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Treatment of locally advanced lung cancer is limited by toxicity and insufficient local control. Particle therapy could enable more conformal treatment than intensity modulated photon therapy, but is challenged by irregular tumor motion, associated range changes and tumor deformations.We propose a new strategy for robust, online adaptive particle therapy, synergizing 4D-optimization with real-time adaptive beam tracking. The strategy was tested and the required motion monitoring precision was determined.In multiphase 4D dose delivery (MP4D), a dedicated quasi-static treatment plan is delivered to each motion phase of a periodic 4DCT. In the new extension, 'MP4D with residual tracking' (MP4DRT), lateral beam tracking compensates for the displacement of the tumor center-of-mass relative to the current phase in the planning 4DCT. We implemented this method into the dose delivery system of a clinical carbon facility and tested it experimentally for a lung cancer plan based on a periodic subset of a virtual lung 4DCT (planned motion amplitude 20 mm). Treatments were delivered in a QA-like setting to a moving IC array. We considered variable motion amplitudes and baseline drifts. The required motion monitoring precision was evaluated by adding noise to the motion signal. Log-file based dose reconstructions were performed in silico on the entire 4DCT phantom data capable of simulating non-periodic motion. MP4DRT was compared to MP4D, rescanned beam tracking and ITV plans. Treatment quality was assessed in terms of target coverage (D95), dose homogeneity (D5-D95), conformity number and dose to heart and lung.For all considered motion scenarios and metrics, MP4DRT produced the most favorable metrics amongst the tested motion mitigation strategies and delivered high quality treatments. The conformity was similar to static treatments. The motion monitoring precision required for D9595% was 1.9 mm.With clinically feasible motion monitoring, MP4DRT is able to deliver highly conformal dose distributions to irregularly moving targets.

Fragmented heavy-ion beams obtained from the interaction of highly energetic ions with thick targets relative to the ion ranges are proposed to mimic the high-penetration linear energy transfer (LET) spectrum present in space and for electronics testing. Our experimental data characterizing fragmented heavy-ion beams show an excellent level of agreement with the Monte Carlo simulations, serving as an initial proof-of-concept of the proposed single-event effect (SEE) testing approach. Fragmented heavy-ion beams obtained from the interaction of highly energetic ions with thick targets relative to the ion ranges are proposed to mimic the high-penetration linear energy transfer (LET) spectrum present in space and for electronics testing. Our experimental data characterizing fragmented heavy-ion beams show an excellent level of agreement with the Monte Carlo simulations, serving as an initial proofof-concept of the proposed single-event effect (SEE) testing approach.

In the upcoming years, agriculture will have a central role not only in feeding a growing population worldwide, but also in Space-related research, through the implementation of protected cultivation systems. To make it possible, it is fundamental to understand plants’ ability to cope with a dynamic environment, made worst by harsh Space conditions including microgravity and ionizing radiation.Plant plasticity in adaptation relies on the development of both structural and physiological traits, which are deeply influenced by the environment; therefore, leaf morpho-anatomical traits are critical for balancing plant water and CO2 exchange and determine the efficiency of CO2 diffusion within the mesophyll. Their relationship has been widely studied; however, it remains unclear at what extent leaf anatomical traits may drive leaf hydraulic and photosynthetic acclimation to Space environmental stressors.Previous studies have proven that ionizing radiation can induce positive, null or negative effects depending on the radiation type, dose and exposure (acute or chronic) as well as plant developmental stage and species.In this study, we compared functional, anatomical (e.g., leaf area, leaf dry matter content, leaf mass per area, stomatal and vein size and density, mesophyll organization, chloroplast distribution) and biochemical traits (e.g. chlorophyll and carotenoids content, polyphenols, ascorbic acid) of brassica microgreens (Brassica rapa L. subsp. sylvestris var. esculenta) exposed to three different types of radiation (X-rays, Carbon ion 12C, Iron ion 56Fe) at the same doses (0-control, 0.3, 1, 10, 20, and 25 Gy). Irradiation took place at the GSI Helmholtzzentrum für Schwerionenforschung GmbH, and then microgreens were cultivated in a growth chamber under controlled condition. Microgreens were chosen as study model for two main reasons. First, microgreens are good candidates for the diet integration of astronauts because they are rich in nutraceutical compounds and can be cultivated directly in Space with very low input resources. From a fundamental science viewpoint, understanding the morpho-functional responses of microgreens is needed because at this stage of development plants are very vulnerable: overcoming the microgreens stage may represent a bottleneck in the cultivation of adult plants in bioregenerative life support systems.The results suggest the different radiation type and doses determined alterations in morpo-anatomical and biochemical traits which may determine the limits of crop responses and biomass production. These findings should be considered when studying plant adaptation to Space environment, trying to optimize plant growth in controlled environment to achieve the sustainability of the system. Part of the results presented here is based on the experiment Bio_08_DeMicco, which was performed at the SIS18 at the GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt (Germany) in the frame of FAIR Phase-0.

