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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.

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.

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.

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.

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

The combination of immune therapy with radiation offers an exciting and promising treatment modality in cancer therapy. It has been hypothesized that radiation induces damage signals within the tumor, making it more detectable for the immune system. In combination with inhibiting immune checkpoints an effective anti-tumor immune response may be established. This inversion from tumor immune evasion raises numerous questions to be solved to support an effective clinical implementation: These include the optimum immune drug and radiation dose time courses, the amount of damage and associated doses required to stimulate an immune response, and the impact of lymphocyte status and dynamics. Biophysical modeling can offer unique insights, providing quantitative information addressing these factors and highlighting mechanisms of action. In this work we review the existing modeling approaches of combined ‘radioimmune’ response, as well as associated fields of study. We propose modeling attempts that appear relevant for an effective and predictive model. We emphasize the importance of the time course of drug and dose delivery in view to the time course of the triggered biological processes. Special attention is also paid to the dose distribution to circulating blood lymphocytes and the effect this has on immune competence.

Medical physics 49(3), 1974 - 1992 (2022). doi:10.1002/mp.15135, Published by AAPM, College Park, Md.

Radiotherapy should have low toxicity in the entrance channel (normal tissue) and be very effective in cell killing in the target region (tumour). In this regard, ions heavier than protons have both physical and radiobiological advantages over conventional X-rays. Carbon ions represent an excellent combination of physical and biological advantages. There are a dozen carbon-ion clinical centres in Europe and Asia, and more under construction or at the planning stage, including the first in the USA. Clinical results from Japan and Germany are promising, but a heated debate on the cost-effectiveness is ongoing in the clinical community, owing to the larger footprint and greater expense of heavy ion facilities compared with proton therapy centres. We review here the physical basis and the clinical data with carbon ions and the use of different ions, such as helium and oxygen. Research towards smaller and cheaper machines with more effective beam delivery is necessary to make particle therapy affordable. The potential of heavy ions has not been fully exploited in clinics and, rather than there being a single ‘silver bullet’, different particles and their combination can provide a breakthrough in radiotherapy treatments in specific cases. Radiotherapy with accelerated heavy ions is a potential breakthrough in cancer therapy. This Review discusses the challenges in physics and radiobiology to make this therapy affordable and to fully exploit the clinical benefits.

Frontiers in physics 8, 568145 (2020). doi:10.3389/fphy.2020.568145, Published by Frontiers Media, Lausanne

Cognitive dysfunction induced by ionizing radiation remains a major concern in radiation therapy as well as in space mission projects. Both fields require sophisticated approaches to improve protection of the brain and its neuronal circuits. Radiation therapy related research focusses on advanced techniques imposing maximal effect on the tumor while minimizing toxicity to the surrounding tissue. Research for example has led to the revival of spatially fractionated radiation therapy (SFRT) and the advent of FLASH radiotherapy. To investigate the influence of the space radiation environment on brain cells, low dose, high LET radiation in addition to simulated microgravity have to be studied. Both research areas, however, call for cutting-edge cellular systems that faithfully resemble the architecture of the human brain, its development and its regeneration to understand the mechanisms of radiation-induced neurotoxicity and their prevention. In this review, we discuss the proposed mechanisms of neurotoxicity such as the loss of complexity within the neuronal networks, vascular changes, or neuroinflammation. We compare the current in vivo and in vitro studies of neurotoxicity including animal models, animal and human neural stem cells, and neurosphere models. Particularly, we will address the new and promising technique of generating human brain organoids and their potential use in radiation biology.

Intensity modulated particle therapy (IMPT) with carbon ions can generate highly conformal treatment plans; however, IMPT is limited in robustness against range and positioning uncertainty. This is particularly true for moving targets, even though all motion states of a 4DCT are considered in 4D-IMPT. Here, we expand 4D-IMPT to include robust non-linear RBE-weighted optimization to explore its potential in improving plan robustness and sparing critical organs. In this study, robust 4D-optimization—based on worst-case optimization on 9 scenarios—was compared to conventional 4D-optimization with PTV margins using 4D dose calculation and robustness analysis for 21 uncertainty scenarios. Slice-by-slice rescanning was used for motion mitigation. Both 4D-optimization strategies were tested on a cohort of 8 multi-lesion lung cancer patients with the goal of prioritizing OAR sparing in a hypofractionated treatment plan. Planning objectives were to keep the OAR volume doses below corresponding limits while simultaneously achieve CTV coverage with D95% ≥ 95 %. For the conventional plans, average D95% was at 98.7% which fulfilled the target objective in 83.2% of scenarios. For the robust plans, average D95% was reduced to 97.6% which still fulfilled the target objective in 80.7% of cases, but led to significantly improved overall OAR sparing: Volume doses were below the limits in 96.2% of cases for the conventional and 99.5% for the robust plans. When considering the particularly critical smaller airways only, fulfillment rates could be increased from 76.2% to 96% for the robust plans. This study has shown that plan robustness of 4D-IMPT could be improved by using robust 4D-optimization, offering greater control over uncertainties in the actual delivered dose. In some cases, this required sacrificing target coverage for the benefit of better OAR sparing.

