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.

Background: In nuclear medicine, numerous cancer types are treated via internal irradiation with radiopharmaceuticals, including low-LET (linear energy transfer) beta-emitting radionuclides like Lu-177. In most cases, such treatments lead to low-dose exposure of organ systems with β-irradiation, which induces only few isolated DSBs (double-strand breaks) in the nuclei of hit cells, the most threatening DNA damage type. That damaging effect contrasts with the clustering of DNA damage and DSBs in nuclei traversed by high-LET particles (α particles, ions, etc.). Methods: After in-solution β-irradiation for 1 h with Lu-177 leading to an absorbed dose of about 100 mGy, we investigated the spatial nano-organization of chromatin at DSB damage sites, of repair proteins and of heterochromatin marks via single-molecule localization microscopy (SMLM) in PBMCs. For evaluation, mathematical approaches were used (Ripley distance frequency statistics, DBScan clustering, persistent homology and similarity measurements). Results: We analyzed, at the nanoscale, the distribution of the DNA damage response (DDR) proteins γH2AX, 53BP1, MRE11 and pATM in the chromatin regions surrounding a DSB. Furthermore, local changes in spatial H3K9me3 heterochromatin organization were analyzed relative to γH2AX distribution. SMLM measurements of the different fluorescent molecule tags revealed characteristic clustering of the DDR markers around one or two damage foci per PBMC cell nucleus. Ripley distance histograms suggested the concentration of MRE11 molecules inside γH2AX-clusters, while 53BP1 was present throughout the entire γH2AX clusters. Persistent homology comparisons for 53BP1, MRE11 and γH2AX by Jaccard index calculation revealed significant topological similarities for each of these markers. Since the heterochromatin organization of cell nuclei determines the identity of cell nuclei and correlates to genome activity, it also influences DNA repair. Therefore, the histone H3 tri methyl mark H3K9me3 was analyzed for its topology. In contrast to typical results obtained through photon irradiation, where γH2AX and H3K9me3 markers were well separated, the results obtained here also showed a close spatial proximity (“co-localization”) in many cases (minimum distance of markers = marker size), even with the strictest co-localization distance threshold (20 nm) for γH2AX and H3K9me3. The data support the results from the literature where only one DSB induced by low-dose low LET irradiation (<100 mGy) can remain without heterochromatin relaxation for subsequent repair.

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.

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.

This study by the EANM radiobiology working group aims to analyze the efficacy and toxicity of targeted radionuclide therapy (TRT) using radiopharmaceuticals approved by the EMA and FDA for neuroendocrine tumors and prostate cancer. It seeks to understand the correlation between physical parameters such as absorbed dose and TRT outcomes, alongside other biological factors. We reviewed clinical studies on TRT, focusing on the relationship between physical parameters and treatment outcomes, and applying basic radiobiological principles to radiopharmaceutical therapy to identify key factors affecting therapeutic success. The analysis revealed that mean absorbed dose alone is insufficient to predict treatment response or toxicity. For absorbed doses below a certain threshold, outcomes are unpredictable, while doses above this threshold improve the likelihood of biological responses. However, even at higher absorbed doses, response plateaus indicate the need for additional parameters to explain outcome variability, including heterogeneity in target expression, anatomical disease location, (epi)genetics, DNA repair capacity, and the tumor microenvironment, aspects that will be discussed in Part II of this analysis. Understanding radiobiology is crucial for optimizing TRT. More dosimetric data is needed to refine treatment protocols. While absorbed dose is critical, it alone does not determine TRT outcomes. Future research should integrate biological parameters with physical dosimetry to enhance efficacy and minimize toxicity.

The combination of high and low LET radionuclides has been tested in several patient studies to improve treatment response. Radionuclide mixtures can also be released in nuclear power plant accidents or nuclear bomb deployment. This study investigated the DNA damage response and DNA double-strand break (DSB) repair in peripheral blood mononuclear cells (PBMCs) after internal exposure of blood samples of 10 healthy volunteers to either no radiation (baseline) or different radionuclide mixtures of the α- and β-emitters [223Ra]RaCl2 and [177Lu]LuCl3, i.e., 25 mGy/75 mGy, 50 mGy/50 mGy and 75 mGy/25 mGy, respectively. DSB foci and γ-H2AX α-track enumeration directly after 1 h of exposure or after 4 h or 24 h of repair revealed that radiation-induced foci (RIF) and α-track induction in 100 cells was similar for mixed α/β and pure internal α- or β-irradiation, as were the repair rates for all radiation qualities. In contrast, the fraction of unrepaired RIF (Qβ) in PBMCs after mixed α/β-irradiation (50% 223Ra & 50% 177Lu: Qβ = 0.23 ± 0.10) was significantly elevated relative to pure β-irradiation (50 mGy: Qβ, pure = 0.06 ± 0.02), with a similar trend being noted for all mixtures. This α-dose-dependent increase in persistent foci likely relates to the formation of complex DNA damage that remains difficult to repair.

