@article{MTMT:34327444, title = {Dosimetric and biologic intercomparison between electron and proton FLASH beams}, url = {https://m2.mtmt.hu/api/publication/34327444}, author = {Almeida, A. and Togno, M. and Ballesteros-Zebadua, P. and Franco-Perez, J. and Geyer, R. and Schaefer, R. and Petit, B. and Grilj, V. and Meer, D. and Safai, S. and Lomax, T. and Weber, D.C. and Bailat, C. and Psoroulas, S. and Vozenin, M.-C.}, doi = {10.1016/j.radonc.2023.109953}, journal-iso = {RADIOTHER ONCOL}, journal = {RADIOTHERAPY AND ONCOLOGY}, volume = {190}, unique-id = {34327444}, issn = {0167-8140}, abstract = {Background and purpose: The FLASH effect has been validated in different preclinical experiments with electrons (eFLASH) and protons (pFLASH) operating at an average dose rate above 40 Gy/s. However, no systematic intercomparison of the FLASH effect produced by eFLASH vs. pFLASH has yet been performed and constitutes the aim of the present study. Materials and methods: The electron eRT6/Oriatron/CHUV/5.5 MeV and proton Gantry1/PSI/170 MeV were used to deliver conventional (0.1 Gy/s eCONV and pCONV) and FLASH (≥110 Gy/s eFLASH and pFLASH) dose rates. Protons were delivered in transmission. Dosimetric and biologic intercomparisons were performed using previously validated dosimetric approaches and experimental murine models. Results: The difference between the average absorbed dose measured at Gantry 1 with PSI reference dosimeters and with CHUV/IRA dosimeters was −1.9 % (0.1 Gy/s) and + 2.5 % (110 Gy/s). The neurocognitive capacity of eFLASH and pFLASH irradiated mice was indistinguishable from the control, while both eCONV and pCONV irradiated cohorts showed cognitive decrements. Complete tumor response was obtained after an ablative dose of 20 Gy delivered with the two beams at CONV and FLASH dose rates. Tumor rejection upon rechallenge indicates that anti-tumor immunity was activated independently of the beam-type and the dose-rate. Conclusion: Despite major differences in the temporal microstructure of proton and electron beams, this study shows that dosimetric standards can be established. Normal brain protection and tumor control were produced by the two beams. More specifically, normal brain protection was achieved when a single dose of 10 Gy was delivered in 90 ms or less, suggesting that the most important physical parameter driving the FLASH sparing effect might be the mean dose rate. In addition, a systemic anti-tumor immunological memory response was observed in mice exposed to high ablative dose of electron and proton delivered at CONV and FLASH dose rate. © 2023 The Authors}, keywords = {Female; ARTICLE; MOUSE; controlled study; nonhuman; animal model; animal experiment; PROTON; ELECTRON; radiation dose; proton therapy; MURINE MODEL; tumor immunity; Dosimetry; Dosimetry; physical parameters; electron beam; Intercomparison; Neurocognition; TUMOR RESPONSE; FLASH; brain radiation; tumor rejection}, year = {2024}, eissn = {1879-0887} } @article{MTMT:34750077, title = {FLASH Radiotherapy: Expectations, Challenges, and Current Knowledge}, url = {https://m2.mtmt.hu/api/publication/34750077}, author = {Borghini, A. and Labate, L. and Piccinini, S. and Panaino, C.M.V. and Andreassi, M.G. and Gizzi, L.A.}, doi = {10.3390/ijms25052546}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {25}, unique-id = {34750077}, issn = {1661-6596}, abstract = {Major strides have been made in the development of FLASH radiotherapy (FLASH RT) in the last ten years, but there are still many obstacles to overcome for transfer to the clinic to become a reality. Although preclinical and first-in-human clinical evidence suggests that ultra-high dose rates (UHDRs) induce a sparing effect in normal tissue without modifying the therapeutic effect on the tumor, successful clinical translation of FLASH-RT depends on a better understanding of the biological mechanisms underpinning the sparing effect. Suitable in vitro studies are required to fully understand the radiobiological mechanisms associated with UHDRs. From a technical point of view, it is also crucial to develop optimal technologies in terms of beam irradiation parameters for producing FLASH conditions. This review provides an overview of the research progress of FLASH RT and discusses the potential challenges to be faced before its clinical application. We critically summarize the preclinical evidence and in vitro studies on DNA damage following UHDR irradiation. We also highlight the ongoing developments of technologies for delivering FLASH-compliant beams, with a focus on laser-driven plasma accelerators suitable for performing basic radiobiological research on the UHDR effects. © 2024 by the authors.}, keywords = {Humans; PLASMA; PLASMA; human; mitochondrial DNA; Motivation; Motivation; DNA Damage; DNA Damage; head; head; TUMOR RESPONSE; radiobiology; radiobiology; FLASH radiotherapy; ultra-high dose rate; FLASH effect; Normal tissue response; very high-energy electrons; CBMN assay; nuclear DNA damage; γ-H2AX}, year = {2024}, eissn = {1422-0067} } @article{MTMT:34572862, title = {Technical note: A small animal irradiation platform for investigating the dependence of the FLASH effect on electron beam parameters}, url = {https://m2.mtmt.hu/api/publication/34572862}, author = {Byrne, K.E. and Poirier, Y. and Xu, J. and Gerry, A. and Foley, M.J. and Jackson, I.L. and Sawant, A. and Jiang, K.}, doi = {10.1002/mp.16909}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {51}, unique-id = {34572862}, issn = {0094-2405}, abstract = {Background: The recent rediscovery of the FLASH effect, a normal tissue sparing phenomenon observed in ultra-high dose rate (UHDR) irradiations, has instigated a surge of research endeavors aiming to close the gap between experimental observation and clinical treatment. However, the dependences of the FLASH effect and its underpinning mechanisms on beam parameters are not well known, and large-scale in vivo studies using murine models of human cancer are needed for these investigations. Purpose: To commission a high-throughput, variable dose rate platform providing uniform electron fields (≥15 cm diameter) at conventional (CONV) and UHDRs for in vivo investigations of the FLASH effect and its dependences on pulsed electron beam parameters. Methods: A murine whole-thoracic lung irradiation (WTLI) platform was constructed using a 1.3 cm thick Cerrobend collimator forming a 15 × 1.6 cm2 slit. Control of dose and dose rate were realized by adjusting the number of monitor units and couch vertical position, respectively. Achievable doses and dose rates were investigated using Gafchromic EBT-XD film at 1 cm depth in solid water and lung-density phantoms. Percent depth dose (PDD) and dose profiles at CONV and various UHDRs were also measured at depths from 0 to 2 cm. A radiation survey was performed to assess radioactivation of the Cerrobend collimator by the UHDR electron beam in comparison to a precision-machined copper alternative. Results: This platform allows for the simultaneous thoracic irradiation of at least three mice. A linear relationship between dose and number of monitor units at a given UHDR was established to guide the selection of dose, and an inverse-square relationship between dose rate and source distance was established to guide the selection of dose rate between 20 and 120 Gy·s−1. At depths of 0.5 to 1.5 cm, the depth range relevant to murine lung irradiation, measured PDDs varied within ±1.5%. Similar lateral dose profiles were observed at CONV and UHDRs with the dose penumbrae widening from 0.3 mm at 0 cm depth to 5.1 mm at 2.0 cm. The presence of lung-density plastic slabs had minimal effect on dose distributions as compared to measurements made with only solid water slabs. Instantaneous dose rate measurements of the activated copper collimator were up to two orders of magnitude higher than that of the Cerrobend collimator. Conclusions: A high-throughput, variable dose rate platform has been developed and commissioned for murine WTLI electron FLASH radiotherapy. The wide field of our UHDR-enabled linac allows for the simultaneous WTLI of at least three mice, and for the average dose rate to be modified by changing the source distance, without affecting dose distribution. The platform exhibits uniform, and comparable dose distributions at CONV and UHDRs up to 120 Gy·s−1, owing to matched and flattened 16 MeV CONV and UHDR electron beams. Considering radioactivation and exposure to staff, Cerrobend collimators are recommended above copper alternatives for electron FLASH research. This platform enables high-throughput animal irradiation, which is preferred for experiments using a large number of animals, which are required to effectively determine UHDR treatment efficacies. © 2024 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.}, keywords = {MICE; MOUSE; IRRADIATION; Electrons; ELECTRON; MAMMALS; Electron beams; Biological organs; clinical research; Small animals; Linear accelerators; small animal; Ultra-high; High dose rate; FLASH; FLASH; Linac; Linac; ultra-high dose rate; ultra-high dose rate; UHDR}, year = {2024}, eissn = {2473-4209}, pages = {1421-1432} } @article{MTMT:34746004, title = {Mini-GRID radiotherapy on the CLEAR very-high-energy electron beamline: collimator optimization, film dosimetry, and Monte Carlo simulations}, url = {https://m2.mtmt.hu/api/publication/34746004}, author = {Clements, Nathan and Esplen, Nolan and Bateman, Joseph and Robertson, Cameron and Dosanjh, Manjit and Korysko, Pierre and Farabolini, Wilfrid and Corsini, Roberto and Bazalova-Carter, Magdalena}, doi = {10.1088/1361-6560/ad247d}, journal-iso = {PHYS MED BIOL}, journal = {PHYSICS IN MEDICINE AND BIOLOGY}, volume = {69}, unique-id = {34746004}, issn = {0031-9155}, abstract = {Objective. Spatially-fractionated radiotherapy (SFRT) delivered with a very-high-energy electron (VHEE) beam and a mini-GRID collimator was investigated to achieve synergistic normal tissue-sparing through spatial fractionation and the FLASH effect. Approach. A tungsten mini-GRID collimator for delivering VHEE SFRT was optimized using Monte Carlo (MC) simulations. Peak-to-valley dose ratios (PVDRs), depths of convergence (DoCs, PVDR <= 1.1), and peak and valley doses in a water phantom from a simulated 150 MeV VHEE source were evaluated. Collimator thickness, hole width, and septal width were varied to determine an optimal value for each parameter that maximized PVDR and DoC. The optimized collimator (20 mm thick rectangular prism with a 15 mm x 15 mm face with a 7 x 7 array of 0.5 mm holes separated by 1.1 mm septa) was 3D-printed and used for VHEE irradiations with the CERN linear electron accelerator for research beam. Open beam and mini-GRID irradiations were performed at 140, 175, and 200 MeV and dose was recorded with radiochromic films in a water tank. PVDR, central-axis (CAX) and valley dose rates and DoCs were evaluated. Main results. Films demonstrated peak and valley dose rates on the order of 100 s of MGy/s, which could promote FLASH-sparing effects. Across the three energies, PVDRs of 2-4 at 13 mm depth and DoCs between 39 and 47 mm were achieved. Open beam and mini-GRID MC simulations were run to replicate the film results at 200 MeV. For the mini-GRID irradiations, the film CAX dose was on average 15% higher, the film valley dose was 28% higher, and the film PVDR was 15% lower than calculated by MC. Significance. Ultimately, the PVDRs and DoCs were determined to be too low for a significant potential for SFRT tissue-sparing effects to be present, particularly at depth. Further beam delivery optimization and investigations of new means of spatial fractionation are warranted.}, keywords = {IRRADIATION; TOXICITY; BEAMS; photon; Monte Carlo simulation; Grid; Engineering, Biomedical; Film dosimetry; FLASH; FLASH; VMAT; TOPAS; VHEE; FRACTIONATED RADIATION-THERAPY; very-high-energy electrons}, year = {2024}, eissn = {1361-6560}, orcid-numbers = {Clements, Nathan/0000-0001-8911-997X; Esplen, Nolan/0000-0002-8347-8653; Bateman, Joseph/0000-0002-5967-6748; Dosanjh, Manjit/0000-0003-1378-349X; Corsini, Roberto/0000-0002-0934-8199; Bazalova-Carter, Magdalena/0000-0002-9365-2889} } @article{MTMT:34746073, title = {Recent research progress on metal halide perovskite based visible light active photoanode for photoelectrochemical water splitting}, url = {https://m2.mtmt.hu/api/publication/34746073}, author = {Darsan, A.S. and Pandikumar, A.}, doi = {10.1016/j.mssp.2024.108203}, journal-iso = {MAT SCI SEMICON PROC}, journal = {MATERIALS SCIENCE IN SEMICONDUCTOR PROCESSING}, volume = {174}, unique-id = {34746073}, issn = {1369-8001}, abstract = {The wheels of the future generation will be driven by hydrogen fuel. Hydrogen is the potential, sustainable and clean energy vector, with high energy density, high heating value, and greenhouse gas-free combustion. Artificial photosynthesis especially photoelectrocatalytic (PEC) and photocatalytic (PC) water splitting reactions are widely investigated over gasification, electrolysis, thermochemical and photobiological systems for green hydrogen production. Metal Halide Perovskites (MHPs) with ABX3 stoichiometry have piqued researcher's curiosity because of their peculiar electronic, thermal and optical properties, including long carrier diffusion lengths, outstanding tolerance factors, high light absorption coefficients, large thermal expansion coefficient and ultralow thermal conductivity. The optoelectronic properties of MHPs can be modified using band-gap tuning and defect engineering techniques, and they can be used for photocatalytic and photoelectrocatalytic applications in water splitting, nitrogen fixation, and CO2 reduction. Many review articles have summarized the synthesis, properties and application in the above-mentioned area by using MHPs. Few review articles exclusively focused on MHP based photocatalytic systems for water splitting and there is no dedicated review article is available to date for MHP-based PEC water splitting. In this article, we reviewed the latest research trends and developments in the field of PEC water splitting using MHPs. This also provides details about the optical, electronic, and thermal aspects of MHPs, along with feasible changes, limitations, and stability concerns, as well as viable ways to overcome such hurdles. © 2024 Elsevier Ltd}, keywords = {Hydrogen production; Hydrogen production; thermal conductivity; light absorption; Energy gap; Greenhouse gases; Thermal expansion; Visible light; PHOTOCATALYTIC ACTIVITY; Solar power generation; Metal halides; water splitting; water splitting; Artificial photosynthesis; Photoelectrochemical cells; Photoelectrochemical cells; Solar fuels; Recent researches; photoelectrocatalytic; halide perovskites; metal halide perovskite; metal halide perovskite; Photoelectrodes; Green hydrogen; Green hydrogen; photoelectrochemical water splitting; Photoelectrode; Photo-anodes; perovskite}, year = {2024}, eissn = {1873-4081} } @article{MTMT:34327447, title = {Direct Measurements of FLASH-Induced Changes in Intracellular Oxygenation}, url = {https://m2.mtmt.hu/api/publication/34327447}, author = {El, Khatib M. and Motlagh, A.O. and Beyer, J.N. and Troxler, T. and Allu, S.R. and Sun, Q. and Burslem, G.M. and Vinogradov, S.A.}, doi = {10.1016/j.ijrobp.2023.09.019}, journal-iso = {INT J RADIAT ONCOL}, journal = {INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS}, volume = {118}, unique-id = {34327447}, issn = {0360-3016}, abstract = {Purpose: The goal of our study was to characterize the dynamics of intracellular oxygen during application of radiation at conventional (CONV) and FLASH dose rates and obtain evidence for or against the oxygen depletion hypothesis as a mechanism of the FLASH effect. Methods and Materials: The measurements were performed by the phosphorescence quenching method using probe Oxyphor PtG4, which was delivered into the cellular cytosol by electroporation. Results: Intracellular radiochemical oxygen depletion (ROD) g-value for a dose rate of 100 Gy/s in the normoxic range was found to be 0.58 ± 0.03 μM/Gy. Intracellular ROD g-values for FLASH and CONV dose rates in the normoxic range were found to be nearly equal. As in solution-based studies, intracellular ROD was found to exhibit strong dependence on oxygen concentration in the range of 0 to ∼40 μM [O2]. Conclusions: Depletion of oxygen in cells in vitro by a clinical dose of proton radiation delivered as FLASH is unable to produce a transient state of hypoxia and, therefore, unable to induce radioprotection. The difference between ROD g-values for FLASH and CONV dose rates, detected previously in solutions-based experiments, disappears when measurements are conducted inside cells. Understanding this phenomenon should provide additional insight into the role of oxygen in FLASH radiation therapy and help to decipher the mechanism of the FLASH effect. © 2023 Elsevier Inc.}, keywords = {OXYGEN; Direct measurement; Electroporation; Phosphorescence quenching; Cellulars; Measurements of; Dose rate; Oxygen depletion; Cytosols; methods and materials; G-values}, year = {2024}, eissn = {1879-355X}, pages = {781-789} } @article{MTMT:34750076, title = {Dose and dose rate dependence of the tissue sparing effect at ultra-high dose rate studied for proton and electron beams using the zebrafish embryo model}, url = {https://m2.mtmt.hu/api/publication/34750076}, author = {Horst, F. and Bodenstein, E. and Brand, M. and Hans, S. and Karsch, L. and Lessmann, E. and Löck, S. and Schürer, M. and Pawelke, J. and Beyreuther, E.}, doi = {10.1016/j.radonc.2024.110197}, journal-iso = {RADIOTHER ONCOL}, journal = {RADIOTHERAPY AND ONCOLOGY}, volume = {194}, unique-id = {34750076}, issn = {0167-8140}, abstract = {Purpose: A better characterization of the dependence of the tissue sparing effect at ultra-high dose rate (UHDR) on physical beam parameters (dose, dose rate, radiation quality) would be helpful towards a mechanistic understanding of the FLASH effect and for its broader clinical translation. To address this, a comprehensive study on the normal tissue sparing at UHDR using the zebrafish embryo (ZFE) model was conducted. Methods: One-day-old ZFE were irradiated over a wide dose range (15–95 Gy) in three different beams (proton entrance channel, proton spread out Bragg peak and 30 MeV electrons) at UHDR and reference dose rate. After irradiation the ZFE were incubated for 4 days and then analyzed for four different biological endpoints (pericardial edema, curved spine, embryo length and eye diameter). Results: Dose-effect curves were obtained and a sparing effect at UHDR was observed for all three beams. It was demonstrated that proton relative biological effectiveness and UHDR sparing are both relevant to predict the resulting dose response. Dose dependent FLASH modifying factors (FMF) for ZFE were found to be compatible with rodent data from the literature. It was found that the UHDR sparing effect saturates at doses above ∼ 50 Gy with an FMF of ∼ 0.7–0.8. A strong dose rate dependence of the tissue sparing effect in ZFE was observed. The magnitude of the maximum sparing effect was comparable for all studied biological endpoints. Conclusion: The ZFE model was shown to be a suitable pre-clinical high-throughput model for radiobiological studies on FLASH radiotherapy, providing results comparable to rodent models. This underlines the relevance of ZFE studies for FLASH radiotherapy research. © 2024 The Author(s)}, keywords = {Electrons; Protons; FLASH effect; ultra-high dose rate (UHDR); NTCP curves; Zebrafish embryo (ZFE)}, year = {2024}, eissn = {1879-0887} } @article{MTMT:34502368, title = {C. elegans: A potent model for high-throughput screening experiments investigating the FLASH effect}, url = {https://m2.mtmt.hu/api/publication/34502368}, author = {Schoenauen, L. and Stubbe, F.-X. and Van, Gestel D. and Penninckx, S. and Heuskin, A.-C.}, doi = {10.1016/j.ctro.2023.100712}, journal-iso = {CLIN TRANSL RADIAT ONCOL (CTRO)}, journal = {CLINICAL AND TRANSLATIONAL RADIATION ONCOLOGY}, volume = {45}, unique-id = {34502368}, abstract = {This study explores the effects of UHDR irradiation on Caenorhabditis elegans embryos. UHDR proton and electron beams demonstrate a sparing effect, aligning with literature findings. This highlights C. elegans suitability as a screening model for studying the LET impact on the FLASH effect, reinforcing its potential in radiation research. © 2023 The Author(s)}, keywords = {ARTICLE; MICROSCOPY; Cell Differentiation; Escherichia coli; controlled study; nonhuman; animal experiment; IRRADIATION; image analysis; embryo; radiation exposure; clonogenic assay; Caenorhabditis elegans; theoretical model; validation process; radiosensitivity; high throughput screening; Dosimetry; Raman spectrometry; embryo (anatomy); electron beam; proton radiation; colony formation; C. elegans embryo; X irradiation; radiation dose response; conventional radiotherapy; FLASH radiotherapy; electron FLASH; Proton FLASH}, year = {2024}, eissn = {2405-6308} } @article{MTMT:34199443, title = {Diamond detectors for dose and instantaneous dose-rate measurements for ultra-high dose-rate scanned helium ion beams}, url = {https://m2.mtmt.hu/api/publication/34199443}, author = {Tessonnier, T. and Verona-Rinati, G. and Rank, L. and Kranzer, R. and Mairani, A. and Marinelli, M.}, doi = {10.1002/mp.16757}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {51}, unique-id = {34199443}, issn = {0094-2405}, abstract = {Background: The possible emergence of the FLASH effect—the sparing of normal tissue while maintaining tumor control—after irradiations at dose-rates exceeding several tens of Gy per second, has recently spurred a surge of studies attempting to characterize and rationalize the phenomenon. Investigating and reporting the dose and instantaneous dose-rate of ultra-high dose-rate (UHDR) particle radiotherapy beams is crucial for understanding and assessing the FLASH effect, towards pre-clinical application and quality assurance programs. Purpose: The purpose of the present work is to investigate a novel diamond-based detector system for dose and instantaneous dose-rate measurements in UHDR particle beams. Methods: Two types of diamond detectors, a microDiamond (PTW 60019) and a diamond detector prototype specifically designed for operation in UHDR beams (flashDiamond), and two different readout electronic chains, were investigated for absorbed dose and instantaneous dose-rate measurements. The detectors were irradiated with a helium beam of 145.7 MeV/u under conventional and UHDR delivery. Dose-rate delivery records by the monitoring ionization chamber and diamond detectors were studied for single spot irradiations. Dose linearity at 5 cm depth and in-depth dose response from 2 to 16 cm were investigated for both measurement chains and both detectors in a water tank. Measurements with cylindrical and plane-parallel ionization chambers as well as Monte-Carlo simulations were performed for comparisons. Results: Diamond detectors allowed for recording the temporal structure of the beam, in good agreement with the one obtained by the monitoring ionization chamber. A better time resolution of the order of few μs was observed as compared to the approximately 50 μs of the monitoring ionization chamber. Both diamonds detectors show an excellent linearity response in both delivery modalities. Dose values derived by integrating the measured instantaneous dose-rates are in very good agreement with the ones obtained by the standard electrometer readings. Bragg peak curves confirmed the consistency of the charge measurements by the two systems. Conclusions: The proposed novel dosimetric system allows for a detailed investigation of the temporal evolution of UHDR beams. As a result, reliable and accurate determinations of dose and instantaneous dose-rate are possible, both required for a comprehensive characterization of UHDR beams and relevant for FLASH effect assessment in clinical treatments. © 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.}, keywords = {intelligent systems; Monte Carlo methods; Helium; Quality assurance; Diamonds; Ionization of liquids; Ionization Chambers; Water tanks; Ultra-high; Application programs; High dose rate; particle therapy; particle therapy; Diamond detector; FLASH; FLASH; Dose rate; Diamond Detectors; Helium ion beams; ultra-high dose-rate; ultra-high dose-rate; instantateneous dose-rate; instantateneous dose-rate; Electrometers; Dose rate measurements}, year = {2024}, eissn = {2473-4209}, pages = {1450-1459} } @article{MTMT:33937484, title = {The current status of FLASH particle therapy: a systematic review}, url = {https://m2.mtmt.hu/api/publication/33937484}, author = {Atkinson, Jake and Bezak, Eva and Le, Hien and Kempson, Ivan}, doi = {10.1007/s13246-023-01266-z}, journal-iso = {PHYS ENG SCI MED}, journal = {PHYSICAL AND ENGINEERING SCIENCES IN MEDICINE}, volume = {46}, unique-id = {33937484}, issn = {2662-4729}, abstract = {Particle therapies are becoming increasingly available clinically due to their beneficial energy deposition profile, sparing healthy tissues. This may be further promoted with ultra-high dose rates, termed FLASH. This review comprehensively summarises current knowledge based on studies relevant to proton- and carbon-FLASH therapy. As electron-FLASH literature presents important radiobiological findings that form the basis of proton and carbon-based FLASH studies, a summary of key electron-FLASH papers is also included. Preclinical data suggest three key mechanisms by which proton and carbon-FLASH are able to reduce normal tissue toxicities compared to conventional dose rates, with equipotent, or enhanced, tumour kill efficacy. However, a degree of caution is needed in clinically translating these findings as: most studies use transmission and do not conform the Bragg peak to tumour volume; mechanistic understanding is still in its infancy; stringent verification of dosimetry is rarely provided; biological assays are prone to limitations which need greater acknowledgement.}, keywords = {proton therapy; Cancer treatment; Biological mechanisms; carbon therapy; Normal tissue sparing; FLASH radiotherapy; ultra-high dose rate}, year = {2023}, eissn = {2662-4737}, pages = {529-560}, orcid-numbers = {Kempson, Ivan/0000-0002-3886-9516} } @article{MTMT:34143219, title = {Characterisation of the UK high energy proton research beamline for high and ultra-high dose rate (FLASH) irradiation}, url = {https://m2.mtmt.hu/api/publication/34143219}, author = {Aylward, J. D. and Henthorn, N. and Manger, S. and Warmenhoven, J. W. and Merchant, M. J. and Taylor, M. J. and Mackay, R. I and Kirkby, K. J.