Relative biological effectiveness (RBE) variations are thought to be one of the primary causes of unexpected normal-tissue toxicities during tumor treatments with charged particles. Unlike carbon therapy, where treatment planning is optimized on the basis of the RBE-weighted dose, a constant RBE value of 1.1 is currently used in proton therapy. Assuming a uniform value can lead to under- or over-dosage, not just to the tumor but also to surrounding normal tissue. RBE changes have been linked with dose/fraction, the biological endpoint and beam properties. Understanding radiation quality and the associated RBE can improve the prediction of normal-tissue toxicities. In this study, we exploited microdosimetry for characterizing radiation quality in proton therapy in-field, and off-beam at 20 (beam edge), 50 (close out-of-field) and 100 (far out-of-field) mm from the beam center. We measured the lineal energy y spectra in a water phantom irradiated with 152 MeV protons, from which beam quality as well as the physical dose could be obtained. Taking advantage of the linear quadratic model and a modified version of the microdosimetric kinetic model, the microdosimetric data were combined with radiobiological parameters (α and β) of human salivary gland tumor cells for assessing cell survival RBE and RBE-weighted dose. The results indicate that if a dose of 60 Gy is delivered to the peak, the beam edge receives up to 6 Gy while the close and far out-of-field regions receive doses on the order of 10-3 Gy and 10-4 Gy, respectively. The RBE estimate in-beam shows large variations, ranging from 1.0 ± 0.2 at the entrance channel to 2.51 ± 0.15 at the tail. The beam edge follows a similar trend but the RBE calculated at the Bragg peak depth is 2.27 ± 0.17, i.e. twice the RBE in-beam (1.05 ± 0.15). Out-of-field, the estimated RBE is always significantly higher than 1.1 and increases with increasing lateral distance, reaching the overall highest value of 3.4 ± 0.3 at a depth of 206 mm and a lateral distance of 10 mm. The combination of RBE and dose into the biological dose points to the beam edge and the end-of-range in-beam as the areas with the highest risk of potential toxicities.

Radiation therapy (RT) of thoracic cancers may cause severe radiation dermatitis (RD), which impacts on the quality of a patient's life. Aim of this study was to analyze the incidence of acute RD and develop normal tissue complication probability (NTCP) models for severe RD in thoracic cancer patients treated with Intensity-Modulated RT (IMRT) or Passive Scattering Proton Therapy (PSPT). We analyzed 166 Non-Small-Cell Lung Cancer (NSCLC) patients prospectively treated at a single institution with IMRT (103 patients) or PSPT (63 patients). All patients were treated to a prescribed dose of 60 to 74 Gy in conventional daily fractionation with concurrent chemotherapy. RD was scored according to CTCAE v3 scoring system. For each patient, the epidermis structure (skin) was automatically defined by an in house developed segmentation algorithm. The absolute dose-surface histogram (DSH) of the skin were extracted and normalized using the Body Surface Area (BSA) index as scaling factor. Patient and treatment-related characteristics were analyzed. The Lyman-Kutcher-Burman (LKB) NTCP model recast for DSH and the multivariable logistic model were adopted. Models were internally validated by Leave-One-Out method. Model performance was evaluated by the area under the receiver operator characteristic curve, and calibration plot parameters. Fifteen of 166 (9%) patients developed severe dermatitis (grade 3). RT technique did not impact RD incidence. Total gross tumor volume (GTV) size was the only non dosimetric variable significantly correlated with severe RD (p = 0.027). Multivariable logistic modeling resulted in a single variable model including S 20Gy, the relative skin surface receiving more than 20 Gy (OR = 31.4). The cut off for S 20Gy was 1.1% of the BSA. LKB model parameters were TD50 = 9.5 Gy, m = 0.24, n = 0.62. Both NTCP models showed comparably high prediction and calibration performances. Despite skin toxicity has long been considered a potential limiting factor in the clinical use of PSPT, no significant differences in RD incidence was found between RT modalities. Once externally validated, the availability of NTCP models for prediction of severe RD may advance treatment planning optimization.

International journal of molecular sciences 21(24), 9592 (2020). doi:10.3390/ijms21249592, Published by Molecular Diversity Preservation International, Basel

Journal of applied clinical medical physics 21(10), 227 - 232 (2020). doi:10.1002/acm2.12996, Published by ACMP, Reston, Va.

Heavy ion therapy can deliver high doses with high precision. However, image guidance is needed to reduce range uncertainty. Radioactive ions are potentially ideal projectiles for radiotherapy because their decay can be used to visualize the beam. Positron-emitting ions that can be visualized with PET imaging were already studied for therapy application during the pilot therapy project at the Lawrence Berkeley Laboratory, and later within the EULIMA EU project, the GSI therapy trial in Germany, MEDICIS at CERN, and at HIMAC in Japan. The results show that radioactive ion beams provide a large improvement in image quality and signal-to-noise ratio compared to stable ions. The main hindrance toward a clinical use of radioactive ions is their challenging production and the low intensities of the beams. New research projects are ongoing in Europe and Japan to assess the advantages of radioactive ion beams for therapy, to develop new detectors, and to build sources of radioactive ions for medical synchrotrons.

Compared with photon and proton therapy, carbon ion radiotherapy (CIRT) offers potentially superior dose distributions, which may permit dose escalation with the potential for improved sparing of adjacent normal tissues. CIRT has increased biological effectiveness leading to increased tumour killing compared with other radiation modalities. Here we review these biophysical properties and provide a comprehensive evaluation of the current clinical evidence available for different tumour types treated with CIRT. We suggest that patient selection for CIRT should move away from the traditional viewpoint, which confines use to deep-seated hypoxic tumours that are adjacent to radiosensitive structures. A more integrated translational approach is required for the future as densely ionising C-ions elicit a distinct signal response pathway compared with sparsely ionising X-rays. This makes CIRT a biologically distinct treatment compared with conventional radiotherapy.

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.