To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [177Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs). 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. 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

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.

Radioligand therapy is an emerging and effective treatment option for various types of malignancies, but may be intricately linked to hematological side effects such as anemia, lymphopenia or thrombocytopenia. The safety and efficacy of novel theranostic agents, targeting increasingly complex targets, can be well served by comprehensive dosimetry. However, optimization in patient management and patient selection based on risk-factors predicting adverse events and built upon reliable dose-response relations is still an open demand. In this context, artificial intelligence methods, especially machine learning and deep learning algorithms, may play a crucial role. This review provides an overview of upcoming opportunities for integrating artificial intelligence methods into the field of dosimetry in nuclear medicine by improving bone marrow and blood dosimetry accuracy, enabling early identification of potential hematological risk-factors, and allowing for adaptive treatment planning. It will further exemplify inspirational success stories from neighboring disciplines that may be translated to nuclear medicine practices, and will provide conceptual suggestions for future directions. In the future, we expect artificial intelligence-assisted (predictive) dosimetry combined with clinical parameters to pave the way towards truly personalized theranostics in radioligand therapy.

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.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.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.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.

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 [ 18 F]FDG-PET scans performed within the EuroNet-PHL-C2 trial, the administered [ 18 F]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 [ 18 F]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 [ 18 F]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 [ 18 F]FDG-PET/CT scans performed with conventional PET/CT systems. Graphical abstract

BACKGROUND:In prostate cancer (PCa), questions remain on indications for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging and PSMA radioligand therapy, integration of advanced imaging in nomogram-based decision-making, dosimetry, and development of new theranostic applications. OBJECTIVE:We aimed to critically review developments in molecular hybrid imaging and systemic radioligand therapy, to reach a multidisciplinary consensus on the current state of the art in PCa. DESIGN, SETTING, AND PARTICIPANTS:The results of a systematic literature search informed a two-round Delphi process with a panel of 28 PCa experts in medical or radiation oncology, urology, radiology, medical physics, and nuclear medicine. The results were discussed and ratified in a consensus meeting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Forty-eight statements were scored on a Likert agreement scale and six as ranking options. Agreement statements were analysed using the RAND appropriateness method. Ranking statements were analysed using weighted summed scores. RESULTS AND LIMITATIONS:After two Delphi rounds, there was consensus on 42/48 (87.5%) of the statements. The expert panel recommends PSMA PET to be used for staging the majority of patients with unfavourable intermediate and high risk, and for restaging of suspected recurrent PCa. There was consensus that oligometastatic disease should be defined as up to five metastases, even using advanced imaging modalities. The group agreed that [177Lu]Lu-PSMA should not be administered only after progression to cabazitaxel and that [223Ra]RaCl2 remains a valid therapeutic option in bone-only metastatic castration-resistant PCa. Uncertainty remains on various topics, including the need for concordant findings on both [18F]FDG and PSMA PET prior to [177Lu]Lu-PSMA therapy. CONCLUSIONS:There was a high proportion of agreement among a panel of experts on the use of molecular imaging and theranostics in PCa. Although consensus statements cannot replace high-certainty evidence, these can aid in the interpretation and dissemination of best practice from centres of excellence to the wider clinical community. PATIENT SUMMARY:There are situations when dealing with prostate cancer (PCa) where both the doctors who diagnose and track the disease development and response to treatment, and those who give treatments are unsure about what the best course of action is. Examples include what methods they should use to obtain images of the cancer and what to do when the cancer has returned or spread. We reviewed published research studies and provided a summary to a panel of experts in imaging and treating PCa. We also used the research summary to develop a questionnaire whereby we asked the experts to state whether or not they agreed with a list of statements. We used these results to provide guidance to other health care professionals on how best to image men with PCa and what treatments to give, when, and in what order, based on the information the images provide.

