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[Display omitted] • A remote sensing method to inform chemical changes under ionizing radiation. • Probing nanostructures under irradiation with Cherenkov emissions. • Cathodoluminescence. • Material characterization via Cherenkov and Cathodoluminescence. • Chemical sensing for industrial and health applications of ionizing radiation. Technologies leveraging the spectroscopic and photometric properties of Cherenkov radiation have been, by our estimation, tragically underdeveloped. This work introduces a novel method of material characterization via Cherenkov and in general ionizing particle radiation induced Luminescence produced by a material under irradiation. Wavelengths corresponding to the localized plasmon resonance frequencies of extremely small particle-concentrations of dispersed gold nanostructures were extracted using the luminescence produced in samples under pulses of electron irradiation. Such measurements are fast, simple, and consistent with standard methods of materials characterization in solution, demonstrating the potential of charged particle induced luminescence Emissions as a general-use remote chemical probe for nuclear applications. [ABSTRACT FROM AUTHOR]

Recently, as the biological effects of ultrahigh-dose-rate radiation therapy (flash RT) have been verified, many kinds of research on the clinical application of high-dose-rate radiation therapy have been performed. Moreover, various studies are being performed to determine the absorbed dose in the volume of cancers. In this study, to evaluate the absorbed dose of the human body during high-dose-rate radiation therapy, a dosimeter system was developed using a tissue equivalent plastic scintillator having the same geometric structure as the Farmer-type ionization chamber, and its characteristics were evaluated. The plastic scintillator was based on PMMA, and PPO was used as the primary scintillator and POPOP as the wavelength shifter. An Irgacure 819 photo-initiator and a Hg lamp were used to polymerize of PMMA plastic scintillator. The fabricated plastic scintillator was characterized for conventional LINAC X-ray and 45 MeV proton beams. The results of this study combined with 3D printing technology are planned to be used as dosimeters for volumetric dosimetry of normal and cancerous tissues during radiation therapy. • A PMMA scintillator can be used for dosimetry because of tissue-equivalent. • The PMMA-based plastic scintillators could be applied 3d DLP printing. • An integral mode of the DAQ system can measure a very high dose rate. [ABSTRACT FROM AUTHOR]

• Customized Timepix3 detector for characterization of stray radiation in UHDR beams. • The deposited energy, DR, and LET spectra were measured. • LET spectra exhibits the same characteristics regardless of the delivered DR. • At higher beam intensities a rescaling of LET can be performed. • A linear response of measured deposited energy was obtained at various DRs. Stray radiation produced by ultra-high dose-rates (UHDR) proton pencil beams is characterized using ASIC-chip semiconductor pixel detectors. A proton pencil beam with an energy of 220 MeV was utilized to deliver dose rates (DR) ranging from conventional radiotherapy DRs up to 270 Gy/s. A MiniPIX Timepix3 detector equipped with a silicon sensor and integrated readout electronics was used. The chip-sensor assembly and chipboard on water-equivalent backing were detached and immersed in the water-phantom. The deposited energy, particle flux, DR, and the linear energy transfer (LET(Si)) spectra were measured in the silicon sensor at different positions both laterally, at different depths, and behind the Bragg peak. At low-intensity beams, the detector is operated in the event-by-event data-driven mode for high-resolution spectral tracking of individual particles. This technique provides precise energy loss response and LET(Si) spectra with radiation field composition resolving power. At higher beam intensities a rescaling of LET(Si) can be performed as the distribution of the LET(Si) spectra exhibits the same characteristics regardless of the delivered DR. The integrated deposited energy and the absorbed dose can be thus measured in a wide range. A linear response of measured absorbed dose was obtained by gradually increasing the delivered DR to reach UHDR beams. Particle tracking of scattered radiation in data-driven mode could be performed at DRs up to 0.27 Gy/s. In integrated mode, the saturation limits were not reached at the measured out-of-field locations up to the delivered DR of over 270 Gy/s. A good agreement was found between measured and simulated absorbed doses. [ABSTRACT FROM AUTHOR]