The effects of microgravity and cosmic rays on the cardiovascular system are major health concerns for astronauts in space. In this Review, Hughson and colleagues summarize the current evidence on risk estimation and dysfunction of the cardiovascular system in space, and discuss potential countermeasures, including physical exercise, antioxidants, nutraceuticals, and radiation shielding. National space agencies and private corporations aim at an extended presence of humans in space in the medium to long term. Together with currently suboptimal technology, microgravity and cosmic rays raise health concerns about deep-space exploration missions. Both of these physical factors affect the cardiovascular system, whose gravity-dependence is pronounced. Heart and vascular function are, therefore, susceptible to substantial changes in weightlessness. The altered cardiovascular function in space causes physiological problems in the postflight period. A compromised cardiovascular system can be excessively vulnerable to space radiation, synergistically resulting in increased damage. The space radiation dose is significantly lower than in patients undergoing radiotherapy, in whom cardiac damage is well-documented following cancer therapy in the thoracic region. Nevertheless, epidemiological findings suggest an increased risk of late cardiovascular disease even with low doses of radiation. Moreover, the peculiar biological effectiveness of heavy ions in cosmic rays might increase this risk substantially. However, whether radiation-induced cardiovascular effects have a threshold at low doses is still unclear. The main countermeasures to mitigate the effect of the space environment on cardiac function are physical exercise, antioxidants, nutraceuticals, and radiation shielding.

There is increasing interest in using helium ions for radiotherapy, complementary to protons and carbon ions. A large number of patients were treated with 4He ions in the US heavy ion therapy project and novel 4He ion treatment programs are under preparation, for instance in Germany and Japan. 3He ions have been proposed as an alternative to 4He ions because the acceleration of 3He is technically less difficult than 4He. In particular, beam contaminations have been pointed out as a potential safety issue for 4He ion beams. This motivated a series of experiments with 3He ion beams at Gesellschaft für Schwerionenforschung (GSI), Darmstadt. Measured 3He Bragg curves and fragmentation data in water are presented in this work. Those experimental data are compared with FLUKA Monte Carlo simulations. The physical characteristics of 3He ion beams are compared to those of 4He, for which a large set of data became available in recent years from the preparation work at the Heidelberger Ionenstrahl-Therapiezentrum (HIT). The dose distributions (spread out Bragg peaks, lateral profiles) that can be achieved with 3He ions are found to be competitive to 4He dose distributions. The effect of beam contaminations on 4He depth dose distribution is also addressed. It is concluded that 3He ions can be a viable alternative to 4He, especially for future compact therapy accelerator designs and upgrades of existing ion therapy facilities.

Noninvasive ablation of cardiac arrhythmia by scanned particle radiotherapy is highly promising, but especially challenging due to cardiac and respiratory motion. Irradiations for catheter-free ablation in intact pigs were carried out at the GSI Helmholtz Center in Darmstadt using scanned carbon ions. Here, we present real-time electrocardiogram (ECG) data to estimate time-resolved (4D) delivered dose. For 11 animals, surface ECGs and temporal structure of beam delivery were acquired during irradiation. R waves were automatically detected from surface ECGs. Pre-treatment ECG-triggered 4D-CT phases were synchronized to the R-R interval. 4D-dose calculation was performed using GSI's in-house 4D treatment planning system. Resulting dose distributions were assessed with respect to coverage (D95 and V95), heterogeneity (HI = D5-D95) and normal tissue exposure. Final results shown here were performed offline, but first calculations were started shortly after irradiation The D95 for TV and PTV was above 95% for 10 and 8 out of 11 animals, respectively. HI was reduced for PTV versus TV volumes, especially for some of the animals targeted at the atrioventricular junction, indicating residual interplay effects due to cardiac motion. Risk structure exposure was comparable to static and 4D treatment planning simulations. ECG-based 4D-dose reconstruction is technically feasible in a patient treatment-like setting. Further development of the presented approach, such as real-time dose calculation, may contribute to safe, successful treatments using scanned ion beams for cardiac arrhythmia ablation.

Summary: Charged particle therapy exploits proton or 12C beams to treat deep-seated solid tumors. Due to the advantageous characteristics of charged particles energy deposition in matter, the maximum of the dose is released to the tumor at the end of the beam range, in the Bragg peak region. However, the beam nuclear interactions with the patient tissues induces fragmentation both of projectile and target nuclei and needs to be carefully taken into account. In proton treatments, target fragmentation produces low energy, short range fragments along all the beam range, which deposit a non negligible dose in the entry channel. In 12C treatments the main concern is represented by long range fragments due to beam fragmentation that release their dose in the healthy tissues beyond the tumor. The FOOT experiment (FragmentatiOn Of Target) of INFN is designed to study these processes, in order to improve the nuclear fragmentation description in next generation Treatment Planning Systems and the treatment plans quality. Target (16O and 12C nuclei) fragmentation induced by –proton beams at therapeutic energies will be studied via an inverse kinematic approach, where 16O and 12C therapeutic beams impinge on graphite and hydrocarbon targets to provide the nuclear fragmentation cross section on hydrogen. Projectile fragmentation of 16O and 12C beams will be explored as well. The FOOT detector includes a magnetic spectrometer for the fragments momentum measurement, a plastic scintillator for ΔE and time of flight measurements and a crystal calorimeter to measure the fragments kinetic energy. These measurements will be combined in order to make an accurate fragment charge and isotopic identification. Keywords: Hadrontherapy, Nuclear fragmentation cross sections, Tracking detectors, Scintillating detectors