}, doi = {10.1088/2057-1976/acef25}, journal-iso = {BIOMED PHYS ENGINEERING EXPRESS}, journal = {BIOMEDICAL PHYSICS AND ENGINEERING EXPRESS}, volume = {9}, unique-id = {34143219}, issn = {2057-1976}, abstract = {Objective. This work sets out the capabilities of the high energy proton research beamline developed in the Christie proton therapy centre for Ultra-High Dose Rate (UHDR) irradiation and FLASH experiments. It also characterises the lower limits of UHDR operation for this Pencil Beam Scanning (PBS) proton hardware. Approach. Energy dependent nozzle transmission was measured using a Faraday Cup beam collector. Spot size was measured at the reference plane using a 2D scintillation detector. Integrated depth doses (IDDs) were measured. EBT3 Gafchromic film was used to compare UHDR and conventional dose rate spots. Our beam monitor calibration methodolgy for UHDR is described. A microDiamond detector was used to determine dose rates at zref. Instantaneous depth dose rates were calculated for 70-245 MeV. PBS dose rate distributions were calculated using Folkerts and Van der Water definitions. Main results. Transmission of 7.05 & PLUSMN; 0.1% is achieveable corresponding to a peak instantaneous dose rate of 112.7 Gy s-1. Beam parameters are comparable in conventional and UHDR mode with a spot size of & sigma; x = 4.6 mm, & sigma; y = 6.6 mm. Dead time in the beam monitoring electonics warrants a beam current dependent MU correction in the present configuration. Fast beam scanning of 26.4 m s-1 (X) and 12.1 m s-1 (Y) allows PBS dose rates of the order tens of Grays per second. Significance. UHDR delivery is possible for small field sizes and high energies enabling research into the FLASH effect with PBS protons at our facility. To our knowledge this is also the first thorough characterisation of UHDR irradiation using the hardware of this clinical accelerator at energies less than 250 MeV. The data set out in this publication can be used for designing experiments at this UK research facility and inform the possible future clinical translation of UHDR PBS proton therapy.}, keywords = {PROTON; Dosimetry; ultra-high dose rate (UHDR)}, year = {2023} } @inproceedings{MTMT:34496095, title = {How flash-RT can change the way we treat cancer}, url = {https://m2.mtmt.hu/api/publication/34496095}, author = {Ballesteros-Zebadua, P. and Franco-Perez, J. and Vozenin, M.-C.}, booktitle = {17th Mexican Symposium on Medical Physics 2022, MSMP 2022}, doi = {10.1063/5.0161154}, volume = {2947}, unique-id = {34496095}, abstract = {In recent years, we have conceptualized and implemented a new irradiation modality at ultra-high dose rates, named FLASH-RT. Performed studies on different organs of several animal species have shown that this irradiation at ultra-high dose rates induces a remarkable FLASH effect. This effect is characterized by preserving normal tissue integrity but maintaining anti-tumor efficacy. The FLASH effect was first described using electron beams; however, evidence now indicates that similar findings are observed after the treatment of animal models with photon and proton beams. FLASH-RT has rapidly become a new field of research and consequently points towards translational medicine. Experimental evidence supports the clinical translation of FLASH; however, it is undeniable that several technological, physical, and biological aspects remain to be investigated before safe application in human patients. © 2023 AIP Publishing LLC.}, year = {2023} } @article{MTMT:33810126, title = {Delivery of proton FLASH at the TRIUMF Proton Therapy Research Centre}, url = {https://m2.mtmt.hu/api/publication/33810126}, author = {Bélanger-Champagne, C. and Roddy, D. and Penner, C. and Tattenberg, S. and Trinczek, M. and Yen, S. and Blackmore, E. and Hoehr, C.}, doi = {10.1016/j.nima.2023.168243}, journal-iso = {NUCL INSTRUM METH A}, journal = {NUCLEAR INSTRUMENTS & METHODS IN PHYSICS RESEARCH SECTION A-ACCELERATORS SPECTROMETERS DETECTORS AND ASSOCIATED EQUIPMENT}, volume = {1052}, unique-id = {33810126}, issn = {0168-9002}, abstract = {The TRIUMF particle accelerator center in Vancouver, British Columbia, Canada houses a proton therapy beam line formerly used for the treatment of ocular cancer. This existing Proton Therapy Research Centre (PTRC) was upgraded to deliver protons at ultra-high dose rates which would be required for FLASH radiotherapy treatments. A peak dose rate of 110 Gy/s over an area of 20 mm2 was delivered at a beam energy of 21 MeV. This was achieved by degrading the cyclotron extracted beam energy of 70 MeV using polymethyl methacrylate (PMMA) plates. In addition, a fast, versatile and reliable method for producing static ridge filters has been developed to spread the proton beam to the entirety of the target axially (i.e., in depth). FLASH dose rates were maintained with a spread-out Bragg peak of 0.5 cm. © 2023 Elsevier B.V.}, keywords = {RADIOTHERAPY; proton therapy; proton therapy; Polymethyl methacrylates; Proton beams; PROTON ENERGY; BEAM ENERGIES; Proton beam therapy; Dose rate; research center; beam delivery; beam delivery; FLASH radiotherapy; FLASH radiotherapy; ridge filter; ridge filter; Energy modulation; Proton energy modulation; Proton energy modulation}, year = {2023}, eissn = {1872-9576} } @{MTMT:33810135, title = {Radiation-induced immune response in novel radiotherapy approaches FLASH and spatially fractionated radiotherapies}, url = {https://m2.mtmt.hu/api/publication/33810135}, author = {Bertho, A. and Iturri, L. and Prezado, Y.}, booktitle = {Ionizing Radiation and the Immune Response - Part A}, doi = {10.1016/bs.ircmb.2022.11.005}, volume = {376}, unique-id = {33810135}, abstract = {The last several years have revealed increasing evidence of the immunomodulatory role of radiation therapy. Radiotherapy reshapes the tumoral microenvironment can shift the balance toward a more immunostimulatory or immunosuppressive microenvironment. The immune response to radiation therapy appears to depend on the irradiation configuration (dose, particle, fractionation) and delivery modes (dose rate, spatial distributions). Although an optimal irradiation configuration (dose, temporal fractionation, spatial dose distribution, etc.) has not yet been determined, temporal schemes employing high doses per fraction appear to favor radiation-induced immune response through immunogenic cell death. Through the release of damage-associated molecular patterns and the sensing of double-stranded DNA and RNA breaks, immunogenic cell death activates the innate and adaptive immune response, leading to tumor infiltration by effector T cells and the abscopal effect. Novel radiotherapy approaches such as FLASH and spatially fractionated radiotherapies (SFRT) strongly modulate the dose delivery method. FLASH-RT and SFRT have the potential to trigger the immune system effectively while preserving healthy surrounding tissues. This manuscript reviews the current state of knowledge on the immunomodulation effects of these two new radiotherapy techniques in the tumor, healthy immune cells and non-targeted regions, as well as their therapeutic potential in combination with immunotherapy. © 2023 Elsevier Inc.}, keywords = {Humans; IMMUNOMODULATION; IMMUNOMODULATION; human; immunotherapy; immunotherapy; Neoplasms; neoplasm; ADAPTIVE IMMUNITY; ADAPTIVE IMMUNITY; Tumor microenvironment; Tumor microenvironment; procedures; Immunogenic cell death; Dose Fractionation, Radiation; spatially fractionated radiation therapy; FLASH therapy; Novel dose delivery methods; Radiation-immune response}, year = {2023}, pages = {37-68} } @article{MTMT:33810127, title = {Comparison of Gonadal Toxicity of Single-Fraction Ultra-High Dose Rate and Conventional Radiation in Mice}, url = {https://m2.mtmt.hu/api/publication/33810127}, author = {Cuitiño, M.C. and Fleming, J.L. and Jain, S. and Cetnar, A. and Ayan, A.S. and Woollard, J. and Manring, H. and Meng, W. and McElroy, J.P. and Blakaj, D.M. and Gupta, N. and Chakravarti, A.}, doi = {10.1016/j.adro.2023.101201}, journal-iso = {Advances in Radiation Oncology}, journal = {Advances in Radiation Oncology}, volume = {8}, unique-id = {33810127}, issn = {2452-1094}, abstract = {Purpose: Increasing evidence suggests that ultra-high-dose-rate (UHDR) radiation could result in similar tumor control as conventional (CONV) radiation therapy (RT) while reducing toxicity to surrounding healthy tissues. Considering that radiation toxicity to gonadal tissues can cause hormone disturbances and infertility in young patients with cancer, the purpose of this study was to assess the possible role of UHDR-RT in reducing toxicity to healthy gonads in mice compared with CONV-RT. Methods and Materials: Radiation was delivered to the abdomen or pelvis of female (8 or 16 Gy) and male (5 Gy) C57BL/6J mice, respectively, at conventional (∼0.4 Gy/s) or ultrahigh (>100 Gy/s) dose rates using an IntraOp Mobetron linear accelerator. Organ weights along with histopathology and immunostaining of irradiated gonads were used to compare toxicity between radiation modalities. Results: CONV-RT and UHDR-RT induced a similar decrease in uterine weights at both studied doses (∼50% of controls), which indicated similarly reduced ovarian follicular activity. Histologically, ovaries of CONV- and UHDR-irradiated mice exhibited a comparable lack of follicles. Weights of CONV- and UHDR-irradiated testes were reduced to ∼30% of controls, and the percentage of degenerate seminiferous tubules was also similar between radiation modalities (∼80% above controls). Pairwise comparisons of all quantitative data indicated statistical significance between irradiated (CONV or UHDR) and control groups (from P ≤ .01 to P ≤ .0001) but not between radiation modalities. Conclusions: The data presented here suggest that the short-term effects of UHDR-RT on the mouse gonads are comparable to those of CONV-RT. © 2023 The Authors}, keywords = {Adult; Female; Male; immunohistochemistry; ARTICLE; MOUSE; comparative study; statistical significance; controlled study; nonhuman; animal tissue; animal model; animal experiment; Histopathology; organ weight; IRRADIATION; infertility; radiation dose; clinical effectiveness; ovary follicle; testis weight; endocrine disease; C57BL 6 mouse; seminiferous tubule; radiation sickness; ovary function; gonad; malignant neoplasm; uterus weight}, year = {2023} } @article{MTMT:33809995, title = {Design of an X-ray irradiator based on a standard imaging X-ray tube with FLASH dose-rate capabilities for preclinical research}, url = {https://m2.mtmt.hu/api/publication/33809995}, author = {Espinosa-Rodriguez, A. and Villa-Abaunza, A. and Diaz, N. and Perez-Diaz, M. and Sanchez-Parcerisa, D. and Udias, J. M. and Ibanez, P.}, doi = {10.1016/j.radphyschem.2023.110760}, journal-iso = {RADIAT PHYS CHEM}, journal = {RADIATION PHYSICS AND CHEMISTRY: THE JOURNAL FOR RADIATION PHYSICS RADIATION CHEMISTRY AND RADIATION PROCESSING}, volume = {206}, unique-id = {33809995}, issn = {0969-806X}, abstract = {We propose a new concept of small animal X-ray irradiator based on a conventional imaging X-ray tube for preclinical research. In this work we assessed its feasibility to deliver FLASH dose rates. Our design puts the imaging X-ray tube into a shielded cabinet, which makes the system affordable and suitable to use without disruption in existing laboratories and with minimum regulatory burden. Two conventional 150 kVp X-ray tubes were characterized with Gafchromic films for dose rates and dose uniformity. Monte Carlo simulations were also performed to model the irradiator, and the efficiencies of the tube and dose rates (with and without additional filtration) were calculated and compared with measurements. The feasibility of achieving ultra-high dose rates was determined from the rating charts provided by the manufacturer and measurements. The small animal irradiator proposed in this work was able to deliver conventional dose rate irradiation (0.5-1 Gy/min) at 150 kVp at 20 cm distance with minimum amount of filtration. FLASH irradiations (a 10 Gy dose delivered at >40 Gy/s) were also possible at the maximum capabilities of the tubes by placing the samples at the closest possible distances from the sources. A first prototype has already been built and characterized.}, keywords = {Chemistry, Physical; RADIOTHERAPY; RADIATION-THERAPY; X-RAYS; PLATFORM; Nuclear Science & Technology; Film dosimetry; FLASH; Irradiator}, year = {2023}, eissn = {1879-0895} } @article{MTMT:34136192, title = {Effects of the Oxygen depletion in FLASH irradiation investigated through Geant4-DNA toolkit}, url = {https://m2.mtmt.hu/api/publication/34136192}, author = {Farokhi, F. and Shirani, B. and Fattori, S. and Ali, Asgarian M. and Cuttone, G. and Jia, S.B. and Petringa, G. and Sciuto, A. and Pablo, Cirrone G.A.}, doi = {10.1016/j.radphyschem.2023.111184}, journal-iso = {RADIAT PHYS CHEM}, journal = {RADIATION PHYSICS AND CHEMISTRY: THE JOURNAL FOR RADIATION PHYSICS RADIATION CHEMISTRY AND RADIATION PROCESSING}, volume = {212}, unique-id = {34136192}, issn = {0969-806X}, abstract = {FLASH radiotherapy (or FLASH-RT) is a novel radiotherapy technology consisting of radiation delivery at dose rates several orders of magnitude higher (≥40Gy/s) than the currently used in conventional clinical radiotherapy. Many recent in-vivo preclinical studies indicate that FLASH-RT can greatly spare healthy tissues while maintaining unchanged tumour control. The generally acknowledged, though not entirely substantiated, explanation for the FLASH effect relates to the oxygen depletion that occurs after the radiation passage. On the other hand, oxygen depletion or, more in general, oxygen-related effects are still not fully clarified. Different research groups carried out the Monte Carlo simulations of electron and proton irradiations in oxygenated water to evaluate the oxygen-concentration-related effects at the cell-scale level. We analysed and compared the simulation results of the oxygen effect under the FLASH condition (considering the time-dependent G-values and the oxygen enhancement ratio-weighted dose) we obtained with GEANT4-DNA against TRAX-CHEM code results in the literature. Our results indicate that oxygen depletion has a negligible effect on radiosensitivity via oxygen enhancement, showing a close agreement with the TRAX-CHEM code. The conclusion is that the Geant4-DNA toolkit can be a valid instrument to study the FLASH effect. © 2023 Elsevier Ltd}, keywords = {DNA; OXYGEN; intelligent systems; RADIOTHERAPY; Monte Carlo methods; proton irradiation; Orders of magnitude; Monte Carlo simulation; bioinformatics; Codes (symbols); Gene encoding; Dose rate; Geant4-DNA; Geant4-DNA; Oxygen depletion; Oxygen depletion; FLASH-RT; FLASH-RT; oxygen enhancement ratio; oxygen enhancement ratio; Monte Carlo's simulation; Enhancement ratios; Oxygen enhancement; Radiation delivery}, year = {2023}, eissn = {1879-0895} } @article{MTMT:34089796, title = {Passive SOBP generation from a static proton pencil beam using 3D-printed range modulators for FLASH experiments}, url = {https://m2.mtmt.hu/api/publication/34089796}, author = {Horst, Felix and Beyreuther, Elke and Bodenstein, Elisabeth and Gantz, Sebastian and Misseroni, Diego and Pugno, Nicola M. and Schuy, Christoph and Tommasino, Francesco and Weber, Uli and Pawelke, Joerg}, doi = {10.3389/fphy.2023.1213779}, journal-iso = {FRONT PHYS-LAUSANNE}, journal = {FRONTIERS IN PHYSICS}, volume = {11}, unique-id = {34089796}, abstract = {The University Proton Therapy facility in Dresden (UPTD), Germany, is equipped with an experimental room with a beamline providing a static pencil beam. High proton beam currents can be achieved at this beamline which makes it suitable for FLASH experiments. However, the established experimental setup uses only the entrance channel of the proton Bragg curve. In this work, a set of 3D-printed range modulators designed to generate spread out Bragg peaks (SOBPs) for radiobiological experiments at ultra-high dose rate at this beamline is described. A new method to optimize range modulators specifically for the case of a static pencil beam based on the central depth dose profile is introduced. Modulators for two different irradiation setups were produced and characterized experimentally by measurements of lateral and depth dose distributions using different detectors. In addition, Monte Carlo simulations were performed to assess profiles of the dose averaged linear energy transfer (LETD) in water. These newly produced range modulators will allow future proton FLASH experiments in the SOBP at UPTD with two different experimental setups.}, keywords = {RECOMBINATION; RADIATION; proton therapy; MONTE-CARLO SIMULATIONS; 3D-printing; FLASH effect; range modulator; spread out Bragg peak}, year = {2023}, eissn = {2296-424X} } @article{MTMT:34089795, title = {FLASH dose rate calculation based on log files in proton pencil beam scanning therapy}, url = {https://m2.mtmt.hu/api/publication/34089795}, author = {Jeon, Chanil and Ahn, Sunghwan and Amano, Daizo and Kamiguchi, Nagaaki and Cho, Sungkoo and Sheen, Heesoon and Park, Hee Chul and Han, Youngyih}, doi = {10.1002/mp.16575}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {50}, unique-id = {34089795}, issn = {0094-2405}, abstract = {BackgroundIn radiation therapy, irradiating healthy normal tissues in the beam trajectories is inevitable. This unnecessary dose means that patients undergoing treatment risk developing side effects. Recently, FLASH radiotherapy delivering ultra-high-dose-rate beams has been re-examined because of its normal-tissue-sparing effect. To confirm the mean and instantaneous dose rates of the FLASH beam, stable and accurate dosimetry is required. PurposeDetailed verification of the FLASH effect requires dosimeters and a method to measure the average and instantaneous dose rate stably for 2- or 3-dimensional dose distributions. To verify the delivered FLASH beam, we utilized machine log files from the built-in monitor chamber to develop a dosimetry method to calculate the dose and average/instantaneous dose rate distributions in two or three dimensions in a phantom. MethodsTo create a spread-out Bragg peak (SOBP) and deliver a uniform dose in a target, a mini-ridge filter was created with a 3D printer. Proton pencil beam line scanning plans of 2 x 2 cm(2), 3 x 3 cm(2), 4 x 4 cm(2), and round shapes with 2.3 cm diameter patterns delivering 230 MeV energy protons were created. The absorbed dose in the solid water phantom of each plan was measured using a PPC05 ionization chamber (IBA Dosimetry, Virginia, USA) in the SOBP region, and the log files for each plan were exported from the treatment control system console. Using these log files, the delivered dose and average dose rate were calculated using two methods: a direct method and a Monte Carlo (MC) simulation method that uses log file information. The computed and average dose rates were compared with the ionization chamber measurements. Additionally, instantaneous dose rates in user-defined volumes were calculated using the MC simulation method with a temporal resolution of 5 ms. ResultsCompared to ionization chamber dosimetry, 10 of 12 cases using the direct calculation method and 9 of 11 cases using the MC method had a dose difference below & PLUSMN;3%. Nine of 12 cases using the direct calculation method and 8 of 11 cases using the MC method had dose rate differences below & PLUSMN;3%. The average and maximum dose differences for the direct calculation and MC method were-0.17, +0.72%, and -3.15, +3.32%, respectively. For the dose rate difference, the average and maximum for the direct calculation and MC method were +1.26, +1.12%, and +3.75, +3.15%, respectively. In the instantaneous dose rate calculation with the MC simulation, a large fluctuation with a maximum of 163 Gy/s and a minimum of 4.29 Gy/s instantaneous dose rate was observed in a specific position, whereas the mean dose rate was 62 Gy/s. ConclusionsWe successfully developed methods in which machine log files are used to calculate the dose and the average and instantaneous dose rates for FLASH radiotherapy and demonstrated the feasibility of verifying the delivered FLASH beams.}, keywords = {IRRADIATION; RADIATION-THERAPY; Ion recombination}, year = {2023}, eissn = {2473-4209}, pages = {7154-7166}, orcid-numbers = {Jeon, Chanil/0000-0003-3451-9161} } @article{MTMT:33810129, title = {Pencil-beam Delivery Pattern Optimization Increases Dose Rate for Stereotactic FLASH Proton Therapy}, url = {https://m2.mtmt.hu/api/publication/33810129}, author = {José, Santo R. and Habraken, S.J.M. and Breedveld, S. and Hoogeman, M.S.}, doi = {10.1016/j.ijrobp.2022.08.053}, journal-iso = {INT J RADIAT ONCOL}, journal = {INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS}, volume = {115}, unique-id = {33810129}, issn = {0360-3016}, abstract = {Purpose: FLASH dose rates >40 Gy/s are readily available in proton therapy (PT) with cyclotron-accelerated beams and pencil-beam scanning (PBS). The PBS delivery pattern will affect the local dose rate, as quantified by the PBS dose rate (PBS-DR), and therefore needs to be accounted for in FLASH-PT with PBS, but it is not yet clear how. Our aim was to optimize patient-specific scan patterns for stereotactic FLASH-PT of early-stage lung cancer and lung metastases, maximizing the volume irradiated with PBS-DR >40 Gy/s of the organs at risk voxels irradiated to >8 Gy (FLASH coverage). Methods and Materials: Plans to 54 Gy/3 fractions with 3 equiangular coplanar 244 MeV proton shoot-through transmission beams for 20 patients were optimized with in-house developed software. Planning target volume-based planning with a 5 mm margin was used. Planning target volume ranged from 4.4 to 84 cc. Scan-pattern optimization was performed with a Genetic Algorithm, run in parallel for 20 independent populations (islands). Mapped crossover, inversion, swap, and shift operators were applied to achieve (local) optimality on each island, with migration between them for global optimality. The cost function was chosen to maximize the FLASH coverage per beam at >8 Gy, >40 Gy/s, and 40 nA beam current. The optimized patterns were evaluated on FLASH coverage, PBS-DR distribution, and population PBS-DR-volume histograms, compared with standard line-by-line scanning. Robustness against beam current variation was investigated. Results: The optimized patterns have a snowflake-like structure, combined with outward swirling for larger targets. A population median FLASH coverage of 29.0% was obtained for optimized patterns compared with 6.9% for standard patterns, illustrating a significant increase in FLASH coverage for optimized patterns. For beam current variations of 5 nA, FLASH coverage varied between –6.1%-point and 2.2%-point for optimized patterns. Conclusions: Significant improvements on the PBS-DR and, hence, on FLASH coverage and potential healthy-tissue sparing are obtained by sequential scan-pattern optimization. The optimizer is flexible and may be further fine-tuned, based on the exact conditions for FLASH. © 2022 The Authors}, keywords = {Adult; Female; Middle Aged; Humans; ARTICLE; human; controlled study; clinical article; PROTON; Diagnostic Imaging; GENETIC ALGORITHMS; clinical protocol; Lung; Lung; human tissue; lung tumor; Lung Neoplasms; Radiotherapy Dosage; Radiotherapy Dosage; cancer patient; treatment planning; cancer staging; cancer radiotherapy; process optimization; GENETIC ALGORITHM; Radiotherapy Planning, Computer-Assisted; proton therapy; proton therapy; proton therapy; population size; Proton beams; proton radiation; Biological organs; maximum permissible dose; Cost functions; Rapid prototyping; dimpylate; Beam currents; procedures; Radiotherapy, Intensity-Modulated; adverse event; obstetric delivery; organs at risk; organs at risk; Patient specific; Proton beam therapy; Dose rate; Intensity modulated radiation therapy; clinical target volume; Scan patterns; pencil beam; Gross tumor volume; radiotherapy planning system; planning target volume; Pattern optimization; Beam-scanning; Early-stage lung cancers; Planning target volumes}, year = {2023}, eissn = {1879-355X}, pages = {759-767} } @article{MTMT:34327445, title = {Evaluation of the water-equivalent characteristics of the SP34 plastic phantom for film dosimetry in a clinical linear accelerator}, url = {https://m2.mtmt.hu/api/publication/34327445}, author = {Kim, K.-T. and Choi, Y. and Cho, G.-S. and Jang, W.-I. and Yang, K.-M. and Lee, S.-S. and Bahng, J.}, doi = {10.1371/journal.pone.0293191}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {18}, unique-id = {34327445}, issn = {1932-6203}, abstract = {In this study, some confusing points about electron film dosimetry using white polystyrene suggested by international protocols were verified using a clinical linear accelerator (LINAC). According to international protocol recommendations, ionometric measurements and film dosimetry were performed on an SP34 slab phantom at various electron energies. Scaling factor analysis using ionometric measurements yielded a depth scaling factor of 0.923 and a fluence scaling factor of 1.019 at an electron beam energy of <10 MeV (i.e., R50 < 4.0 g/cm2). It was confirmed that the water-equivalent characteristics were similar because they have values similar to white polystyrene (i.e., depth scaling factor of 0.922 and fluence scaling factor of 1.019) presented in international protocols. Furthermore, percentage depth dose (PDD) curve analysis using film dosimetry showed that when the density thickness of the SP34 slab phantom was assumed to be water-equivalent, it was found to be most similar to the PDD curve measured using an ionization chamber in water as a reference medium. Therefore, we proved that the international protocol recommendation that no correction for measured depth dose is required means that no scaling factor correction for the plastic phantom is necessary. This study confirmed two confusing points that could occur while determining beam characteristics using electron film dosimetry, and it is expected to be used as basic data for future research on clinical LINACs. © 2023 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.