Objective. In FLASH radiotherapy (dose rates ≥40 Gy s -1 ), a reduced normal tissue toxicity has been observed, while maintaining the same tumor control compared to conventional radiotherapy (dose rates ≤0.03 Gy s -1 ). This protecting effect could not be fully explained yet. One assumption is that interactions between the chemicals of different primary ionizing particles, so-called inter-track interactions, trigger this outcome. In this work, we included inter-track interactions in Monte Carlo track structure simulations and investigated the yield of chemicals ( G -value) produced by ionizing particles. Approach. For the simulations, we used the Monte Carlo toolkit TOPAS, in which inter-track interactions cannot be implemented without further effort. Thus, we developed a method enabling the simultaneous simulation of N original histories in one event allowing chemical species to interact with each other. To investigate the effect of inter-track interactions we analyzed the G -value of different chemicals using various radiation sources. We used electrons with an energy of 60 eV in different spatial arrangements as well as a 10 MeV and 100 MeV proton source. For electrons we set N between 1 and 60, for protons between 1 and 100. Main results. In all simulations, the total G -value decreases with increasing N . In detail, the G -value for • OH , H 3 O and e aq decreases with increasing N , whereas the G -value of OH - , H 2 O 2 and H 2 increases slightly. The reason is that with increasing N , the concentration of chemical radicals increases allowing for more chemical reactions between the radicals resulting in a change of the dynamics of the chemical stage. Significance. Inter-track interactions resulting in a variation of the yield of chemical species, may be a factor explaining the FLASH effect. To verify this hypothesis, further simulations are necessary in order to evaluate the impact of varying G -values on the yield of DNA damages., (Creative Commons Attribution license.)

Focal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent need for an improved understanding of the interaction between RT and IT in both preclinical and clinical scenarios. Every year since 2016, ImmunoRad gathers experts working at the interface between RT and IT to provide a forum for education and discussion, with the ultimate goal of fostering progress in the field at both preclinical and clinical levels. Here, we summarize the key concepts and findings presented at the Sixth Annual ImmunoRad conference., Competing Interests: MHBH is or has have been a recipient of research grants paid to UCSF or in-kind resources from Roche-Genentech, Varian Medical Systems, Eli Lilly, Pathway Innovations and has received fees for consulting from EMD-Serono, Varian Medical Systems, Genentech, Pathway Innovation, Scholar Rock. KHhas Honoraria: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Codiak Biosciences (Inst), F-Star Therapeutics (Inst), Inzen Therapeutics (Inst), Merck Serono (Inst), MSD (Inst), Oncolys Biopharma (Inst), Pfizer (Inst), Replimune (Inst), VacV Biotherapeutics (Inst); Consulting or Advisory Role: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Inzen Therapeutics (Inst), Merck Serono (Inst), MSD (Inst), Oncolys BioPharma (Inst), Replimune (Inst); Speakers’ Bureau: BMS (Inst), Merck Serono (Inst), MSD (Inst); Research Funding: AstraZeneca (Inst), Boehringer Ingelheim (Inst), Merck Sharp & Dohme (Inst), Replimune (Inst). FGH received Grant or Research Support Companies from Accuray inc, Bioprotect, Bristol-Myers Squibb, Roche-ImFlame/ImCore, Nanobiotix, AstraZeneca, Debio Pharmaceuticals, Seagen, Eisai, MSD; Grant or Research Support Foundations from Prostate Cancer Foundation, San Salvatore Foundation; Investigator or Co-Investigator Clinical Trials in Bristol-Myers Squibb; Consultations: Johnson & Johnson; Academic Collaborations: EORTC chairman Gynecology Cancer Group, ESMO Scientific Committee member for drug development, ASTRO Scientific Committee Annual Meeting. TH has Consulting: Synthetic Biologics, Novocure, Boston Scientific, Inivata, Merck, GSK; Scientific Advisory Board: PanTher