Charged Particle Therapy (CPT) is a powerful radiotherapy technique for the treatment of deep-seated tumours characterized by a large dose released in the Bragg peak area (corresponding to the tumour region) and a small dose delivered to the surrounding healthy tissues. The precise measurement of the fragments produced in the nuclear interactions of charged particle beams with patient tissues is a crucial task to improve the clinical treatment plans. The FOOT (FragmentatiOn Of Target) experiment is an international project, funded by the Istituto Nazionale di Fisica Nucleare (INFN), aimed to study the dose released by the tissues and particle beams fragmentation. The target (16O, 12C) fragmentation induced by 150-400 MeV/n proton beams will be studied via the inverse kinematic approach, where 16O and 12C therapeutic beams collide on graphite and hydrocarbon target to provide the cross section on Hydrogen. A table-top detector is being developed and it includes a drift chamber as a beam monitor upstream of the target to measure the beam direction, a magnetic spectrometer based on silicon pixel and strip detectors, a scintillating crystal calorimeter able to stop the heavier produced fragments, and a ΔE detector, with TOF capability, for the particle identification. A setup based on the concept of the “Emulsion Cloud Chamber”, coupled with the interaction region of the electronic FOOT setup, will complement the physics program by measuring lighter charged fragments to extend the angular acceptance up to about 70 degrees. In this work, the experimental design and the requirements of the FOOT experiment will be discussed and preliminary results on the emulsion spectrometer tests will be presented.

Noninvasive X-ray stereotactic treatment is considered a promising alternative to catheter ablation in patients affected by severe heart arrhythmia. High-energy heavy ions can deliver high radiation doses in small targets with reduced damage to the normal tissue compared to conventional X-rays. For this reason, charged particle therapy, widely used in oncology, can be a powerful tool for radiosurgery in cardiac diseases. We have recently performed a feasibility study in a swine model using high doses of high-energy C-ions to target specific cardiac structures. Interruption of cardiac conduction was observed in some animals. Here we report the biological effects measured in the pig heart tissue of the same animals six months after the treatment. Immunohistological analysis of the target tissue showed (1.) long-lasting vascular damage, i.e. persistent hemorrhage, loss of microvessels, and occurrence of siderophages, (2.) fibrosis and (3.) loss of polarity of targeted cardiomyocytes and wavy fibers with vacuolization. We conclude that the observed physiological changes in heart function are produced by radiation-induced fibrosis and cardiomyocyte functional inactivation. No effects were observed in the normal tissue traversed by the particle beam, suggesting that charged particles have the potential to produce ablation of specific heart targets with minimal side effects.

The combination of radiotherapy and immunotherapy is one of the most promising strategies for cancer treatment. Recent clinical results support the pre-clinical experiments pointing to a benefit for the combined treatment in metastatic patients. Charged particle therapy (using protons or heavier ions) is considered one of the most advanced radiotherapy techniques, but its cost remains higher than conventional X-ray therapy. The most important question to be addressed to justify a more widespread use of particle therapy is whether they can be more effective than X-rays in combination with immunotherapy. Protons and heavy ions have physical advantages compared to X-rays that lead to a reduced damage to the immune cells, that are required for an effective immune response. Moreover, densely ionizing radiation may have biological advantages, due to different cell death pathways and release of cytokine mediators of inflammation. We will discuss results in esophageal cancer patients showing that charged particles can reduce the damage to blood lymphocytes compared to X-rays, and preliminary in vitro studies pointing to an increased release of immune-stimulating cytokines after heavy ion exposure. Pre-clinical and clinical studies are ongoing to test these hypotheses.

Measured cross sections for the production of the PET isotopes , and from carbon and oxygen targets induced by protons (40–220 ) and carbon ions (65–430 ) are presented. These data were obtained via activation measurements of irradiated graphite and beryllium oxide targets using a set of three scintillators coupled by a coincidence logic. The measured cross sections are relevant for the PET particle range verification method where accurate predictions of the emitter distribution produced by therapeutic beams in the patient tissue are required. The presented dataset is useful for validation and optimization of the nuclear reaction models within Monte Carlo transport codes. For protons the agreement of a radiation transport calculation using the measured cross sections with a thick target PET measurement is demonstrated.

Applied nuclear physics is an essential part of the research activity at many particle accelerators. New, large accelerator facilities are currently under construction in Europe, Asia, and USA. These machines will be able to produce radioactive ion beams, and to increase the intensity and the energy of the heavy ions well beyond the limits currently available at the therapy or research facilities. The upcoming facilities open new opportunities for research in biomedical applications that require these special properties, such as particle radiography, radioactive beam imaging, ultra-high dose rates and new ions for therapy. Moreover, space radiation research and materials science can successfully exploit these new centers. The new facilities can pave the way to many future applications of nuclear physics for the benefit of the society. In this paper we will summarize the current status of applied sciences at high-energy accelerators, describe the characteristics of some of the machines under construction (FAIR, NICA, RAON, ELI) and discuss the new opportunities offered by these facilities in applied sciences.

Background and purpose Scanned particle beam therapy may result in over and under dosages within the target volume. This study quantifies how CTV dose coverage improves with number of fractions and fields. Materials and methods Based on 4DCTs of nine lung tumor patients, treatment plans were optimized separately for four different fields using an ITV approach. 4D RBE-weighted dose distributions were calculated for varying motion parameters and fraction numbers. The total RBE-weighted dose was determined for one and four-field application per fraction. DVHs were analyzed for the tumor and interpreted based on statistical modeling. Results Dose homogeneity within the CTV increased with the fraction number, but depends significantly on the tumor motion amplitude. For single-field schedules and amplitudes >6mm, the dose coverage indices (V95 min =90.7% and V107 max =0.4%) differed to the stationary case even after 40 fractions. Target coverage for a four-field approach followed a proposed model and homogeneous dose distributions could be achieved 6-times faster than single-field treatments. Conclusions Fractionated delivery improves dose homogeneity in scanned ion beam therapy of moving targets. The achievable homogeneity depends mainly on tumor volume and motion amplitude. The outcome of multiple-field irradiations can be predicted based on single-field results and accelerates the achievement of homogeneous dose distributions.