}, keywords = {ARTICLE; PARAMETERS; WATER; WATER; WATER; Software; IRRADIATION; quality control; ultrasound; radiometry; radiometry; GEOMETRY; Phantoms, Imaging; radiation scattering; artifact; Radiotherapy, High-Energy; Polystyrenes; Polystyrene; Particle Accelerators; plastic; electron beam; Factor analysis; Scaling factor; polystyrene derivative; megavoltage radiotherapy; procedures; Film dosimetry; Film dosimetry; radiation depth dose; Water equivalent}, year = {2023}, eissn = {1932-6203} } @article{MTMT:34328495, title = {Shoot-through proton FLASH irradiation lowers linear energy transfer in organs at risk for neurological tumors and is robust against density variations}, url = {https://m2.mtmt.hu/api/publication/34328495}, author = {Kneepkens, Esther and Wolfs, Cecile and Wanders, Roel-Germ and Traneus, Erik and Eekers, Danielle and Verhaegen, Frank}, doi = {10.1088/1361-6560/ad0280}, journal-iso = {PHYS MED BIOL}, journal = {PHYSICS IN MEDICINE AND BIOLOGY}, volume = {68}, unique-id = {34328495}, issn = {0031-9155}, abstract = {Objective. The goal of the study was to test the hypothesis that shoot-through FLASH proton beams would lead to lower dose-averaged LET (LETD) values in critical organs, while providing at least equal normal tissue sparing as clinical proton therapy plans. Approach. For five neurological tumor patients, pencil beam scanning (PBS) shoot-through plans were made, using the maximum energy of 227 MeV and assuming a hypothetical FLASH protective factor (FPF) of 1.5. The effect of different FPF ranging from 1.2 to 1.8 on the clinical goals were also considered. LETD was calculated for the clinical plan and the shoot-through plan, applying a 2 Gy total dose threshold (RayStation 8 A/9B and 9A-IonRPG). Robust evaluation was performed considering density uncertainty (+/- 3% throughout entire volume). Main results. Clinical plans showed large LETD variations compared to shoot-through plans and the maximum LETD in OAR is 1.2-8 times lower for the latter. Although less conformal, shoot-through plans met the same clinical goals as the clinical plans, for FLASH protection factors above 1.4. The FLASH shoot-through plans were more robust to density uncertainties with a maximum OAR D2% increase of 0.6 Gy versus 5.7 Gy in the clinical plans. Significance. Shoot-through proton FLASH beams avoid uncertainties in LETD distributions and proton range, provide adequate target coverage, meet planning constraints and are robust to density variations.}, keywords = {proton therapy; Relative Biological Effectiveness; Linear Energy Transfer; FLASH}, year = {2023}, eissn = {1361-6560}, orcid-numbers = {Wolfs, Cecile/0000-0001-6428-2762; Wanders, Roel-Germ/0000-0001-9720-1666; Eekers, Danielle/0000-0003-1917-6279} } @article{MTMT:33809992, title = {On the potential biological impact of radiation-induced acoustic emissions during ultra-high dose rate electron radiotherapy: a preliminary study}, url = {https://m2.mtmt.hu/api/publication/33809992}, author = {Lascaud, Julie and Parodi, Katia}, doi = {10.1088/1361-6560/acb9ce}, journal-iso = {PHYS MED BIOL}, journal = {PHYSICS IN MEDICINE AND BIOLOGY}, volume = {68}, unique-id = {33809992}, issn = {0031-9155}, abstract = {Ionizing radiation pulses delivered at ultra-high dose rates in emerging FLASH radiotherapy can result in high-intensity low-frequency thermoacoustic emissions that may have a biological impact. This study aims at providing insights into the thermoacoustic emissions expected during FLASH radiotherapy and their likelihood of inducing acoustic cavitation. The characteristics of acoustic waves induced by the energy deposition of a pulsed electron beam similar to previous pre-clinical FLASH radiotherapy studies and their propagation in murine head-like phantoms are investigated in-silico. The results show that the generated pressures are sufficient to produce acoustic cavitation due to resonance in the irradiated object. It suggests that thermoacoustics may, in some irradiation scenarios, contribute to the widely misunderstood FLASH effect or cause adverse effects if not taken into account at the treatment planning stage.}, keywords = {DAMAGE; Biology; IRRADIATION; CAVITATION; Engineering, Biomedical; Thermoacoustics; FLASH-RT}, year = {2023}, eissn = {1361-6560}, orcid-numbers = {Lascaud, Julie/0000-0002-7649-6909; Parodi, Katia/0000-0001-7779-6690} } @article{MTMT:34199442, title = {Pencil Beam Scanning Bragg Peak FLASH Technique for Ultra-High Dose Rate Intensity-Modulated Proton Therapy in Early-Stage Breast Cancer Treatment}, url = {https://m2.mtmt.hu/api/publication/34199442}, author = {Lattery, G. and Kaulfers, T. and Cheng, C. and Zhao, X. and Selvaraj, B. and Lin, H. and Simone, C.B. II and Choi, J.I. and Chang, J. and Kang, M.}, doi = {10.3390/cancers15184560}, journal-iso = {CANCERS}, journal = {CANCERS}, volume = {15}, unique-id = {34199442}, abstract = {Bragg peak FLASH-RT can deliver highly conformal treatment and potentially offer improved normal tissue protection for radiotherapy patients. This study focused on developing ultra-high dose rate (≥40 Gy × RBE/s) intensity-modulated proton therapy (IMPT) for hypofractionated treatment of early-stage breast cancer. A novel tracking technique was developed to enable pencil beaming scanning (PBS) of single-energy protons to adapt the Bragg peak (BP) to the target distally. Standard-of-care PBS treatment plans of consecutively treated early-stage breast cancer patients using multiple energy layers were reoptimized using this technique, and dose metrics were compared between single-energy layer BP FLASH and conventional IMPT plans. FLASH dose rate coverage by volume (V40Gy/s) was also evaluated for the FLASH sparing effect. Distal tracking can precisely stop BP at the target distal edge. All plans (n = 10) achieved conformal IMPT-like dose distributions under clinical machine parameters. No statistically significant differences were observed in any dose metrics for heart, ipsilateral lung, most ipsilateral breast, and CTV metrics (p > 0.05 for all). Conventional plans yielded slightly superior target and skin dose uniformities with 4.5% and 12.9% lower dose maxes, respectively. FLASH-RT plans reached 46.7% and 61.9% average-dose rate FLASH coverage for tissues receiving more than 1 and 5 Gy plan dose total under the 250 minimum MU condition. Bragg peak FLASH-RT techniques achieved comparable plan quality to conventional IMPT while reaching adequate dose rate ratios, demonstrating the feasibility of early-stage breast cancer clinical applications. © 2023 by the authors.}, keywords = {breast cancer; intensity-modulated proton therapy; FLASH radiotherapy; ultra-high dose rate; Proton pencil beam scanning; single-energy Bragg peak}, year = {2023}, eissn = {2072-6694} } @article{MTMT:33810131, title = {Ion recombination correction factors and detector comparison in a very-high dose rate proton scanning beam}, url = {https://m2.mtmt.hu/api/publication/33810131}, author = {Leite, A.M.M. and Cavallone, M. and Ronga, M.G. and Trompier, F. and Ristic, Y. and Patriarca, A. and De, Marzi L.}, doi = {10.1016/j.ejmp.2022.102518}, journal-iso = {PHYS MEDICA}, journal = {PHYSICA MEDICA-EUROPEAN JOURNAL OF MEDICAL PHYSICS}, volume = {106}, unique-id = {33810131}, issn = {1120-1797}, abstract = {Purpose: Accurate dosimetry is paramount to study the FLASH biological effect since dose and dose rate are critical dosimetric parameters governing its underlying mechanisms. With the goal of assessing the suitability of standard clinical dosimeters in a very-high dose rate (VHDR) experimental setup, we evaluated the ion collection efficiency of several commercially available air-vented ionization chambers (IC) in conventional and VHDR proton irradiation conditions. Methods: A cyclotron at the Orsay Proton Therapy Center was used to deliver VHDR pencil beam scanning irradiation. Ion recombination correction factors (ks) were determined for several detectors (Advanced Markus, PPC05, Nano Razor, CC01) at the entrance of the plateau and at the Bragg peak, using the Niatel model, the Two-voltage method and Boag's analytical formula for continuous beams. Results: Mean dose rates ranged from 4 Gy/s to 385 Gy/s, and instantaneous dose rates up to 1000 Gy/s were obtained with the experimental set-up. Recombination correction factors below 2 % were obtained for all chambers, except for the Nano Razor, at VHDRs with variations among detectors, while ks values were significantly smaller (0.8 %) for conventional dose rates. Conclusions: While the collection efficiency of the probed ICs in scanned VHDR proton therapy is comparable to those in the conventional regime with recombination coefficiens smaller than 1 % for mean dose rates up to 177 Gy/s, the reduction in collection efficiency for higher dose rates cannot be ignored when measuring the absorbed dose in pre-clinical proton scanned FLASH experiments and clinical trials. © 2023 Associazione Italiana di Fisica Medica e Sanitaria}, keywords = {ARTICLE; controlled study; PROTON; radiation dose; radiometry; radiometry; Protons; electric potential; proton therapy; proton therapy; proton therapy; Dosimetry; radiation absorption; dosimeter; CYCLOTRON; proton radiation; Cyclotrons; radiological parameters; Ion recombination; procedures; FLASH; experimental dosimetry; Ion chamber; Radiation Dosimeters; Very-high dose rate; ion recombination correction factor; very high dose rate}, year = {2023}, eissn = {1724-191X} } @article{MTMT:34421171, title = {Key changes in the future clinical application of ultra-high dose rate radiotherapy}, url = {https://m2.mtmt.hu/api/publication/34421171}, author = {Lin, Binwei and Fan, Mi and Niu, Tingting and Liang, Yuwen and Xu, Haonan and Tang, Wenqiang and Du, Xiaobo}, doi = {10.3389/fonc.2023.1244488}, journal-iso = {FRONT ONCOL}, journal = {FRONTIERS IN ONCOLOGY}, volume = {13}, unique-id = {34421171}, issn = {2234-943X}, abstract = {Ultra-high dose rate radiotherapy (FLASH-RT) is an external beam radiotherapy strategy that uses an extremely high dose rate (>= 40 Gy/s). Compared with conventional dose rate radiotherapy (<= 0.1 Gy/s), the main advantage of FLASH-RT is that it can reduce damage of organs at risk surrounding the cancer and retain the anti-tumor effect. An important feature of FLASH-RT is that an extremely high dose rate leads to an extremely short treatment time; therefore, in clinical applications, the steps of radiotherapy may need to be adjusted. In this review, we discuss the selection of indications, simulations, target delineation, selection of radiotherapy technologies, and treatment plan evaluation for FLASH-RT to provide a theoretical basis for future research.}, keywords = {SIMULATIONS; TOXICITY; PROTOCOL; Lung; RADIATION-THERAPY; radiosurgery; absence; clinical application; stereotactic body radiotherapy; brain metastases; FLASH-RT; Target delineation; FLASH IRRADIATION}, year = {2023}, eissn = {2234-943X} } @article{MTMT:33810133, title = {Visualization of the current research status of FLASH radiotherapy}, url = {https://m2.mtmt.hu/api/publication/33810133}, author = {Luo, H.-T. and Shi, J. and Liu, R.-F. and Liu, Z.-Q. and Sun, S.-L. and Zhang, Q.-N. and Wang, X.-H.}, doi = {10.16073/j.cnki.cjcpt.2023.02.07}, journal-iso = {CHIN J CANCER PREV TREATM}, journal = {CHINESE JOURNAL OF CANCER PREVENTION AND TREATMENT}, volume = {30}, unique-id = {33810133}, issn = {1673-5269}, abstract = {Objective To visually analyze the current research status, hotspots and trends in the field of FLASH radiotherapy by bibliometric methods based on the web of science (WOS). Methods Using " FLASH radiotherapy OR ultrahigh dose-rate radiotherapy OR FLASH irradiation" as the subject terms, the relevant literature of FLASH radiotherapy were searched in the core collection of WOS database from the inception of database to January 18, 2022. The included literature were visually analyzed the trend, country, institution of the publications and research hotspots using WOS self-contained citation analysis function and CiteSpace (5. 8. R3) software. The corresponding visual knowledge map was drawn. Results A total of 144 articles and 22 reviews were included in the analysis, and the literature were mainly published m 2019-2021 with 22, 48, and 76 papers published in each year, respectively. The United States has the largest number of papers published (61), and China ranks the seventh (15). The University Hospital of Lausanne published the largest number of papers (15). Vozenin MC published the most papers (17). Eight clusters were formed based on key words, including electron beams, beam, liquid water, ultra-high dose rate, proton therapy, radiation therapy, immune system, ionization chamber, preclinical models. The frontier of FLASH radiotherapy focused on the biological mechanism exploration, physical technology development and FLASH radiotherapy equipment development. The trend in the field of FLASH radiotherapy is to transform into clinical application. Conclusion FLASH radiotherapy is expected to be one of the revolutionary new techniques in radiotherapy. The clinical transformation of this technique still faces many problems to be solved. Chinese scholars should strengthen internal cooperation and actively cooperate with external scientific research institutions to promote the safe transformation of this technology in clinical practice. © 2023 Chinese Journal of Cancer Prevention and Treatment, Editorial board. All rights reserved.}, keywords = {ARTICLE; human; WATER; visual analysis; RADIOTHERAPY; systematic review; radiation response; Research trends; FLASH; research status; radiation effect; FLASH radiotherapy}, year = {2023}, pages = {104-113} } @article{MTMT:33809994, title = {Characterization of LiF:Mg,Ti thermoluminescence detectors in low-LET proton beams at ultra-high dose rates}, url = {https://m2.mtmt.hu/api/publication/33809994}, author = {Motta, S. and Christensen, J. B. and Togno, M. and Schafer, R. and Safai, S. and Lomax, A. J. and Yukihara, E. G.}, doi = {10.1088/1361-6560/acb634}, journal-iso = {PHYS MED BIOL}, journal = {PHYSICS IN MEDICINE AND BIOLOGY}, volume = {68}, unique-id = {33809994}, issn = {0031-9155}, abstract = {Objective. This work aims at characterizing LiF:Mg,Ti thermoluminescence detectors (TLDs) for dosimetry of a 250 MeV proton beam delivered at ultra-high dose rates (UHDR). Possible dose rate effects in LiF:Mg,Ti, as well as its usability for dosimetry of narrow proton beams are investigated. Approach. LiF:Mg,Ti (TLD-100 (TM) Microcubes, 1 mm x 1 mm x 1 mm) was packaged in matrices of 5 x 5 detectors. The center of each matrix was irradiated with single-spot low-LET (energy > 244 MeV) proton beam in the (1-4500) Gy s(-1) average dose rates range. A beam reconstruction procedure was applied to the detectors irradiated at the highest dose rate (Gaussian beam sigma < 2 mm) to correct for volumetric averaging effects. Reference dosimetry was carried out with a diamond detector and radiochromic films. The delivered number of protons was measured by a Faraday cup, which was employed to normalize the detector responses. Main results. The lateral beam spread obtained from the beam reconstruction agreed with the one derived from the radiochromic film measurements. No dose rates effects were observed in LiF:Mg,Ti for the investigated dose rates within 3% (k = 1). On average, the dose response of the TLDs agreed with the reference detectors within their uncertainties. The largest deviation (-5%) was measured at 4500 Gy s(-1). Significance. The dose rate independence of LiF:Mg,Ti TLDs makes them suitable for dosimetry of UHDR proton beams. Additionally, the combination of a matrix of TLDs and the beam reconstruction can be applied to determine the beam profile of narrow proton beams.}, keywords = {EFFICIENCY; Dosimetry; Engineering, Biomedical; LiF:Mg,Ti; proton dosimetry; dose rate dependence; FLASH dosimetry}, year = {2023}, eissn = {1361-6560} } @article{MTMT:34089794, title = {Investigation of TL and OSL detectors in ultra-high dose rate electron beams}, url = {https://m2.mtmt.hu/api/publication/34089794}, author = {Motta, S. and Christensen, J. B. and Frei, F. and Peier, P. and Yukihara, E. G.}, doi = {10.1088/1361-6560/acdfb2}, journal-iso = {PHYS MED BIOL}, journal = {PHYSICS IN MEDICINE AND BIOLOGY}, volume = {68}, unique-id = {34089794}, issn = {0031-9155}, abstract = {Objective. This work aims at investigating the response of various thermally stimulated luminescence detectors (TLDs) and optically stimulated luminescence detectors (OSLDs) for dosimetry of ultra-high dose rate electron beams. The study was driven by the challenges of dosimetry at ultra-high dose rates and the importance of dosimetry for FLASH radiotherapy and radiobiology experiments. Approach. Three types of TLDs (LiF:Mg,Ti; LiF:Mg,Cu,P; CaF2:Tm) and one type of OSLD (Al2O3:C) were irradiated in a 15 MeV electron beam with instantaneous dose rates in the (1-324) kGy s(-1) range. Reference dosimetry was carried out with an integrating current transformer, which was calibrated in absorbed dose to water against a reference ionization chamber. Additionally, dose rate independent BeO OSLDs were employed as a reference. Beam non-uniformity was addressed using a matrix of TLDs/OSLDs. Main results. The investigated TLDs were shown to be dose rate independent within the experimental uncertainties, which take into account the uncertainty of the dosimetry protocol and the irradiation uncertainty. The relative deviation between the TLDs and the reference dose was lower than 4 % for all dose rates. A decreasing response with the dose rate was observed for Al2O3:C OSLDs, but still within 10 % from the reference dose. Significance. The precision of the investigated luminescence detectors make them suitable for dosimetry of ultra-high dose rate electron beams. Specifically, the dose rate independence of the TLDs can support the investigation of the beam uniformity as a function of the dose rate, which is one of the challenges of the employed beam. Al2O3:C OSLDs provided high precision measurements, but the decreasing response with the dose rate needs to be confirmed by additional experiments.}, keywords = {thermoluminescence dosimetry; Ion recombination; optically stimulated luminescence; Engineering, Biomedical; Rate dependence; dose rate dependence; optically stimulated luminescence dosimetry; HIGH-ENERGY PHOTON}, year = {2023}, eissn = {1361-6560} } @article{MTMT:34170015, title = {In vivo dosimetry in cancer patients undergoing intraoperative radiation therapy}, url = {https://m2.mtmt.hu/api/publication/34170015}, author = {Petoukhova, Anna and Snijder, Roland and Vissers, Thomas and Ceha, Heleen and Struikmans, Henk}, doi = {10.1088/1361-6560/acf2e4}, journal-iso = {PHYS MED BIOL}, journal = {PHYSICS IN MEDICINE AND BIOLOGY}, volume = {68}, unique-id = {34170015}, issn = {0031-9155}, abstract = {In vivo dosimetry (IVD) is an important tool in external beam radiotherapy (EBRT) to detect major errors by assessing differences between expected and delivered dose and to record the received dose by individual patients. Also, in intraoperative radiation therapy (IORT), IVD is highly relevant to register the delivered dose. This is especially relevant in low-risk breast cancer patients since a high dose of IORT is delivered in a single fraction. In contrast to EBRT, online treatment planning based on intraoperative imaging is only under development for IORT. Up to date, two commercial treatment planning systems proposed intraoperative ultrasound or in-room cone-beam CT for real-time IORT planning. This makes IVD even more important because of the possibility for real-time treatment adaptation. Here, we summarize recent developments and applications of IVD methods for IORT in clinical practice, highlighting important contributions and identifying specific challenges such as a treatment planning system for IORT. HDR brachytherapy as a delivery technique was not considered. We add IVD for ultrahigh dose rate (FLASH) radiotherapy that promises to improve the treatment efficacy, when compared to conventional radiotherapy by limiting the rate of toxicity while maintaining similar tumour control probabilities. To date, FLASH IORT is not yet in clinical use.}, keywords = {BREAST-CANCER; AMERICAN SOCIETY; Engineering, Biomedical; Radiochromic films; Intraoperative radiation therapy (IORT); ELECTRON-BEAM RADIOTHERAPY; in vivo dosimetry (IVD); TASK FORCE/ACROP RECOMMENDATIONS; ESTRO/ACROP IORT RECOMMENDATIONS; MONTE-CARLO DOSIMETRY; GAFCHROMIC EBT2 FILM; SETUP VERIFICATION}, year = {2023}, eissn = {1361-6560}, orcid-numbers = {Petoukhova, Anna/0000-0003-4617-0622} } @article{MTMT:34328496, title = {Flash Therapy for Cancer: A Potentially New Radiotherapy Methodology}, url = {https://m2.mtmt.hu/api/publication/34328496}, author = {Polevoy, Georgiy Georgievich and Kumar, Devika S. and Daripelli, Sushma and Prasanna Sr, Muthu}, doi = {10.7759/cureus.46928}, journal-iso = {CUREUS}, journal = {CUREUS}, volume = {15}, unique-id = {34328496}, abstract = {In traditional treatment modalities and standard clinical practices, FLASH radiotherapy (FL-RT) administers radiation therapy at an exceptionally high dosage rate. When compared to standard dose rate radiation therapy, numerous preclinical investigations have demonstrated that FL-RT provides similar benefits in conserving normal tissue while maintaining equal antitumor efficacy, a phenomenon possible due to the 'FLASH effect' (FE) of FL-RT. The methodologies involve proton radiotherapy, intensity-modulated radiation treatment, and managing high-throughput damage by radiation to solid tissues. Recent results from animal studies indicate that FL-RT can reduce radiation-induced tissue damage, significantly enhancing anticancer potency. Focusing on the potential benefits of FL proton beam treatment in the years to come, this review details the FL-RT research that has been done so far and the existing theories illuminating the FL effects. This subject remains of interest, with many issues still needing to be answered. We offer a brief review to emphasize a few of the key efforts and difficulties in moving FL radiation research forward. The existing research state of FL-RT, its affecting variables, and its different specific impacts are presented in this current review. Key topics discussed include the biochemical mechanism during FL therapy, beam sources for FL therapy, the FL effect on immunity, clinical and preclinical studies on the protective effect of FL therapy, and parameters for effective FL therapy.}, keywords = {FLASH; FLASH radiotherapy; FLASH effect; Reactive-oxygen-species; ultra-high-dose-rate}, year = {2023}, eissn = {2168-8184} } @article{MTMT:33809993, title = {First Characterization of Novel Silicon Carbide Detectors with Ultra-High Dose Rate Electron Beams for FLASH Radiotherapy}, url = {https://m2.mtmt.hu/api/publication/33809993}, author = {Romano, Francesco and Milluzzo, Giuliana and Di, Martino Fabio and D'Oca, Maria Cristina and Felici, Giuseppe and Galante, Federica and Gasparini, Alessia and Mariani, Giulia and Marrale, Maurizio and Medina, Elisabetta and Pacitti, Matteo and Sangregorio, Enrico and Vanreusel, Verdi and Verellen, Dirk and Vignati, Anna and Camarda, Massimo}, doi = {10.3390/app13052986}, journal-iso = {APPL SCI-BASEL}, journal = {APPLIED SCIENCES-BASEL}, volume = {13}, unique-id = {33809993}, abstract = {Ultra-high dose rate (UHDR) beams for FLASH radiotherapy present significant dosimetric challenges. Although novel approaches for decreasing or correcting ion recombination in ionization chambers are being proposed, applicability of ionimetric dosimetry to UHDR beams is still under investigation. Solid-state sensors have been recently investigated as a valuable alternative for real-time measurements, especially for relative dosimetry and beam monitoring. Among them, Silicon Carbide (SiC) represents a very promising candidate, compromising between the maturity of Silicon and the robustness of diamond. Its features allow for large area sensors and high electric fields, required to avoid ion recombination in UHDR beams. In this study, we present simulations and experimental measurements with the low energy UHDR electron beams accelerated with the ElectronFLASH machine developed by the SIT Sordina company (IT). The response of a newly developed 1 x 1 cm(2) SiC sensor in charge as a function of the dose-per-pulse and its radiation hardness up to a total delivered dose of 90 kGy, was investigated during a dedicated experimental campaign, which is, to our knowledge, the first characterization ever done of SiC with UHDR-pulsed beams accelerated by a dedicated ElectronFLASH LINAC. Results are encouraging and show a linear response of the SiC detector up to 2 Gy/pulse and a variation in the charge per pulse measured for a cumulative delivered dose of 90 kGy, within +/- 0.75%.}, keywords = {silicon carbide; Dosimetry; beam monitoring; Ion recombination; Materials Science, Multidisciplinary; Chemistry, Multidisciplinary; Engineering, Multidisciplinary; FLASH radiotherapy}, year = {2023}, eissn = {2076-3417}, orcid-numbers = {Felici, Giuseppe/0000-0002-3302-3765; Gasparini, Alessia/0000-0001-5078-5131; Vanreusel, Verdi/0000-0001-7287-133X} } @article{MTMT:33699713, title = {Ultrahigh-Dose-Rate Proton Irradiation Elicits Reduced Toxicity in Zebrafish Embryos}, url = {https://m2.mtmt.hu/api/publication/33699713}, author = {Saade, G. and Bogaerts, E. and Chiavassa, S. and Blain, G. and Delpon, G. and Evin, M. and Ghannam, Y. and Haddad, F. and Haustermans, K. and Koumeir, C. and Macaeva, E. and Maigne, L. and Mouchard, Q. and Servagent, N. and Sterpin, E. and Supiot, S. and Potiron, V.}, doi = {10.1016/j.adro.2022.101124}, journal-iso = {Advances in Radiation Oncology}, journal = {Advances in Radiation Oncology}, volume = {8}, unique-id = {33699713}, issn = {2452-1094}, abstract = {Purpose: Recently, ultrahigh-dose-rate radiation therapy (UHDR-RT) has emerged as a promising strategy to increase the benefit/risk ratio of external RT. Extensive work is on the way to characterize the physical and biological parameters that control the so-called “Flash” effect. However, this healthy/tumor differential effect is observable in in vivo models, which thereby drastically limits the amount of work that is achievable in a timely manner. Methods and Materials: In this study, zebrafish embryos were used to compare the effect of UHDR irradiation (8-9 kGy/s) to conventional RT dose rate (0.2 Gy/s) with a 68 MeV proton beam. Viability, body length, spine curvature, and pericardial edema were measured 4 days postirradiation. Results: We show that body length is significantly greater after UHDR-RT compared with conventional RT by 180 µm at 30 Gy and 90 µm at 40 Gy, while pericardial edema is only reduced at 30 Gy. No differences were obtained in terms of survival or spine curvature. Conclusions: Zebrafish embryo length appears as a robust endpoint, and we anticipate that this model will substantially fasten the study of UHDR proton-beam parameters necessary for “Flash.” © 2022 The Authors}, keywords = {SURVIVAL; ARTICLE; controlled study; nonhuman; animal model; animal experiment; intermethod comparison; Body Height; embryo; radiation injury; Radiotherapy Dosage; proton therapy; zebra fish; embryo development; pericardial disease; radiation dose response; heart edema; ultrahigh dose rate radiation therapy}, year = {2023} } @article{MTMT:33937488, title = {In situ correction of recombination effects in ultra-high dose rate irradiations with protons}, url = {https://m2.mtmt.hu/api/publication/33937488}, author = {Schaefer, R. and Psoroulas, S. and Weber, D. C.