The presence of unique environmental factors such as ionizing radiation (IR) in Space may be a major hindrance to the survival of terrestrial organisms. Therefore, understanding the impact of Space radiation on organisms is an essential part of exploration research to successfully inhabit Moon and Mars.Given the pivotal role of plants in sustainable closed artificial ecosystems in Space (i.e. Bioregenerative Life Support Systems) as food producers and bio-regenerators of environmental resources such as oxygen and water, and, plant resistance to IR is undoubtedly one of the first trait to consider. Indeed, IR may influence plants growth and development, potentially affecting their bioregenerative performance, jeopardizing astronaut survival and in turn the success of future Space missions. Notwithstanding, available information on plants' responses to IR remain unclear, and intrinsic IR and plant factors (e.g., type of radiation, dose, plant species, cultivar, and developmental stage at the time of irradiation) interactions must be considered.The purpose of this study was to test the radio resistance of the Salanova® lettuce (Lactuca sativa L. var. capitata) to different doses of high-LET (Linear Energy Transfer) radiation, in terms of morpho-anatomical and nutritional traits. At the GSI Helmholtzzentrum für Schwerionenforschung GmbH, dry seeds were exposed to increasing doses (0-control, 0.3, 1, 10, 20, and 25 Gy) of iron ions (56Fe) (one of the most damaging ions in the galactic cosmic ray spectrum). Following irradiation, plants were grown in a growth chamber under controlled light, temperature, and relative humidity conditions.Seed germination percentage, as well as plant growth and leaf photosynthesis performances were monitored during cultivation.Morpho-biometric parameters such as plant total leaf area, number of leaves, and fresh and dry biomass were quantified at harvest. Leaf functional anatomical traits (e.g., lamina thickness, stomatal frequency and size, vein density) were also analyzed using light and epifluorescence microscopy and digital image analysis. Finally, to assess the phytochemical and nutritional profile, the antioxidant capacity, chlorophylls, carotenoid, and mineral composition content were determined.Results showed that responses of Salanova lettuce from irradiated seeds changed depending on the IR dose delivered, with the occurrence of both hormetic and detrimental outcomes, as well as possible plant radioprotective strategies. This information will be helpful to unveil the mechanisms behind plant radiotolerance and to define the shielding requirements for Space cultivation facilities.Part of the results presented here is based on the experiment Bio_08_DeMicco, which was performed at the SIS18 at the GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt (Germany) in the frame of FAIR Phase-0.

Carbon ion therapy (CIT) offers several potential advantages for treating cancers compared with X-ray and proton radiotherapy, including increased biological efficacy and more conformal dosimetry. However, CIT potency has not been characterized in primary tumor animal models. Here, we calculate the relative biological effectiveness (RBE) of carbon ions compared with X-rays in an autochthonous mouse model of soft tissue sarcoma. We used Cre/loxP technology to generate primary sarcomas in KrasLSL-G12D/+; p53fl/fl mice. Primary tumors were irradiated with a single fraction of carbon ions (10 Gy), X-rays (20 Gy, 25 Gy, or 30 Gy), or observed as controls. The RBE was calculated by determining the dose of X-rays that resulted in similar time to posttreatment tumor volume quintupling and exponential growth rate as 10 Gy carbon ions. The median tumor volume quintupling time and exponential growth rate of sarcomas treated with 10 Gy carbon ions and 30 Gy X-rays were similar: 27.3 and 28.1 days and 0.060 and 0.059 mm3/day, respectively. Tumors treated with lower doses of X-rays had faster regrowth. Thus, the RBE of carbon ions in this primary tumor model is 3. When isoeffective treatments of carbon ions and X-rays were compared, we observed significant differences in tumor growth kinetics, proliferative indices, and immune infiltrates. We found that carbon ions were three times as potent as X-rays in this aggressive tumor model and identified unanticipated differences in radiation response that may have clinical implications. Mol Cancer Ther; 17(4); 858–68. ©2018 AACR.

Serial tumor volume measurements on individual mice. Absolute tumor volume in mm3 is shown for individual mice on each measurement day following irradiation (in treated mice) or once tumors reached 40 mm3 (in untreated controls). Measurements were taken until the predefined experiment endpoint.

Comparing the effect anesthetic agent and housing location on tumor quintupling. A) Tumor quintupling times in mice treated with 20 Gy X-rays who were anesthetized with ketamine/xylazine vs. isoflurane, demonstrating no significant differences. B) Tumor quintupling time in untreated controls followed at Brookhaven National Laboratory vs. Duke University Medical Center, demonstrating no significant differences.

Quantification of TUNEL staining for sarcomas at 24 or 48 hours after 10 Gy carbon ions or 30 Gy X-rays. A) TUNEL staining was similar, indicating that there were no significant differences in cell death. B) TUNEL staining at 24 and 48 hours.