INTRODUCTION Catheter ablation with isolation of the pulmonary veins is a common treatment option for atrial fibrillation but still has insufficient success rates and carries several interventional risks. These treatment planning studies assessed if high-dose single fraction treatment with scanned carbon ions (12C) can be reliably delivered for AF ablation, while sparing risk structures and considering respiratory and contractile target motion. METHODS AND RESULTS Time resolved CT scans of complete respiratory and cardiac cycles of 9 and 5 patients, respectively, were obtained. Ablation lesions and organs at risk for beam delivery were contoured. Single fraction intensity-modulated particle therapy with target doses of 25 and 40 Gy were studied and motion influences on these deliveries mitigated. Respiration had a large influence on lesion displacement (≤ 2 cm). End expiration could be exploited as a stable gating window. Smaller, but less predictable, heartbeat displacements (< 6 mm) remained to be mitigated because cardiac contraction resulted in insufficient dose coverage (V95 < 90%) if uncompensated. Repeated irradiation (12C beam rescanning) during breath hold was used to accommodate contractile motion, resulting in good dose coverage. Dose depositions to all organs at risk were carefully examined and did not exceed values for X-ray cancer treatment. CONCLUSION Treatment planning of 12C with delivery of physical ionizing radiation doses that have been described to induce complete block is feasible for AF ablation, considering human anatomy, dose constraints, and encasing underlying motion patterns from respiration and cardiac contraction at the LA-PV junction into treatment planning.

Radiation-induced chromosomal aberrations represent an early marker of late effects, including cell killing and transformation. The measurement of cytogenetic damage in tissues, generally in blood lymphocytes, from patients treated with radiotherapy has been studied for many years to predict individual sensitivity and late morbidity. Acentric fragments are lost during mitosis and create micronuclei (MN), which are well correlated to cell killing. Immunotherapy is rapidly becoming a most promising new strategy for metastatic tumors, and combination with radiotherapy is explored in several pre-clinical studies and clinical trials. Recent evidence has shown that the presence of cytosolic DNA activates immune response via the cyclic GMP-AMP synthase/stimulator of interferon genes pathway, which induces type I interferon transcription. Cytosolic DNA can be found after exposure to ionizing radiation either as MN or as small fragments leaking through nuclear envelope ruptures. The study of the dependence of cytosolic DNA and MN on dose and radiation quality can guide the optimal combination of radiotherapy and immunotherapy. The role of densely ionizing charged particles is under active investigation to define their impact on the activation of the interferon pathway.

The increasing number of centers providing proton or carbon beam therapy underlines the growing importance of charged particle therapy within the spectrum of cancer radiotherapy. Whereas protons are more widely used around the world, carbon ions, which are known to bear a higher efficacy as compared to protons, are still neglected to some extent, especially due to a lack of clinical data on adverse side effects. Yet, an increasing amount of clinical data indicates the distinguished efficacy of carbon ion therapy. Notwithstanding, the radiobiological mechanisms of particle radiation are not completely understood and lag behind advances in technology, which potentially enable new therapy regimens. However, an increased knowledge is required for their application with maximal benefit and sufficient risk estimation. Differential gene expression, distinct molecular mechanisms and signal pathways in the radiation response, and systemic effects, such as increased immunogenicity, and the possibilities of combined treatments arising from them, are important fields of particle radiobiology in which new discoveries and advances have occurred. These aspects are contemplated with respect to an individualization of radiotherapy; radiation type and treatment regimen might be chosen on the basis of the radiosensitivity of the individual and the cancer type. Here, we provide an update on a few recent findings and advances in particle radiobiology. A comprehensive essay on the basics of particle radiobiology is beyond the scope of this article. The focus is directed on a few subjects currently undergoing intense study and which are of current interest with respect to advances in therapy.

Clinical trials and case reports of cancer therapies combining radiation therapy with immunotherapy have at times demonstrated total reduction or elimination of metastatic disease. While virtually all trials focus on the use of immunotherapy combined with conventional photon irradiation, the dose-distributive benefits of particles, in particular the distinct biological effects of heavy ions, have unknown potential vis-a-vis systemic disease response. Here, we review recent developments and evidence with a focus on the potential for heavy-ion combination therapy.

Intensity modulated particle therapy (IMPT) can produce highly conformal plans, but is limited in advanced lung cancer patients with multiple lesions due to motion and planning complexity. A 4D IMPT optimization including all motion states was expanded to include multiple targets, where each target (isocenter) is designated to specific field(s). Furthermore, to achieve stereotactic treatment planning objectives, target and OAR weights plus objective doses were automatically iteratively adapted. Finally, 4D doses were calculated for different motion scenarios. The results from our algorithm were compared to clinical stereotactic body radiation treatment (SBRT) plans. The study included eight patients with 24 lesions in total. Intended dose regimen for SBRT was 24 Gy in one fraction, but lower fractionated doses had to be delivered in three cases due to OAR constraints or failed plan quality assurance. The resulting IMPT treatment plans had no significant difference in target coverage compared to SBRT treatment plans. Average maximum point dose and dose to specific volume in OARs were on average 65% and 22% smaller with IMPT. IMPT could also deliver 24 Gy in one fraction in a patient where SBRT was limited due to the OAR vicinity. The developed algorithm shows the potential of IMPT in treatment of multiple moving targets in a complex geometry.