}, doi = {10.1088/1361-6560/accf5c}, journal-iso = {PHYS MED BIOL}, journal = {PHYSICS IN MEDICINE AND BIOLOGY}, volume = {68}, unique-id = {33937488}, issn = {0031-9155}, abstract = {Background. At the Center for Proton Therapy at the Paul Scherrer Institute (PSI) the delivery of proton radiation is controlled via gas-based ionization chambers: the beam is turned off when a certain amount of preset charge has been collected. At low dose rates the charge collection efficiency in these detectors is unity, at ultra-high dose rates it is less due to induced charge recombination effects. If not corrected, the latter would lead to an overdosage. Purpose. In the scope of this work, we developed a novel approach to an in situ charge recombination correction for our dose defining detectors, when irradiated with a proton beam at ultra-high dose rates. This approach is based on the Two-Voltage-Method. Methods. We have translated this method to two separate devices operated simultaneously at different conditions. By doing so, the charge collection losses can be corrected directly and without the need for empirical correction values. This approach has been tested at ultra-high dose rates; proton beam was delivered by the COMET cyclotron to Gantry 1 at PSI. Results. We were able to correct the charge losses caused by recombination effects at local beam currents of approximately 700 nA (i.e. instantaneous dose rate of 3600 Gy s(-1) at isocenter). The corrected collected charges in our gaseous detectors were compared against recombination-free measurements with a Faraday cup. The ratio of both quantities shows no significant dose rate dependence within their respective combined uncertainties. Conclusions. Correcting recombination effects in our gas-based detectors with the novel method greatly eases the handling of Gantry 1 as 'FLASH test bench'. Not only is the application of a preset dose more accurate compared to using an empirical correction curve, also the re-determination of empirical correction curves in the case of a beam phase space change can be omitted.}, keywords = {Proton beams; FLASH; ultra-high dose rates; recombination effects; gas-based ionization chamber}, year = {2023}, eissn = {1361-6560} } @article{MTMT:34059892, title = {Investigation of contrast mechanisms for MRI phase signal-based proton beam visualization in water phantoms}, url = {https://m2.mtmt.hu/api/publication/34059892}, author = {Schieferecke, J. and Gantz, S. and Hoffmann, A. and Pawelke, J.}, doi = {10.1002/mrm.29752}, journal-iso = {MAGN RESON MED}, journal = {MAGNETIC RESONANCE IN MEDICINE}, volume = {90}, unique-id = {34059892}, issn = {0740-3194}, abstract = {Purpose: The low sensitivity and limitation to water phantoms of convection-dependent MRI magnitude signal-based proton beam visualization hinder its in vivo applicability in MR-integrated proton beam therapy. The purpose of the present study was, therefore, to assess possible contrast mechanisms for MRI phase signal-based proton beam visualization that can potentially be exploited to enhance the sensitivity of the method and extend its applicability to tissue materials. Methods: To assess whether proton beam-induced magnetic field perturbations, changes in material susceptibility or convection result in detectable changes in the MRI phase signal, water phantom characteristics, experiment timing, and imaging parameters were varied in combined irradiation and imaging experiments using a time-of-flight angiography pulse sequence on a prototype in-beam MRI scanner. Velocity encoding was used to further probe and quantify beam-induced convection. Results: MRI phase signal-based proton beam visualization proved feasible. The observed phase difference contrast was evoked by beam-induced buoyant convection with flow velocities in the mm/s range. Proton beam-induced magnetic field perturbations or changes in magnetic susceptibility did not influence the MRI phase signal. Velocity encoding was identified as a means to enhance the detection sensitivity. Conclusion: Because the MRI phase difference contrast observed during proton beam irradiation of water phantoms is caused by beam-induced convection, this method will unlikely be transferable to tightly compartmentalized tissue wherein flow effects are restricted. However, strong velocity encoded pulse sequences were identified as promising candidates for the future development of MRI-based methods for water phantom-based geometric quality assurance in MR-integrated proton beam therapy. © 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.}, keywords = {TISSUE; VISUALIZATION; Magnetic Resonance Imaging; CONVECTION; CONVECTION; magnetic fields; magnetic resonance; proton therapy; proton therapy; Quality assurance; Magnetic susceptibility; Proton beams; Encoding (symbols); Signal encoding; Encodings; PHANTOMS; Phase difference; phase difference imaging; phase difference imaging; in-beam MRI; in-beam MRI; proton beam visualization; proton beam visualization; velocity encoding; velocity encoding; Difference imaging; Phase signals}, year = {2023}, eissn = {1522-2594}, pages = {1776-1788} } @article{MTMT:34170016, title = {MRI magnitude signal-based proton beam visualisation in water phantoms reflects composite effects of beam-induced buoyant convection and radiation chemistry}, url = {https://m2.mtmt.hu/api/publication/34170016}, author = {Schieferecke, Juliane and Gantz, Sebastian and Karsch, Leonhard and Pawelke, Joerg and Hoffmann, Aswin}, doi = {10.1088/1361-6560/acf2e0}, journal-iso = {PHYS MED BIOL}, journal = {PHYSICS IN MEDICINE AND BIOLOGY}, volume = {68}, unique-id = {34170016}, issn = {0031-9155}, abstract = {Objective. Local magnetic resonance (MR) signal loss was previously observed during proton beam irradiation of free-floating water phantoms at ambient temperature using a research prototype in-beam magnetic resonance imaging (MRI) scanner. The emergence of this MR signal loss was hypothesised to be dependent on beam-induced convection. The aim of this study was therefore to unravel whether physical conditions allowing the development of convection must prevail for the beam-induced MRI signatures to emerge. Approach. The convection dependence of MRI magnitude signal-based proton beam visualisation was investigated in combined irradiation and imaging experiments using a gradient echo (GE)-based time-of-flight (ToF) angiography pulse sequence, which was first tested for its suitability for proton beam visualisation in free-floating water phantoms at ambient temperature. Subsequently, buoyant convection was selectively suppressed in water phantoms using either mechanical barriers or temperature control of water expansivity. The underlying contrast mechanism was further assessed using sagittal imaging and variation of T1 relaxation time-weighting. Main results. In the absence of convection-driven water flow, weak beam-induced MR signal changes occurred, whereas strong changes did occur when convection was not mechanically or thermally inhibited. Moreover, the degree of signal loss was found to change with the variation of T1-weighting. Consequently, beam-induced MR signal loss in free-floating water phantoms at ambient temperature does not exclusively originate from buoyant convection, but is caused by local composite effects of beam-induced motion and radiation chemistry resulting in a local change in the water T1 relaxation time. Significance. The identification of ToF angiography sequence-based proton beam visualisation in water phantoms to result from composite effects of beam-induced motion and radiation chemistry represents the starting point for the future elucidation of the currently unexplained motion-based MRI contrast mechanism and the identification of the proton beam-induced material change causing T1 relaxation time lengthening.}, keywords = {FLOW; Magnetic Resonance Imaging; CONVECTION; MRI; proton therapy; Engineering, Biomedical; range verification; in-beam MRI; proton beam visualisation}, year = {2023}, eissn = {1361-6560}, orcid-numbers = {Schieferecke, Juliane/0000-0001-9719-8196; Gantz, Sebastian/0000-0003-1070-5090} } @article{MTMT:33823658, title = {Transformative Technology for FLASH Radiation Therapy}, url = {https://m2.mtmt.hu/api/publication/33823658}, author = {Schulte, R. and Johnstone, C. and Boucher, S. and Esarey, E. and Geddes, C.G.R. and Kravchenko, M. and Kutsaev, S. and Loo, B.W. Jr. and Méot, F. and Mustapha, B. and Nakamura, K. and Nanni, E.A. and Obst-Huebl, L. and Sampayan, S.E. and Schroeder, C.B. and Sheng, K. and Snijders, A.M. and Snively, E. and Tantawi, S.G. and Van, Tilborg J.}, doi = {10.3390/app13085021}, journal-iso = {APPL SCI-BASEL}, journal = {APPLIED SCIENCES-BASEL}, volume = {13}, unique-id = {33823658}, abstract = {Featured Application: We report on new accelerator technology that has applications in FLASH radiation therapy. FLASH radiation therapy may have profound implications in cancer therapy because it may significantly spare normal tissues and solve the problem of tumors in motion due to the short time interval (sub-second) during which it is delivered. The general concept of radiation therapy used in conventional cancer treatment is to increase the therapeutic index by creating a physical dose differential between tumors and normal tissues through precision dose targeting, image guidance, and radiation beams that deliver a radiation dose with high conformality, e.g., protons and ions. However, the treatment and cure are still limited by normal tissue radiation toxicity, with the corresponding side effects. A fundamentally different paradigm for increasing the therapeutic index of radiation therapy has emerged recently, supported by preclinical research, and based on the FLASH radiation effect. FLASH radiation therapy (FLASH-RT) is an ultra-high-dose-rate delivery of a therapeutic radiation dose within a fraction of a second. Experimental studies have shown that normal tissues seem to be universally spared at these high dose rates, whereas tumors are not. While dose delivery conditions to achieve a FLASH effect are not yet fully characterized, it is currently estimated that doses delivered in less than 200 ms produce normal-tissue-sparing effects, yet effectively kill tumor cells. Despite a great opportunity, there are many technical challenges for the accelerator community to create the required dose rates with novel compact accelerators to ensure the safe delivery of FLASH radiation beams. © 2023 by the authors.}, keywords = {Radiation therapy; Particle Accelerators; FLASH effect}, year = {2023}, eissn = {2076-3417} } @article{MTMT:34222211, title = {Design of a rapid-cycling synchrotron for flash proton therapy}, url = {https://m2.mtmt.hu/api/publication/34222211}, author = {Shi, Ying and Zhang, Man-Zhou and Ou-Yang, Lian-Hua and Chen, Zhi-Ling and Li, Xiu-Fang and Li, De-Ming}, doi = {10.1007/s41365-023-01283-3}, journal-iso = {NUCL SCI TECH}, journal = {NUCLEAR SCIENCE AND TECHNIQUES}, volume = {34}, unique-id = {34222211}, issn = {1001-8042}, abstract = {The purpose of this study was to design a rapid-cycling synchrotron, making it capable of proton beam ultrahigh dose rate irradiation, inspired by laser accelerators. The design had to be cheap and simple. We consider our design from six aspects: the lattice, injection, extraction, space charge effects, eddy current effects and energy switching. Efficiency and particle quantity must be addressed when injected. The space charge effects at the injection could affect particles' number. The eddy current effects in the vacuum chambers would affect the magnetic field itself and generate heat, all of which need to be taken into account. Fast extraction can obtain 10(10) protons/pulse, equal to instantaneous dose rate up to 10(7) Gy/s in a very short time, while changing various extraction energies rapidly and easily to various deposition depths. In the further research, we expect to combine a delivery system with this accelerator to realize the FLASH irradiation.}, keywords = {Nuclear Science & Technology; FLASH; Rapid-cycling synchrotron}, year = {2023}, eissn = {2210-3147} } @article{MTMT:34496094, title = {Simulation study of a novel small animal FLASH irradiator (SAFI) with integrated inverse-geometry CT based on circularly distributed kV X-ray sources}, url = {https://m2.mtmt.hu/api/publication/34496094}, author = {Tan, Y. and Zhou, S. and Haefner, J. and Chen, Q. and Mazur, T.R. and Darafsheh, A. and Zhang, T.}, doi = {10.1038/s41598-023-47421-0}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {13}, unique-id = {34496094}, issn = {2045-2322}, abstract = {Ultra-high dose rate (UHDR) radiotherapy (RT) or FLASH-RT can potentially reduce normal tissue toxicity. A small animal irradiator that can deliver FLASH-RT treatments similar to clinical RT treatments is needed for pre-clinical studies of FLASH-RT. We designed and simulated a novel small animal FLASH irradiator (SAFI) based on distributed x-ray source technology. The SAFI system comprises a distributed x-ray source with 51 focal spots equally distributed on a 20 cm diameter ring, which are used for both FLASH-RT and onboard micro-CT imaging. Monte Carlo simulation was performed to estimate the dosimetric characteristics of the SAFI treatment beams. The maximum dose rate, which is limited by the power density of the tungsten target, was estimated based on finite-element analysis (FEA). The maximum DC electron beam current density is 2.6 mA/mm2, limited by the tungsten target's linear focal spot power density. At 160 kVp, 51 focal spots, each with a dimension of 2 × 20 mm2 and 10° anode angle, can produce up to 120 Gy/s maximum DC irradiation at the center of a cylindrical water phantom. We further demonstrate forward and inverse FLASH-RT planning, as well as inverse-geometry micro-CT with circular source array imaging via numerical simulations. © 2023, The Author(s).}, keywords = {Animals; animal; Radiation Dosage; Monte Carlo method; Monte Carlo method; Radiotherapy Dosage; Radiotherapy Dosage; radiation dose; X ray; X-RAYS; radiometry; radiometry; Phantoms, Imaging; X-Ray Microtomography; micro-computed tomography; tungsten; tungsten}, year = {2023}, eissn = {2045-2322} } @article{MTMT:33810132, title = {Advances in Proton Therapy for the Management of Head and Neck Tumors}, url = {https://m2.mtmt.hu/api/publication/33810132}, author = {Trotter, J. and Lin, A.}, doi = {10.1016/j.soc.2023.03.003}, journal-iso = {SURG ONCOL CLIN N AM}, journal = {SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA}, volume = {32}, unique-id = {33810132}, issn = {1055-3207}, keywords = {proton therapy; head and neck tumors; Intensity-modulated radiotherapy}, year = {2023}, eissn = {1558-5042}, pages = {587-598} } @article{MTMT:33744730, title = {Novel unconventional radiotherapy techniques: Current status and future perspectives – Report from the 2nd international radiation oncology online seminar}, url = {https://m2.mtmt.hu/api/publication/33744730}, author = {Tubin, S. and Vozenin, M.C. and Prezado, Y. and Durante, M. and Prise, K.M. and Lara, P.C. and Greco, C. and Massaccesi, M. and Guha, C. and Wu, X. and Mohiuddin, M.M. and Vestergaard, A. and Bassler, N. and Gupta, S. and Stock, M. and Timmerman, R.}, doi = {10.1016/j.ctro.2023.100605}, journal-iso = {CLIN TRANSL RADIAT ONCOL (CTRO)}, journal = {CLINICAL AND TRANSLATIONAL RADIATION ONCOLOGY}, volume = {40}, unique-id = {33744730}, year = {2023}, eissn = {2405-6308}, orcid-numbers = {Vozenin, M.C./0000-0002-2109-8073; Vestergaard, A./0000-0003-1398-6377; Gupta, S./0000-0003-0106-595X} } @article{MTMT:34092629, title = {Luminescence imaging of water irradiated by protons under FLASH radiation therapy conditions}, url = {https://m2.mtmt.hu/api/publication/34092629}, author = {Yogo, Katsunori and Kodaira, Satoshi and Kusumoto, Tamon and Kitamura, Hisashi and Toshito, Toshiyuki and Iwata, Hiromitsu and Umezawa, Masumi and Yamada, Masashi and Miyoshi, Takuto and Komori, Masataka and Yasuda, Hiroshi and Kataoka, Jun and Yamamoto, Seiichi}, doi = {10.1088/1361-6560/ace60b}, journal-iso = {PHYS MED BIOL}, journal = {PHYSICS IN MEDICINE AND BIOLOGY}, volume = {68}, unique-id = {34092629}, issn = {0031-9155}, abstract = {Objective. FLASH radiation therapy with ultrahigh dose rates (UHDR) has the potential to reduce damage to normal tissue while maintaining anti-tumor efficacy. However, rapid and precise dose distribution measurements remain difficult for FLASH radiation therapy with proton beams. To solve this problem, we performed luminescence imaging of water following irradiation by a UHDR proton beam captured using a charge-coupled device camera. Approach. We used 60 MeV proton beams with dose rates of 0.03-837 Gy s(-1) from a cyclotron. Therapeutic 139.3 MeV proton beams with dose rates of 0.45-4320 Gy s(-1) delivered by a synchrotron-based proton therapy system were also tested. The luminescent light intensity induced by the UHDR beams was compared with that produced by conventional beams to compare the dose rate dependency of the light intensity and its profile. Main results. Luminescence images of water were clearly visualized under UHDR conditions, with significantly shorter exposure times than those with conventional beams. The light intensity was linearly proportional to the delivered dose, which is similar to that of conventional beams. No significant dose-rate dependency was observed for 0.03-837 Gy s(-1). The light-intensity profiles of the UHDR beams agreed with those of conventional beams. The results did not differ between accelerators (synchrotron or cyclotron) and beam energies. Significance. Luminescence imaging of water is achievable with UHDR proton beams as well as with conventional beams. The proposed method should be suitable for rapid and easy quality assurance investigations for proton FLASH therapy, because it facilitates real-time, filmless measurements of dose distributions, and is useful for rapid feedback.}, keywords = {proton therapy; Engineering, Biomedical; Dose distribution; ultrahigh dose rate; water luminescence; FLASH beam}, year = {2023}, eissn = {1361-6560}, orcid-numbers = {Yogo, Katsunori/0000-0001-9555-2147; Toshito, Toshiyuki/0000-0002-6762-0015; Iwata, Hiromitsu/0000-0001-9809-9800; Komori, Masataka/0000-0002-4545-4917} } @article{MTMT:34638788, title = {Considerations and current status of treatment planning for proton FLASH radiotherapy}, url = {https://m2.mtmt.hu/api/publication/34638788}, author = {Zeng, Yiling and Quan, Hong}, doi = {10.1360/TB-2023-0291}, journal-iso = {KEXUE TONGBAO / CHINESE SCIENCE BULLETIN}, journal = {KEXUE TONGBAO / CHINESE SCIENCE BULLETIN}, volume = {68}, unique-id = {34638788}, issn = {0023-074X}, keywords = {proton therapy; pencil beam scanning; passive scattering; FLASH effect}, year = {2023}, pages = {4231-4244} } @article{MTMT:33809997, title = {Comparison of intratumor and local immune response between MV X-ray FLASH and conventional radiotherapies}, url = {https://m2.mtmt.hu/api/publication/33809997}, author = {Zhu, Hongyu and Xie, Dehuan and Wang, Ying and Huang, Runda and Chen, Xi and Yang, Yiwei and Wang, Bin and Peng, Yinglin and Wang, Jianxin and Xiao, Dexin and Wu, Dai and Qian, Chao-Nan and Deng, Xiaowu}, doi = {10.1016/j.ctro.2022.11.005}, journal-iso = {CLIN TRANSL RADIAT ONCOL (CTRO)}, journal = {CLINICAL AND TRANSLATIONAL RADIATION ONCOLOGY}, volume = {38}, unique-id = {33809997}, abstract = {Background/Purpose: Investigating the antitumor effect and intratumor as well as local immune response in breast cancer-bearing mice after MV X-ray ultra-high dose rate radiotherapy (FLASH-RT) and conventional dose rate radiotherapy (CONV-RT). Materials/Methods: Six-week-old female C57BL/6 mice were inoculated subcutaneously with Py8119 and Py230 breast tumor cells in the inguinal mammary gland and administered 10 Gy abdominal 6 MV X-ray FLASH-RT (125 Gy/s) or CONV-RT (0.2 Gy/s) 15 days after tumor inoculation. Tumor and spleen tissues were obtained at different time points post-irradiation (PI) for analysis of immune cell infiltration using flow cytometry and immunohistochemical (IHC) staining. Intestine tissues were collected 3 days PI to evaluate normal tissue damage and immune cell infiltration.Results: Both FLASH-RT and CONV-RT significantly delayed tumor growth. Flow cytometry showed increased CD8+/CD3 + and CD8+/CD4 + ratios, and IHC confirmed a similar increased CD8 + T cell infiltration at 2 weeks PI in Py8119 tumor tissues in both irradiation groups. No statistical difference was observed between the irradiation groups in terms of tumor growth and increased T cell infiltration in the tumor. Unexpectedly, significantly smaller spleen weight and substantially higher CD8+/CD3 + and lower CD4+/CD3 + ratios were observed in the spleens of the FLASH-RT group than in the spleens of the non-irradiated control and CONV-RT groups 4 weeks PI. Pathological analysis revealed severe red pulp expansion in several spleens from the CONV-RT group, but not in the spleens of the FLASH-RT group. Reduced intestinal damage, macrophage and neutrophil infiltration were observed in the FLASH-RT group compared with CONV-RT group.Conclusions: FLASH-RT and CONV-RT effectively suppressed tumor growth and promoted CD8 + T cell influx into tumors. FLASH-RT can induce different splenic immune responses and reduce radiation-induced damage in the spleen and intestine, which may potentially enhance the therapeutic ratio of FLASH-RT.}, keywords = {T-CELLS; IRRADIATION; Oncology; Tumor control; ANTITUMOR IMMUNITY; Tissue toxicity; FLASH-RT; Ultra -high dose rate radiotherapy; DOSE-RATES}, year = {2023}, eissn = {2405-6308}, pages = {138-146} } @article{MTMT:34092633, title = {Framework for Quality Assurance of Ultrahigh Dose Rate Clinical Trials Investigating FLASH Effects and Current Technology Gaps}, url = {https://m2.mtmt.hu/api/publication/34092633}, author = {Zou, W. and Zhang, R. and Schüler, E. and Taylor, P.A. and Mascia, A.E. and Diffenderfer, E.S. and Zhao, T. and Ayan, A.S. and Sharma, M. and Yu, S.-J. and Lu, W. and Bosch, W.R. and Tsien, C. and Surucu, M. and Pollard-Larkin, J.M. and Schuemann, J. and Moros, E.G. and Bazalova-Carter, M. and Gladstone, D.J. and Li, H. and Simone, C.B. II and Petersson, K. and Kry, S.F. and Maity, A. and Loo, B.W. Jr and Dong, L. and Maxim, P.G. and Xiao, Y. and Buchsbaum, J.C.}, doi = {10.1016/j.ijrobp.2023.04.018}, journal-iso = {INT J RADIAT ONCOL}, journal = {INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS}, volume = {116}, unique-id = {34092633}, issn = {0360-3016}, abstract = {FLASH radiation therapy (FLASH-RT), delivered with ultrahigh dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared with currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology FLASH working group on quality assurance of potential UHDR clinical trials and reviews current technology gaps to overcome. An important but separate consideration is the appropriate design of trials to most effectively answer clinical and scientific questions about FLASH. This paper begins with an overview of UHDR RT delivery methods. UHDR beam delivery parameters are then covered, with a focus on electron and proton modalities. The definition and control of safe UHDR beam delivery and current and needed dosimetry technologies are reviewed and discussed. System and site credentialing for large, multi-institution trials are reviewed. Quality assurance is then discussed, and new requirements are presented for treatment system standard analysis, patient positioning, and treatment planning. The tables and figures in this paper are meant to serve as reference points as we move toward FLASH-RT clinical trial performance. Some major questions regarding FLASH-RT are discussed, and next steps in this field are proposed. FLASH-RT has potential but is associated with significant risks and complexities. We need to redefine optimization to focus not only on the dose but also on the dose rate in a manner that is robust and understandable and that can be prescribed, validated, and confirmed in real time. Robust patient safety systems and access to treatment data will be critical as FLASH-RT moves into the clinical trials. © 2023 The Authors}, keywords = {Humans; human; clinical trial; TECHNOLOGY; TECHNOLOGY; Electrons; quality control; ELECTRON; Oncology; RADIOTHERAPY; Radiotherapy Dosage; Radiotherapy Dosage; Quality assurance; accreditation; health care facility; Health Facilities; Radiation Oncology; patient positioning; patient positioning; Medical applications; Current technology; Technology gap; Dose rate; credentialing; Working groups; NORMAL-TISSUE TOXICITY; Appropriate designs; Therapeutic ratios; Tumor dose}, year = {2023}, eissn = {1879-355X}, pages = {1202-1217} } @article{MTMT:33809999, title = {Normal Tissue Sparing by FLASH as a Function of Single-Fraction Dose: A Quantitative Analysis}, url = {https://m2.mtmt.hu/api/publication/33809999}, author = {Boehlen, Till Tobias and Germond, Jean-Francois and Bourhis, Jean and Vozenin, Marie-Catherine and Ozsahin, Esat Mahmut and Bochud, Francois and Bailat, Claude and Moeckli, Raphael}, doi = {10.1016/j.ijrobp.2022.05.038}, journal-iso = {INT J RADIAT ONCOL}, journal = {INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS}, volume = {114}, unique-id = {33809999}, issn = {0360-3016}, abstract = {Purpose: The FLASH effect designates normal tissue sparing by ultra-high dose rate (UHDR) compared with conventional dose rate irradiation without compromising tumor control. Understanding the magnitude of this effect and its dependency on dose are essential requirements for an optimized clinical translation of FLASH radiation therapy. In this context, we evaluated available experimental data on the magnitudes of normal tissue sparing provided by the FLASH effect as a function of dose, and followed a phenomenological data-driven approach for its parameterization. Methods and Materials: We gathered available in vivo data of normal tissue sparing of conventional (CONV) versus UHDR single-fraction doses and converted these to a common scale using isoeffect dose ratios, hereafter referred to as FLASH-modifying factors (FMF= (DCONV/DUHDR)|isoeffect). We then evaluated the suitability of a piecewise linear function with 2 pieces to parametrize FMF pound DUHDR as a function of dose DUHDR. Results: We found that the magnitude of FMF generally decreases (ie, sparing increases) as a function of single-fraction dose, and that individual data series can be described by the piecewise linear function. The sparing magnitude appears organ-specific, and pooled skin-reaction data followed a consistent trend as a function of dose. Average FMF values and their standard deviations were 0.95 0.11 for all data <10 Gy, 0.92