The exposure to galactic cosmic radiation (GCR) is a major health concern for astronauts. Crewed missions with durations of several years are foreseen in future space exploration projects such as permanent habitats on the Moon and flights to Mars. This aim requires elaborate space radiation shielding concepts and a proper understanding of the underlying radiation physics and radiobiology as well as their interplay. In the present work, Monte Carlo simulations to assess the performance of different materials (polyethylene, aluminum, Moon regolith) as thick shields (up to 400 g/cm

Fragmented heavy ion beams obtained from the interaction of highly energetic ions with thick targets relative to the ion ranges are proposed to mimic the high-penetration linear energy transfer spectrum present in space and for electronics testing. Our experimental data characterizing fragmented heavy ion beams shows an excellent level of agreement with the Monte Carlo simulations, serving as an initial proof-of-concept of the proposed Single Event Effects testing approach.

npj microgravity 9(1), 8 (2023). doi:10.1038/s41526-023-00262-7, Published by Nature Publ. Group, [New York, NY]

Frontiers in oncology 13, 1175511 (2023). doi:10.3389/fonc.2023.1175511, Published by Frontiers Media, Lausanne

International journal of molecular sciences 24(11), 9398 (2023). doi:10.3390/ijms24119398, Published by Molecular Diversity Preservation International, Basel

Owing to the favorable depth-dose distribution and the radiobiological properties of heavy ion radiation, ion beam therapy shows an improved success/toxicity ratio compared to conventional radiotherapy. The sharp dose gradients and very high doses in the Bragg peak region, which represent the larger physical advantage of ion beam therapy, make it also extremely sensitive to range uncertainties. The use of

The ultimate goal of radiation oncology is to eradicate tumours without toxicity to non-malignant tissues. FLASH radiotherapy, or the delivery of ultra-high dose rates of radiation (40 Gy/s), emerged as a modality of irradiation that enables tumour control to be maintained while reducing toxicity to surrounding non-malignant tissues. In the past few years, preclinical studies have shown that FLASH radiotherapy can be delivered in very short times and substantially can widen the therapeutic window of radiotherapy. This ultra-fast radiation delivery could reduce toxicity and thus enable dose escalation to enhance antitumour efficacy, with the additional benefits of reducing treatment time and organ motion-related issues, eventually increasing the number of patients who can be treated. At present, FLASH is recognized as one of the most promising breakthroughs in radiation oncology, standing at the crossroads between technology, physics, chemistry and biology; however, several hurdles make its clinical translation difficult, including the need for a better understanding of the biological mechanisms, optimization of parameters and technological challenges. In this Perspective, we provide an overview of the principles underlying FLASH radiotherapy and discuss the challenges along the path towards its clinical application.

Cancer therapy with accelerated charged particles is one of the most valuable biomedical applications of nuclear physics. The technology has vastly evolved in the past 50 years, the number of clinical centers is exponentially growing, and recent clinical results support the physics and radiobiology rationale that particles should be less toxic and more effective than conventional X-rays for many cancer patients. Charged particles are also the most mature technology for clinical translation of ultra-high dose rate (FLASH) radiotherapy. However, the fraction of patients treated with accelerated particles is still very small and the therapy is only applied to a few solid cancer indications. The growth of particle therapy strongly depends on technological innovations aiming to make the therapy cheaper, more conformal and faster. The most promising solutions to reach these goals are superconductive magnets to build compact accelerators; gantryless beam delivery; online image-guidance and adaptive therapy with the support of machine learning algorithms; and high-intensity accelerators coupled to online imaging. Large international collaborations are needed to hasten the clinical translation of the research results.

In this study, we performed biological verification measurements of cell survival of aWe established the protocol for a 3D culture setup where xrs-5 cells were grown inside a layered matrigel structure in 384-well plates. Their radiosensitivity to conventional andDose response curves following X-ray andWe conclude that the V-bottom 384-well plates in combination with the radiation-sensitive xrs-5 cell line constitute a suitable radiobiological verification tool which can be used especially for low doses. Furthermore, the measured survival of xrs-5 cells show a good agreement with the expected survival in the low-dose out-of-field regions, both laterally and downstream of the target.