Recent results from the Franco-Swiss team of Institute Curie and Centre Hospitalier Universitaire Vaudois demonstrate a remarkable sparing of normal tissue after irradiation at ultra-high dose rate (>40 Gy s−1). The “FLASH” radiotherapy maintains tumour control level, suggesting that ultra-high dose rate can substantially enhance the therapeutic window in radiotherapy. The results have been obtained so far only with 4–6 MeV electrons in lung and brain mouse model. Nevertheless, they have attracted a great attention for the potential clinical applications. Oxygen depletion had been discussed many years ago as a possible mechanism for reduction of the damage after exposure to ultra-high dose rate. However, the mechanism underlying the effect observed in the FLASH radiotherapy remains to be elucidated.

Purpose To define the physical parameters needed to characterize a particle beam in order to allow intercomparison of different experiments performed using different ions at the same facility and using the same ion at different facilities. Methods At the request of the National Cancer Institute (NCI), a special panel was convened to review the current status of the field and to provide suggested metrics for reporting the physical parameters of particle beams to be used for biological research. A set of physical parameters and measurements that should be performed by facilities and understood and reported by researchers supported by NCI to perform pre-clinical radiobiology and medical physics of heavy ions were generated. Results Standard measures such as radiation delivery technique, beam modifiers used, nominal energy, field size, physical dose and dose rate should all be reported. However, more advanced physical measurements, including detailed characterization of beam quality by microdosimetric spectrum and fragmentation spectra, should also be established and reported. Details regarding how such data should be incorporated into Monte Carlo simulations and the proper reporting of simulation details are also discussed. Conclusions In order to allow for a clear relation of physical parameters to biological effects, facilities and researchers should establish and report detailed physical characteristics of the irradiation beams utilized including both standard and advanced measures. Biological researchers are encouraged to actively engage facility staff and physicists in the design and conduct of experiments. Modeling individual experimental setups will allow for the reporting of the uncertainties in the measurement or calculation of physical parameters which should be routinely reported.

Equivalent dose from neutrons produced during proton radiotherapy increases the predicted risk of radiogenic late effects. However, out-of-field neutron dose is not taken into account by commercial proton radiotherapy treatment planning systems. The purpose of this study was to demonstrate the feasibility of implementing an analytical model to calculate leakage neutron equivalent dose in a treatment planning system. Passive scattering proton treatment plans were created for a water phantom and for a patient. For both the phantom and patient, the neutron equivalent doses were small but non-negligible and extended far beyond the therapeutic field. The time required for neutron equivalent dose calculation was 1.6 times longer than that required for proton dose calculation, with a total calculation time of less than 1 h on one processor for both treatment plans. Our results demonstrate that it is feasible to predict neutron equivalent dose distributions using an analytical dose algorithm for individual patients with irregular surfaces and internal tissue heterogeneities. Eventually, personalized estimates of neutron equivalent dose to organs far from the treatment field may guide clinicians to create treatment plans that reduce the risk of late effects.

Purpose: Different ion types offer different physical and biological advantages for therapeutic applications. The purpose of this work is to assess the advantages of the most commonly used ions in particle therapy, i.e., carbon (12C), helium (4He), and protons (1H) for different treatment scenarios. Methods: A treatment planning analysis based on idealized target geometries was performed using the treatment planning software TRiP98. For the prediction of the relative biological effectiveness (RBE) that is required for biological optimization in treatment planning the local effect model (LEM IV) was used. To compare the three ion types, the peak-to-entrance ratio (PER) was determined for the physical dose (PERPHY S), the RBE (PERRBE), and the RBE-weighted dose (PERBIO) resulting for different dose-levels, field configurations, and tissue types. Further, the dose contribution to artificial organs at risk (OAR) was assessed and a comparison of the dose distribution for the different ion types was performed for a patient with chordoma of the skull base. Results: The study showed that the advantages of the ions depend on the physical and biological properties and the interplay of both. In the case of protons, the consideration of a variable RBE instead of the clinically applied generic RBE of 1.1 indicates an advantage in terms of an increased PERRBE for the analyzed configurations. Due to the fact that protons show a somewhat better PERPHY S compared to helium and carbon ions whereas helium shows a higher PERRBE compared to protons, both protons and helium ions show a similar RBE-weighted dose distribution. Carbon ions show the largest variation of the PERRBE with tissue type and a benefit for radioresistant tumor types due to their higher LET. Furthermore, in the case of a two-field irradiation, an additional gain in terms of PERBIO is observed when using an orthogonal field configuration for carbon ions as compared to opposing fields. In contrast, for protons, the PERBIO is almost independent on the field configuration. Concerning the artificial lateral OAR, the volume receiving 20% of the prescribed RBE-weighted dose (V20) was reduced by over 35% using helium ions and by over 40% using carbon ions compared to protons. The analysis of the patient plan showed that protons, helium, and carbon ions are similar in terms of target coverage whereas the dose to the surrounding tissue is increasing from carbon ions toward protons. The mean dose to the brain stem can be reduced by more than 55% when using helium ions and by further 25% when using carbon ions instead of protons. Conclusions: The comparison of the PERRBE and PERPHY S of the three ion types suggests a strong dependence of the advantages of the three ions on the dose-level, tissue type, and field configuration. In terms of conformity, i.e., dose to the normal tissue, a clear gain is expected using carbon or helium ions compared to protons.