0.06 for mouse gut data between 10 and 25 Gy, and 0.96 0.07 and 0.71 0.06 for mammalian skin-reaction data between 10 and 25 Gy and >25 Gy, respectively. Conclusions: The magnitude of normal tissue sparing by FLASH increases with dose and is dependent on the irradiated tissue. A piecewise linear function can parameterize currently available individual data series. (c) 2022 Elsevier Inc. All rights reserved.}, keywords = {CELLS; IRRADIATION; TOXICITY; RADIATION; RATES; Oncology}, year = {2022}, eissn = {1879-355X}, pages = {1032-1044}, orcid-numbers = {Bailat, Claude/0000-0002-0386-4782} } @article{MTMT:33423748, title = {Practice-oriented solutions integrating intraoperative electron irradiation and personalized proton therapy for recurrent or unresectable cancers: Proof of concept and potential for dual FLASH effect}, url = {https://m2.mtmt.hu/api/publication/33423748}, author = {Calvo, Felipe A. and Ayestaran, Adriana and Serrano, Javier and Cambeiro, Mauricio and Palma, Jacobo and Meirino, Rosa and Morcillo, Miguel A. and Lapuente, Fernando and Chiva, Luis and Aguilar, Borja and Azcona, Diego and Pedrero, Diego and Pascau, Javier and Delgado, Jose Miguel and Aristu, Javier and Prezado, Yolanda}, doi = {10.3389/fonc.2022.1037262}, journal-iso = {FRONT ONCOL}, journal = {FRONTIERS IN ONCOLOGY}, volume = {12}, unique-id = {33423748}, issn = {2234-943X}, abstract = {Background: Oligo-recurrent disease has a consolidated evidence of long-term surviving patients due to the use of intense local cancer therapy. The latter combines real-time surgical exploration/resection with high-energy electron beam single dose of irradiation. This results in a very precise radiation dose deposit, which is an essential element of contemporary multidisciplinary individualized oncology. Methods: Patient candidates to proton therapy were evaluated in Multidisciplinary Tumor Board to consider improved treatment options based on the institutional resources and expertise. Proton therapy was delivered by a synchrotron-based pencil beam scanning technology with energy levels from 70.2 to 228.7 MeV, whereas intraoperative electrons were generated in a miniaturized linear accelerator with dose rates ranging from 22 to 36 Gy/min (at Dmax) and energies from 6 to 12 MeV. Results: In a period of 24 months, 327 patients were treated with proton therapy: 218 were adults, 97 had recurrent cancer, and 54 required re-irradiation. The specific radiation modalities selected in five cases included an integral strategy to optimize the local disease management by the combination of surgery, intraoperative electron boost, and external pencil beam proton therapy as components of the radiotherapy management. Recurrent cancer was present in four cases (cervix, sarcoma, melanoma, and rectum), and one patient had a primary unresectable locally advanced pancreatic adenocarcinoma. In re-irradiated patients (cervix and rectum), a tentative radical total dose was achieved by integrating beams of electrons (ranging from 10- to 20-Gy single dose) and protons (30 to 54-Gy Relative Biological Effectiveness (RBE), in 10-25 fractions). Conclusions: Individual case solution strategies combining intraoperative electron radiation therapy and proton therapy for patients with oligo-recurrent or unresectable localized cancer are feasible. The potential of this combination can be clinically explored with electron and proton FLASH beams.}, keywords = {CANCER; reirradiation; electron FLASH; proton therapy FLASH; oligorrecurrent}, year = {2022}, eissn = {2234-943X} } @article{MTMT:32672622, title = {The current status of preclinical proton FLASH radiation and future directions}, url = {https://m2.mtmt.hu/api/publication/32672622}, author = {Diffenderfer, E.S. and Sørensen, B.S. and Mazal, A. and Carlson, D.J.}, doi = {10.1002/mp.15276}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {49}, unique-id = {32672622}, issn = {0094-2405}, year = {2022}, eissn = {2473-4209}, pages = {2039-2054} } @article{MTMT:33423772, title = {Ultrafast Tracking of Oxygen Dynamics During Proton FLASH}, url = {https://m2.mtmt.hu/api/publication/33423772}, author = {El Khatib, Mirna and van Slyke, Alexander L. and Velalopoulou, Anastasia and Kim, Michele M. and Shoniyozov, Khayrullo and Allu, Srinivasa Rao and Diffenderfer, Eric E. and Busch, Theresa M. and Wiersma, Rodney D. and Koch, Cameron J. and Vinogradov, Sergei A.}, doi = {10.1016/j.ijrobp.2022.03.016}, journal-iso = {INT J RADIAT ONCOL}, journal = {INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS}, volume = {113}, unique-id = {33423772}, issn = {0360-3016}, abstract = {Purpose: Radiation therapy delivered at ultrafast dose rates, known as FLASH RT, has been shown to provide a therapeutic advantage compared with conventional radiation therapy by selectively protecting normal tissues. Radiochemical depletion of oxygen has been proposed to underpin the FLASH effect; however, experimental validation of this hypothesis has been lacking, in part owing to the inability to measure oxygenation at rates compatible with FLASH.Methods and Materials: We present a new variant of the phosphorescence quenching method for tracking oxygen dynamics with rates reaching up to similar to 3.3 kHz. Using soluble Oxyphor probes we were able to resolve, both in vitro and in vivo, oxygen dynamics during the time of delivery of proton FLASH.Results: In vitro in solutions containing bovine serum albumin the O-2 depletion g values (moles/L of O-2 depleted per radiation dose, eg, mu M/Gy) are higher for conventional irradiation (by similar to 13% at 75 mM [O-2]) than for FLASH, and in the low-oxygen region (<25 mu M [O-2]) they decrease with oxygen concentration. In vivo, depletion of oxygen by a single FLASH is insufficient to achieve severe hypoxia in initially well-oxygenated tissue, and the g values measured appear to correlate with baseline oxygen levels.Conclusions: The developed method should be instrumental in radiobiological studies, such as studies aimed at unraveling the mechanism of the FLASH effect. The FLASH effect could in part originate from the difference in the oxygen dependencies of the oxygen consumption g values for conventional versus FLASH RT. (C) 2022 Elsevier Inc. All rights reserved.}, year = {2022}, eissn = {1879-355X}, pages = {624-634} } @article{MTMT:33423779, title = {Design optimization of an electron-to-photon conversion target for ultra-high dose rate x-ray (FLASH) experiments at TRIUMF}, url = {https://m2.mtmt.hu/api/publication/33423779}, author = {Esplen, Nolan and Egoriti, Luca and Paley, Bill and Planche, Thomas and Hoehr, Cornelia and Gottberg, Alexander and Bazalova-Carter, Magdalena}, doi = {10.1088/1361-6560/ac5ed6}, journal-iso = {PHYS MED BIOL}, journal = {PHYSICS IN MEDICINE AND BIOLOGY}, volume = {67}, unique-id = {33423779}, issn = {0031-9155}, abstract = {Objective. To develop a bremsstrahlung target and megavoltage (MV) x-ray irradiation platform for ultrahigh dose-rate (UHDR) irradiation of small-animals on the Advanced Rare Isotope Laboratory (ARIEL) electron linac (e-linac) at TRIUMF. Approach. An electron-to-photon converter design for UHDR radiotherapy (RT) was centered around optimization of a tantalum-aluminum (Ta-Al) explosion-bonded target. Energy deposition within a homogeneous water-phantom and the target itself were evaluated using EGSnrc and FLUKA MC codes, respectively, for various target thicknesses (0.5-1.5 mm), beam energies (Ee- = 8, 10 MeV) and electron (Gaussian) beam sizes (2 sigma = 2-10 mm). Depth dose-rates in a 3D-printed mouse phantom were also calculated to infer the compatibility of the 10 MV dose distributions for FLASH-RT in small-animal models. Coupled thermo-mechanical FEA simulations in ANSYS were subsequently used to inform the stress-strain conditions and fatigue life of the target assembly. Main results. Dose-rates of up to 128 Gy s(-1) at the phantom surface, or 85 Gy s(-1) at 1 cm depth, were obtained for a 1 x 1 cm(2) field size, 1 mm thick Ta target and 7.5 cm source-to-surface distance using the FLASH-mode beam (Ee- = 10 MeV, 2 sigma = 5 mm, P = 1 kW); furthermore, removal of the collimation assembly and using a shorter (3.5 cm) SSD afforded doserates >600 Gy s(-1), albeit at the expense of field conformality. Target temperatures were maintained below the tantalum, aluminum and cooling-water thresholds of 2000 degrees C, 300 degrees C and 100 degrees C, respectively, while the aluminum strain behavior remained everywhere elastic and helped ensure the converter survives its prescribed 5 yr operational lifetime. Significance. Effective design iteration, target cooling and failure mitigation have culminated in a robust target compatible with intensive transient (FLASH) and steady-state (diagnostic) applications. The ARIEL UHDR photon source will facilitate FLASH-RT experiments concerned with sub-second, pulsed or continuous beam irradiations at dose rates in excess of 40 Gy s(-1).}, keywords = {Monte Carlo; RADIOTHERAPY; Thermomechanical; FLASH; Target design; ultrahigh dose-rate; megavoltage x-ray}, year = {2022}, eissn = {1361-6560}, orcid-numbers = {Esplen, Nolan/0000-0002-8347-8653} } @article{MTMT:32672606, title = {First demonstration of the FLASH effect with ultrahigh dose rate high-energy X-rays}, url = {https://m2.mtmt.hu/api/publication/32672606}, author = {Gao, F. and Yang, Y. and Zhu, H. and Wang, J. and Xiao, D. and Zhou, Z. and Dai, T. and Zhang, Y. and Feng, G. and Li, J. and Lin, B. and Xie, G. and Ke, Q. and Zhou, K. and Li, P. and Shen, X. and Wang, H. and Yan, L. and Lao, C. and Shan, L. and Li, M. and Lu, Y. and Chen, M. and Feng, S. and Zhao, J. and Wu, D. and Du, X.}, doi = {10.1016/j.radonc.2021.11.004}, journal-iso = {RADIOTHER ONCOL}, journal = {RADIOTHERAPY AND ONCOLOGY}, volume = {166}, unique-id = {32672606}, issn = {0167-8140}, year = {2022}, eissn = {1879-0887}, pages = {44-50} } @article{MTMT:33423764, title = {A potential revolution in cancer treatment: A topical review of FLASH radiotherapy}, url = {https://m2.mtmt.hu/api/publication/33423764}, author = {Gao, Yuan and Liu, Ruirui and Chang, Chih-Wei and Charyyev, Serdar and Zhou, Jun and Bradley, Jeffrey D. and Liu, Tian and Yang, Xiaofeng}, doi = {10.1002/acm2.13790}, journal-iso = {J APPL CLIN MED PHYS}, journal = {JOURNAL OF APPLIED CLINICAL MEDICAL PHYSICS}, volume = {23}, unique-id = {33423764}, issn = {1526-9914}, abstract = {FLASH radiotherapy (RT) is a novel technique in which the ultrahigh dose rate (UHDR) (>= 40 Gy/s) is delivered to the entire treatment volume. Recent outcomes of in vivo studies show that the UHDR RT has the potential to spare normal tissue without sacrificing tumor control. There is a growing interest in the application of FLASH RT, and the ultrahigh dose irradiation delivery has been achieved by a few experimental and modified linear accelerators. The underlying mechanism of FLASH effect is yet to be fully understood, but the oxygen depletion in normal tissue providing extra protection during FLASH irradiation is a hypothesis that attracts most attention currently. Monte Carlo simulation is playing an important role in FLASH, enabling the understanding of its dosimetry calculations and hardware design. More advanced Monte Carlo simulation tools are under development to fulfill the challenge of reproducing the radiolysis and radiobiology processes in FLASH irradiation. FLASH RT may become one of standard treatment modalities for tumor treatment in the future. This paper presents the history and status of FLASH RT studies with a focus on FLASH irradiation delivery modalities, underlying mechanism of FLASH effect, in vivo and vitro experiments, and simulation studies. Existing challenges and prospects of this novel technique are discussed in this manuscript.}, keywords = {CANCER; RADIOTHERAPY; FLASH}, year = {2022}, eissn = {1526-9914}, orcid-numbers = {Chang, Chih-Wei/0000-0002-3818-4381; Zhou, Jun/0000-0002-6078-9424} } @article{MTMT:33810000, title = {Proton radiotherapy for glioma and glioblastoma}, url = {https://m2.mtmt.hu/api/publication/33810000}, author = {Goff, Kevin M. and Zheng, Chuqi and Alonso-Basanta, Michelle}, doi = {10.21037/cco-22-92}, journal-iso = {CHIN CLIN ONCOL}, journal = {CHINESE CLINICAL ONCOLOGY}, volume = {11}, unique-id = {33810000}, issn = {2304-3865}, abstract = {Radiotherapy (RT) continues to be an important component of treatment of glioma, particularly high-grade glioma and glioblastoma multiforme (GBM). GBM is one of the most aggressive central nervous system (CNS) tumors, with high rates of recurrence and very low rates of long-term survival. However, outcomes in these patients are improving with modern genetic profiling and multimodal therapy, which leads to more consideration for the risk for toxicities associated with traditional photon-based RT. Proton therapy (PT) is an increasingly available method to reduce off-target irradiation in CNS tumors due to the intrinsic properties of heavy-particle irradiation. Here, we review currently available data examining the used of PT in glioma patients, including dose escalation for GBM, re-irradiation (reRT) of recurrent glioma, and the potential cognitive sparing effects of conventional dose PT. We discuss the incorporation of PT into the multimodal therapy of GBM patients, and how the aggressive nature of the disease poses a unique challenge to PT study design. We also describe how PT may provide the most feasible method for implementing high rate 'FLASH' RT and the implications for glioma patients. We conclude with a discussion of ongoing clinical trials, the necessity of continued research, and how we interpret and incorporate available data into our current practice.}, keywords = {GLIOMA; RADIATION-THERAPY; beam therapy; CLINICAL-OUTCOMES; TUMOR PROGRESSION; CHALLENGES; low-grade glioma; reirradiation; glioblastoma multiforme (GBM); Proton therapy (PT); MULTIFORME; PROTON/PHOTON IRRADIATION}, year = {2022}, eissn = {2304-3873}, orcid-numbers = {Goff, Kevin M./0000-0001-5862-0219} } @{MTMT:34327448, title = {The biology of FLASH-a critical appraisal for clinical translation}, url = {https://m2.mtmt.hu/api/publication/34327448}, author = {Grilj, V. and Vozenin, M.-C.}, booktitle = {Spatially Fractionated, Microbeam and Flash Radiation Therapy: Physics and Multidisciplinary Approach}, doi = {10.1088/978-0-7503-4046-5ch4}, unique-id = {34327448}, abstract = {Grilj and Vozenin critically appraise the technological basis, experimental data and emerging clinical investigations of FLASH therapy in chapter 4. © IOP Publishing Ltd 2023. All rights reserved.}, year = {2022}, pages = {4.1-4.20} } @article{MTMT:33423754, title = {Trade-off in healthy tissue sparing of FLASH and fractionation in stereotactic proton therapy of lung lesions with transmission beams}, url = {https://m2.mtmt.hu/api/publication/33423754}, author = {Habraken, Steven and Breedveld, Sebastiaan and Groen, Jort and Nuyttens, Joost and Hoogeman, Mischa}, doi = {10.1016/j.radonc.2022.08.015}, journal-iso = {RADIOTHER ONCOL}, journal = {RADIOTHERAPY AND ONCOLOGY}, volume = {175}, unique-id = {33423754}, issn = {0167-8140}, abstract = {Purpose and objective: Besides a dose-rate threshold of 40-100 Gy/s, the FLASH effect may require a dose > 3.5-7 Gy. Even in hypofractioned treatments, with all beams delivered in each fraction (ABEF), most healthy tissue is irradiated to a lower fraction dose. This can be circumvented by single-beamper-fraction (SBPF) delivery, with a loss of healthy tissue sparing by fractionation. We investigated the trade-off between FLASH and loss of fractionation in SBPF stereotactic proton therapy of lung cancer and determined break-even FLASH-enhancement ratios (FERs).Materials and Methods: Treatment plans for 12 patients were generated. GTV delineations were available and a 5 mm GTV-PTV margin was applied. Equiangular arrangements of 3, 5, 7, and 9 244 MeV proton transmission beams were used. To facilitate SBPF, the number of fractions was equal to the number of beams. Iso-effective fractionation schedules with a single field uniform dose prescription were used: D95%,PTV = 100%Dpres per beam. All plans were evaluated in terms of dose to lung and conformity of dose to target of FLASH-enhanced biologically equivalent dose (EQD2).Results: Compared to ABEF, SBPF resulted in a median increase of EQD2mean to healthy lung of 56%, 58%, 55% and 54% in plans with 3, 5, 7 and 9 fractions respectively and of 236%, 78%, 50% and 41% in V100% EQD2, quantifying conformity. This can be compensated for by FERs of at least 1.28, 1.32, 1.30 and 1.23 respectively for EQD2mean and 1.29, 1.18, 1.28 and 1.15 for V100%,EQD2.Conclusion: A FLASH effect outweighing the loss of fractionation in SBPF may be achieved in stereotactic lung treatments. The trade-off with fractionation depends on the conditions under which the FLASH effect occurs. Better understanding of the underlying biology and the impact of delivery conditions is needed.(c) 2022 The Authors. Published by Elsevier B.V. Radiotherapy and Oncology 175 (2022) 231-237}, keywords = {treatment planning; proton therapy; FLASH radiotherapy; Stereotactic lung treatment; Radiobiological modeling}, year = {2022}, eissn = {1879-0887}, pages = {231-237} } @article{MTMT:33423760, title = {Radiobiological Aspects of FLASH Radiotherapy}, url = {https://m2.mtmt.hu/api/publication/33423760}, author = {Hageman, Eline and Che, Pei-Pei and Dahele, Max and Slotman, Ben J. and Sminia, Peter}, doi = {10.3390/biom12101376}, journal-iso = {BIOMOLECULES}, journal = {BIOMOLECULES}, volume = {12}, unique-id = {33423760}, issn = {2218-273X}, abstract = {Radiotherapy (RT) is one of the primary treatment modalities for cancer patients. The clinical use of RT requires a balance to be struck between tumor effect and the risk of toxicity. Sparing normal tissue is the cornerstone of reducing toxicity. Advances in physical targeting and dose-shaping technology have helped to achieve this. FLASH RT is a promising, novel treatment technique that seeks to exploit a potential normal tissue-sparing effect of ultra-high dose rate irradiation. A significant body of in vitro and in vivo data has highlighted a decrease in acute and late radiation toxicities, while preserving the radiation effect in tumor cells. The underlying biological mechanisms of FLASH RT, however, remain unclear. Three main mechanisms have been hypothesized to account for this differential FLASH RT effect between the tumor and healthy tissue: the oxygen depletion, the DNA damage, and the immune-mediated hypothesis. These hypotheses and molecular mechanisms have been evaluated both in vitro and in vivo. Furthermore, the effect of ultra-high dose rate radiation with extremely short delivery times on the dynamic tumor microenvironment involving circulating blood cells and immune cells in humans is essentially unknown. Therefore, while there is great interest in FLASH RT as a means of targeting tumors with the promise of an increased therapeutic ratio, evidence of a generalized FLASH effect in humans and data to show that FLASH in humans is safe and at least effective against tumors as standard photon RT is currently lacking. FLASH RT needs further preclinical investigation and well-designed in-human studies before it can be introduced into clinical practice.}, keywords = {RADIOTHERAPY; Tumor control; radiobiology; FLASH; ultra-high dose rate; healthy tissue sparing}, year = {2022}, eissn = {2218-273X}, orcid-numbers = {Sminia, Peter/0000-0002-9531-5704} } @article{MTMT:32672620, title = {Understanding the FLASH effect to unravel the potential of ultra-high dose rate irradiation}, url = {https://m2.mtmt.hu/api/publication/32672620}, author = {Kacem, H. and Almeida, A. and Cherbuin, N. and Vozenin, M.-C.}, doi = {10.1080/09553002.2021.2004328}, journal-iso = {INT J RADIAT BIOL}, journal = {INTERNATIONAL JOURNAL OF RADIATION BIOLOGY}, volume = {98}, unique-id = {32672620}, issn = {0955-3002}, year = {2022}, eissn = {1362-3095}, pages = {506-516} } @article{MTMT:33423759, title = {Comparing radiolytic production of H2O2 and development of Zebrafish embryos after ultra high dose rate exposure with electron and transmission proton beams}, url = {https://m2.mtmt.hu/api/publication/33423759}, author = {Kacem, Houda and Psoroulas, Serena and Boivin, Gael and Folkerts, Michael and Grilj, Veljko and Lomax, Tony and Martinotti, Adrien and Meer, David and Ollivier, Jonathan and Petit, Benoit and Safai, Sairos and Sharma, Ricky A. and Togno, Michele and Vilalta, Marta and Weber, Damien C. and Vozenin, Marie -Catherine}, doi = {10.1016/j.radonc.2022.07.011}, journal-iso = {RADIOTHER ONCOL}, journal = {RADIOTHERAPY AND ONCOLOGY}, volume = {175}, unique-id = {33423759}, issn = {0167-8140}, abstract = {The physico-chemical and biological response to conventional and UHDR electron and proton beams was investigated, along with conventional photons. The temporal structure and nature of the beam affected both, with electron beam at >= 1400 Gy/s and proton beam at 0.1 and 1260 Gy/s found to be isoefficient at sparing zebrafish embryos.(c) 2022 The Authors. Published by Elsevier B.V. Radiotherapy and Oncology 175 (2022) 197-202 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).}, keywords = {ZEBRAFISH EMBRYOS; electron FLASH; Proton FLASH; Hydrogen peroxyde}, year = {2022}, eissn = {1879-0887}, pages = {197-202}, orcid-numbers = {Psoroulas, Serena/0000-0001-7576-3238; Safai, Sairos/0000-0002-0459-4534; Togno, Michele/0000-0001-6840-814X} } @article{MTMT:32868094, title = {Beam pulse structure and dose rate as determinants for the flash effect observed in zebrafish embryo}, url = {https://m2.mtmt.hu/api/publication/32868094}, author = {Karsch, Leonhard and Pawelke, Jörg and Brand, Michael and Hans, Stefan and Hideghéty, Katalin and Jansen, Jeannette and Lessmann, Elisabeth and Löck, Steffen and Schürer, Michael and Schurig, Rico and Seco, Joao and Szabó, Emilia Rita and Beyreuther, Elke}, doi = {10.1016/j.radonc.2022.05.025}, journal-iso = {RADIOTHER ONCOL}, journal = {RADIOTHERAPY AND ONCOLOGY}, volume = {173}, unique-id = {32868094}, issn = {0167-8140}, year = {2022}, eissn = {1879-0887}, pages = {49-54}, orcid-numbers = {Hideghéty, Katalin/0000-0001-7080-2365; Szabó, Emilia Rita/0000-0003-3611-2066} } @article{MTMT:33423789, title = {Development of Ultra-High Dose-Rate (FLASH) Particle Therapy}, url = {https://m2.mtmt.hu/api/publication/33423789}, author = {Kim, Michele M. and Darafsheh, Arash and Schuemann, Jan and Dokic, Ivana and Lundh, Olle and Zhao, Tianyu and Ramos-Mendez, Jose and Dong, Lei and Petersson, Kristoffer}, doi = {10.1109/TRPMS.2021.3091406}, journal-iso = {IEEE T RADIAT PLASMA}, journal = {IEEE TRANSACTIONS ON RADIATION AND PLASMA MEDICAL SCIENCES}, volume = {6}, unique-id = {33423789}, issn = {2469-7311}, abstract = {Research efforts in FLASH radiotherapy (FLASH-RT) have increased at an accelerated pace recently. FLASH-RT involves ultra-high dose rates and has been shown to reduce toxicity to normal tissue while maintaining tumor response in preclinical studies when compared to conventional dose rate radiotherapy. The goal of this review is to summarize the studies performed to date with proton, electron, and heavy-ion FLASH-RT, with particular emphasis on the physical aspects of each study and the advantages and disadvantages of each modality. Beam delivery parameters, experimental setup, and the dosimetry tools used are described for each FLASH modality. In addition, modeling efforts and treatment planning for FLASH-RT are discussed along with potential drawbacks when translated into the clinical setting. The final section concludes with further questions that have yet to be answered before safe clinical implementation of FLASH-RT.}, keywords = {proton radiation; Electron radiation; heavy-ion radiation; FLASH effect modeling; FLASH radiotherapy (FLASH-RT)}, year = {2022}, eissn = {2469-7303}, pages = {252-262}, orcid-numbers = {Darafsheh, Arash/0000-0003-4148-0891; Zhao, Tianyu/0000-0002-5503-123X; Dong, Lei/0000-0003-2623-3198; Petersson, Kristoffer/0000-0003-0300-5790} } @article{MTMT:32672604, title = {A quantitative FLASH effectiveness model to reveal potentials and pitfalls of high dose rate proton therapy}, url = {https://m2.mtmt.hu/api/publication/32672604}, author = {Krieger, M. and van, de Water S. and Folkerts, M.M. and Mazal, A. and Fabiano, S. and Bizzocchi, N. and Weber, D.C. and Safai, S. and Lomax, A.J.}, doi = {10.1002/mp.15459}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {49}, unique-id = {32672604}, issn = {0094-2405}, year = {2022}, eissn = {2473-4209}, pages = {2026-2038} } @article{MTMT:33361716, title = {Tumour irradiation in mice with a laser-accelerated proton beam}, url = {https://m2.mtmt.hu/api/publication/33361716}, author = {Kroll, Florian and Brack, Florian-Emanuel and Bernert, Constantin and Bock, Stefan and Bodenstein, Elisabeth and Bruechner, Kerstin and Cowan, Thomas E. and Gaus, Lennart and Gebhardt, Rene and Helbig, Uwe and Karsch, Leonhard and Kluge, Thomas and Kraft, Stephan and Krause, Mechthild and Lessmann, Elisabeth and Masood, Umar and Meister, Sebastian and Metzkes-Ng, Josefine and Nossula, Alexej and Pawelke, Joerg and Pietzsch, Jens and Pueschel, Thomas and Reimold, Marvin and Rehwald, Martin and Richter, Christian and Schlenvoigt, Hans-Peter and Schramm, Ulrich and Umlandt, Marvin E. P. and Ziegler, Tim and Zeil, Karl and Beyreuther, Elke}, doi = {10.1038/s41567-022-01520-3}, journal-iso = {NAT PHYS}, journal = {NATURE PHYSICS}, volume = {18}, unique-id = {33361716}, issn = {1745-2473}, abstract = {Recent oncological studies identified beneficial properties of radiation applied at ultrahigh dose rates, several orders of magnitude higher than the clinical standard of the order of Gy min(-1). Sources capable of providing these ultrahigh dose rates are under investigation. Here we show that a stable, compact laser-driven proton source with energies greater than 60 MeV enables radiobiological in vivo studies. We performed a pilot irradiation study on human tumours in a mouse model, showing the concerted preparation of mice and laser accelerator, dose-controlled, tumour-conform irradiation using a laser-driven as well as a clinical reference proton source, and the radiobiological evaluation of irradiated and unirradiated mice for radiation-induced tumour growth delay. The prescribed homogeneous dose of 4 Gy was precisely delivered at the laser-driven source. The results demonstrate a complete laser-driven proton research platform for diverse user-specific small animal models, able to deliver tunable single-shot doses up to around 20 Gy to millimetre-scale volumes on nanosecond timescales, equivalent to around 10(9) Gy s(-1), spatially homogenized and tailored to the sample. The platform provides a unique infrastructure for translational research with protons at ultrahigh dose rates.A laser-plasma accelerator provides proton beams for the precise irradiation of human tumours in a mouse model. This work advances translational research with ultrahigh proton dose rates at laser-driven sources.