This paper introduces the concept of a 2D range-modulator as a static device for generating spread-out Bragg peaks at very small distances to the target. The 2D range-modulator has some distinct advantages that can be highly useful for different research projects in particle therapy facilities. Most importantly, it creates an instantaneous, quasi-static irradiation field with only one energy, thus decreasing irradiation time tremendously. In addition, it can be manufactured fast and cost efficiently and its SOBP width and shape can be adjusted easily for the specific purpose/experiment. As the modulator is a static element, there is no need for rotation (e.g. like in a modulation wheel) or lateral oscillation and due to the small base structure period it can be positioned close to the target. Two different rapid prototyping manufacturing techniques were utilized. The modulation properties of one polymer and one steel modulator were investigated with both simulations and measurements. For this purpose, a sophisticated water phantom system (WERNER), that can perform fast, completely automated and high resolution dose measurements, was developed. Using WERNER, the dose distribution of a modulator can be verified quickly and reliably, both during experiments, as well as in a time constrained clinical environment. The maximum deviation between the Monte Carlo simulations and dose measurements in the spread-out Bragg peak region was 1.4% and 4% for the polymer and steel modulator respectively. They were able to create spread-out Bragg peaks with a high degree of dose homogeneity , thus validating the whole process chain, from the mathematical optimization and modulator development, to manufacturing, MC simulations and dose measurements. Combining the convenience, flexibility and cost-effectiveness of rapid prototyping with the advantages of highly customizable modulators, that can be adapted for different experiments, the 2D range-modulator is considered a very useful tool for a variety of research objectives. Moreover, we have successfully shown that the manufacturing of 2D modulators with high quality and high degree of homogeneity is possible, paving the way for the further development of the more complex 3D range-modulators, which are considered a viable option for the very fast treatment of moving targets and/or FLASH irradiation.

Cells 11(16), 2561 (2022). doi:10.3390/cells11162561, Published by MDPI, Basel

This flyer has been created with the aim of presenting the HITRIplusproject Clinical Transnational Access opportunity to the scientific community

Radiotherapy escalating dose rates above 50GysTherefore, saturation curves at high intensities were measured for the currently used fill gases Ar/COEven at high intensities the He/CO

The success of future long-term manned missions in Space is strictly related to the development and setup of sustainable closed artificial ecosystems, defined as Bioregenerative Life Support Systems (BLSSs). In these BLSSs, the cultivation of higher plants represents the core element, given its role in primary resources (e.g., oxygen, water) regeneration and in fresh food production, also helping to counteract the emergence of Space-induced diseases in astronauts. However, Space farming may be constrained by Space ionizing radiation for its influence on plant growth and biomass production, depending on radiation properties and plant intrinsic factors (e.g., type of radiation, dose, plant species, cultivar, developmental stage at the time of irradiation). This study aimed to evaluate the effects of the different types and doses of low and high-LET (Linear Energy Transfer) radiation on morpho-anatomical traits and antioxidant content of Brassica rapa L. subsp. sylvestris var. esculenta microgreens. Dry seeds were exposed to different doses (0-control, 0.3, 1, 10, 20, and 30 Gy) of X-rays (the reference Low-LET radiation) at Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, and to two types of Heavy Ions, namely 12C and 56Fe (to simulate the High-LET radiation) at different doses (0-control, 0.3, 1, 10, 20, and 25 Gy) at GSI Helmholtzzentrum für Schwerionenforschung GmbH. After the irradiation, seeds were sowed and microgreens were cultivated in a growth chamber under controlled environmental conditions, monitoring germination and survival, as well as growth performances. At the harvest, morpho-biometric traits, such as stem elongation, fresh and dry biomass, and total leaf area were measured. Leaf functional anatomical traits (e.g., lamina thickness, localization of phenolics, stomatal frequency) were quantified through light and epifluorescence microscopy and digital image analysis. The antioxidant charge of microgreens was evaluated considering antioxidant capacity, and polyphenols, chlorophylls, and carotenoid content. Results highlighted that the responses of microgreens, from irradiated seeds, were dose and radiation-type specific. This study furnished useful insights to evaluate plant radio-resistance at early stages of development, namely seedling establishment, that is a very critical phase in the plant life cycle. Gained information is useful to support the decision actions about the choice of suitable species to be cultivated in the BLSSs in Space and the definition of the shielding requirements for Space cultivation facilities.Part of the results presented here is based on the experiment Bio_08_DeMicco, which was performed at the SIS18 at the GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt (Germany) in the frame of FAIR Phase-0.

Radiation oncology 17(1), 50 (2022). doi:10.1186/s13014-022-02022-5, Published by BioMed Central, London

Purpose The purpose of this study was to develop a modular dose-delivery system (DDS) for scanned-ion radiotherapy that mitigates against organ motion artifacts by synchronizing the motion of the beam with that of the moving anatomy. Methods We integrated a new motion synchronization system and an existing DDS into two centers. The modular approach to integration utilized an adaptive layer of software and hardware interfaces. The method of synchronization comprised three major tasks, namely, the creation of 3D treatment plans (each representing one phase of respiratory motion and together comprising a 4D plan), monitoring anatomic motion during treatment, and synchronization of the beam to anatomic motion. The synchronization was accomplished in real time by repeatedly selecting and delivering a 3D plan, i.e., the one that most closely corresponded to the current anatomic state, until all plans were delivered. The performance characteristics of the motion mitigation system were tested by delivering 4D treatment plans to a moving phantom and comparing planned and measured dose distributions. Dosimetric performance was considered acceptable when the gamma-index pass rate was >90%, homogeneity-index value was >95%, and conformity-index value was >60%. Selected safety characteristics were tested by introducing errors during treatment and testing DDS response. Results Acceptable dosimetric performance and safety characteristics were observed for all treatment plans. Conclusions We demonstrated, for the first time, that a modular prototype system, synchronizing scanned ion beams with moving targets can deliver conformal, motion-compensated dose distributions. The prototype system was implemented and characterized at GSI and CNAO.