Background and Purpose. Radiotherapy is an essential tool for cancer treatment. In order to spare normal tissues and to reduce the risk of normal tissue complications, particle therapy is a method of choice. Although a large part of healthy tissues can be spared due to improved depth dose characteristics, little is known about the biological and molecular mechanisms altered after particle irradiation in healthy tissues. Elucidation of these effects is also required in the context of long term space flights, as particle radiation is the main contributor to the radiation effects observed in space. Endothelial cells, forming the inner layer of all vascular structures, are especially sensitive to irradiation and, if damaged, contribute to radiation-induced cardiovascular disease. Materials and Methods. Transcriptomics, proteomics and cytokine analyses were used to compare the response of endothelial cells irradiated or not with a single 2 Gy dose of X-rays or Fe ions measured one and seven days post-irradiation. To support the observed inflammatory effects, monocyte adhesion on endothelial cells was also assessed. Results. Experimental data indicate time- and radiation quality-dependent changes of the endothelial cell response to irradiation. The irradiation impact was more pronounced and longer lasting for Fe ions than for X-rays. Both radiation qualities decreased the expression of genes involved in cell-cell adhesion and enhanced the expression of proteins involved in caveolar mediated endocytosis signaling. Endothelial inflammation and adhesiveness were increased with X-rays, but decreased after Fe ion exposure. Conclusions. Fe ions induce pro-atherosclerotic processes in endothelial cells that are different in nature and kinetics than those induced by X-rays, highlighting radiation quality-dependent differences which can be linked to the induction and progression of cardiovascular diseases. Our findings give a better understanding of the underlying processes triggered by particle irradiation in endothelial cells, a crucial aspect for the development of protective measures for cancer patients undergoing particle therapy and for astronauts in space.

Radiotherapy with high-energy charged particles has become an attractive therapeutic option for patients with several tumour types because this approach better spares healthy tissue from radiation than conventional photon therapy. The cost associated with the delivery of charged particles, however, is higher than that of even the most elaborate photon-delivery technologies. Reliable evidence of the relative cost-effectiveness of both modalities can only come from the results of randomized clinical trials. Thus, the hurdles that currently limit direct comparisons of these two approaches in clinical trials, especially those related to insurance coverage, should be removed. Herein, we review several randomized trials of charged-particle therapies that are ongoing, with results that will enable selective delivery to patients who are most likely to benefit from them. We also discuss aspects related to radiobiology, including the immune response and hypoxia, which will need to be taken into consideration in future randomized trials to fully exploit the potential of charged particles.

Proton beam therapy represents a promising modality for left-side breast cancer (BC) treatment, but concerns have been raised about skin toxicity and poor cosmesis. The aim of this study is to apply skin normal tissue complication probability (NTCP) model for intensity modulated proton therapy (IMPT) optimization in left-side BC.Ten left-side BC patients undergoing photon irradiation after breast-conserving surgery were randomly selected from our clinical database. Intensity modulated photon (IMRT) and IMPT plans were calculated with iso-tumor-coverage criteria and according to RTOG 1005 guidelines. Proton plans were computed with and without skin optimization. Published NTCP models were employed to estimate the risk of different toxicity endpoints for skin, lung, heart and its substructures.Acute skin NTCP evaluation suggests a lower toxicity level with IMPT compared to IMRT when the skin is included in proton optimization strategy (0.1% versus 1.7%, p 0.001). Dosimetric results show that, with the same level of tumor coverage, IMPT attains significant heart and lung dose sparing compared with IMRT. By NTCP model-based analysis, an overall reduction in the cardiopulmonary toxicity risk prediction can be observed for all IMPT compared to IMRT plans: the relative risk reduction from protons varies between 0.1 and 0.7 depending on the considered toxicity endpoint.Our analysis suggests that IMPT might be safely applied without increasing the risk of severe acute radiation induced skin toxicity. The quantitative risk estimates also support the potential clinical benefits of IMPT for left-side BC irradiation due to lower risk of cardiac and pulmonary morbidity. The applied approach might be relevant on the long term for the setup of cost-effectiveness evaluation strategies based on NTCP predictions.

Cancer treatment, today, consists of surgery, chemotherapy, radiation, and most recently immunotherapy. Combination immunotherapy-radiotherapy (CIR) has experienced a surge in public attention due to numerous clinical publications outlining the reduction or elimination of metastatic disease, following treatment with specifically ipilimumab and radiotherapy. The mechanism behind CIR, however, remains unclear, though it is hypothesized that radiation transforms the tumor into an in situ vaccine which immunotherapy modulates into a larger immune response. To date, the majority of attention has focused on rotating out immunotherapeutics with conventional radiation; however, the unique biological and physical benefits of particle irradiation may prove superior in generation of systemic effect. Here, we review recent advances in CIR, with a particular focus on the usage of charged particles to induce or enhance response to cancerous disease.

