Assessing radiation dosimetry for microorganisms in naturally radioactive mineral springs using GATE and Geant4-DNA Monte Carlo simulations.

Mineral springs in Massif Central, France can be characterized by higher levels of natural radioactivity in comparison to the background. The biota in these waters is constantly under radiation exposure mainly from the α-emitters of the natural decay chains, with 226Ra in sediments ranging from 21 Bq/g to 43 Bq/g and 222Rn activity concentrations in water up to 4600 Bq/L. This study couples for the first time micro- and nanodosimetric approaches to radioecology by combining GATE and Geant4-DNA to assess the dose rates and DNA damages to microorganisms living in these naturally radioactive ecosystems. It focuses on unicellular eukaryotic microalgae (diatoms) which display an exceptional abundance of teratological forms in the most radioactive mineral springs in Auvergne. Using spherical geometries for the microorganisms and based on γ-spectrometric analyses, we evaluate the impact of the external exposure to 1000 Bq/L 222Rn dissolved in the water and 30 Bq/g 226Ra in the sediments. Our results show that the external dose rates for diatoms are significant (9.7 µGy/h) and comparable to the threshold (10 µGy/h) for the protection of the ecosystems suggested by the literature. In a first attempt of simulating the radiation induced DNA damage on this species, the rate of DNA Double Strand Breaks per day is estimated to 1.11E-04. Our study confirms the significant mutational pressure from natural radioactivity to which microbial biodiversity has been exposed since Earth origin in hydrothermal springs.

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.

Assessment of 99mTc-NTP 15-5 uptake on cartilage, a new proteoglycan tracer: Study protocol for a phase I trial (CARSPECT).

Background: 99mTc-NTP 15-5 is a SPECT radiotracer targeting proteoglycans (PG), components of the cartilaginous extracellular matrix. Imaging of PGs would be useful for the early detection of cartilage disorders (osteoarthritis, arthritis and chondrosarcoma, Aromatase Inhibitor associated arthralgia (AIA) in breast cancer), and the follow-up of patients under treatment. According to preclinical study results, 99mTc-NTP 15-5, is a good candidate for a specific functional molecular imaging of joints. We intend to initiate a first in-human study to confirm and quantify 99mTc-NTP 15-5 uptake in healthy joints. Methods: As the clinical development of this radiotracer would be oriented toward the functional imaging of joint pathologies, we have chosen to include patients with healthy joints (unilateral osteoarthritis of the knee or breast cancer with indication of AI treatment). This phase I study will be an open-label, multicenter, dose-escalation trial of a radiopharmaceutical orientation to determine the recommended level of activity of 99mTc-NTP 15-5 to obtain the best joint tracer contrasts on images, without dose limiting toxicity (DLT). The secondary objectives will include the study of the pharmacology, biodistribution (using planar whole body and SPECT-CT acquisitions), toxicity, and dosimetry of this radiotracer. The dose escalation with 3 activity levels (5, 10, and 15 MBq/kg), will be conditioned by the absence at the previous level of DLT and of a visualized tracer accumulation on more than 80% of healthy joints as observed on scintigraphy performed at ≤ 2 h post-injection. Discussion: This first in-human phase I trial will be proof-of-concept of the relevance of 99mTc-NTP 15-5 as a cartilage tracer, with the determination of the optimal methodology (dose and acquisition time) to obtain the best contrast to provide a functional image of joints with SPECT-CT. Trial registration number: Clinicaltrials.gov: NCT04481230. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2020-000495-37.

Proton Irradiations at Ultra-High Dose Rate vs. Conventional Dose Rate: Strong Impact on Hydrogen Peroxide Yield.

During ultra-high dose rate (UHDR) external radiation therapy, healthy tissues appear to be spared while tumor control remains the same compared to conventional dose rate. However, the understanding of radiochemical and biological mechanisms involved are still to be discussed. This study shows how the hydrogen peroxide (H2O2) production, one of the reactive oxygen species (ROS), could be controlled by early heterogenous radiolysis processes in water during UHDR proton-beam irradiations. Pure water was irradiated in the plateau region (track-segment) with 68 MeV protons under conventional (0.2 Gy/s) and several UHDR conditions (40 Gy/s to 60 kGy/s) at the ARRONAX cyclotron. Production of H2O2 was then monitored using the Ghormley triiodide method. New values of GTS(H2O2) were added in conventional dose rate. A substantial decrease in H2O2 production was observed from 0.2 to 1.5 kGy/s with a more dramatic decrease below 100 Gy/ s. At higher dose rate, up to 60 kGy/s, the H2O2 production stayed stable with a mean decrease of 38% ± 4%. This finding, associated to the decrease in the production of hydroxyl radical (•OH) already observed in other studies in similar conditions can be explained by the well-known spur theory in radiation chemistry. Thus, a two-step FLASH-RT mechanism can be envisioned: an early step at the microsecond scale mainly controlled by heterogenous radiolysis, and a second, slower, dominated by O2 depletion and biochemical processes. To validate this hypothesis, more measurements of radiolytic species will soon be performed, including radicals and associated lifetimes.