Therapeutics (Equity), Lustgarten; Research Funding (Clinical Trials): Taiho, AstraZeneca, BMS, GSK, IntraOp, Ipsen. EJ reports other support from Abmeta and Adventris, personal fees from Achilles, Dragonfly, Mestag, The Medical Home Group, and Surgtx, other support from Parker Institute, grants and other support from the Lustgarten Foundation, Genentech, BMS, and Break Through Cancer outside the submitted work. SDK receives clinical funding from AstraZeneca, Genentech, and Ionis; she also receives preclinical research funding from Roche. KS is founder and consultant for Faeth Therapeutics and Transomic Technologies. CK is the co-recipient of a Sponsored Research Agreement from Ion Beam Applications (IBA). AM is funded by the Associazione Italiana per la Ricerca sul Cancro (AIRC IG 2018 Id.21763 and AIRC Programma di ricerca 5 per Mille 2019 Id.22737). MM declare grants from Boehringer Ingelheim, AC Biosciences and MSD outside the submitted work. ZSM has Scientific Advisory Board roles and equity options with Archeus Technologies and Seneca Therapeutics. JS owns stock and is a member of the Scientific Advisory Board of Surface Oncology, and is a member of the Scientific Advisory Board of Domain Therapeutics. RT has research grants to his institution from: Varian Medical Systems, Elekta Oncology, Accuray, Inc; scientific advisory board member for: Reflexion Medical, ImmuneSensor Therapeutics. AW acknowledge funding from AstraZeneca and imCORE. RW has stock and other ownership interests with Boost Therapeutics, Immvira LLC, Reflexion Pharmaceuticals, Coordination Pharmaceuticals Inc., Magi Therapeutics, Oncosenescence, Aqualung Therapeutics Corporation, and Cyntegron; he has served in a consulting or advisory role for Aettis Inc., AstraZeneca, Coordination Pharmaceuticals, Genus, Merck Serono S.A., Nano Proteagen, NKGen Biotech, Shuttle Pharmaceuticals, Highlight Therapeutics, S.L., Aqualung Therapeutics Corporation; he has research grants with Varian and Regeneron. RZ is scientific advisory board member of iTeos Therapeutics, receives research grant support from Bristol Myers Squibb and AstraZeneca, and is inventor on patent applications related to work on GITR, CTLA-4, and PD-1 (patent numbers: US20180244793A1; US10323091B2; WO2018106864A1; WO2019094352A1). SD has received compensation for consultant/advisory services from Lytix Biopharma, Mersana Therapeutics, EMD Serono, Ono Pharmaceutical, and Genentech, and research support from Lytix Biopharma and Boehringer-Ingelheim for unrelated projects. LG is/has been holding research contracts with Lytix Biopharma, Promontory and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, and the Luke Heller TECPR2 Foundation, and holds Promontory stock options. ED reports grants and personal fees from Roche Genentech; grants from Servier; grants from AstraZeneca; grants and personal fees from Merck-Serono; grants from BMS; and grants from MSD outside the submitted work. SCF has Consultant: Bayer, Bristol Myers Squibb, Varian, ViewRay, Accuray, Elekta, Janssen, Regeneron, GlaxoSmithKline, Eisai, Astra Zeneca, MedImmune, Merck US, EMD Serono/Merck, Genentech/ROCHE, Boehringer Ingelheim, Nanobiotix and Grant/Research: support from: Bristol Myers Squibb, Varian, Regeneron, Merck, Celldex. All other authors have no conflict of interest to declare., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Ultrahigh-dose rate FLASH radiotherapy (FLASH-RT) is a potentially paradigm-shifting treatment modality that holds the promise of expanding the therapeutic index for nearly any cancer. At the heart of this exciting technology comes the capability to ameliorate major normal tissue complications without compromising the efficacy of tumor killing. This combination of benefits has now been termed the FLASH effect and relies on an in vivo validation to rigorously demonstrate the absence of normal tissue toxicity. The FLASH effect occurs when the overall irradiation time is extremely short (<500 ms), and in this review we attempt to understand how FLASH-RT can kill tumors but spare normal tissues-likely the single most pressing question confronting the field today.