Particle therapy using protons or heavier ions is currently the most advanced form of radiotherapy and offers new opportunities for improving cancer care and research. Ions deposit the dose with a sharp maximum – the Bragg peak – and normal tissue receives a much lower dose than what is delivered by X‐ray therapy. Particle therapy has also biological advantages due to the high linear energy transfer of the charged particles around the Bragg peak. The introduction of particle therapy has been slow in Europe, but within the last decade, more than 20 clinical facilities have opened and facilitated access to this frontline therapy. In this review article, the basic concepts of particle therapy are reviewed along with a presentation of the current clinical indications, the European clinical research, and the established networks., Particle therapy using protons, or heavier ions, is the most advanced form of radiotherapy today and offers new opportunities for improving cancer care and research. Within the last decade, more than 20 new clinical facilities have opened in Europe, facilitating access to this frontline therapy. This review presents the physics, biology, and clinical aspects of particle therapy.

Physics 4(1), 172 - 184 (2022). doi:10.3390/physics4010013, Published by MDPI, Basel

Galactic cosmic rays (GCR) are among the main deterrents to manned space exploration. Currently, the most realistic way to reduce the dangers caused by GCR to acceptable levels is passive shielding. Light materials guarantee the strongest dose attenuation per unit mass. High-density polyethylene is considered the gold standard for radiation protection in space. Nevertheless, accelerator-based experimental campaigns already showed the advantages of more hydrogen-rich innovative shielding materials such as lithium hydride. The experimental campaigns of this work focused on the absorbed dose attenuation properties of lithium-based hydrides chemically stabilized with a paraffin matrix. Such materials were compared to pure lithium-based hydrides, polyethylene, structural materials such as spacecraft aluminum alloys and lithium batteries, and in situ shielding materials such as Moon regolith and its main components silicon and silicon dioxide. The experimental results were compared to simulations performed with PHITS, FLUKA, and Geant4, which are among the most used Monte Carlo codes for radiation protection in space. The simulations showed systematic differences and highlighted the pressing need for reliable nuclear cross-section models.

The European physical journal / Web of Conferences 261, 03002 (2022). doi:10.1051/epjconf/202226103002, Published by EDP Sciences, Les Ulis

Immunotherapy and targeted therapy are now commonly used in clinical trials in combination with radiotherapy for several cancers. While results are promising and encouraging, the molecular mechanisms of the interaction between the drugs and radiation remain largely unknown. This is especially important when switching from conventional photon therapy to particle therapy using protons or heavier ions. Different dose deposition patterns and molecular radiobiology can in fact modify the interaction with drugs and their effectiveness. We will show here that whilst the main molecular players are the same after low and high linear energy transfer radiation exposure, significant differences are observed in post-exposure signalling pathways that may lead to different effects of the drugs. We will also emphasise that the problem of the timing between drug administration and radiation and the fractionation regime are critical issues that need to be addressed urgently to achieve optimal results in combined treatments with particle therapy.

DNA double-strand breaks (DSBs) can induce chromosomal aberrations and carcinogenesis and their correct repair is crucial for genetic stability. The cellular response to DSBs depends on damage signaling including the phosphorylation of the histone H2AX (��H2AX). However, a lack of ��H2AX formation in heterochromatin (HC) is generally observed after DNA damage induction. Here, we examine ��H2AX and repair protein foci along linear ion tracks traversing heterochromatic regions in human or murine cells and find the DSBs and damage signal streaks bending around highly compacted DNA. Given the linear particle path, such bending indicates a relocation of damage from the initial induction site to the periphery of HC. Real-time imaging of the repair protein GFP-XRCC1 confirms fast recruitment to heterochromatic lesions inside murine chromocenters. Using single-ion microirradiation to induce localized DSBs directly within chromocenters, we demonstrate that H2AX is early phosphorylated within HC, but the damage site is subsequently expelled from the center to the periphery of chromocenters within ���20 min. While this process can occur in the absence of ATM kinase, the repair of DSBs bordering HC requires the protein. Finally, we describe a local decondensation of HC at the sites of ion hits, potentially allowing for DSB movement via physical forces.

