to standardization of quantitative imaging and dosimetry and comprises the results of several European research projects on practices regarding radiopharmaceutical therapies (RPTs). Because the European Union has regulatory requirements concerning dosimetry in RPTs, the European Association of Nuclear Medicine released a position paper in 2021 on the use of dosimetry under these requirements. The importance of radiobiology for RPTs is elucidated in another position paper by the European Association of Nuclear Medicine. Furthermore, how dosimetry interacts with clinical requirements is described, with several clinical examples. In the future, more efforts need to be undertaken to increase teaching and standardization efforts and to incorporate radiobiology for further individualizing patient treatment, with the aim of improving the outcome and safety of RPTs.

A multicentre and multi-national evaluation of the accuracy of quantitative Lu-177 SPECT/CT imaging performed within the MRTDosimetry project.

PURPOSE: Patient-specific dosimetry is required to ensure the safety of molecular radiotherapy and to predict response. Dosimetry involves several steps, the first of which is the determination of the activity of the radiopharmaceutical taken up by an organ/lesion over time. As uncertainties propagate along each of the subsequent steps (integration of the time-activity curve, absorbed dose calculation), establishing a reliable activity quantification is essential. The MRTDosimetry project was a European initiative to bring together expertise in metrology and nuclear medicine research, with one main goal of standardizing quantitative 177Lu SPECT/CT imaging based on a calibration protocol developed and tested in a multicentre inter-comparison. This study presents the setup and results of this comparison exercise. METHODS: The inter-comparison included nine SPECT/CT systems. Each site performed a set of three measurements with the same setup (system, acquisition and reconstruction): (1) Determination of an image calibration for conversion from counts to activity concentration (large cylinder phantom), (2) determination of recovery coefficients for partial volume correction (IEC NEMA PET body phantom with sphere inserts), (3) validation of the established quantitative imaging setup using a 3D printed two-organ phantom (ICRP110-based kidney and spleen). In contrast to previous efforts, traceability of the activity measurement was required for each participant, and all participants were asked to calculate uncertainties for their SPECT-based activities. RESULTS: Similar combinations of imaging system and reconstruction lead to similar image calibration factors. The activity ratio results of the anthropomorphic phantom validation demonstrate significant harmonization of quantitative imaging performance between the sites with all sites falling within one standard deviation of the mean values for all inserts. Activity recovery was underestimated for total kidney, spleen, and kidney cortex, while it was overestimated for the medulla. CONCLUSION: This international comparison exercise demonstrates that harmonization of quantitative SPECT/CT is feasible when following very specific instructions of a dedicated calibration protocol, as developed within the MRTDosimetry project. While quantitative imaging performance demonstrates significant harmonization, an over- and underestimation of the activity recovery highlights the limitations of any partial volume correction in the presence of spill-in and spill-out between two adjacent volumes of interests.