Phase I study of [131I] ICF01012, a targeted radionuclide therapy, in metastatic melanoma: MELRIV-1 protocol.

BACKGROUND: Benzamide-based radioligands targeting melanin were first developed for imaging melanoma and then for therapeutic purpose with targeted radionuclide therapy (TRT). [131I]ICF01012 presents a highly favorable pharmacokinetics profile in vivo for therapy. Tumour growth reduction and increase survival have been established in preclinical models of melanoma. According the these preclinical results, we initiate a first-in-human study aimed to determine the recommended dose of [131I]ICF01012 to administer for the treatment of patients with pigmented metastatic melanoma. METHODS: The MELRIV-1 trial is an open-label, multicentric, dose-escalation phase I trial. The study is divided in 2 steps, a selection part with an IV injection of low activity of [131I]ICF01012 (185 MBq at D0) to select patients who might benefit from [131I]ICF01012 TRT in therapeutic part, i.e. patient presenting at least one tumour lesion with [131I]ICF01012 uptake and an acceptable personalized dosimetry to critical organs (liver, kidney, lung and retina). According to dose escalation scheme driven by a Continual Reassessment Method (CRM) design, a single therapeutic injection of 800 MBq/m2, or 1600 MBq/m2, or 2700 MBq/m2 or 4000 MBq/m2 of [131I]ICF01012 will be administered at D11 (± 4 days). The primary endpoint is the recommended therapeutic dose of [131I]ICF01012, with DLT defined as any grade 3-4 NCI-CT toxicity during the 6 weeks following therapeutic dose. Safety, pharmacokinetic, biodistribution (using planar whole body and SPECT-CT acquisitions), sensitivity / specificity of [131I]ICF01012, and therapeutic efficacy will be assessed as secondary objectives. Patients who received therapeutic injection will be followed until 3 months after TRT. Since 6 to 18 patients are needed for the therapeutic part, up to 36 patients will be enrolled in the selection part. DISCUSSION: This study is a first-in-human trial evaluating the [131I]ICF01012 TRT in metastatic malignant melanomas with a diagnostic dose of the [131I]ICF01012 to select the patients who may benefit from a therapeutic dose of [131I]ICF01012, with at least one tumor lesion with [131I]ICF01012 uptake and an acceptable AD to healthy organ. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03784625 . Registered on December 24, 2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2016-002444-17.

Internal dosimetry of [99m Tc]NTP15-5 radiotracer for cartilage imaging in preclinical and clinical models using the GATE Monte Carlo platform.

PURPOSE: This study aims to perform dosimetry for [99m Tc]NTP15-5 radiotracer used in imaging of articular cartilage in rabbits and humans. The radiotracer (covered by a world patent WO 01/00621 A1) has been proposed in the previous years for the study of cartilage in osteoarthritis diseases. A sensitive imaging approach is essential to quantify osteoarthritis progression and monitor response to new therapies. [99m Tc]NTP15-5 binds to cartilage proteoglycans whose decreased content is associated to a loss of biomedical function of cartilage. We have implemented the whole dosimetry study concerning this new radiotracer for rabbits and humans using the GATE Monte Carlo platform. MATERIALS AND METHODS: Absorbed doses to critical organs are determined using the MIRD formalism. Biodistribution data are obtained by organ sampling, measuring the activity in organs for three rabbits sacrificed at various times postadministration, and by SPECT/CT imaging at different times after injection. Most important sources are cartilages (in knees and intervertebral discs), due to localization together with the liver and kidneys due to excretion of the agent. S-values are calculated from rabbit's CT scan and human CT scan using the GATE v8.0 Monte Carlo platform. Cumulated activity in humans is extrapolated from animals using the %kg-dose/g method. Particular attention is given to dose calculation in bones, bone marrow and organs at risk. RESULTS: The dosimetry performed in rabbits shows highest absorbed doses for liver and kidneys with respectively 22.5 and 43.8 µGy per MBq of injected activity. In humans, we found absorbed doses for a maximum injected activity of 15 MBq/kg, that is, 1050 MBq for an adult of 70 kgs of 9.03 mGy for kidneys and 4.16 mGy for knee cartilages. Effective dose is 2.69 µSv/MBq. CONCLUSIONS: The dosimetry profile of [99m Tc]NTP15-5 in the context of preclinical trials is of major importance in order to make sure that organs at risk are not overexposed. GATE provides all the capability needed to calculate dose profiles for internal dosimetry. The extrapolation of the dose for a human model is a first step towards clinical trials.

Tetraspanin 8 (TSPAN 8) as a potential target for radio-immunotherapy of colorectal cancer.