Frontiers in oncology 11, 788182 (2021). doi:10.3389/fonc.2021.788182, Published by Frontiers Media, Lausanne

Stopping power predictions in radiation transport codes are based on the Bethe-Bloch formula and different corrections. For very heavy ions at relativistic energies the available experimental data are scarce and therefore verification of stopping power predictions is only possible to a limited extent. In this work, a full experimental Bragg curve for 800 MeV/u 238U ions stopping in polyethylene is presented. The measurements were conducted at the experimental area Cave A at GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt, Germany. The 800 MeV/u 238U beam was provided by the SIS18 heavy ion synchrotron. The Bragg curve was measured with a setup consisting of a binary range shifter and two large area parallel plate ionization chambers. Complementary Monte Carlo simulations using the FLUKA code were performed and compared with the experimental Bragg curve. The mean ionization potential of polyethylene was fine-tuned to match the measured primary ion range with FLUKA simulations. The impact of the Bloch and Mott corrections to the stopping power calculation were studied by switching them off intentionally in separate simulations. A detailed description of the implementation of the stopping power formulae and the Mott correction in FLUKA is provided. Supplementary data for this article is available online.

Purpose: We investigated the relationship between RBE-weighted dose (DRBE) calculated with constant (cRBE) and variable RBE (vRBE), dose-averaged linear energy transfer (LETd) and the risk of radiographic changes in skull base patients treated with protons. Methods: Clinical treatment plans of 45 patients were recalculated with Monte Carlo tool FRED. Radiographic changes (i.e. edema and/or necrosis) were identified by MRI. Dosimetric parameters for cRBE and vRBE were computed. Biological margin extension and voxel-based analysis were employed looking for association of DRBE(vRBE) and LETd with brain edema and/or necrosis. Results: When using vRBE, Dmax in the brain was above the highest dose limits for 38% of patients, while such limit was never exceeded assuming cRBE. Similar values of Dmax were observed in necrotic regions, brain and temporal lobes. Most of the brain necrosis was in proximity to the PTV. The voxel-based analysis did not show evidence of an association with high LETd values. Conclusions: When looking at standard dosimetric parameters, the higher dose associated with vRBE seems to be responsible for an enhanced risk of radiographic changes. However, as revealed by a voxel-based analysis, the large inter-patient variability hinders the identification of a clear effect for high LETd. (c) 2021 The Authors. Published by Elsevier B.V. Radiotherapy and Oncology 163 (2021) 143-149 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Several techniques are under development for image-guidance in particle therapy. Positron (β+) emission tomography (PET) is in use since many years, because accelerated ions generate positron-emitting isotopes by nuclear fragmentation in the human body. In heavy ion therapy, a major part of the PET signals is produced by β+-emitters generated via projectile fragmentation. A much higher intensity for the PET signal can be obtained using β+-radioactive beams directly for treatment. This idea has always been hampered by the low intensity of the secondary beams, produced by fragmentation of the primary, stable beams. With the intensity upgrade of the SIS-18 synchrotron and the isotopic separation with the fragment separator FRS in the FAIR-phase-0 in Darmstadt, it is now possible to reach radioactive ion beams with sufficient intensity to treat a tumor in small animals. This was the motivation of the BARB (Biomedical Applications of Radioactive ion Beams) experiment that is ongoing at GSI in Darmstadt. This paper will present the plans and instruments developed by the BARB collaboration for testing the use of radioactive beams in cancer therapy.

Purpose Radiation pneumonitis (RP) is commonly associated with thoracic radiation therapy, and its incidence is related to dose and volume of the normal lung in the path of radiation. Our aim was to investigate dose patterns associated with RP in patients enrolled in a randomized trial of intensity modulated radiation therapy (IMRT) versus passive scattering proton therapy (PSPT) for locally advanced non-small cell lung cancer. Methods We analyzed 178 patients prospectively treated with PSPT or IMRT for non-small cell lung cancer to a prescribed dose of 66 or 74 Gy in conventional daily fractionation with concurrent chemotherapy. Forty patients (22%) developed clinically symptomatic RP. Voxel-based analysis of local dose differences was done with a nonparametric permutation test accounting for multiple comparisons. From the obtained 3-dimensional significance maps, we derived clusters of voxels that exhibited dose differences between groups at a statistical significance level of 0.05. Results The voxel-based analysis highlighted that (1) significant dose differences between patients with and without RP were found in the lower part of the lungs and in the heart and (2) the anatomic regions significantly spared by PSPT and the clusters in which doses were significantly correlated with RP development were disjoint. Conclusions The analyzed trial data provide an unprecedented opportunity to substantiate previous hypotheses regarding the role of the heart and the lower lungs in the development of RP. Knowledge of this relationship between RP and thoracic regional radiosensitivity should be considered in clinical practice and in the design of future trials.