}, year = {2022}, eissn = {1745-2481}, pages = {316-+}, orcid-numbers = {Kroll, Florian/0000-0002-0275-9892; Brack, Florian-Emanuel/0000-0002-9859-2408; Bernert, Constantin/0000-0003-1739-0159; Bock, Stefan/0000-0002-1919-8585; Gaus, Lennart/0000-0002-6914-4083; Nossula, Alexej/0000-0002-6571-0332; Pietzsch, Jens/0000-0002-1610-1493; Rehwald, Martin/0000-0001-6200-6406; Richter, Christian/0000-0003-4261-4214; Schlenvoigt, Hans-Peter/0000-0003-4400-1315; Schramm, Ulrich/0000-0003-0390-7671; Ziegler, Tim/0000-0002-3727-7017} } @article{MTMT:33423768, title = {Radiation Chemical Yields of 7-Hydroxy-Coumarin-3-Carboxylic Acid for Proton- and Carbon-Ion Beams at Ultra-High Dose Rates: Potential Roles in FLASH Effects}, url = {https://m2.mtmt.hu/api/publication/33423768}, author = {Kusumoto, Tamon and Inaniwa, Taku and Mizushima, Kota and Sato, Shinji and Hojo, Satoru and Kitamura, Hisashi and Konishi, Teruaki and Kodaira, Satoshi}, doi = {10.1667/RADE-21-00.230.1}, journal-iso = {RADIAT RES}, journal = {RADIATION RESEARCH}, volume = {198}, unique-id = {33423768}, issn = {0033-7587}, abstract = {It has been observed that healthy tissues are spared at ultra-high dose rate (UHDR:.40 Gy/s), so called FLASH effect. To elucidate the mechanism of FLASH effect, we evaluate changes in radiation chemical yield (G value) of 7-hydroxy-coumarin-3-carboxylic acid (7OH-C3CA), which is formed by the reaction of hydroxyl radicals with coumarin-3- carboxylic acid (C3CA), under carbon ions (140 MeV/u) and protons (27.5 and 55 MeV) in a wide-dose-rate range up to 100 Gy/s. The relative G value, which is the G value at each dose rate normalized by that at the conventional dose (CONV: 0.1 Gy/s.), 140 MeV/u carbon-ion beam is almost equivalent to 27.5 and 55 MeV proton beams. This finding implies that UHDR irradiations using carbon-ion beams have a potential to spare healthy tissues. Furthermore, we evaluate the G value of 7OH-C3CA under the de-oxygenated condition to investigate roles of oxygen to the generation of 7OH-C3CA effect. The G value of 7OH-C3CA under the deoxygenated condition is lower than that under the oxygenated condition. The G value of 7OH-C3CA under the deoxygenated condition is higher than those under UHDR irradiations. By direct measurements of the oxygen concentration during 55 MeV proton irradiations, the oxygen concentration drops by 0.1%/Gy, which is independent of the dose rate. When the oxygen concentration directly affects to yields of 7OH-C3CA, the rate of decrease in the oxygen concentration may be correlated with that of decrease in the G value of 7OH-C3CA. However, the reduction rate of G value under UHDR is significantly higher than the oxygen consumption. This finding implied that the influence of the reaction between water radiolysis species formed by neighborhood tracks could be strongly related to the mechanisms of UHDR effect. (C) 2022 by Radiation Research Society}, year = {2022}, eissn = {1938-5404}, pages = {255-262}, orcid-numbers = {Kusumoto, Tamon/0000-0002-2145-4496; Konishi, Teruaki/0000-0002-2485-9659} } @article{MTMT:33810139, title = {A review of the impact of FLASH radiotherapy on the central nervous system and glioma}, url = {https://m2.mtmt.hu/api/publication/33810139}, author = {Li, L. and Yuan, Y. and Zuo, Y.}, doi = {10.1016/j.radmp.2022.10.002}, journal-iso = {RADIAT MED PROT}, journal = {RADIATION MEDICINE AND PROTECTION}, volume = {3}, unique-id = {33810139}, issn = {2097-0439}, abstract = {Glioma has received considerable attention because of its potential of inducing high rates of morbidity, disability, and mortality. FLASH radiotherapy (FLASH-RT) has emerged as a popular topic in current research because of its ability to protect normal tissues. The present review summarized the current development of FLASH-RT in both the central nervous system and glioblastomas, explored the potential mechanisms underlying FLASH-RT-mediated protective effects on the central nervous system, and revealed the advantages of this new technique for glioma therapy. This study highlights the benefits and challenges of the present research and provides a reference for future research. © 2022 Chinese Medical Association}, keywords = {GLIOMA; Nervous System; conventional radiotherapy; FLASH radiotherapy}, year = {2022}, eissn = {2666-5557}, pages = {208-212} } @article{MTMT:33423762, title = {FLASH radiotherapy: A promising new method for radiotherapy}, url = {https://m2.mtmt.hu/api/publication/33423762}, author = {Lv, Yinghao and Lv, Yue and Wang, Zhen and Lan, Tian and Feng, Xuping and Chen, Hao and Zhu, Jiang and Ma, Xiao and Du, Jinpeng and Hou, Guimin and Liao, Wenwei and Yuan, Kefei and Wu, Hong}, doi = {10.3892/ol.2022.13539}, journal-iso = {ONCOL LETT}, journal = {ONCOLOGY LETTERS}, volume = {24}, unique-id = {33423762}, issn = {1792-1074}, abstract = {Among the treatments for malignant tumors, radiotherapy is of great significance both as a main treatment and as an adjuvant treatment. Radiation therapy damages cancer cells with ionizing radiation, leading to their death. However, radiation-induced toxicity limits the dose delivered to the tumor, thereby constraining the control effect of radiotherapy on tumor growth. In addition, the delayed toxicity caused by radiotherapy significantly harms the physical and mental health of patients. FLASH-RT, an emerging class of radiotherapy, causes a phenomenon known as the 'FLASH effect', which delivers radiotherapy at an ultra-high dose rate with lower toxicity to normal tissue than conventional radiotherapy to achieve local tumor control. Although its mechanism remains to be fully elucidated, this modality constitutes a potential new approach to treating malignant tumors. In the present review, the current research progress of FLASH-RT and its various particular effects are described, including the status of research on FLASH-RT and its influencing factors. The hypothetic mechanism of action of FLASH-RT is also summarized, providing insight into future tumor treatments.}, keywords = {CANCER; diagnosis; RADIATION; Dose; FLASH}, year = {2022}, eissn = {1792-1082} } @article{MTMT:33423766, title = {FLASH radiotherapy: an emerging approach in radiation therapy}, url = {https://m2.mtmt.hu/api/publication/33423766}, author = {Matuszak, Natalia and Suchorska, Wiktoria Maria and Milecki, Piotr and Kruszyna-Mochalska, Marta and Misiarz, Agnieszka and Pracz, Jacek and Malicki, Julian}, doi = {10.5603/RPOR.a2022.0038}, journal-iso = {REP PRACT ONCOL RADI}, journal = {REPORTS OF PRACTICAL ONCOLOGY AND RADIOTHERAPY}, volume = {27}, unique-id = {33423766}, issn = {1507-1367}, abstract = {FLASH radiotherapy (RT) is a technique involving the delivery of ultra-high dose rate radiation to the target. FLASH-RT has been shown to reduce radiation-induced toxicity in healthy tissues without compromising the anti-cancer effects of treatment compared to conventional radiation therapy. In the present article, we review the published data on FLASH-RT and discuss the current state of knowledge of this novel approach. We also highlight the technological constraints and complexity of FLASH-RT and describe the physics underlying this modality, particularly how technology supports energy transfer by ionising radiation (e.g., beam on/off sequence, pulse-energy load, intervals). We emphasise that current preclinical experience is mostly based on FLASH electrons and that clinical application of FLASH-RT is very limited. The incorporation of FLASH-RT into routine clinical radiotherapy will require the development of devices capable of producing FLASH photon beams.}, keywords = {RADIOTHERAPY; Biological effect; ionising radiation; dosimetric parameters; ultra-high dose rate; FLASH RT; FLASH electrons; FLASH photons}, year = {2022}, eissn = {2083-4640}, pages = {344-351} } @article{MTMT:33810144, title = {Research progresses of Flash radiotherapy technique}, url = {https://m2.mtmt.hu/api/publication/33810144}, author = {Qi, Y. and Gao, N. and Lu, X. and Qian, D. and Xu, X.}, doi = {10.13929/j.issn.1003-3289.2022.01.035}, journal-iso = {CHINESE J MED IMAG TECH}, journal = {ZHONGGUO YIXUE YINGXIANG JISHU / CHINESE JOURNAL OF MEDICAL IMAGING TECHNOLOGY}, volume = {38}, unique-id = {33810144}, issn = {1003-3289}, abstract = {Flash radiotherapy (Flash-RT) has become a hot topic in the field of radiotherapy owing to its unique radiobiological characteristics and potentials in clinical application, yet researches of mechanism and clinical application of Flash-RT remained in preliminary stage. The progresses of Flash-RT were reviewed in this paper. Copyright © 2022 by the Press of Chinese Journal of Medical Imaging and Technology.}, keywords = {review; human; RADIOTHERAPY; RADIOTHERAPY; FLASH; ultra-high dose rate}, year = {2022}, pages = {146-149} } @article{MTMT:33423781, title = {Ultra-high dose rate dosimetry: Challenges and opportunities for FLASH radiation therapy}, url = {https://m2.mtmt.hu/api/publication/33423781}, author = {Romano, Francesco and Bailat, Claude and Jorge, Patrik Goncalves and Lerch, Michael Lloyd Franz and Darafsheh, Arash}, doi = {10.1002/mp.15649}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {49}, unique-id = {33423781}, issn = {0094-2405}, abstract = {The clinical translation of FLASH radiotherapy (RT) requires challenges related to dosimetry and beam monitoring of ultra-high dose rate (UHDR) beams to be addressed. Detectors currently in use suffer from saturation effects under UHDR regimes, requiring the introduction of correction factors. There is significant interest from the scientific community to identify the most reliable solutions and suitable experimental approaches for UHDR dosimetry. This interest is manifested through the increasing number of national and international projects recently proposed concerning UHDR dosimetry. Attaining the desired solutions and approaches requires further optimization of already established technologies as well as the investigation of novel radiation detection and dosimetry methods. New knowledge will also emerge to fill the gap in terms of validated protocols, assessing new dosimetric procedures and standardized methods. In this paper, we discuss the main challenges coming from the peculiar beam parameters characterizing UHDR beams for FLASH RT. These challenges vary considerably depending on the accelerator type and technique used to produce the relevant UHDR radiation environment. We also introduce some general considerations on how the different time structure in the production of the radiation beams, as well as the dose and dose-rate per pulse, can affect the detector response. Finally, we discuss the requirements that must characterize any proposed dosimeters for use in UDHR radiation environments. A detailed status of the current technology is provided, with the aim of discussing the detector features and their performance characteristics and/or limitations in UHDR regimes. We report on further developments for established detectors and novel approaches currently under investigation with a view to predict future directions in terms of dosimetry approaches, practical procedures, and protocols. Due to several on-going detector and dosimetry developments associated with UHDR radiation environment for FLASH RT it is not possible to provide a simple list of recommendations for the most suitable detectors for FLASH RT dosimetry. However, this article does provide the reader with a detailed description of the most up-to-date dosimetric approaches, and describes the behavior of the detectors operated under UHDR irradiation conditions and offers expert discussion on the current challenges which we believe are important and still need to be addressed in the clinical translation of FLASH RT.}, keywords = {RADIOTHERAPY; proton therapy; Dosimetry; FLASH; ultra-high dose rate}, year = {2022}, eissn = {2473-4209}, pages = {4912-4932}, orcid-numbers = {Bailat, Claude/0000-0002-0386-4782} } @{MTMT:33810145, title = {FLASH Radiotherapy}, url = {https://m2.mtmt.hu/api/publication/33810145}, author = {Samanta, S. and Mossahebi, S. and Miller, R.C.}, booktitle = {Principles and Practice of Particle Therapy}, doi = {10.1002/9781119707530.ch8}, unique-id = {33810145}, abstract = {Ionizing radiation with ultrahigh dose rates (>40 Gy/s), known as FLASH radiotherapy, has been recently shown to markedly reduce radiation toxicity to normal healthy tissues while inhibiting tumor growth with similar efficacy as compared to conventional dose-rate radiation. The two major hypotheses to explain FLASH include the oxygen depletion hypothesis and the immune hypothesis. Bourhis et al. conducted the first human patient study to demonstrate feasibility and safety with favorable outcomes using FLASH-RT therapy. FLASH-RT involves dose delivery at ultrahigh dose rates generally several thousand times higher than the ones currently used in routine clinical practice. The clinical translation of FLASH-RT has been substantiated by multiple experiments that confirm the differential effect between the tumors and the normal tissue, as compared to conventional dose-rate radiation. Recent clinical studies further validate the potential benefits of FLASH-RT. © 2022 John Wiley and Sons Ltd. All rights reserved.}, keywords = {Clinical studies; Dose delivery; FLASH radiotherapy; oxygen depletion hypothesis; Dose-rate radiation; Human patient study; Immune hypothesis}, year = {2022}, pages = {115-120} } @article{MTMT:33423756, title = {Combining FLASH and spatially fractionated radiation therapy: The best of both worlds}, url = {https://m2.mtmt.hu/api/publication/33423756}, author = {Schneider, Tim and Fernandez-Palomo, Cristian and Bertho, Annaig and Fazzari, Jennifer and Iturri, Lorea and Martin, Olga A. and Trappetti, Verdiana and Djonov, Valentin and Prezado, Yolanda}, doi = {10.1016/j.radonc.2022.08.004}, journal-iso = {RADIOTHER ONCOL}, journal = {RADIOTHERAPY AND ONCOLOGY}, volume = {175}, unique-id = {33423756}, issn = {0167-8140}, abstract = {FLASH radiotherapy (FLASH-RT) and spatially fractionated radiation therapy (SFRT) are two new thera-peutical strategies that use non-standard dose delivery methods to reduce normal tissue toxicity and increase the therapeutic index. Although likely based on different mechanisms, both FLASH-RT and SFRT have shown to elicit radiobiological effects that significantly differ from those induced by conven-tional radiotherapy. With the therapeutic potential having been established separately for each tech-nique, the combination of FLASH-RT and SFRT could therefore represent a winning alliance. In this review, we discuss the state of the art, advantages and current limitations, potential synergies, and where a combination of these two techniques could be implemented today or in the near future.(c) 2022 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 175 (2022) 169-177}, keywords = {normal tissue toxicity; spatially fractionated radiation therapy; FLASH therapy}, year = {2022}, eissn = {1879-0887}, pages = {169-177}, orcid-numbers = {Fazzari, Jennifer/0000-0002-3634-4070; Iturri, Lorea/0000-0002-7911-3117} } @article{MTMT:32672567, title = {Ultra-high dose rate electron beams and the FLASH effect: From preclinical evidence to a new radiotherapy paradigm}, url = {https://m2.mtmt.hu/api/publication/32672567}, author = {Schuler, Emil and Acharya, Munjal and Montay-Gruel, Pierre and Loo, Billy W. Jr Jr and Vozenin, Marie-Catherine and Maxim, Peter G.}, doi = {10.1002/mp.15442}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {49}, unique-id = {32672567}, issn = {0094-2405}, abstract = {In their seminal paper from 2014, Fauvadon et al. coined the term FLASH irradiation to describe ultra-high-dose rate irradiation with dose rates greater than 40 Gy/s, which results in delivery times of fractions of a second. The experiments presented in that paper were performed with a high-dose-per-pulse 4.5 MeV electron beam, and the results served as the basis for the modern-day field of FLASH radiation therapy (RT). In this article, we review the studies that have been published after those early experiments, demonstrating the robust effects of FLASH RT on normal tissue sparing in preclinical models. We also outline the various irradiation parameters that have been used. Although the robustness of the biological response has been established, the mechanisms behind the FLASH effect are currently under investigation in a number of laboratories. However, differences in the magnitude of the FLASH effect between experiments in different labs have been reported. Reasons for these differences even within the same animal model are currently unknown, but likely has to do with the marked differences in irradiation parameter settings used. Here, we show that these parameters are often not reported, which complicates large multistudy comparisons. For this reason, we propose a new standard for beam parameter reporting and discuss a systematic path to the clinical translation of FLASH RT.}, keywords = {Brain; CELLS; IN-VITRO; IRRADIATION; RADIATION-THERAPY; Dosimetry; Dosimetry; Biological effects; Oxygen depletion; Rate dependence; electron FLASH; FLASH effect; PLASTIC SCINTILLATION DETECTORS}, year = {2022}, eissn = {2473-4209}, pages = {2082-2095} } @article{MTMT:33423788, title = {Treatment planning for Flash radiotherapy: General aspects and applications to proton beams}, url = {https://m2.mtmt.hu/api/publication/33423788}, author = {Schwarz, Marco and Traneus, Erik and Safai, Sairos and Kolano, Anna and van de Water, Steven}, doi = {10.1002/mp.15579}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {49}, unique-id = {33423788}, issn = {0094-2405}, abstract = {The increased radioresistence of healthy tissues when irradiated at very high dose rates (known as the Flash effect) is a radiobiological mechanism that is currently investigated to increase the therapeutic ratio of radiotherapy treatments. To maximize the benefits of the clinical application of Flash, a patient-specific balance between different properties of the dose distribution should be found, that is, Flash needs to be one of the variables considered in treatment planning. We investigated the Flash potential of three proton therapy planning and beam delivery techniques, each on a different anatomical region. Based on a set of beam delivery parameters, on hypotheses on the dose and dose rate thresholds needed for the Flash effect to occur, and on two definitions of Flash dose rate, we generated exemplary illustrations of the capabilities of current proton therapy equipment to generate Flash dose distributions. All techniques investigated could both produce dose distributions comparable with a conventional proton plan and reach the Flash regime, to an extent that was strongly dependent on the dose per fraction and the Flash dose threshold. The beam current, Flash dose rate threshold, and dose rate definition typically had a more moderate effect on the amount of Flash dose in normal tissue. A systematic estimation of the impact of Flash on different patient anatomies and treatment protocols is possible only if Flash-specific treatment planning features become readily available. Planning evaluation tools such as a voxel-based dose delivery time structure, and the inclusion in the optimization cost function of parameters directly associated with Flash (e.g., beam current, spot delivery sequence, and scanning speed), are needed to generate treatment plans that are taking full advantage of the potential benefits of the Flash effect.}, keywords = {treatment planning; Protons; FLASH}, year = {2022}, eissn = {2473-4209}, pages = {2861-2874}, orcid-numbers = {Safai, Sairos/0000-0002-0459-4534} } @article{MTMT:32672601, title = {In vivo validation and tissue sparing factor for acute damage of pencil beam scanning proton FLASH}, url = {https://m2.mtmt.hu/api/publication/32672601}, author = {Singers, Sørensen B. and Krzysztof, Sitarz M. and Ankjærgaard, C. and Johansen, J. and Andersen, C.E. and Kanouta, E. and Overgaard, C. and Grau, C. and Poulsen, P.}, doi = {10.1016/j.radonc.2021.12.022}, journal-iso = {RADIOTHER ONCOL}, journal = {RADIOTHERAPY AND ONCOLOGY}, volume = {167}, unique-id = {32672601}, issn = {0167-8140}, year = {2022}, eissn = {1879-0887}, pages = {109-115} } @article{MTMT:33423777, title = {First Human Cell Experiments With FLASH Carbon Ions}, url = {https://m2.mtmt.hu/api/publication/33423777}, author = {Tashiro, Mutsumi and Yoshida, Yukari and Oike, Takahiro and Nakao, Masao and Yusa, Ken and Hirota, Yuka and Ohno, Tatsuya}, doi = {10.21873/anticanres.15725}, journal-iso = {ANTICANCER RES}, journal = {ANTICANCER RESEARCH}, volume = {42}, unique-id = {33423777}, issn = {0250-7005}, abstract = {Background/Aim: This study aimed to establish a setup for ultra-high-dose-rate (FLASH) carbon-ion irradiation, and to conduct the first human cell experiments using FLASH carbon ions. Materials and Methods: A system for FLASH carbon-ion irradiation (1-3 Gy at 13 or 50 keV/,um) was developed. The growth and senescence of HFL1 lung fibroblasts were assessed by crystal violet staining assays and senescence associated ??-galactosidase staining, respectively. Survival of HSGc-C5 cancer cells was assessed by clonogenic assays. Results: The dose rates of carbon ions ranged from 96-195 Gy/s, meeting the definition of FLASH. With both 13 and 50 keV/,um beams, no FLASH sparing effect was observed on the growth suppression and senescence of HFL1 cells, nor on the survival of HSGc-C5 cells. Conclusion: We successfully conducted the first human cell experiments with FLASH carbon ions. No FLASH effect was observed under the conditions examined.}, keywords = {CANCER; RADIATION; FIBROBLAST; FLASH; carbon ions; ultra-high dose rate}, year = {2022}, eissn = {1791-7530}, pages = {2469-2477}, orcid-numbers = {Tashiro, Mutsumi/0000-0003-3253-0527} } @article{MTMT:32672605, title = {Design and validation of a synchrotron proton beam line for FLASH radiotherapy preclinical research experiments}, url = {https://m2.mtmt.hu/api/publication/32672605}, author = {Titt, U. and Yang, M. and Wang, X. and Iga, K. and Fredette, N. and Schueler, E. and Lin, S.H. and Zhu, X.R. and Sahoo, N. and Koong, A.C. and Zhang, X. and Mohan, R.}, doi = {10.1002/mp.15370}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {49}, unique-id = {32672605}, issn = {0094-2405}, year = {2022}, eissn = {2473-4209}, pages = {497-509} } @article{MTMT:33810138, title = {Ultra-high dose rate dosimetry for pre-clinical experiments with mm-small proton fields}, url = {https://m2.mtmt.hu/api/publication/33810138}, author = {Togno, M. and Nesteruk, K.P. and Schäfer, R. and Psoroulas, S. and Meer, D. and Grossmann, M. and Christensen, J.B. and Yukihara, E.G. and Lomax, A.J. and Weber, D.C. and Safai, S.}, doi = {10.1016/j.ejmp.2022.10.019}, journal-iso = {PHYS MEDICA}, journal = {PHYSICA MEDICA-EUROPEAN JOURNAL OF MEDICAL PHYSICS}, volume = {104}, unique-id = {33810138}, issn = {1120-1797}, abstract = {Purpose: To characterize an experimental setup for ultra-high dose rate (UHDR) proton irradiations, and to address the challenges of dosimetry in millimetre-small pencil proton beams. Methods: At the PSI Gantry 1, high-energy transmission pencil beams can be delivered to biological samples and detectors up to a maximum local dose rate of ∼9000 Gy/s. In the presented setup, a Faraday cup is used to measure the delivered number of protons up to ultra-high dose rates. The response of transmission ion-chambers, as well as of different field detectors, was characterized over a wide range of dose rates using the Faraday cup as reference. Results: The reproducibility of the delivered proton charge was better than 1 % in the proposed experimental setup. EBT3 films, Al2O3:C optically stimulated luminescence detectors and a PTW microDiamond were used to validate the predicted dose. Transmission ionization chambers showed significant volume ion-recombination (>30 % in the tested conditions) which can be parametrized as a function of the maximum proton current density. Over the considered range, EBT3 films, inorganic scintillator-based screens and the PTW microDiamond were demonstrated to be dose rate independent within ±3 %, ±1.8 % and ±1 %, respectively. Conclusions: Faraday cups are versatile dosimetry instruments that can be used for dose estimation, field detector characterization and on-line dose verification for pre-clinical experiments in UHDR proton pencil beams. Among the tested detectors, the commercial PTW microDiamond was found to be a suitable option to measure real time the dosimetric properties of narrow pencil proton beams for dose rates up to 2.2 kGy/s. © 2022 Associazione Italiana di Fisica Medica e Sanitaria}, keywords = {ARTICLE; human; drug megadose; PROTON; Reproducibility of Results; reproducibility; radiation dose; Protons; radiation scattering; Dosimetry; proton radiation; photosystem I}, year = {2022}, eissn = {1724-191X}, pages = {101-111} } @article{MTMT:33423770, title = {Oxygen Monitoring in Model Solutions and In Vivo in Mice During Proton Irradiation at Conventional and FLASH Dose Rates}, url = {https://m2.mtmt.hu/api/publication/33423770}, author = {Van Slyke, Alexander L. and El Khatib, Mirna and Velalopoulou, Anastasia and Diffenderfer, Eric and Shoniyozov, Khayrullo and Kim, Michele M. and Karagounis, Ilias V and Busch, Theresa M. and Vinogradov, Sergei A. and Koch, Cameron J. and Wiersma, Rodney D.