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Purpose: Proton minibeam radiation therapy (pMBRT) is an innovative radiation therapy approach that highly modulates the spatial dimension of the dose delivery using narrow, parallel, and submillimetric proton beamlets. pMBRT has proven its remarkable healthy tissue preservation in the brain and skin. This study assesses the potential advantages of pMBRT for thoracic irradiations compared with conventional radiation therapy in terms of normal tissue toxicity. The challenge here was the influence of respiratory motion on the typical peak and valley dose patterns of pMBRT and its potential biologic effect., Methods and Materials: The whole thorax of naïve C57BL/6 mice received one fraction of high dose (18 Gy) pMBRT or conventional proton therapy (CPT) without any respiratory control. The development of radiation-induced pulmonary fibrosis was longitudinally monitored using cone beam computed tomography. Anatomopathologic analysis was carried out at 9 months postirradiation and focused on the reaction of the lungs' parenchyma and the response of cell types involved in the development of radiation-induced fibrosis and lung regeneration as alveolar type II epithelial cells, club cells, and macrophages., Results: pMBRT has milder effects on survival, skin reactions, and lung fibrosis compared with CPT. The pMBRT-induced lung changes were more regional and less severe, with evidence of potential reactive proliferation of alveolar type II epithelial cells and less extensive depletion of club cells and macrophage invasion than the more damaging effects observed in CPT., Conclusions: pMBRT appears suitable to treat moving targets, holding a significant ability to preserve healthy lung tissue, even without respiratory control or precise targeting., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: FLASH radiation therapy (FLASH-RT) is a promising radiation technique that uses ultrahigh doses of radiation to increase the therapeutic window of the treatment. FLASH-RT has been observed to provide normal tissue sparing at high dose rates and similar tumor control compared with conventional RT, yet the biological processes governing these radiobiological effects are still unknown. In this study, we sought to investigate the potential immune response generated by FLASH-RT in a high dose of proton therapy in an orthotopic glioma rat model., Methods and Materials: We cranially irradiated rats with a single high dose (25 Gy) using FLASH dose rate proton irradiation (257 ± 2 Gy/s) or conventional dose rate proton irradiation (4 ± 0.02 Gy/s). We first assessed the protective FLASH effect that resulted in our setup through behavioral studies in naïve rats. This was followed by a comprehensive analysis of immune cells in blood, healthy tissue of the brain, and tumor microenvironment by flow cytometry., Results: Proton FLASH-RT spared memory impairment produced by conventional high-dose proton therapy and induced a similar tumor infiltrating lymphocyte recruitment. Additionally, a general neuroinflammation that was similar in both dose rates was observed., Conclusions: Overall, this study demonstrated that FLASH proton therapy offers a neuro-protective effect even at high doses while mounting an effective lymphoid immune response in the tumor., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: For many years, the effect of dose rate (DR) was considered negligible in external beam radiation therapy (EBRT) until very-high DR (>10 Gy/min) became possible and ultrahigh DR (>40 Gy/s) showed dramatic protection of normal tissues in preclinical experiments. We propose a critical review of preclinical and clinical studies to investigate the biological and clinical effects of DR variation in the range covering brachytherapy to flattening filter free EBRT and FLASH., Methods and Materials: Preclinical and clinical studies investigating biological and clinical DR effects were reviewed extensively. We also conducted an in silico study to assess the effect of pulse DR (DR p ), taking into account the mean time between 2 tracks during the pulse., Results: Preclinical studies have shown that an increase in DR in the range of 0.01 to 20 Gy/min (not including ultralow or ultrahigh DR) resulted in decreased survival of both normal and tumor cells. This effect was attributed primarily to increasingly unrepaired "sublethal" DNA damage with increasing the DR. However, the models and irradiation conditions have often been very different from one radiobiological study to another. Moreover, the physical parameters on the spatial and temporal