FLASH Radiotherapy is currently being studied and actively explored by medical and radiobiology communities as one of the most promising technological break-through in the future of cancer treatment as it could considerably improve the sparing of healthy tissues when compared to conventional radiotherapy. However, the FLASH effect activation mechanism still needs a thorough investigation before the characteristics of a therapeutic beam could be properly defined. In this manuscript, a new method for the on-line monitoring of therapeutic beams at FLASH intensities, based on air fluorescence and developed within the FlashDC project, is presented. [ABSTRACT FROM AUTHOR]

Purpose: In recent years, the FLASH effect, in which ultrahigh dose rate (UHDR) radiotherapy (RT) can significantly reduce toxicity to normal tissue while maintaining antitumor efficacy, has been verified in many studies and even applied in human clinical cases. This work evaluates whether a room-temperature radio-frequency (RF) linear accelerator (linac) system can produce UHDR high-energy X-rays exceeding a dose rate of 40 Gy/s at a clinical source-surface distance (SSD), exploring the possibility of a compact and economical clinical FLASH RT machine suitable for most hospital treatmentrooms., Methods: A 1.65 m long S-band backward-traveling-wave (BTW) electron linac was developed to generate high-current electron beams, supplied by a commercial klystron-based power source. A tungsten-copper electron-to-photon conversion target for UHDR X-rays was designed and optimized with Monte Carlo (MC) simulations using Geant4 and thermal finite element analysis (FEA) simulations using ANSYS. EBT3 and EBT-XD radiochromic films, which were calibrated with a clinical machine Varian VitalBeam, were used for absolute dose measurements. A PTW ionization chamber detector was used to measure the relative total dose and a plane-parallel ionization chamber detector was used to measure the relative normalized dose of each pulse., Results: The BTW linac generated 300-mA-pulse-current 11 MeV electron beams with 29 kW mean beam power, and the conversion target could sustain this high beam power within a maximum irradiation duration of 0.75 s. The mean energy of the produced X-rays was 1.66 MeV in the MC simulation. The measured flat-filter-free (FFF) maximum mean dose rate of the room-temperature linac exceeded 80 Gy/s at an SSD of 50 cm and 45 Gy/s at an SSD of 67.9 cm, both at a 2.1 cm depth of the water phantom. The FFF radiation fields at 50 cm and 67.9 cm SSD at a 2.1 cm depth of the water phantom showed Gaussian-like distributions with 14.3 and 20 cm full-width at half-maximum (FWHM) values, respectively., Conclusion: This work demonstrated the feasibility of UHDR X-rays produced by a room-temperature RF linac, and explored the further optimization of system stability. It shows that a simple and compact UHDR X-ray solution can be facilitated for both FLASH-RT scientific research and clinical applications., (© 2022 American Association of Physicists in Medicine.)

A new proton beam-line dedicated to R&D programs has been developed at Centre Antoine Lacassagne (CAL), in Nice (France), in collaboration with the Centre national d'études spatiales (CNES). This is the second beam-line of the MEDICYC 65 MeV cyclotron that is currently in operation, the first being the clinical 'eye-line' used for ocular proton therapy. The R&D beam-line is proposed with two configurations, the first producing a Gaussian narrow beam of a few mm width, the second a 100 mm diameter flat beam with a homogeneity better than ±3%. The energy range is (20 - ∼60) MeV, where the exact upper limit depends on the beam configuration being used. The energy spread of the non-degraded beam is (0.3 ± 0.1) MeV. A beam current between 10 pA and 10 μA can be produced with a stability better than 0.2% above 100 pA, and 2% below. The beam can be monitored online at a precision better than 5% in the flux range 1E5 (1E6) – 1E9 (1E10) p/cm2/s for a flat (Gaussian) configuration, although work is in progress to extend this range. Targeted applications for the R&D beam-line are instrumentation research, radiation tolerance tests of components and radiobiology. • A high-availability 60 MeV proton beam-line dedicated for R&D is operational. • The beam-line can provide a 100 mm homogenous beam over a large flux interval. • Alternatively, a Gaussian beam of a few mm standard deviation can be produced. • The beam-line has been designed for radiation tolerance tests, instrumentation R&D and research in radiobiology. [ABSTRACT FROM AUTHOR]

FLASH radiotherapy (FLASH-RT) is a novel radiotherapy technology defined as ultra-high dose rate (≥ 40 Gy/s) radiotherapy. The biological effects of FLASH-RT include two aspects: first, compared with conventional dose rate radiotherapy, FLASH-RT can reduce radiation-induced damage in healthy tissue, and second, FLASH-RT can retain antitumor effectiveness. Current research shows that mechanisms of the biological effects of FLASH-RT are related to oxygen. However, due to the short time of FLASH-RT, evidences related to the mechanisms are indirect, and the exact mechanisms of the biological effects of FLASH-RT are not completely clear and some are even contradictory. This review focuses on the mechanisms of the biological effects of FLASH-RT and proposes future research directions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lin, Huang, Gao, Yang, Wu, Zhang, Feng, Dai and Du.)