}, doi = {10.1667/RADE-21-00232.1}, journal-iso = {RADIAT RES}, journal = {RADIATION RESEARCH}, volume = {198}, unique-id = {33423770}, issn = {0033-7587}, abstract = {FLASH is a high-dose-rate form of radiation therapy that has the reported ability, compared with conventional dose rates, to spare normal tissues while being equipotent in tumor control, thereby increasing the therapeutic ratio. The mechanism underlying this normal tissue sparing effect is currently unknown, however one possibility is radiochemical oxygen depletion (ROD) during dose delivery in tissue at FLASH dose rates. In order to investigate this possibility, we used the phosphorescence quenching method to measure oxygen partial pressure before, during and after proton radiation delivery in model solutions and in normal muscle and sarcoma tumors in mice, at both conventional (Conv) (similar to 0.5 Gy/s) and FLASH (similar to 100 Gy/s) dose rates. Radiation dosimetry was determined by Advanced Markus Chamber and EBT-XL film. For solutions contained in sealed glass vials, phosphorescent probe Oxyphor PtG4 (1 mu M) was dissolved in a buffer (10 mM HEPES) containing glycerol (1 M), glucose (5 mM) and glutathione (5 mM), designed to mimic the reducing and free radical-scavenging nature of the intracellular environment. In vivo oxygen measurements were performed 24 h after injection of PtG4 into the interstitial space of either normal thigh muscle or subcutaneous sarcoma tumors in mice. The "g-value" for ROD is reported in mmHg/Gy, which represents a slight modification of the more standard chemical definition (mu M/Gy). In solutions, proton irradiation at conventional dose rates resulted in a g-value for ROD of up to 0.55 mmHg/Gy, consistent with earlier studies using X or gamma rays. At FLASH dose rates, the g-value for ROD was similar to 25% lower, 0.37 mmHg/Gy. pO(2) levels were stable after each dose delivery. For normal muscle in vivo, oxygen depletion during irradiation was counterbalanced by resupply from the vasculature. This process was fast enough to maintain tissue pO(2) virtually unchanged at Conv dose rates. However, during FLASH irradiation there was a stepwise decrease in pO(2) (g-value similar to 0.28 mmHg/Gy), followed by a rebound to the initial level after similar to 8 s. The g-values were smaller and recovery times longer in tumor tissue when compared to muscle and may be related to the lower initial endogenous pO(2) levels in the former. Considering that the FLASH effect is seen in vivo even at doses as low as 10 Gy, it is difficult to reconcile the amount of protection seen by oxygen depletion alone. However, the phosphorescence probe in our experiments was confined to the extracellular space, and it remains possible that intracellular oxygen depletion was greater than observed herein. In cell-mimicking solutions the oxygen depletion g-vales were indeed significantly higher than observed in vivo. (C) 2022 by Radiation Research Society}, year = {2022}, eissn = {1938-5404}, pages = {181-189} } @article{MTMT:33423793, title = {Proton beam dosimetry at ultra-high dose rates (FLASH): Evaluation of GAFchromic (TM) (EBT3, EBT-XD) and OrthoChromic (OC-1) film performances}, url = {https://m2.mtmt.hu/api/publication/33423793}, author = {Villoing, Daphnee and Koumeir, Charbel and Bongrand, Arthur and Guertin, Arnaud and Haddad, Ferid and Metivier, Vincent and Poirier, Freddy and Potiron, Vincent and Servagent, Noel and Supiot, Stephane and Delpon, Gregory and Chiavassa, Sophie}, doi = {10.1002/mp.15526}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {49}, unique-id = {33423793}, issn = {0094-2405}, abstract = {Purpose The ARRONAX cyclotron facility offers the possibility to deliver proton beams from low to ultra-high dose rates (UHDR). As a good control of the dosimetry is a prerequisite of UHDR experimentations, we evaluated in different conditions the usability and the dose rate dependency of several radiochromic films commonly used for dosimetry in radiotherapy. Methods We compared the dose rate dependency of three types of radiochromic films: GAFchromic (TM) EBT3 and GAFchromic (TM) EBT-XD (Ashland Inc., Wayne, NJ, USA), and OrthoChromic OC-1 (OrthoChrome Inc., Hillsborough, NJ, USA), after proton irradiations at various mean dose rates (0.25, 40, 1500, and 7500 Gy/s) and for 10 doses (2-130 Gy). We also evaluated the dose rate dependency of each film considering beam structures, from single pulse to multiple pulses with various frequencies. Results EBT3 and EBT-XD films showed differences of response between conventional (0.25 Gy/s) and UHDR (7500 Gy/s) conditions, above 10 Gy. On the contrary, OC-1 films did not present overall difference of response for doses except below 3 Gy. We observed an increase of the netOD with the mean dose rate for EBT3 and EBT-XD films. OC-1 films did not show any impact of the mean dose rate up to 7500 Gy/s, above 3 Gy. No difference was found based on the beam structure, for all three types of films. Conclusions EBT3 and EBT-XD radiochromic films should be used with caution for the dosimetry of UHDR proton beams over 10 Gy. Their overresponse, which increases with mean dose rate and dose, could lead to non-negligible overestimations of the absolute dose. OC-1 films are dose rate independent up to 7500 Gy/s in proton beams. Films response is not impacted by the beam structure. A broader investigation of the usability of OC-1 films in UHDR conditions should be conducted at intermediate and higher mean dose rates and other beam energies.}, keywords = {Film dosimetry; Proton beam therapy; FLASH; Radiochromic films; ultra-high dose rates}, year = {2022}, eissn = {2473-4209}, pages = {2732-2745} } @article{MTMT:33423752, title = {Towards clinical translation of FLASH radiotherapy}, url = {https://m2.mtmt.hu/api/publication/33423752}, author = {Vozenin, Marie-Catherine and Bourhis, Jean and Durante, Marco}, doi = {10.1038/s41571-022-00697-z}, journal-iso = {NAT REV CLIN ONCOL}, journal = {NATURE REVIEWS CLINICAL ONCOLOGY}, volume = {19}, unique-id = {33423752}, issn = {1759-4774}, abstract = {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.FLASH radiotherapy involves delivering ultra-high dose rates of radiation, which enables sustained tumour control with reduced toxicity to surrounding tissues. The authors of this Perspective describe the principles underlying FLASH radiotherapy, present the available evidence from preclinical studies testing this modality and discuss the challenges for its application in routine clinical practice.}, year = {2022}, eissn = {1759-4782}, pages = {791-803}, orcid-numbers = {Durante, Marco/0000-0002-4615-553X} } @article{MTMT:32672603, title = {FLASH Radiotherapy Using Single-Energy Proton PBS Transmission Beams for Hypofractionation Liver Cancer: Dose and Dose Rate Quantification}, url = {https://m2.mtmt.hu/api/publication/32672603}, author = {Wei, S. and Lin, H. and Choi, J.I. and Press, R.H. and Lazarev, S. and Kabarriti, R. and Hajj, C. and Hasan, S. and Chhabra, A.M. and Simone, C.B. II and Kang, M.}, doi = {10.3389/fonc.2021.813063}, journal-iso = {FRONT ONCOL}, journal = {FRONTIERS IN ONCOLOGY}, volume = {11}, unique-id = {32672603}, issn = {2234-943X}, year = {2022}, eissn = {2234-943X} } @article{MTMT:33423757, title = {Advanced pencil beam scanning Bragg peak FLASH-RT delivery technique can enhance lung cancer planning treatment outcomes compared to conventional multiple-energy proton PBS techniques}, url = {https://m2.mtmt.hu/api/publication/33423757}, author = {Wei, Shouyi and Lin, Haibo and Choi, Isabelle and Shi, Chengyu and Ii, Charles B. Simone and Kang, Minglei}, doi = {10.1016/j.radonc.2022.08.005}, journal-iso = {RADIOTHER ONCOL}, journal = {RADIOTHERAPY AND ONCOLOGY}, volume = {175}, unique-id = {33423757}, issn = {0167-8140}, abstract = {Purpose: To investigate the dosimetric characteristics between an advanced proton pencil beam scanning (PBS) Bragg peak FLASH technique and conventional PBS planning technique in lung tumors. To evaluate the "FLASHness" of single-field in a multiple-field delivery scheme for a hypofractionation regimen and move a step forward to clinical application.Methods: Single-energy PBS Bragg peak FLASH treatment plans were optimized based on a novel Bragg peak tracking technique to enable Bragg peaks to stop at the distal edge of the target. Inverse treatment planning using multiple-field optimization (MFO) can achieve sufficient FLASH dose rate and intensitymodulated proton therapy (IMPT)-equivalent dosimetric quality. The dose rate of organs-at-risk (OARs) and the target were calculated under FLASH machine parameters. A group of 10 consecutive lung SBRT patients was optimized to 34 Gy/fraction using a standard treatment of PBS technique with multiple energy layers as references to the Bragg peak plans. The dosimetric quality was compared between Bragg peak FLASH and conventional plans based on RTOG0915 dose metrics. FLASH dose rate ratios (V40Gy/s) were calculated as a metric of the FLASH-sparing effect. Results: For higher dose thresholds, the Bragg peak plans achieved greater V40Gy/s FLASH coverage for all major OARs. The V40Gy/s was close to 100% for all OARs when the dose thresholds were > 5 Gy for full plan and single beam evaluations. The less "FLASHness" region was associated with a low dose distribution, mainly occurring in the PBS field penumbra region. The conventional IMPT treatment plans yielded slightly superior target dose uniformity with a D2%(%) of 108.02% versus that of Bragg peak 300 MU plans of 111.81% (p < 0.01) and that of Bragg peak 1200 MU plans of 115.95% (p < 0.01). No significant difference in dose metrics was found between Bragg peak and IMPT treatment plans for the spinal cord, esophagus, heart, or lung-GTV (all p > 0.05).Conclusion: Hypofractionated lung Bragg peak plans can maintain comparable plan quality to conventional PBS while achieving sufficient FLASH dose rate coverage for major OARs for each field under the multiple-field delivery scheme. The novel Bragg peak FLASH technique has the potential to enhance lung cancer planning treatment outcomes compared to standard PBS treatment techniques.(c) 2022 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 175 (2022) 238-247}, keywords = {FLASH radiotherapy; lung hypofractionation; Proton pencil beam scanning; Bragg peak FLASH; Transmission FLASH; Lung stereotactic body radiation therapy}, year = {2022}, eissn = {1879-0887}, pages = {238-247} } @article{MTMT:33423791, title = {Evaluation of Two-Voltage and Three-Voltage Linear Methods for Deriving Ion Recombination Correction Factors in Proton FLASH Irradiation}, url = {https://m2.mtmt.hu/api/publication/33423791}, author = {Yin, Lingshu and Zou, Wei and Kim, Michele M. and Avery, Stephen M. and Wiersma, Rodney D. and Teo, Boon-Keng K. and Dong, Lei and Diffenderfer, Eric S.}, doi = {10.1109/TRPMS.2021.3078885}, journal-iso = {IEEE T RADIAT PLASMA}, journal = {IEEE TRANSACTIONS ON RADIATION AND PLASMA MEDICAL SCIENCES}, volume = {6}, unique-id = {33423791}, issn = {2469-7311}, abstract = {Ultrahigh dose-rate (FLASH) proton therapy is of great interest due to potential reduced normal tissue toxicities without compromising tumor-killing effect compared to current clinical proton practices. However, the ionization chamber response to proton beams under ultrahigh dose rates (>40 Gy/s) has not been thoroughly investigated. In this study, four different ion chambers (PTW 34045 Advanced Markus, PPC-40, CC-04, and CC-13 from IBA Dosimetry) were irradiated with 230 MeV proton beams at 1.5, 63.7, and 127.6 Gy/s dose rates. Theoretical values of ion recombination correction factor (k(s)) were calculated from saturation curves using Niatel's model. The theoretical k(s) values were compared to the values using the two-voltage (2V) method from standard dosimetry protocols and the three-voltage linear (3VL) method proposed by Rossomme et al. Both parallel plate chambers and CC-04 demonstrated adequate ion collection efficiency at the highest dose rate. For these three chambers, there is no statistically significant difference between theoretical k(s) values and those calculated with 2V and 3VL methods. However, significant ion recombination correction was found in CC-13 (k(s) > 1.50) when dose rate reached 63.7 Gy/s. The assumption of insignificant initial recombination in standard dosimetry protocols also underestimated the ion recombination effect in this scenario.}, keywords = {Ion recombination; FLASH; proton dosimetry; Ion chamber}, year = {2022}, eissn = {2469-7303}, pages = {263-270}, orcid-numbers = {Dong, Lei/0000-0003-2623-3198} } @article{MTMT:33423750, title = {Radiation-Induced Rescue Effect: Insights from Microbeam Experiments}, url = {https://m2.mtmt.hu/api/publication/33423750}, author = {Yu, Kwan Ngok}, doi = {10.3390/biology11111548}, journal-iso = {BIOLOGY-BASEL}, journal = {BIOLOGY-BASEL}, volume = {11}, unique-id = {33423750}, abstract = {Simple Summary The present paper introduces a radiobiological phenomenon known as the Radiation-Induced Rescue Effect (RIRE), where the radiobiological effects developed in cells irradiated with ionizing radiations are mitigated by non-irradiated cells. The primary objective of a radiotherapy treatment is to kill cancer cells with ionizing radiation while at the same time sparing the normal cells. However, RIRE was found capable of saving some of the irradiated cancer cells, so the efficacy and outcome of radiotherapy might be undermined. As such, it would be pertinent to have a better understanding of RIRE, including its underlying mechanisms and its relationships with other non-traditional radiobiological phenomena. Microbeam irradiations have some unique features that could help research on RIRE, which are explained. The paper also reviews the insights gained from previous microbeam experiments on RIRE. Some thoughts on future priorities and directions of research on RIRE exploiting unique features of microbeam radiations are presented in the last section. The present paper reviews a non-targeted effect in radiobiology known as the Radiation-Induced Rescue Effect (RIRE) and insights gained from previous microbeam experiments on RIRE. RIRE describes the mitigation of radiobiological effects in targeted irradiated cells after they receive feedback signals from co-cultured non-irradiated bystander cells, or from the medium previously conditioning those co-cultured non-irradiated bystander cells. RIRE has established or has the potential of establishing relationships with other non-traditional new developments in the fields of radiobiology, including Radiation-Induced Bystander Effect (RIBE), Radiation-Induced Field Size Effect (RIFSE) and ultra-high dose rate (FLASH) effect, which are explained. The paper first introduces RIRE, summarizes previous findings, and surveys the mechanisms proposed for observations. Unique opportunities offered by microbeam irradiations for RIRE research and some previous microbeam studies on RIRE are then described. Some thoughts on future priorities and directions of research on RIRE exploiting unique features of microbeam radiations are presented in the last section.}, keywords = {Microbeam; non-targeted effect; Radiation biology}, year = {2022}, eissn = {2079-7737} } @article{MTMT:33423775, title = {Design of static and dynamic ridge filters for FLASH-IMPT: A simulation study}, url = {https://m2.mtmt.hu/api/publication/33423775}, author = {Zhang, Guoliang and Gao, Wenchao and Peng, Hao}, doi = {10.1002/mp.15717}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {49}, unique-id = {33423775}, issn = {0094-2405}, abstract = {Purpose This paper focused on the design and optimization of ridge filter-based intensity-modulated proton therapy (IMPT), and its potential applications for FLASH. Differing from the standard pencil beam scanning (PBS) mode, no energy/layer switching is required and total treatment time can be shortened. Methods Unique dose-influence matrices were generated as a proton beam traverses through slabs of different thicknesses (i.e., modulation by different layers). To establish the references for comparison, conventional IMPT plans (single field) were created using a large-scale nonlinear solver. The spot weights from the reference IMPT plans were used as inputs for optimizing the design of ridge filters. Two designs were evaluated: model A (static) and model B (dynamic). The ridge filter designs were first verified (by GEANT4 simulation) in a water phantom and then in an H&N case. A direct comparison was made between the GEANT4 simulation results of two models and their respective references, with regard to plan quality, dose-averaged dose rate, and total treatment time. Results In both the water phantom and the H&N case, two models are able to modulate dose distributions with high conformity, showing no significant difference relative to the reference plans. Dose rate-volume histograms suggest that in order to achieve a dose rate of 40 Gy/s over 90% PTV, the beam intensity needs to be 2.5 x 10(11) protons/s for both models. For a fraction dose of 10 Gy, the total treatment time (including both irradiation time and dead time) can be shortened by a factor of 4.9 (model A) and 6.5 (model B), relative to the reference plans. Conclusion Two proposed designs (both static and dynamic) can be used for PBS-IMPT requiring no layer switching. They are promising candidates for FLASH-IMPT capable of reducing treatment time and achieving high dose rates while maintaining dose conformity simultaneously.}, keywords = {proton therapy; FLASH; Dose rate; IMPT; ridge filter}, year = {2022}, eissn = {2473-4209}, pages = {5387-5399} } @article{MTMT:33423783, title = {Radioprotective effect of X-ray abdominal FLASH irradiation: Adaptation to oxidative damage and inflammatory response may be benefiting factors}, url = {https://m2.mtmt.hu/api/publication/33423783}, author = {Zhu, Hongyu and Xie, Dehuan and Yang, Yiwei and Huang, Shaomin and Gao, Xingwang and Peng, Yinglin and Wang, Bin and Wang, Jianxin and Xiao, Dexin and Wu, Dai and Li, Changzhi and Li, Chenghua and Qian, Chao-Nan and Deng, Xiaowu}, doi = {10.1002/mp.15680}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {49}, unique-id = {33423783}, issn = {0094-2405}, abstract = {Background Ultrahigh dose-rate irradiation (FLASH-IR) was reported to be efficient in tumor control while reducing normal tissue radiotoxicity. However, the mechanism of such phenomenon is still unclear. Besides, the FLASH experiments using high energy X-ray, the most common modality in clinical radiotherapy, are rarely reported. This study aims to investigate the radiobiological response using 6 MV X-ray FLASH-IR or conventional dose-rate IR (CONV-IR). Methods The superconducting linac of Chengdu THz Free Electron Laser (CTFEL) facility was used for FLASH-IR, a diamond radiation detector and a CeBr3 scintillation detector were used to monitor the time structure and dose rate of FLASH pulses. BALB/c nude mice received whole abdominal 6 MV X-ray FLASH-IR or CONV-IR, the prescribed dose was 15 Gy or 10 Gy and the delivered absolute dose was monitored with EBT3 films. The mice were either euthanized 24 h post-IR to evaluate acute tissue responses or followed up for 6 weeks to observe late-stage responses and survival probability. Complete blood count, histological analyses, and measurement of cytokine expression and redox status were performed. Results The mean dose rate of >150 Gy/s and instantaneous dose rate of >5.5 x 10(5) Gy/s was reached in FLASH-IR at the center of mice body. After 6 weeks' follow-up of mice that received 15 Gy IR, the FLASH group showed faster body weight recovery and higher survival probability than the CONV group. Histological analysis showed that FLASH-IR induced less acute intestinal damage than CONV-IR. Complete blood count and cytokine concentration measurement found that the inflammatory blood cell counts and pro-inflammatory cytokine concentrations were elevated at the acute stage after both FLASH-IR and CONV-IR. However, FLASH irradiated mice had significantly fewer inflammatory blood cells and diminished pro-inflammatory cytokine at the late stage. Moreover, higher reactive oxygen species (ROS) signal intensities but significantly reduced lipid peroxidation were found in the FLASH group than in the CONV group in the acute stage. Conclusions The radioprotective effect of 6 MV X-ray FLASH-IR was observed. The differences in inflammatory responses and redox status between the two groups may be the factors responsible for reduced radiotoxicities following FLASH-IR. Further studies are required to thoroughly evaluate the impact of ROS on FLASH effect.}, keywords = {RADIOTHERAPY; FLASH; ultrahigh dose rate; radioprotective effect}, year = {2022}, eissn = {2473-4209}, pages = {4812-4822} } @article{MTMT:33810140, title = {A phenomenological model of proton FLASH oxygen depletion effects depending on tissue vasculature and oxygen supply}, url = {https://m2.mtmt.hu/api/publication/33810140}, author = {Zou, W. and Kim, H. and Diffenderfer, E.S. and Carlson, D.J. and Koch, C.J. and Xiao, Y. and Teo, B.K. and Kim, M.M. and Metz, J.M. and Fan, Y. and Maity, A. and Koumenis, C. and Busch, T.M. and Wiersma, R. and Cengel, K.A. and Dong, L.}, doi = {10.3389/fonc.2022.1004121}, journal-iso = {FRONT ONCOL}, journal = {FRONTIERS IN ONCOLOGY}, volume = {12}, unique-id = {33810140}, issn = {2234-943X}, abstract = {Introduction: Radiation-induced oxygen depletion in tissue is assumed as a contributor to the FLASH sparing effects. In this study, we simulated the heterogeneous oxygen depletion in the tissue surrounding the vessels and calculated the proton FLASH effective-dose-modifying factor (FEDMF), which could be used for biology-based treatment planning. Methods: The dose and dose-weighted linear energy transfer (LET) of a small animal proton irradiator was simulated with Monte Carlo simulation. We deployed a parabolic partial differential equation to account for the generalized radiation oxygen depletion, tissue oxygen diffusion, and metabolic processes to investigate oxygen distribution in 1D, 2D, and 3D solution space. Dose and dose rates, particle LET, vasculature spacing, and blood oxygen supplies were considered. Using a similar framework for the hypoxic reduction factor (HRF) developed previously, the FEDMF was derived as the ratio of the cumulative normoxic-equivalent dose (CNED) between CONV and UHDR deliveries. Results: Dynamic equilibrium between oxygen diffusion and tissue metabolism can result in tissue hypoxia. The hypoxic region displayed enhanced radio-resistance and resulted in lower CNED under UHDR deliveries. In 1D solution, comparing 15 Gy proton dose delivered at CONV 0.5 and UHDR 125 Gy/s, 61.5% of the tissue exhibited ≥20% FEDMF at 175 μm vasculature spacing and 18.9 μM boundary condition. This percentage reduced to 34.5% and 0% for 8 and 2 Gy deliveries, respectively. Similar trends were observed in the 3D solution space. The FLASH versus CONV differential effect remained at larger vasculature spacings. A higher FLASH dose rate showed an increased region with ≥20% FEDMF. A higher LET near the proton Bragg peak region did not appear to alter the FLASH effect. Conclusion: We developed 1D, 2D, and 3D oxygen depletion simulation process to obtain the dynamic HRF and derive the proton FEDMF related to the dose delivery parameters and the local tissue vasculature information. The phenomenological model can be used to simulate or predict FLASH effects based on tissue vasculature and oxygen concentration data obtained from other experiments. Copyright © 2022 Zou, Kim, Diffenderfer, Carlson, Koch, Xiao, Teo, Kim, Metz, Fan, Maity, Koumenis, Busch, Wiersma, Cengel and Dong.}, keywords = {ARTICLE; MOUSE; OXYGEN; nonhuman; animal tissue; animal model; animal experiment; simulation; PROTON; PROTON; scanning electron microscopy; vascularization; phenomenology; radiation dose; overall survival; treatment planning; mathematical model; endothelium cell; finite element analysis; micro-computed tomography; HYPOXIA; radiosensitivity; proton therapy; Linear Energy Transfer; VASCULATURE; Oxygen Concentration; spatiotemporal analysis; Oxygen diffusion; oxygen supply; oxygen blood level; tissue metabolism; Oxygen depletion; procedures, parameters and devices; digital imaging and communications in medicine; FLASH effect; hypoxic reduction factor; hypoxic reduction factor; cumulative normoxic equivalent dose; FLASH effective dose modifying factor; proton flash radiotherapy; ultra high dose rate}, year = {2022}, eissn = {2234-943X} } @article{MTMT:32381414, title = {Al2O3:C optically stimulated luminescence dosimeters (OSLDs) for ultra-high dose rate proton dosimetry}, url = {https://m2.mtmt.hu/api/publication/32381414}, author = {Christensen, Jeppe Brage and Togno, Michele and Nesteruk, Konrad Pawel and Psoroulas, Serena and Meer, David and Weber, Damien Charles and Lomax, Tony and Yukihara, Eduardo G. and Safai, Sairos}, doi = {10.1088/1361-6560/abe554}, journal-iso = {PHYS MED BIOL}, journal = {PHYSICS IN MEDICINE AND BIOLOGY}, volume = {66}, unique-id = {32381414}, issn = {0031-9155}, abstract = {The response of Al2O3:C optically stimulated luminescence detectors (OSLDs) was investigated in a 250 MeV pencil proton beam. The OSLD response was mapped for a wide range of average dose rates up to 9000 Gy s(-1), corresponding to a similar to 150 kGy s(-1) instantaneous dose rate in each pulse. Two setups for ultra-high dose rate (FLASH) experiments are presented, which enable OSLDs or biological samples to be irradiated in either water-filled vials or cylinders. The OSLDs were found to be dose rate independent for all dose rates, with an average deviation <1% relative to the nominal dose for average dose rates of (1-1000) Gy s(-1) when irradiated in the two setups. A third setup for irradiations in a 9000 Gy s(-1) pencil beam is presented, where OSLDs are distributed in a 3 x 4 grid. Calculations of the signal averaging of the beam over the OSLDs were in agreement with the measured response at 9000 Gy s(-1). Furthermore, a new method was presented to extract the beam spot size of narrow pencil beams, which is in agreement within a standard deviation with results derived from radiochromic films. The Al2O3:C OSLDs were found applicable to support radiobiological experiments in proton beams at ultra-high dose rates.}, keywords = {Al2O3; C; optically stimulated luminescence; FLASH; proton dosimetry; ultra-high dose rate}, year = {2021}, eissn = {1361-6560}, orcid-numbers = {Christensen, Jeppe Brage/0000-0002-6894-381X; Togno, Michele/0000-0001-6840-814X; Psoroulas, Serena/0000-0001-7576-3238} } @article{MTMT:32381407, title = {Spread-out Bragg peak proton FLASH irradiation using a clinical synchrocyclotron: Proof of concept and ion chamber characterization}, url = {https://m2.mtmt.hu/api/publication/32381407}, author = {Darafsheh, Arash and Hao, Yao and Zhao, Xiandong and Zwart, Townsend and Wagner, Miles and Evans, Tucker and Reynoso, Francisco and Zhao, Tianyu}, doi = {10.1002/mp.15021}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {48}, unique-id = {32381407}, issn = {0094-2405}, abstract = {Purpose The purpose of this work is to (a) demonstrate the feasibility of delivering a spread-out Bragg peak (SOBP) proton beam in ultra-high dose rate (FLASH) using a proton therapy synchrocyclotron as a major step toward realizing an experimental platform for preclinical studies, and (b) evaluate the response of four models of ionization chambers in such a radiation field. Methods A clinical Mevion HYPERSCAN(R) synchrocyclotron was adjusted for ultra-high dose rate proton delivery. Protons with nominal energy of 230 MeV were delivered in pulses with temporal width ranging from 12.5 mu s to 24 mu s spanning from conventional to FLASH dose rates. A boron carbide absorber and a range modulator block were placed in the beam path for range modulation and creating an SOBP dose profile. The radiation field was defined by a brass aperture with 11 mm diameter. Two Faraday cups were used to determine the number of protons per pulse at various dose rates. The dosimetric response of two cylindrical (IBA CC04 and CC13) and two plane-parallel (IBA PPC05 and PTW Advanced Markus(R)) ionization chambers were evaluated. The dose rate was measured using the plane-parallel ionization chambers. The integral depth dose (IDD) was measured with a PTW Bragg Peak(R) ionization chamber. The lateral beam profile was measured with EBT-XD radiochromic film. Monte Carlo simulation was performed in TOPAS as the secondary check for the measurements and as a tool for further optimization of the range modulators' design. Results Faraday cups measurement showed that the maximum protons per pulse is 39.9 pC at 24 mu s pulse width. A good agreement between the measured and simulated IDD and lateral beam profiles was observed. The cylindrical ionization chambers showed very high ion recombination and deemed not suitable for absolute dosimetry at ultra-high dose rates. The average dose rate measured using the PPC05 ionization chamber was 163 Gy/s at the pristine Bragg peak and 126 Gy/s at 1 cm depth for the SOBP beam. The SOBP beam range and modulation were measured 24.4 mm and 19 mm, respectively. The pristine Bragg peak beam had 25.6 mm range. Simulation results showed that the IDD and profile flatness can be improved by the cavity diameter of the range modulator and the number of scanned spots, respectively. Conclusions Feasibility of delivering protons in an SOBP pattern with >100 Gy/s average dose rate using a clinical synchrocyclotron was demonstrated. The dose heterogeneity can be improved through optimization of the range modulator and number of delivered spots. Plane-parallel chambers with smaller gap between electrodes are more suitable for FLASH dosimetry compared to the other ion chambers used in this work.