Tetraspanin 8 (TSPAN8) overexpression is correlated with poor prognosis in human colorectal cancer (CRC). A murine mAb Ts29.2 specific for human TSPAN8 provided significant efficiency for immunotherapy in CRC pre-clinical models. We therefore evaluate the feasability of targeting TSPAN8 in CRC with radiolabeled Ts29.2. Staining of tissue micro-arrays with Ts29.2 revealed that TSPAN8 espression was restricted to a few human healthy tissues. DOTA-Ts29.2 was radiolabeled with 111In or 177Lu with radiochemical purities >95%, specific activity ranging from 300 to 600 MBq/mg, and radioimmunoreactive fractions >80%. The biodistribution of [111In]DOTA-Ts29.2 in nude mice bearing HT29 or SW480 CRC xenografts showed a high specificity of tumor localization with high tumor/blood ratios (HT29: 4.3; SW480-TSPAN8: 3.9 at 72h and 120h post injection respectively). Tumor-specific absorbed dose calculations for [177Lu]DOTA-Ts29.2 was 1.89 Gy/MBq, establishing the feasibility of using radioimmunotherapy of CRC with this radiolabeled antibody. A significant inhibition of tumor growth in HT29 tumor-bearing mice treated with [177Lu]DOTA-Ts29.2 was observed compared to control groups. Ex vivo experiments revealed specific DNA double strand breaks associated with cell apoptosis in [177Lu]DOTA-Ts29.2 treated tumors compared to controls. Overall, we provide a proof-of-concept for the use of [111In/177Lu]DOTA-Ts29.2 that specifically target in vivo aggressive TSPAN8-positive cells in CRC.

X-ray microbeam irradiation of the contusion-injured rat spinal cord temporarily improves hind-limb function.

Spinal cord injury is a devastating condition with no effective treatment. The physiological processes that impede recovery include potentially detrimental immune responses and the production of reactive astrocytes. Previous work suggested that radiation treatment might be beneficial in spinal cord injury, although the method carries risk of radiation-induced damage. To overcome this obstacle we used arrays of parallel, synchrotron-generated X-ray microbeams (230 µm with 150 µm gaps between them) to irradiate an established model of rat spinal cord contusion injury. This technique is known to have a remarkable sparing effect in tissue, including the central nervous system. Injury was induced in adult female Long-Evans rats at the level of the thoracic vertebrae T9-T10 using 25 mm rod drop on an NYU Impactor. Microbeam irradiation was given to groups of 6-8 rats each, at either Day 10 (50 or 60 Gy in-beam entrance doses) or Day 14 (50, 60 or 70 Gy). The control group was comprised of two subgroups: one studied three months before the irradiation experiment (n = 9) and one at the time of the irradiations (n = 7). Hind-limb function was blindly scored with the Basso, Beattie and Bresnahan (BBB) rating scale on a nearly weekly basis. The scores for the rats irradiated at Day 14 post-injury, when using t test with 7-day data-averaging time bins, showed statistically significant improvement at 28-42 days post-injury (P < 0.038). H&E staining, tissue volume measurements and immunohistochemistry at day ≈ 110 post-injury did not reveal obvious differences between the irradiated and nonirradiated injured rats. The same microbeam irradiation of normal rats at 70 Gy in-beam entrance dose caused no behavioral deficits and no histological effects other than minor microglia activation at 110 days. Functional improvement in the 14-day irradiated group might be due to a reduction in populations of immune cells and/or reactive astrocytes, while the Day 10/Day 14 differences may indicate time-sensitive changes in these cells and their populations. With optimizations, including those of the irradiation time(s), microbeam pattern, dose, and perhaps concomitant treatments such as immunological intervention this method may ultimately reach clinical use.

Interleaved carbon minibeams: an experimental radiosurgery method with clinical potential.

PURPOSE: To evaluate the efficacy of "interleaved carbon minibeams" for ablating a 6.5-mm target in a rabbit brain with little damage to the surrounding brain. The method is based on the well-established tissue-sparing effect of arrays of thin planes of radiation. METHODS AND MATERIALS: Broad carbon beams from the National Aeronautics and Space Agency Space Radiation Facility at Brookhaven National Laboratory were segmented into arrays of parallel, horizontal, 0.3-mm-thick planar beams (minibeams). The minibeams' gradual broadening in tissues resulted in 0.525-mm beam thickness at the target's proximal side in the spread-out Bragg peak. Interleaving was therefore implemented by choosing a 1.05 mm beam spacing on-center. The anesthetized rabbit, positioned vertically on a stage capable of rotating about a vertical axis, was exposed to arrays from four 90° angles, with the stage moving up by 0.525 mm in between. This produced a solid radiation field at the target while exposing the nontargeted tissues to single minibeam arrays. The target "physical" absorbed dose was 40.2 Gy. RESULTS: The rabbit behaved normally during the 6-month observation period. Contrast magnetic resonance imaging and hematoxylin and eosin histology at 6 months showed substantial focal target damage with little damage to the surrounding brain. CONCLUSION: We plan to evaluate the method's therapeutic efficacy by comparing it with broad-beam carbon therapy in animal models. The method's merits would combine those of carbon therapy (i.e., tight target dose because of the carbon's Bragg-peak, sharp dose falloff, and high relative biological effectiveness at the target), together with the method's low impact on the nontargeted tissues. The method's smaller impact on the nontargeted brain might allow carbon therapy at higher target doses and/or lower normal tissue impact, thus leading to a more effective treatment of radioresistant tumors. It should also make the method more amenable to administration in either a single dose fraction or in a small number of fractions.