microstructure of the beam were not considered systematically. In particular, the DR p was rarely mentioned. The in silico studies showed that for the same average DR, increasing DR p induced an increase of mean track rates. These results could explain the presence of more complex damage when the DR p was increased within the range of DR considered, in relation to the time-dependent probability of accumulating unrepaired, "sublethal" DNA lesions in close proximity., Conclusions: Knowledge of the beam microstructure is critical to understanding the biological impact and the clinical outcomes of radiation at the DR commonly used in radiation therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Proton minibeam radiation therapy (pMBRT) is a novel radiation therapy approach that exploits the synergies of proton therapy with the gain in normal tissue preservation observed upon irradiation with narrow, spatially fractionated, beams. The net gain in normal tissue sparing that has been shown by pMBRT may lead to the efficient treatment of very radioresistant tumors, which are currently mostly treated palliatively. The aim of this study was to perform an evaluation of the tumor effectiveness of proton minibeam radiation therapy for the treatment of RG2 glioma-bearing rats., Methods and Materials: Two groups (n = 9) of RG2 glioma-bearing rats were irradiated with either standard proton therapy or with pMBRT, with a dose prescription of 25 Gy in 1 fraction. The animals were followed up for a maximum of 6 months. At the end of the study, histopathological studies were performed to assess both the tumor presence and the possible side effects., Results: Tumor control was achieved in the 2 irradiated series, with superior survival in the pMBRT group compared with the standard proton therapy group. Long-term (>170 days) survival rates of 22% and 67% were obtained in the standard proton therapy and pMBRT groups, respectively. No tumor was observed in the histopathological analysis. Although animals with long-term survival in the standard radiation therapy exhibit substantial brain damage, including marked radionecrosis, less severe toxicity was observed in the pMBRT group., Conclusions: pMBRT offers a significant increase in the therapeutic index of brain tumors: The majority of the glioma-bearing rats (67%) survived 6 months with less severe side effects., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Recent in vivo investigations have shown that short pulses of electrons at very high dose rates (FLASH) are less harmful to healthy tissues but just as efficient as conventional dose-rate radiation to inhibit tumor growth. In view of the potential clinical value of FLASH and the availability of modern proton therapy infrastructures to achieve this goal, we herein describe a series of technological developments required to investigate the biology of FLASH irradiation using a commercially available clinical proton therapy system., Methods and Materials: Numerical simulations and experimental dosimetric characterization of a modified clinical proton beamline, upstream from the isocenter, were performed with a Monte Carlo toolkit and different detectors. A single scattering system was optimized with a ridge filter and a high current monitoring system. In addition, a submillimetric set-up protocol based on image guidance using a digital camera and an animal positioning system was also developed., Results: The dosimetric properties of the resulting beam and monitoring system were characterized; linearity with dose rate and homogeneity for a 12 × 12 mm 2 field size were assessed. Dose rates exceeding 40 Gy/s at energies between 138 and 198 MeV were obtained, enabling uniform irradiation for radiobiology investigations of small animals in a modified clinical proton beam line., Conclusions: This approach will enable us to conduct FLASH proton therapy experiments on small animals, specifically for mouse lung irradiation. Dose rates exceeding 40 Gy/s were achieved, which was not possible with the conventional clinical mode of the existing beamline., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Chondrosarcoma is a rare malignant tumor of the cartilage affecting young adults. Surgery, followed by charged-particle irradiation, is considered the reference standard for the treatment of patients with grade I to II skull base chondrosarcoma. The present study was conducted to assess the effect of the quality of surgery and radiation therapy parameters on local control (LC) and overall survival (OS)., Methods and Materials: From 1996 to 2013, 159 patients (median age 40 