Objective. Lead-doped scintillator dosimeters may be well suited for the dosimetry of FLASH-capable x-ray radiotherapy beams. Our study explores the dose rate dependence and temporal resolution of scintillators that makes them promising in the accurate detection of ultrahigh dose-rate (UHDR) x-rays. Approach. We investigated the response of scintillators with four material compositions to UHDR x-rays produced by a conventional x-ray tube. Scintillator output was measured using the HYPERSCINT-RP100 dosimetry research platform. Measurements were acquired at high frame rates (400 fps) which allowed for accurate dose measurements of sub-second radiation exposures from 1 to 100 ms. Dose-rate dependence was assessed by scaling tube current of the x-ray tube. Scintillator measurements were validated against Monte Carlo simulations of the probe geometries and UHDR x-ray system. Calibration factors converting dose-to-medium to dose-to-water were obtained from simulation data of plastic and lead-doped scintillator materials. Main Results. The results of this work suggest that lead-doped scintillators were dose-rate independent for UHDR x-rays from 1.1 to 40.1 Gy s -1 and capable of measuring conventional radiotherapy dose-rates (0.1 Gy s -1 ) at extended distance from the x-ray focal spot. Dose-to-water measured with a 5% lead-doped scintillator detector agreed with simulations within 0.6%. Significance. Lead-doped scintillators may be a valuable tool for the accurate real-time dosimetry of FLASH-capable UHDR x-ray beams., (Creative Commons Attribution license.)

Radiotherapy (RT) is one of the important modalities for cancer treatments. Mounting evidence suggests that the host immune system is involved in the tumor cell killing during RT, and future RT technology development should aim to minimize radiation dose to the immune system while maintaining a sufficient dose to the tumor. A brief history of RT technology development is first summarized. Three RT technologies, namely FLASH RT, proton therapy, and spatially fractionated RT (SFRT), are singled out for the era of immunotherapy. Besides the technical aspects, the mechanism of FLASH effect is discussed, which is likely the combined results of the recombination effect, oxygen depletion effect and immune sparing effect. The proton therapy should have the advantage of causing much less immune damage in comparison to X-ray based RT due to the Bragg peak. However, the relative biological effectiveness (RBE) uncertainty and range uncertainty may hinder the translation of this advantage into clinical benefit. Research approaches to overcome these two technical hurdles are discussed. Various SFRT approaches and their application are reviewed. These approaches are categorized as single-field 1D/2D SFRT, multi-field 3D SFRT and quasi-3D SFRT techniques. A 3D SFRT approach, which is achieved by placing the Bragg peak of a proton 2D SFRT field in discrete depths, may have special potential because all 3 technologies (FLASH RT, proton therapy and SFRT) may be used in this approach., Competing Interests: The author declares that he has no conflict of interests., (© 2022 Chinese National Cancer Center. Published by Elsevier B.V.)

Simple Summary: This study attempts to answer a novel and clinically relevant question of the value of Bragg-peak-based FLASH planning for lung tumors. Most existing studies and literature are limited to using transmission proton beams at ultra-high dose rates, resulting in unnecessary irradiation exposure to normal tissues beyond the target volume. By combining a new hardware design (universal range shifter and range compensator) and an inverse planning system, the novel Bragg peak method makes the Bragg-peak-based FLASH planning possible. The treatment planning study and dosimetry comparison between single-energy proton Bragg peak beams and transmission proton beams demonstrated superior performances in OAR sparing and comparable FLASH dose rate of the Bragg peak FLASH. Beam angle optimization can further improve Bragg peak FLASH dosimetry performance while maintaining the similar 3D FLASH dose rate coverage for OARs. Purpose: While transmission proton beams have been demonstrated to achieve ultra-high dose rate FLASH therapy delivery, they are unable to spare normal tissues distal to the target. This study aims to compare FLASH treatment planning using single energy Bragg peak proton beams versus transmission proton beams in lung tumors and to evaluate Bragg peak plan optimization, characterize plan quality, and quantify organ-at-risk (OAR) sparing. Materials and Methods: Both Bragg peak and transmission plans were optimized using an in-house platform for 10 consecutive lung patients previously treated with proton stereotactic body radiation therapy (SBRT). To bring the dose rate up to the FLASH-RT threshold, Bragg peak plans with a minimum MU/spot of 1200 and transmission plans with a minimum MU/spot of 400 were developed. Two common prescriptions, 34 Gy in 1 fraction and 54 Gy in 3 fractions, were studied with the same beam arrangement for both Bragg peak and transmission plans (n = 40 plans). RTOG 0915 dosimetry metrics and dose rate metrics based on different dose rate calculations, including average dose rate (ADR), dose-averaged dose rate (DADR), and dose threshold dose rate (DTDR), were investigated. We then evaluated the effect of beam angular optimization on the Bragg peak plans to explore the potential for superior OAR sparing. Results: Bragg peak plans significantly reduced doses to several OAR dose parameters, including lung V7.4Gy and V7Gy by 32.0% (p < 0.01) and 30.4% (p < 0.01) for 34Gy/fx plans, respectively; and by 40.8% (p < 0.01) and 41.2% (p < 0.01) for 18Gy/fx plans, respectively, compared with transmission plans. Bragg peak plans have ~3% less in DADR and ~10% differences in mean OARs in DTDR and DADR relative to transmission plans due to the larger portion of lower dose regions of Bragg peak plans. With angular optimization, optimized Bragg peak plans can further reduce the lung V7Gy by 20.7% (p < 0.01) and V7.4Gy by 19.7% (p < 0.01) compared with Bragg peak plans without angular optimization while achieving a similar 3D dose rate distribution. Conclusion: The single-energy Bragg peak plans achieve superior dosimetry performances in OARs to transmission plans with comparable dose rate performances for lung cancer FLASH therapy. Beam angle optimization can further improve the OAR dosimetry parameters with similar 3D FLASH dose rate coverage. [ABSTRACT FROM AUTHOR]

