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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. [ABSTRACT FROM AUTHOR]

18F-clofarabine, a nucleotide purine analog, is a substrate for deoxycytidine kinase (dCK), a key enzyme in the deoxyribonucleoside salvage pathway. 18F-clofarabine might be used to measure dCK expression and thus serve as a predictive biomarker for tumor responses to dCK-dependent prodrugs or small-molecule dCK inhibitors, respectively. As a prerequisite for clinical translation, we determined the human whole-body and organ dosimetry of 18F-clofarabine. Methods: Five healthy volunteers were injected intravenously with 232.4 ± 1.5 MBq of 18F-clofarabine. Immediately after tracer injection, a dynamic scan of the entire chest was acquired for 30 min. This was followed by 3 static whole-body scans at 45, 90, and 135 min after tracer injection. Regions of interest were drawn around multiple organs on the CT scan and copied to the PET scans. Organ activity was determined and absorbed dose was estimated with OLINDA/EXM software. Results: The urinary bladder (critical organ), liver, kidney, and spleen exhibited the highest uptake. For an activity of 250 MBq, the absorbed doses in the bladder, liver, kidney, and spleen were 58.5, 6.6, 6.3, and 4.3 mGy, respectively. The average effective dose coefficient was 5.1 mSv. Conclusion: Our results hint that 18F-clofarabine can be used safely in humans to measure tissue dCK expression. Future studies will determine whether 18F-clofarabine may serve as a predictive biomarker for responses to dCK-dependent prodrugs or small-molecule dCK inhibitors.

PurposeThe aim of this study was to synthesize and preclinically evaluate an 18F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined.MethodsSeveral conditions for the labeling of 18F-PSMA-11 via 18F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed.ResultsQuantitative labeling yields could be achieved with >97 % radiochemical purity. The 18F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

UnlabelledProstate-specific membrane antigen (PSMA) is a promising target for diagnosis and treatment of prostate cancer. EuK-Subkff-(68)Ga-DOTAGA ((68)Ga-PSMA Imaging & Therapy [PSMA I&T]) is a recently introduced PET tracer for imaging PSMA expression in vivo. Whole-body distribution and radiation dosimetry of this new probe were evaluated.MethodsFive patients with a history of prostate cancer were injected intravenously with 91-148 MBq of (68)Ga-PSMA I&T (mean ± SD, 128 ± 23 MBq). After an initial series of rapid whole-body scans, 3 static whole-body scans were acquired at 1, 2, and 4 h after tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM.ResultsInjection of 150 MBq of (68)Ga-PSMA I&T resulted in an effective dose of 3.0 mSv. The kidneys were the critical organ (33 mGy), followed by the urinary bladder wall and spleen (10 mGy each), salivary glands (9 mGy each), and liver (7 mGy).Conclusion(68)Ga-PSMA I&T exhibits a favorable dosimetry, delivering organ doses that are comparable to (kidneys) or lower than those delivered by (18)F-FDG.

Background: 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. Methods: 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. Results: 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% CI 1.07–5.49, P = 0.02) or more than two RFs (7 months; HR 3.37 95% CI 1.62–7.03, P < 0.001). Conclusion: A lower SUVmean derived from [18F]PSMA-1007, higher CRP, lower hemoglobin, and the presence of liver metastases are associated with reduced OS in patients undergoing RLT. An early RF model also demonstrated that an increasing number of those factors is linked to worse outcome, thereby emphasizing the importance of clinical and imaging parameters for adequate risk stratification. [ABSTRACT FROM AUTHOR]

Purpose: As α-emitters for radiopharmaceutical therapies are administered systemically by intravenous injection, blood will be irradiated by α-particles that induce clustered DNA double-strand breaks (DSBs). Here, we investigated the induction and repair of DSB damage in peripheral blood mononuclear cells (PBMCs) as a function of the absorbed dose to the blood following internal ex vivo irradiation with [223Ra]RaCl2. Methods: Blood samples of ten volunteers were irradiated by adding [223Ra]RaCl2 solution with different activity concentrations resulting in absorbed doses to the blood of 3 mGy, 25 mGy, 50 mGy and 100 mGy. PBMCs were isolated, divided in three parts and either fixed directly (d-samples) or after 4 h or 24 h culture. After immunostaining, the induced γ-H2AX α-tracks were counted. The time-dependent decrease in α-track frequency was described with a model assuming a repair rate R and a fraction of non-repairable damage Q. Results: For 25 mGy, 50 mGy and 100 mGy, the numbers of α-tracks were significantly increased compared to baseline at all time points. Compared to the corresponding d-samples, the α-track frequency decreased significantly after 4 h and after 24 h. The repair rates R were (0.24 ± 0.05) h−1 for 25 mGy, (0.16 ± 0.04) h−1 for 50 mGy and (0.13 ± 0.02) h−1 for 100 mGy, suggesting faster repair at lower absorbed doses, while Q-values were similar. Conclusion: The results obtained suggest that induction and repair of the DSB damage depend on the absorbed dose to the blood. Repair rates were similar to what has been observed for irradiation with low linear energy transfer. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]