Physics in medicine and biology 67(15), 15TR02 (2022). doi:10.1088/1361-6560/ac65d3, Published by IOP Publ., Bristol

Realistic nuclear reaction cross-section models are an essential ingredient of reliable heavy-ion transport codes. Such codes are used for risk evaluation of manned space exploration missions as well as for ion-beam therapy dose calculations and treatment planning. Therefore, in this study, a collection of total nuclear reaction cross-section data has been generated within a GSI-ESA-NASA collaboration. The database includes the experimentally measured total nucleus-nucleus reaction cross-sections. The Tripathi, Kox, Shen, Kox-Shen, and Hybrid-Kurotama models are systematically compared with the collected data. Details about the implementation of the models are given. Literature gaps are pointed out and considerations are made about which models fit best the existing data for the most relevant systems to radiation protection in space and heavy-ion therapy., 40 pages, 17 figures, 1 table

Protection from cosmic radiation of crews of long-term space missions is now becoming an urgent requirement to allow a safe colonization of the moon and Mars. Epidemiology provides little help to quantify the risk, because the astronaut group is small and as yet mostly involved in low-Earth orbit mission, whilst the usual cohorts used for radiation protection on Earth (e.g. atomic bomb survivors) were exposed to a radiation quality substantially different from the energetic charged particle field found in space. However, there are over 260,000 patients treated with accelerated protons or heavier ions for different types of cancer, and this cohort may be useful for quantifying the effects of space-like radiation in humans. Space radiation protection and particle therapy research also share the same tools and devices, such as accelerators and detectors, as well as several research topics, from nuclear fragmentation cross sections to the radiobiology of densely ionizing radiation. The transfer of the information from the cancer radiotherapy field to space is manifestly complicated, yet the two field should strengthen their relationship and exchange methods and data.

Exposing cells to DNA damaging agents, such as ionizing radiation (IR) or cytotoxic chemicals, can cause DNA double-strand breaks (DSBs), which are crucial to repair to maintain genetic integrity. O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a post-translational modification (PTM), which has been reported to be involved in the DNA damage response (DDR) and chromatin remodeling. Here, we investigated the impact of O-GlcNAcylation on the DDR, DSB repair and chromatin status in more detail. We also applied charged particle irradiation to analyze differences of O-GlcNAcylation and its impact on DSB repair in respect of spatial dose deposition and radiation quality. Various techniques were used, such as the γH2AX foci assay, live cell microscopy and Fluorescence Lifetime Microscopy (FLIM) to detect DSB rejoining, protein accumulation and chromatin states after treating the cells with O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) inhibitors. We confirmed that O-GlcNAcylation of MDC1 is increased upon irradiation and identified additional repair factors related to Homologous Recombination (HR), CtIP and BRCA1, which were increasingly O-GlcNAcyated upon irradiation. This is consistent with our findings that the function of HR is affected by OGT inhibition. Besides, we found that OGT and OGA activity modulate chromatin compaction states, providing a potential additional level of DNA-repair regulation.

BackgroundQuality management and safety are integral to modern radiotherapy. New radiotherapy technologies require new consensus guidelines on quality and safety. Established analysis strategies, such as the failure modes and effects analysis (FMEA) and incident learning systems have been developed as tools to assess the safety of several types of radiation therapies. An extensive literature documents the widespread application of risk analysis methods to photon radiation therapy. Relatively little attention has been paid to performing risk analyses of nascent radiation therapy systems to treat moving tumors with scanned heavy ion beams. The purpose of this study was to apply a comprehensive safety analysis strategy to a motion-synchronized dose delivery system (M-DDS) for ion therapy.MethodsWe applied a risk analysis method to new treatment planning and treatment delivery processes with scanned heavy ion beams. The processes utilize a prototype, modular dose delivery system, currently undergoing preclinical testing, that provides new capabilities for treating moving anatomy. Each step in the treatment process was listed in a process map, potential errors for each step were identified and scored using the risk probability number in an FMEA, and the possible causes of each error were described in a fault tree analysis. Solutions were identified to mitigate the risk of these errors, including permanent corrective actions, periodic quality assurance (QA) tests, and patient specific QA (PSQA) tests. Each solution was tested experimentally.ResultsThe analysis revealed 58 potential errors that could compromise beam delivery quality or safety. Each of the 14 binary (pass-or-fail) tests passed. Each of the nine QA and four PSQA tests were within anticipated clinical specifications. The modular M-DDS was modified accordingly, and was found to function at two centers.ConclusionWe have applied a comprehensive risk analysis strategy to the M-DDS and shown that it is a clinically viable motion mitigation strategy. The described strategy can be utilized at any ion therapy center that operates with the modular M-DDS. The approach can also be adapted for use at other facilities and can be combined with existing safety analysis systems.

Heavy ions are riveting in radiation biophysics, particularly in the areas of radiotherapy and space radiation protection. Accelerated charged particles can indeed penetrate deeply in the human body to sterilize tumors, exploiting the favorable depth-dose distribution of ions compared to conventional X rays. Conversely, the high biological effectiveness in inducing late effects presents a hazard for manned space exploration. Even after half a century of accelerator-based experiments, clinical applications and flight research, these two topics remain both fascinating and baffling. Heavy-ion therapy is very expensive, and despite the clinical success it remains controversial. Research on late radiation morbidity in spaceflight led to a reduction in uncertainty, but also pointed to new risks previously underestimated, such as possible damage to the central nervous system. Recently, heavy ions have also been used in other, unanticipated biomedical fields, such as treatment of heart arrhythmia or inactivation of viruses for vaccine development. Heavy-ion science nicely merges physics and biology and remains an extraordinary research field for the 21st century.