years, range 12-83) were treated with either protons alone or a combination of protons and photons. The median total dose delivered was 70.2 Gy (relative biologic effectiveness [RBE]; range 67-71). Debulking and biopsy were performed in 133 and 13 patients, respectively., Results: With a median follow-up of 77 months (range 2-214), 5 tumors relapsed based on the initial gross tumor volume. The 5- and 10-year LC rates were 96.4% and 93.5%, respectively, and the 5- and 10-year OS rates were 94.9% and 87%, respectively. A total of 16 patients died (13 of intercurrent disease, 3 of disease progression). On multivariate analysis, age <40 years and primary disease status were independent favorable prognostic factors for progression-free survival and OS, and local tumor control was an independent favorable predictor of OS. In contrast, the extent of surgery, dosimetric parameters, and adjacent organs at risk were not prognostic factors for LC or OS., Conclusions: Systematic high-dose postoperative proton therapy for skull base chondrosarcoma can achieve a high LC rate with a low toxicity profile. Maximal safe surgery, followed by high-dose conformal proton therapy, is therefore recommended., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Previously we showed that the relative biological efficiency for induced cell killing by the 76-MeV beam used at the Institut Curie Proton Therapy Center in Orsay increased with depth throughout the spread-out Bragg peak (SOBP). To investigate the repair pathways underlying this increase, we used an isogenic human cell model in which individual DNA repair proteins have been depleted, and techniques dedicated to precise measurements of radiation-induced DNA single-strand breaks (SSBs) and double-strand breaks (DSBs)., Methods and Materials: The 3-Gy surviving fractions of HeLa cells individually depleted of Ogg1, XRCC1, and PARP1 (the base excision repair/SSB repair pathway) or of ATM, DNA-PKcs, XRCC4, and Artemis (nonhomologous end-joining pathway) were determined at the 3 positions previously defined in the SOBP. Quantification of incident SSBs and DSBs by the alkaline elution technique and 3-dimensional (3D) immunofluorescence of γ-H2AX foci, respectively, was performed in SQ20 B cells., Results: We showed that the amount of SSBs and DSBs depends directly on the particle fluence and that the increase in relative biological efficiency observed in the distal part of the SOBP is due to a subset of lesions generated under these conditions, leading to cell death via a pathway in which the Artemis protein plays a central role., Conclusions: Because therapies like proton or carbon beams are now being used to treat cancer, it is even more important to dissect the mechanisms implicated in the repair of the lesions generated by these particles. Additionally, alteration of the expression or activity of the Artemis protein could be a novel therapeutic tool before high linear energy transfer irradiation treatment., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To compare treatment planning between combined photon-proton planning (CP) and proton planning (PP) for skull base tumors, so as to assess the potential limitations of CP for these tumors., Methods and Materials: Plans for 10 patients were computed for both CP and PP. Prescribed dose was 67 cobalt Gray equivalent (CGE) for PP; 45 Gy (photons) and 22 CGE (protons) for CP. Dose-volume histograms (DVHs) were calculated for gross target volume (GTV), clinical target volume (CTV), normal tissues (NT), and organs at risk (OARs) for each plan. Results were analyzed using DVH parameters, inhomogeneity coefficient (IC), and conformity index (CI)., Results: Mean doses delivered to the GTVs and CTVs with CP (65.0 and 61.7 CGE) and PP (65.3 and 62.2 Gy CGE) were not significantly different (p > 0.1 and p = 0.72). However, the dose inhomogeneity was drastically increased with CP, with a mean significant incremental IC value of 10.5% and CP of 6.8%, for both the GTV (p = 0.01) and CTV (p = 0.04), respectively. The CI(80%) values for the GTV and CTV were significantly higher with PP compared with CP. Compared with CP, the use of protons only led to a significant reduction of NT and OAR irradiation, in the intermediate-to-low dose (< or =80% isodose line) range., Conclusions: These results suggest that the use of CP results in levels of target dose conformation similar to those with PP. Use of PP significantly reduced the tumor dose inhomogeneity and the delivered intermediate-to-low dose to NT and OARs, leading us to conclude that this treatment is mainly appropriate for tumors in children.