Particle therapy uses protons or $^{12}$C beams for the treatment of deep-seated solid tumors. Due to the features of the energy deposition of charged particles in matter, a limited amount of dose is released to the healthy tissue in the beam entrance region, while the maximum of the dose is released to the tumor at the end of the beam range, in the Bragg peak region. However nuclear interactions between beam and patient tissues induce fragmentation both of projectile and target. This has to be carefully taken into account since different ions have different effectiveness in producing a biological damage. par In $^{12}$C treatments the main concern are long range forward emitted secondary ions produced in projectile fragmentation that release dose in the healthy tissue after the tumor. Instead, in a proton treatment, the target fragmentation produces low energy, short range fragments along all the beam range. The FOOT experiment (FragmentatiOn Of Target) is designed to study these processes. Target nuclei ($^{16}$O, $^{12}$C) fragmentation induced by 150-250 MeV proton beam will be studied by means of the inverse kinematic approach: $^{16}$O,$^{12}$C therapeutic beams, at the quoted kinetic energy per nucleon, collide on graphite and hydrocarbons target. The cross section on Hydrogen can be then extracted by subtraction. This configuration explores also the projectile fragmentation of these O and C beams, or other ions of therapeutic interest, such as $^4$He for instance. The detector includes a magnetic spectrometer based on silicon pixel and strip detectors, a scintillating crystal calorimeter able to stop the heavier produced fragments, and a $\Delta E$ detector, with TOF capability, to achieve the needed energy resolution and particle identification. In addition to the electronic apparatus, an alternative setup based on the concept of the "Emulsion Cloud Chamber", coupled with the interaction region of the electronic FOOT setup, will provide the measurement of lighter charged fragments: protons, deuterons, tritons and Helium nuclei. The FOOT data taking is foreseen in the available experimental rooms existing in the presently operational charged particle therapy facilities in Europe, and possibly at GSI. An initial phase with the emulsion setup will start in early 2018, while the complete electronic detector will take data starting in 2019. In this work a general description of the FOOT experiment and of its expected performances is presented.

Purpose: To develop a simple model of therapeutic and stray absorbed dose for a variety of treatment machines and techniques without relying on proprietary machine-specific parameters. Methods: Dosimetry measurements conducted in this study and from the literature were used to develop an analytical model of absorbed dose from a variety of treatment machines and techniques in the 6 to 25 MV interval. A modified one-dimensional gamma-index analysis was performed to evaluate dosimetric accuracy of the model on an independent dataset consisting of measured dose profiles from seven treatment units spanning four manufacturers. Results: The average difference between the calculated and measured absorbed dose values was 9.9% for those datasets on which the model was trained. Additionally, these results indicate that the model can provide accurate calculations of both therapeutic and stray radiation dose from a wide variety of radiotherapy units and techniques. Conclusions: We have developed a simple analytical model of absorbed dose from external beam radiotherapy treatments in the 6 to 25 MV beam energy range. The model has been tested on measured data from multiple treatment machines and techniques, and is broadly applicable to contemporary external beam radiation therapy.

Introduction Whereas hadron therapy of static targets is clinically established, treatment of moving organs remains a challenge. One strategy is to minimize motion of surrounding tissue mechanically and to mitigate residual motion with an appropriate irradiation technique. In this technical note, we present and characterize such an immobilization technique for a novel noncancerous application: the irradiation of small targets in hearts with scanned carbon ion beams in a porcine model for elimination of arrhythmias. Material and methods A device for immobilization was custom-built. Both for the treatment planning 4D-CT scan and for irradiation, breath-hold at end-exhale was enforced using a remotely-controlled respirator. Target motion was thus reduced to heartbeat only. Positioning was verified by orthogonal X-rays followed by couch shift if necessary. Reproducibility of bony anatomy, diaphragm, and heart position after repositioning and between repeated breath-hold maneuvers was evaluated on X-rays and cardiac-gated 4D-CTs. Treatment was post hoc simulated on sequential 4D-CTs for a subset of animals, after immediate repositioning and after a delay of one week, similar to the delay between imaging and irradiation. Results Breath-hold without repositioning was highly reproducible with an RMS deviation of at most one millimeter. 4D-CTs showed larger deformations in soft tissue, but treatment simulation on sequential images resulted in full target coverage (V95 >95%). Conclusion The method of immobilization permitted reproducible positioning of mobile, thoracic targets for range-sensitive particle therapy. The presented immobilization strategy could be a reasonable approach for future animal investigations with the ultimate goal of translation to therapy in men.

Radiosurgery was introduced over half a century ago for treatment of intracranial lesions. In more recent years, stereotactic radiotherapy has rapidly advanced and is now commonly used for treatments of both cranial and extracranial lesions with high doses delivered in a few, down to a single fraction. The results of a workshop on Particle radiosurgery: A new frontier of physics in medicine held at Obergurgl, Austria during August 25-29 2013 are summarized in this issue with an overview presented in this paper. The focus was laid on particle radiosurgery but the content also includes current practice in x-ray radiosurgery and the overarching research in radiobiology and motion management for extracranial lesions. The results and discussions showed that especially research in radiobiology of high-dose charged-particles and motion management are necessary for the success of particle radiosurgery. © 2014 Associazione Italiana di Fisica Medica.

The radiation used in hadrontherapy treatments interacts with the patient body producing secondary particles, either neutral or charged, that can be used for dose and Bragg peak monitoring and to provide a fast feedback on the treatment plans. Recent results obtained from the authors on simplified setups (mono-energetic primary beams interacting with homogeneous tissue-like target) have already indicated the correlation that exists between the flux of these secondaries coming from the target (e.g. protons and photons) and the position of the primary beam Bragg peak. In this paper, the measurements of charged particle fluxes produced by the interaction of a 220 MeV/u carbon ion beam at GSI, Darmstadt, with a polymethyl methacrylate target are reported. The emission region of protons (p), deuterons (d) and tritons (t) has been characterized using a drift chamber while the particle time-of-flight, used to compute the kinetic energy spectra, was measured with a LYSO scintillator. The energy released in the LYSO crystal was used for particle identification purposes. The measurements were repeated with the setup at 60° and 90° with respect to the primary beam direction. The accuracy on the fragments emission profile reconstruction and its relationship with the Bragg peak position have been studied. Based on the acquired experimental evidence, a method to monitor the dose profile and the position of the Bragg peak inside the target is proposed. © 2014 Institute of Physics and Engineering in Medicine.