[Ra-223]RaCl2 and [Ra-224]RaCl2 are bone seekers, emitting high LET, and short range (< 100 mu m) alpha-particles. Both radionuclides show similar decay properties; the total alpha energies are comparable (Ra-223: approximate to 28 MeV, Ra-224: approximate to 26 MeV). [Ra-224]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 [Ra-224]RaCl2. In 2013 [Ra-223]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 (Ra-224:Ra-223) 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 [Ra-224]RaCl2. Two epidemiological studies followed two patient groups treated with [Ra-224]RaCl2 for more than 25 years. One of them was the "Spiess study", a cohort of 899 juvenile patients who received several injections of [Ra-224]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 [Ra-224]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 [Ra-223]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 [Ra-223]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.

8-(Hydroxymethyl)-3,N(4)-etheno-C (8-HM-epsilonC) is an exocyclic adduct resulting from the reaction of dC with glycidaldehyde, a mutagen and animal carcinogen. This compound has now been synthesized and its phosphoramidite incorporated site-specifically into a defined 25-mer oligonucleotide. In this study, the mutagenic potential of this adduct in the 25-mer oligonucleotide was investigated in an in vitro primer-template extension assay using four mammalian DNA polymerases. The miscoding potentials were also compared to those of an analogous derivative, 3,N(4)-etheno C (epsilonC), in the same sequence. Both adducts primarily blocked replication by calf thymus DNA polymerase alpha at the modified base, while human polymerase beta catalyzed measurable replication synthesis through both adducts. Nucleotide insertion experiments showed that dA and dC were incorporated by pol beta opposite either adduct, which would result in a C --> T transition or C --> G transversion. Human polymerase eta, a product of the xeroderma pigmentosum variant (XP-V) gene, catalyzed the most efficient bypass of the two lesions with 25% and 32% for 8-HM-epsilonC and epsilonC bypassed after 15 min. Varying amounts of all four bases opposite the modified bases resulted with pol eta. Human polymerase kappa primarily blocked synthesis at the base prior to the adduct. However, some specific misincorporation of dT resulted, forming an epsilonC.T or 8-HM-epsilonC.T pair. From these data, we conclude that the newly synthesized glycidaldehyde-derived adduct, 8-HM-epsilonC, is a miscoding lesion. The bypass efficiency and insertion specificity of 8-HM-epsilonC and epsilonC were similar for all four polymerases tested, which could be attributed to the similar planarity and sugar conformations for these two derivatives as demonstrated by molecular modeling studies.

Quantification of [68 Ga]-labeled PSMA PET predicts response in patients with prostate cancer (PC) who undergo PSMA-targeted radioligand therapy (RLT). Given the increasing use [18F]-labeled radiotracers, we aimed to determine whether the uptake derived from [18F]PSMA-1007 PET can also identify responders and to assess its prognostic value relative to established clinical parameters. We retrospectively analyzed 103 patients with metastatic, castration-resistant PC who were treated with [177Lu]Lu-PSMA I T. We calculated SUVmean, SUVmax, PSMA-avid tumor volume (TV), and total lesion PSMA (defined as PSMA-TV*SUVmean) on pre-therapeutic [18F]PSMA-1007 PET. Laboratory values for hemoglobin, C-reactive protein (CRP), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alkaline phosphatase (AP) were also collected prior to RLT. We performed univariable Cox regression followed by multivariable and Kaplan–Meier analyses with overall survival (OS) serving as endpoint. Last, we also computed a risk factor (RF) model including all items reaching significance on multivariable analysis to determine whether an increasing number of RFs can improve risk stratification. A total of 48 patients died and median OS was 16 months. On univariable Cox regression, SUVmean, CRP, LDH, hemoglobin, and the presence of liver metastases were significantly associated with OS. On multivariable Cox regression, the following significant prognostic factors for OS were identified: SUVmean (per unit, HR, 0.91; P = 0.04), the presence of liver metastases (HR, 2.37; P = 0.03), CRP (per mg/dl, HR, 1.13; P = 0.003), and hemoglobin (per g/dl, HR, 0.76; P < 0.01). Kaplan–Meier analysis showed significant separation between patients with a SUVmean below or above a median SUVmean of 9.4 (9 vs 19 months, HR 0.57; P = 0.03). Of note, patients with only one RF (median OS not reached) showed longest survival compared to patients with two (11 months; HR 2.43 95