Objective. With increasing investigation of the so-called FLASH effect, the need for accurate real time dosimetry for ultra-high dose rates is also growing. Considering the ultra-high dose-per-pulse (DPP) necessary to produce the ultra-high dose rates for investigations of the FLASH effect, real time dosimetry is a major challenge. In particular, vented ionization chambers, as used for dosimetry in conventional radiotherapy, show significant deviations from linearity with increasing DPP. This is due to recombination losses in the sensitive air volume. Solid state detectors could be an alternative. Due to their good stability of the response with regard to the accumulated dose, diamond detectors such as the microDiamond could be suitable here. The aims of this work are to investigate the response of microDiamond and adapted microDiamond prototypes in ultra-high DPP electron beams, to understand the underlying effects and to draw conclusions for further detector developments. Approach. For the study, an electron beam with a DPP up to 6.5 Gy and a pulse duration of 2.5 μ s was used to fulfill the conditions under which the FLASH effect was observed. As a dose rate-independent reference, alanine dosimeters were used. Main Results. It has been shown that the commercially available microDiamond detectors have limitations in terms of linearity at ultra-high DPP. But this is not an intrinsic limitation of the detector principle. The deviations from linearity were correlated with the series resistance and the sensitivity. It could be shown that the linear range can be extended towards ultra-high DPP range by reducing the sensitivity in combination with a low series resistance of the detectors. Significance. The work shows that synthetic single crystal diamond detectors working as Schottky photodiodes are in principle suitable for FLASH-RT dosimetry at electron linear accelerators., (Creative Commons Attribution license.)

Current radiotherapy facilities are standardized to deliver dose rates around 0.1-0.4 Gy/s in 2 Gy daily fractions, designed to deliver total accumulated doses to reach the tolerance limit of normal tissues undergoing irradiation. FLASH radiotherapy (FLASH-RT), on the other hand, relies on facilities capable of delivering ultrahigh dose rates in large doses in a single microsecond pulse, or in a few pulses given over a very short time sequence. For example, most studies to date have implemented 4-6 MeV electrons with intra-pulse dose rates in the range 10 6 -10 7  Gy/s. The proposed dependence of the FLASH effect on oxygen tension has stimulated several theoretical models based on three different hypotheses: (i) Radiation-induced transient oxygen depletion; (ii) cell-specific differences in the ability to detoxify and/or recover from injury caused by reactive oxygen species; (iii) self-annihilation of radicals by bimolecular recombination. This article focuses on the observations supporting or refuting these models in the frame of the chemical-biological bases of the impact of oxygen on the radiation response of cell free, in vitro and in vivo model systems., (© 2021 American Association of Physicists in Medicine.)

Research efforts in FLASH radiotherapy have increased at an accelerated pace recently. FLASH radiotherapy involves ultra-high dose rates and has shown to reduce toxicity to normal tissue while maintaining tumor response in pre-clinical 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 radiotherapy, with particular emphasis on the physical aspects of each study and the advantages and disadvantages of each modality. Beam delivery parameters, experimental set-up, and the dosimetry tools used are described for each FLASH modality. In addition, modeling efforts and treatment planning for FLASH radiotherapy is 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 radiotherapy.