Purpose To establish a beam monitoring and dosimetry system to enable the FLASH dose-rate carbon ion irradiation and investigate, at different oxygen concentrations, the in vitro biological response in comparison to conventional dose-rate. Methods and Materials CHO-K1 cell response to irradiation at different dose-rates and at different levels of oxygenation was studied using clonogenic assay. The XXX† Heidelberg Ion-Beam Therapy Center (HIT) synchrotron, after technical improvements, was adjusted to extract ≥5 × 108 12C ions within approximately 150 ms. The beam monitors were filled with helium. Results The FLASH irradiation with beam scanning yields a dose of 7.5 Gy (homogeneity of ±5%) for a 280 MeV/u beam in a volume of at least 8 mm in diameter and a corresponding dose rate of 70 Gy s−1 (± 20%). The dose repetition accuracy is better than 2%, the systematic uncertainty is better than 2%. Clonogenic assay demonstrates a significant FLASH sparing effect which is strongly oxygenation-dependent and mostly pronounced at 0.5% O2 but absent at 0% and 21% O2. Conclusion The FLASH dose-rates >40 Gy/s were achieved with carbon beams. Cell survival analysis revealed FLASH dose rate sparing in hypoxia (0.5% - 4% O2).

There is increasing interest in using helium ions for radiotherapy, complementary to protons and carbon ions. A large number of patients were treated with

Cells 10(10), 2608 (2021). doi:10.3390/cells10102608, Published by MDPI, Basel

Purpose The combination of radiation therapy and immunotherapy is recognized as a very promising strategy for metastatic cancer treatment. The purpose of this work is to compare the effectiveness of x-ray and high-energy carbon ion therapy in combination with checkpoint inhibitors in a murine model. Methods and Materials We used an osteosarcoma mouse model irradiated with either carbon ions or x-rays in combination with 2 immune checkpoint inhibitors (anti–PD-1 and anti–CTLA-4). LM8 osteosarcoma cells were injected in both hind limbs of female C3H/He mice 7 days before exposure to carbon ions or x-rays. In experimental groups receiving irradiation, only the tumor on the left limb was exposed, whereas the tumor on the right limb served as an abscopal mimic. Checkpoint inhibitors were injected intraperitoneally 1 day before exposure as well as concomitant to and after exposure. Tumor growth was measured regularly up to day 21 after exposure, when mice were sacrificed. Both tumors as well as lungs were extracted. Results A reduced growth of the abscopal tumor was most pronounced after the combined protocol of carbon ions and the immune checkpoint inhibitors administered sequentially. Radiation or checkpoint inhibitors alone were not sufficient to reduce the growth of the abscopal tumors. Carbon ions alone reduced the number of lung metastases more efficiently than x-rays, and in combination with immunotherapy both radiation types essentially suppressed the metastasis, with carbon ions being again more efficient. Investigation of the infiltration of immune cells in the abscopal tumors of animals treated with combination revealed an increase in CD8+ cells. Conclusions Combination of checkpoint inhibitors with high-energy carbon ion radiation therapy can be an effective strategy for the treatment of advanced tumors.

Frontiers in physics 9, 669271 (2021). doi:10.3389/fphy.2021.669271, Published by Frontiers Media, Lausanne

An alternative approach that is particularly suitable for the radiation health risk assessment (HRA) of astronauts is presented. The quantity, Radiation Attributed Decrease of Survival (RADS), representing the cumulative decrease in the unknown survival curve at a certain attained age, due to the radiation exposure at an earlier age, forms the basis for this alternative approach. Results are provided for all solid cancer plus leukemia incidence RADS from estimated doses from theoretical radiation exposures accumulated during long-term missions to the Moon or Mars. For example, it is shown that a 1000-day Mars exploration mission with a hypothetical mission effective dose of 1.07 Sv at typical astronaut ages around 40 years old, will result in the probability of surviving free of all types of solid cancer and leukemia until retirement age (65 years) being reduced by 4.2% (95% CI 3.2; 5.3) for males and 5.8% (95% CI 4.8; 7.0) for females. RADS dose–responses are given, for the outcomes for incidence of all solid cancer, leukemia, lung and female breast cancer. Results showing how RADS varies with age at exposure, attained age and other factors are also presented. The advantages of this alternative approach, over currently applied methodologies for the long-term radiation protection of astronauts after mission exposures, are presented with example calculations applicable to European astronaut occupational HRA. Some tentative suggestions for new types of occupational risk limits for space missions are given while acknowledging that the setting of astronaut radiation-related risk limits will ultimately be decided by the Space Agencies. Suggestions are provided for further work which builds on and extends this new HRA approach, e.g., by eventually including non-cancer effects and detailed space dosimetry., Radiation and Environmental Biophysics, 60 (2), ISSN:0301-634X, ISSN:1432-2099