}, keywords = {Monte Carlo; proton therapy; FLASH; synchrocyclotron; ultra-high dose rate}, year = {2021}, eissn = {2473-4209}, pages = {4472-4484} } @article{MTMT:32381421, title = {Early Toxicities After High Dose Rate Proton Therapy in Cancer Treatments}, url = {https://m2.mtmt.hu/api/publication/32381421}, author = {Doyen, Jerome and Sunyach, Marie-Pierre and Almairac, Fabien and Bourg, Veronique and Naghavi, Arash O. and Duhil de Benaze, Gwenaelle and Claren, Audrey and Padovani, Laetitia and Benezery, Karen and Noel, Georges and Hannoun-Levi, Jean-Michel and Guedea, Ferran and Giralt, Jordi and Vidal, Marie and Baudin, Guillaume and Opitz, Lucas and Claude, Line and Bondiau, Pierre-Yves}, doi = {10.3389/fonc.2020.613089}, journal-iso = {FRONT ONCOL}, journal = {FRONTIERS IN ONCOLOGY}, volume = {10}, unique-id = {32381421}, issn = {2234-943X}, abstract = {BackgroundThe conventional dose rate of radiation therapy is 0.01-0.05 Gy per second. According to preclinical studies, an increased dose rate may offer similar anti-tumoral effect while dramatically improving normal tissue protection. This study aims at evaluating the early toxicities for patients irradiated with high dose rate pulsed proton therapy (PT).Materials and MethodsA single institution retrospective chart review was performed for patients treated with high dose rate (10 Gy per second) pulsed proton therapy, from September 2016 to April 2020. This included both benign and malignant tumors with >= 3 months follow-up, evaluated for acute (<= 2 months) and subacute (>2 months) toxicity after the completion of PT.ResultsThere were 127 patients identified, with a median follow up of 14.8 months (3-42.9 months). The median age was 55 years (1.6-89). The cohort most commonly consisted of benign disease (55.1%), cranial targets (95.1%), and were treated with surgery prior to PT (56.7%). There was a median total PT dose of 56 Gy (30-74 Gy), dose per fraction of 2 Gy (1-3 Gy), and CTV size of 47.6 ml (5.6-2,106.1 ml). Maximum acute grade >= 2 toxicity were observed in 49 (38.6%) patients, of which 8 (6.3%) experienced grade 3 toxicity. No acute grade 4 or 5 toxicity was observed. Maximum subacute grade 2, 3, and 4 toxicity were discovered in 25 (19.7%), 12 (9.4%), and 1 (0.8%) patient(s), respectively.ConclusionIn this cohort, utilizing high dose rate proton therapy (10 Gy per second) did not result in a major decrease in acute and subacute toxicity. Longer follow-up and comparative studies with conventional dose rate are required to evaluate whether this approach offers a toxicity benefit.}, keywords = {CANCER; TOXICITY; proton therapy; Early; High dose rate; subacute}, year = {2021}, eissn = {2234-943X}, orcid-numbers = {Vidal, Marie/0000-0001-9289-2437} } @article{MTMT:32381404, title = {Quantitative Assessment of 3D Dose Rate for Proton Pencil Beam Scanning FLASH Radiotherapy and Its Application for Lung Hypofractionation Treatment Planning}, url = {https://m2.mtmt.hu/api/publication/32381404}, author = {Kang, Minglei and Wei, Shouyi and Choi, J. Isabelle and Simone, Charles B. and Lin, Haibo}, doi = {10.3390/cancers13143549}, journal-iso = {CANCERS}, journal = {CANCERS}, volume = {13}, unique-id = {32381404}, abstract = {Simple Summary As pencil beam scanning (PBS) proton therapy delivers doses via spot-scanning, the dose rate quantification is very different from the electron and scattering proton techniques in FLASH radiotherapy. Currently, there is no consensus on the definition of the PBS proton therapy dose rate calculation for normal tissues and targets. This study focuses on the dose rate quantification of organs-at-risk and target based on three proposed dose rate metrics using proton transmission beams. The differences in dose rate metrics have led a large variation for organs-at-risk dose rate assessment and may result in a different correlation expectation between dose rate and biological effects for pre-clinical experiments. An awareness of the differences in proton PBS dose rate calculation is important to design experiments and clinical trials to uncover FLASH-RT's biological and physiological mechanisms. To quantitatively assess target and organs-at-risk (OAR) dose rate based on three proposed proton PBS dose rate metrics and study FLASH intensity-modulated proton therapy (IMPT) treatment planning using transmission beams. An in-house FLASH planning platform was developed to optimize transmission (shoot-through) plans for nine consecutive lung cancer patients previously planned with proton SBRT. Dose and dose rate calculation codes were developed to quantify three types of dose rate calculation methods (dose-averaged dose rate (DADR), average dose rate (ADR), and dose-threshold dose rate (DTDR)) based on both phantom and patient treatment plans. Two different minimum MU/spot settings were used to optimize two different dose regimes, 34-Gy in one fraction and 45-Gy in three fractions. The OAR sparing and target coverage can be optimized with good uniformity (hotspot < 110% of prescription dose). ADR, accounting for the spot dwelling and scanning time, gives the lowest dose rate; DTDR, not considering this time but a dose-threshold, gives an intermediate dose rate, whereas DADR gives the highest dose rate without considering any time or dose-threshold. All three dose rates attenuate along the beam direction, and the highest dose rate regions often occur on the field edge for ADR and DTDR, whereas DADR has a better dose rate uniformity. The differences in dose rate metrics have led a large variation for OARs dose rate assessment, posing challenges to FLASH clinical implementation. This is the first attempt to study the impact of the dose rate models, and more investigations and evidence for the details of proton PBS FLASH parameters are needed to explore the correlation between FLASH efficacy and the dose rate metrics.}, keywords = {proton therapy; Dose rate; pencil beam scanning; FLASH radiotherapy; lung hypofractionation}, year = {2021}, eissn = {2072-6694} } @article{MTMT:32381400, title = {Comparison of FLASH Proton Entrance and the Spread-Out Bragg Peak Dose Regions in the Sparing of Mouse Intestinal Crypts and in a Pancreatic Tumor Model}, url = {https://m2.mtmt.hu/api/publication/32381400}, author = {Kim, Michele M. and Verginadis, Ioannis I. and Goia, Denisa and Haertter, Allison and Shoniyozov, Khayrullo and Zou, Wei and Maity, Amit and Busch, Theresa M. and Metz, James M. and Cengel, Keith A. and Dong, Lei and Koumenis, Costas and Diffenderfer, Eric S.}, doi = {10.3390/cancers13164244}, journal-iso = {CANCERS}, journal = {CANCERS}, volume = {13}, unique-id = {32381400}, abstract = {Simple Summary FLASH radiotherapy is a treatment technique of interest that involves radiation delivered at ultra-high dose rates >100 times faster than traditional radiation therapy, which has been shown to spare radiation damage to normal tissue but maintain tumor control capabilities. Proton therapy uses spread-out proton Bragg peaks to reduce radiation dose to normal tissue by directing the highest dose of radiation to the tumor volume. In this study, irradiation of the whole abdomen of mice was performed with proton beams at FLASH dose rates in order to investigate the normal tissue sparing capabilities of the spread-out Bragg peak compared to the entrance region of the proton depth dose curve. Ultra-high dose rate FLASH proton radiotherapy (F-PRT) has been shown to reduce normal tissue toxicity compared to standard dose rate proton radiotherapy (S-PRT) in experiments using the entrance portion of the proton depth dose profile, while proton therapy uses a spread-out Bragg peak (SOBP) with unknown effects on FLASH toxicity sparing. To investigate, the biological effects of F-PRT using an SOBP and the entrance region were compared to S-PRT in mouse intestine. In this study, 8-10-week-old C57BL/6J mice underwent 15 Gy (absorbed dose) whole abdomen irradiation in four groups: (1) SOBP F-PRT, (2) SOBP S-PRT, (3) entrance F-PRT, and (4) entrance S-PRT. Mice were injected with EdU 3.5 days after irradiation, and jejunum segments were harvested and preserved. EdU-positive proliferating cells and regenerated intestinal crypts were quantified. The SOBP had a modulation (width) of 2.5 cm from the proximal to distal 90%. Dose rates with a SOBP for F-PRT or S-PRT were 108.2 +/- 8.3 Gy/s or 0.82 +/- 0.14 Gy/s, respectively. In the entrance region, dose rates were 107.1 +/- 15.2 Gy/s and 0.83 +/- 0.19 Gy/s, respectively. Both entrance and SOBP F-PRT preserved a significantly higher number of EdU + /crypt cells and percentage of regenerated crypts compared to S-PRT. Moreover, tumor growth studies showed no difference between SOBP and entrance for either of the treatment modalities.}, keywords = {spread-out Bragg peak; proton FLASH radiation}, year = {2021}, eissn = {2072-6694} } @article{MTMT:32381413, title = {FLASH proton irradiation setup with a modulator wheel for a single mouse eye}, url = {https://m2.mtmt.hu/api/publication/32381413}, author = {Kourkafas, Georgios and Bundesmann, Juergen and Fanselow, Timo and Denker, Andrea and Ehrhardt, Vincent Henrique and Gollrad, Johannes and Budach, Volker and Weber, Andreas and Kociok, Norbert and Joussen, Antonia M. and Heufelder, Jens}, doi = {10.1002/mp.14730}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {48}, unique-id = {32381413}, issn = {0094-2405}, abstract = {Purpose Recent studies indicate that FLASH irradiation, which involves ultra-high dose rates in a short time window (usually >40 Gy/s in <500 ms), might be equally efficient against tumors but less harmful to healthy tissues, compared to conventional irradiation with the same total dose. Aiming to verify the latter claim for ocular proton radiotherapy, in vivo experiments with mice are being carried out by Charite - Universitatsmedizin Berlin. This work presents the implemented setup for delivering FLASH proton radiation to a single eye of mice at the Helmholtz-Zentrum Berlin fur Materialien und Energie (HZB).Materials and methods The HZB cyclotron is tuned to provide a high-intensity 68 MeV focused proton beam. Outside the vacuum beamline, the protons hit a single scatterer, which also serves as range shifter, and a rotating modulator wheel, which produces a flat depth-dose distribution. Two transmission ionization chambers in between, read out by fast electronics, are used as dose monitors for triggering an in-vacuum beam shutter, which blocks the beam once the desired dose has been delivered. A collimating aperture shapes the radiation field at the isocenter, which is measured by a radioluminescent screen and a CCD camera. At the same position, a parallel-plate ionization chamber of type Advanced Markus(R) is used for absolute dosimetry and characterization of the spread-out Bragg peak inside a water phantom. A thin-foil mirror of adjustable tilt in the beam path assists the correct alignment of the target through side illumination. Radiochromic films of type EBT3 are used to supplement the dosimetry and assist the alignment.Results A dose rate of 75 Gy/s has been measured, delivering within 200 ms 15 Gy (RBE) with a reproducibility better than +/- 1%. A depth-dose curve with a range of 5.2 mm in water, 0.9 mm distal fall-off (90%-10%), and +/- 2.5% ripple has been demonstrated, with a PTV of 6.3 mm diameter, 1.7 mm lateral penumbra (90%-10%), 8% uniformity, and 3% symmetry.Conclusions The implemented setup is able to accommodate ocular irradiation of narcotized mice with protons, targeting selectively the left or the right eye, under conventional and FLASH conditions. Switching between these two modes can be done within half an hour, including the calibration of the dose monitors and the verification of the dose delivery. Further upgrades are planned after the completion of the on-going experiment.}, keywords = {MICE; ocular FLASH proton irradiation; range modulator wheel}, year = {2021}, eissn = {2473-4209}, pages = {1839-1845}, orcid-numbers = {Kourkafas, Georgios/0000-0002-0881-504X; Heufelder, Jens/0000-0002-1782-7376} } @article{MTMT:32381408, title = {Deciphering Time-Dependent DNA Damage Complexity, Repair, and Oxygen Tension: A Mechanistic Model for FLASH-Dose-Rate Radiation Therapy}, url = {https://m2.mtmt.hu/api/publication/32381408}, author = {Liew, Hans and Mein, Stewart and Dokic, Ivana and Haberer, Thomas and Debus, Jurgen and Abdollahi, Amir and Mairani, Andrea}, doi = {10.1016/j.ijrobp.2020.12.048}, journal-iso = {INT J RADIAT ONCOL}, journal = {INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS}, volume = {110}, unique-id = {32381408}, issn = {0360-3016}, abstract = {Purpose: Irradiation with ultrahigh dose rates (FLASH) has reemerged as a promising radiation therapy approach to effectively lower potential damage burden on normal tissue without sacrificing tumor control. However, the large number of recent FLASH studies have been conducted under vastly different experimental conditions and circumstances (ie, investigated biological endpoint, radiation quality, and environmental oxygen level), with unverified biological mechanisms of action and unexplored interplay effect of the main dependencies. To facilitate radiobiological investigation of FLASH phenomena and assessment of clinical applicability, we present an extension of the mechanistic radiobiological model "UNified and VER-Satile bio response Engine" (UNIVERSE).Methods and Materials: The dynamic (time-dependent) extension of UNIVERSE was developed incorporating fundamental temporal mechanisms necessary for dose-rate effect prediction, ie, DNA damage repair kinetics [DDRK], oxygen depletion and reoxygenation during irradiation. Model performance in various experimental conditions is validated based on a large panel of in vitro and in vivo data from the literature. The effect of dose, dose rate, oxygen tension, tissue-type, beam quality and DDRK is analyzed.Results: UNIVERSE adequately reproduces dose-, dose-rate- and oxygen tension-dependent influence on cell killing. For the studied systems, results indicate that the extent of cell/tissue sparing effect, if present at all, strongly depends on DDRK and beam quality used for reference conventional irradiation. A validated mechanistic framework for predicting clinically relevant endpoints comparing conventional and FLASH high-dose-rate effect has been successfully established, relying on time-dependent processing of radiation-induced damage classes taking variable oxygen tension into account.Conclusions: Highlighted by UNIVERSE itself, the multidimensional nature of this relative sparing effect using high-dose-rate radiation compared with conventional means underlines the importance of robust quantification of biophysical characteristics and consistent, well-documented experimental conditions both in vitro and in vivo before clinical translation. To further elucidate underlying mechanisms and appraise clinical viability, UNIVERSE can provide reliable prediction for biophysical investigations of radiation therapy using ultrahigh dose rate. (C) 2021 Elsevier Inc. All rights reserved.}, year = {2021}, eissn = {1879-355X}, pages = {574-586} } @article{MTMT:32381409, title = {FLASH Radiotherapy: History and Future}, url = {https://m2.mtmt.hu/api/publication/32381409}, author = {Lin, Binwei and Gao, Feng and Yang, Yiwei and Wu, Dai and Zhang, Yu and Feng, Gang and Dai, Tangzhi and Du, Xiaobo}, doi = {10.3389/fonc.2021.644400}, journal-iso = {FRONT ONCOL}, journal = {FRONTIERS IN ONCOLOGY}, volume = {11}, unique-id = {32381409}, issn = {2234-943X}, abstract = {The biological effects of radiation dose to organs at risk surrounding tumor target volumes are a major dose-limiting constraint in radiotherapy. This can mean that the tumor cannot be completely destroyed, and the efficacy of radiotherapy will be decreased. Thus, ways to reduce damage to healthy tissue has always been a topic of particular interest in radiotherapy research. Modern radiotherapy technologies such as helical tomotherapy (HT), intensity-modulated radiation therapy (IMRT), and proton radiotherapy can reduce radiation damage to healthy tissues. Recent outcomes of animal experiments show that FLASH radiotherapy (FLASH-RT) can reduce radiation-induced damage in healthy tissue without decreasing antitumor effectiveness. The very short radiotherapy time compared to that of conventional dose-rate radiotherapy is another advantage of FLASH-RT. The first human patient received FLASH-RT in Switzerland in 2018. FLASH-RT may become one of the main radiotherapy technologies in clinical applications in the future. We summarize the history of the development of FLASH-RT, its mechanisms, its influence on radiotherapy, and its future.}, keywords = {MECHANISMS; history; FUTURE; FLASH radiotherapy; conventional dose-rate radiotherapy}, year = {2021}, eissn = {2234-943X} } @article{MTMT:32672611, title = {Application of FLASH radiotherapy with an ultra-high dose rate in malignant tumor}, url = {https://m2.mtmt.hu/api/publication/32672611}, author = {Luo, H. and Yan, M. and Jia, X. and Zhao, R. and Wang, X. and Mao, R. and Ma, L. and Lei, H. and Ge, H.}, doi = {10.3760/cma.j.issn.0254-5098.2021.08.013}, journal-iso = {CHINESE JOURNAL OF RADIOLOGICAL MEDICINE AND PROTECTION}, journal = {ZHONGHUA FANGSHE YIXUE YU FANGHU ZAZHI / CHINESE JOURNAL OF RADIOLOGICAL MEDICINE AND PROTECTION}, volume = {41}, unique-id = {32672611}, issn = {0254-5098}, year = {2021}, pages = {636-640} } @article{MTMT:32381419, title = {ROAD: ROtational direct Aperture optimization with a Decoupled ring-collimator for FLASH radiotherapy}, url = {https://m2.mtmt.hu/api/publication/32381419}, author = {Lyu, Qihui and Neph, Ryan and O'Connor, Daniel and Ruan, Dan and Boucher, Salime and Sheng, Ke}, doi = {10.1088/1361-6560/abcbd0}, journal-iso = {PHYS MED BIOL}, journal = {PHYSICS IN MEDICINE AND BIOLOGY}, volume = {66}, unique-id = {32381419}, issn = {0031-9155}, abstract = {Ultra-high dose rate in radiotherapy (FLASH) has been shown to increase the therapeutic index with markedly reduced normal tissue toxicity and the same or better tumor cell killing. The challenge to achieve FLASH using x-rays, besides developing a high output linac, is to intensity-modulate the high-dose-rate x-rays so that the biological gain is not offset by the lack of physical dose conformity. In this study, we develop the ROtational direct Aperture optimization with a Decoupled ring-collimator (ROAD) to achieve simultaneous ultrafast delivery and complex dose modulation. The ROAD design includes a fast-rotating slip-ring linac and a decoupled collimator-ring with 75 pre-shaped multi-leaf-collimator (MLC) modules. The ring-source rotates at 1 rotation per second (rps) clockwise while the ring-collimator is either static or rotating at 1 rps counterclockwise, achieving 75 (ROAD-75) or 150 (ROAD-150) equal-angular beams for one full arc. The Direct Aperture Optimization (DAO) for ROAD was formulated to include a least-square dose fidelity, an anisotropic total variation term, and a single segment term. The FLASH dose (FD) and FLASH biological equivalent dose (FBED) were computed voxelwise, with the latter using a spatiotemporal model accounting for radiolytic oxygen depletion. ROAD was compared with clinical volumetric modulated arc therapy (VMAT) on a brain, a lung, a prostate, and a head and neck cancer patient. The mean dose rate of ROAD-75 and ROAD-150 are 76.2 Gy s(-1) and 112 Gy s(-1) respectively to deliver 25 Gy single-fraction dose in 1 s. With improved PTV homogeneity, ROAD-150 reduced (max, mean) OAR physical dose by (4.8 Gy, 6.3 Gy). The average R50 and integral dose of (VMAT, ROAD-75, ROAD-150) are (4.8, 3.2, 3.2) and (89, 57, 56) GyxLiter, respectively. The FD and FBED showed model dependent FLASH effects. The novel ROAD design achieves ultrafast dose delivery and improves physical dosimetry compared with clinical VMAT, providing a potentially viable engineering solution for x-ray FLASH radiotherapy.}, keywords = {FLASH; ultra-high dose rate in radiotherapy; ROtational direct Aperture optimization with a Decoupled ring-collimator (ROAD); direct aperture optimization (DAO); FLASH biological equivalent dose (FBED); FLASH dose (FD)}, year = {2021}, eissn = {1361-6560}, orcid-numbers = {Lyu, Qihui/0000-0002-1835-3870; Neph, Ryan/0000-0002-8176-6723; O'Connor, Daniel/0000-0001-7378-1125} } @article{MTMT:32381416, title = {Translational Research in FLASH Radiotherapy-From Radiobiological Mechanisms to In Vivo Results}, url = {https://m2.mtmt.hu/api/publication/32381416}, author = {Marcu, Loredana G. and Bezak, Eva and Peukert, Dylan D. and Wilson, Puthenparampil}, doi = {10.3390/biomedicines9020181}, journal-iso = {BIOMEDICINES}, journal = {BIOMEDICINES}, volume = {9}, unique-id = {32381416}, abstract = {FLASH radiotherapy, or the administration of ultra-high dose rate radiotherapy, is a new radiation delivery method that aims to widen the therapeutic window in radiotherapy. Thus far, most in vitro and in vivo results show a real potential of FLASH to offer superior normal tissue sparing compared to conventionally delivered radiation. While there are several postulations behind the differential behaviour among normal and cancer cells under FLASH, the full spectra of radiobiological mechanisms are yet to be clarified. Currently the number of devices delivering FLASH dose rate is few and is mainly limited to experimental and modified linear accelerators. Nevertheless, FLASH research is increasing with new developments in all the main areas: radiobiology, technology and clinical research. This paper presents the current status of FLASH radiotherapy with the aforementioned aspects in mind, but also to highlight the existing challenges and future prospects to overcome them.}, keywords = {THERAPEUTIC WINDOW; Normal tissue sparing; ultra-high dose rate; FLASH-radiotherapy; FLASH-radiobiology}, year = {2021}, eissn = {2227-9059}, orcid-numbers = {Bezak, Eva/0000-0002-1315-1735; Wilson, Puthenparampil/0000-0002-0448-7691} } @article{MTMT:32381410, title = {Letter in Response to Doyen et al., "Early Toxicities After High Dose Rate Proton Therapy in Cancer Treatments"}, url = {https://m2.mtmt.hu/api/publication/32381410}, author = {Montay-Gruel, Pierre and Vozenin, Marie-Catherine and Limoli, Charles L.}, doi = {10.3389/fonc.2021.687593}, journal-iso = {FRONT ONCOL}, journal = {FRONTIERS IN ONCOLOGY}, volume = {11}, unique-id = {32381410}, issn = {2234-943X}, keywords = {PROTON; lung cancer; High dose rate; FLASH; normal tissue toxicity}, year = {2021}, eissn = {2234-943X} } @article{MTMT:32381402, title = {Commissioning of a clinical pencil beam scanning proton therapy unit for ultra-high dose rates (FLASH)}, url = {https://m2.mtmt.hu/api/publication/32381402}, author = {Nesteruk, Konrad P. and Togno, Michele and Grossmann, Martin and Lomax, Anthony J. and Weber, Damien C. and Schippers, Jacobus M. and Safai, Sairos and Meer, David and Psoroulas, Serena}, doi = {10.1002/mp.14933}, journal-iso = {MED PHYS}, journal = {MEDICAL PHYSICS}, volume = {48}, unique-id = {32381402}, issn = {0094-2405}, abstract = {Purpose The purpose of this work was to provide a flexible platform for FLASH research with protons by adapting a former clinical pencil beam scanning gantry to irradiations with ultra-high dose rates.Methods PSI Gantry 1 treated patients until December 2018. We optimized the beamline parameters to transport the 250 MeV beam extracted from the PSI COMET accelerator to the treatment room, maximizing the transmission of beam intensity to the sample. We characterized a dose monitor on the gantry to ensure good control of the dose, delivered in spot-scanning mode. We characterized the beam for different dose rates and field sizes for transmission irradiations. We explored scanning possibilities in order to enable conformal irradiations or transmission irradiations of large targets (with transverse scanning).Results We achieved a transmission of 86% from the cyclotron to the treatment room. We reached a peak dose rate of 9000 Gy/s at 3 mm water equivalent depth, along the central axis of a single pencil beam. Field sizes of up to 5 x 5 mm(2) were achieved for single-spot FLASH irradiations. Fast transverse scanning allowed to cover a field of 16 x 1.2 cm(2). With the use of a nozzle-mounted range shifter, we are able to span depths in water ranging from 19.6 to 37.9 cm. Various dose levels were delivered with precision within less than 1%.Conclusions We have realized a proton FLASH irradiation setup able to investigate continuously a wide dose rate spectrum, from 1 to 9000 Gy/s in single-spot irradiation as well as in the pencil beam scanning mode. As such, we have developed a versatile test bench for FLASH research.}, keywords = {proton therapy; FLASH; pencil beam scanning; Gantry; ultra‐; high dose rates}, year = {2021}, eissn = {2473-4209}, pages = {4017-4026}, orcid-numbers = {Togno, Michele/0000-0001-6840-814X; Psoroulas, Serena/0000-0001-7576-3238} } @article{MTMT:31903931, title = {Electron dose rate and oxygen depletion protect zebrafish embryos from radiation damage}, url = {https://m2.mtmt.hu/api/publication/31903931}, author = {Pawelke, Jörg and Brand, Michael and Hans, Stefan and Hideghéty, Katalin and Karsch, Leonhard and Lessmann, Elisabeth and Löck, Steffen and Schürer, Michael and Szabó, Emilia Rita and Beyreuther, Elke}, doi = {10.1016/j.radonc.2021.02.003}, journal-iso = {RADIOTHER ONCOL}, journal = {RADIOTHERAPY AND ONCOLOGY}, volume = {158}, unique-id = {31903931}, issn = {0167-8140}, year = {2021}, eissn = {1879-0887}, pages = {7-12}, orcid-numbers = {Brand, Michael/0000-0001-5711-6512; Hideghéty, Katalin/0000-0001-7080-2365; Löck, Steffen/0000-0002-7017-3738; Szabó, Emilia Rita/0000-0003-3611-2066; Beyreuther, Elke/0000-0002-0582-1444} }