The mechanism of the FLASH effect remains unclear and could be revealed by studying chemical reactions during irradiation. Monte Carlo simulation of the radiolytic species is an effective tool to analyze chemical reactions, but the simulation is limited by computing costs of the step-by-step simulation of radiolytic species, especially when considering beam with complex time structure. The complexity of the time structure of beams from accelerators in FLASH radiotherapy requires a high-performance Monte Carlo code. In this work, we develop a CPU-GPU coupling accelerating code with the independent reaction times (IRT) method to extend the chemical module of our nanodosimetry Monte Carlo code NASIC. Every chemical molecule in the microenvironment contains time information to consider the reactions from different tracks and simulate beams with complex time structures. Performance test shows that our code significantly improved the computing efficiency of the chemical module by four orders of magnitude. Then the code is used to study the oxygen depletion hypothesis in FLASH radiotherapy for different conditions by setting different parameters. The transient oxygen consumption rate values in the water are calculated when the pulses width ranges from 2 ps to 2 μ s, the total dose ranges from 0.5 Gy to 100 Gy and the initial oxygen concentration ranges from 0.1% to 21%. The time evolution curves are simulated to study the effect of the time structure of an electron linear accelerator. Results show that the total dose in several microseconds is a better indicator reflecting the radiolytic oxygen consumption rate than the dose rate. The initial oxygen greatly affects the oxygen consumption rate because of the reaction competition. The diffusion of oxygen determined by the physiological parameters is the key factor affecting oxygen depletion during the radiation using electron linear accelerators. Our code provides an efficient tool for simulating water radiolysis in different conditions., (© 2022 IOP Publishing Ltd.)

FLASH radiotherapy is an emerging radiotherapy technique used to spare normal tissues. It employs ultra-high dose rate radiation beams over 40 Gy/s, which is significantly higher than those of conventional radiotherapy. In this study, a fiber-optic radiation sensor (FORS) was fabricated using a plastic scintillator, an optical filter, and a plastic optical fiber to measure the ultra-high dose rate electron beams over 40 Gy/s used in FLASH radiotherapy. The radiation-induced emissions, such as Cherenkov radiation and fluorescence generated in a transmitting optical fiber, were spectrally discriminated from the light outputs of the FORS. To evaluate the linearity and dose rate dependence of the FORS, the outputs of the fiber-optic radiation sensor were measured according to distances from an electron scattering device, and the results were compared with those of an ionization chamber and radiochromic films. Finally, the percentage depth doses were obtained using the FORS as a function of depth in a water phantom. This study found that ultra-high dose rate electron beams over 40 Gy/s could be measured in real time using a FORS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

RadiaBeam has developed a novel, flexible linac for electrons and X-rays (FLEX) capable of energy variation from 2 to 9 MeV within a single RF pulse. This accelerator employs a robust traveling wave accelerating structure with a large energy and power acceptance that allows the unique features of deep energy and current variation required for novel adaptive cargo inspection techniques and Computed Tomography. Robust RF and water-cooling systems allow average beam powers up to 15 kW, upgradable to 57 kW, at 6 MeV, potentially making this accelerator useful for electron beam irradiation applications. The high peak currents of the electron beam produced by FLEX enable novel FLASH radiotherapy methods with fast dose delivery. In this paper, we present the linac design and its components, as well the results of the experimental demonstration of beam acceleration with energy variation. • Novel security, radiotherapy and industrial applications require new accelerators. • Adaptive cargo inspection needs beam parameters variation within a single pulse. • FLASH radiotherapy requires delivery of high X-ray doses within a few seconds. • RadiaBeam developed accelerator with rapid beam energy and current variation. [ABSTRACT FROM AUTHOR]

Major advances in high precision treatment delivery and imaging have greatly improved the tolerance of radiotherapy (RT); however, the selective sparing of normal tissue and the reduction of neurocognitive side effects from radiation-induced toxicities remain significant problems for pediatric patients with brain tumors. While the overall survival of pediatric patients afflicted with medulloblastoma (MB), the most common type primary brain cancer in children, remains high (≥80%), lifelong neurotoxic side-effects are commonplace and adversely impact patients' quality of life. To circumvent these clinical complications, we have investigated the capability of ultra-high dose rate FLASH-radiotherapy (FLASH-RT) to protect the radiosensitive juvenile mouse brain from normal tissue toxicities. Compared to conventional dose rate (CONV) irradiation, FLASH-RT was found to ameliorate radiation-induced cognitive dysfunction in multiple independent behavioral paradigms, preserve developing and mature neurons, minimize microgliosis and limit the reduction of the plasmatic level of growth hormone. The protective "FLASH effect" was pronounced, especially since a similar whole brain dose of 8 Gy delivered with CONV-RT caused marked reductions in multiple indices of behavioral performance (objects in updated location, novel object recognition, fear extinction, light-dark box, social interaction), reductions in the number of immature (doublecortin+) and mature (NeuN+) neurons and increased neuroinflammation, adverse effects that were not found with FLASH-RT. Our data point to a potentially innovative treatment modality that is able to spare, if not prevent, many of the side effects associated with long-term treatment that disrupt the long-term cognitive and emotional well-being of medulloblastoma survivors. [ABSTRACT FROM AUTHOR]

FLASH irradiation has been shown to reduce significantly normal tissue toxicity compared to conventional irradiation, while maintaining tumor control probability at similar level. Clinical translation of FLASH irradiation necessitates comprehensive laboratory studies to elucidate biological effects as well as pertinent technological and physical requirements. At present, FLASH research employs complex accelerator technologies of limited accessibilities. Here, we study the feasibility of a novel self-shielded x-ray irradiation cabinet system, as an enabling technology to enhance the preclinical research capabilities. The proposed system employs two commercially available high capacity 150 kVp fluoroscopy x-ray sources with rotating anode technology in a parallel-opposed arrangement. Simulation was performed with the GEANT4 Monte-Carlo platform. Simulated dosimetric properties of the x-ray beam for both FLASH and conventional dose-rate irradiations were characterized. Dose and dose rate from a single kV x-ray fluoroscopy source in solid water phantom were verified with measurements using Gafchromic films. The parallel-opposed x-ray sources can deliver over 50 Gy doses to a 20 mm thick water equivalent medium at ultrahigh dose-rates of 40-240 Gy s -1 . A uniform depth-dose rate (±5%) is achieved over 8-12 mm in the central region of the phantom. Mirrored beams minimize heel effect of the source and achieve reasonable cross-beam uniformity (±3%). Conventional dose-rate irradiation (≤0.1 Gy s -1 ) can also be achieved by reducing the tube current and increasing the distance between the phantom and tubes. The rotating anode x-ray source can be used to deliver both FLASH and conventional dose-rate irradiations with the field dimensions well suitable for small animal and cell-culture irradiations. For FLASH irradiation using parallel-opposed sources, entrance and exit doses can be higher by 30% than the dose at the phantom center. Beam angling can be employed to minimize the high surface doses. Our proposed system is amendable to self-shielding and enhance research in regular laboratory setting., (© 2021 Institute of Physics and Engineering in Medicine.)

There has been a recent revival of interest in the FLASH effect, after experiments have shown normal tissue sparing capabilities of ultra-high-dose-rate radiation with no compromise on tumour growth restraint. A model has been developed to investigate the relative importance of a number of fundamental parameters considered to be involved in the oxygen depletion paradigm of induced radioresistance. An example eight-dimensional parameter space demonstrates the conditions under which radiation may induce sufficient depletion of oxygen for a diffusion-limited hypoxic cellular response. Initial results support experimental evidence that FLASH sparing is only achieved for dose rates on the order of tens of Gy s -1 or higher, for a sufficiently high dose, and only for tissue that is slightly hypoxic at the time of radiation. We show that the FLASH effect is the result of a number of biological, radiochemical and delivery parameters. Also, the threshold dose for a FLASH effect occurring would be more prominent when the parameterisation was optimised to produce the maximum effect. The model provides a framework for further FLASH-related investigation and experimental design. An understanding of the mechanistic interactions producing an optimised FLASH effect is essential for its translation into clinical practice., (Creative Commons Attribution license.)

Flash radiotherapy is a kind of radiotherapy method using ultra-high dose rate radiation. Compared with the traditional dose rate radiotherapy, it has unique radiobiological advantages. In this paper, the principle of flash radiotherapy, the process and results of biological experiments are summarized. At the same time, the advantages and challenges of flash radiotherapy are analyzed, and the future clinical application is prospected.

FLASH radiotherapy (FLASH-RT) is a technology that could modify the way radiotherapy is delivered in the future. This technique involves the ultra-fast delivery of radiotherapy at dose rates several orders of magnitude higher than those currently used in routine clinical practice. This very short time of exposure leads to the striking observation of relative protection of normal tissues that are exposed to FLASH-RT as compared with conventional dose rate radiotherapy. Here we summarise the current knowledge about the FLASH effect and provide a synthesis of the observations that have been reported on various experimental animal models (mice, zebrafish, pig, cats), various organs (lung, gut, brain, skin) and by various groups across 40 years of research. We also propose possible mechanisms for the FLASH effect, as well as possible paths for clinical application., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)