Ultra-high Dose Research Articles

Investigating the potential contribution of inter-track interactions within ultra-high dose-rate proton therapy

Objective. Laser-accelerated protons offer an alternative delivery mechanism for proton therapy. This technique delivers dose-rates of ≥109 Gy s−1, many orders of magnitude greater than used clinically. Such ultra-high dose-rates reduce delivery time to nanoseconds, equivalent to the lifetime of reactive chemical species within a biological medium. This leads to the possibility of inter-track interactions between successive protons within a pulse, potentially altering the yields of damaging radicals if they are in sufficient spatial proximity. This work investigates the temporal evolution of chemical species for a range of proton energies and doses to quantify the circumstances required for inter-track interactions, and determine any relevance within ultra-high dose-rate proton therapy. Approach. The TOPAS-nBio Monte Carlo toolkit was used to investigate possible inter-track interactions. Firstly, protons between 0.5 and 100 MeV were simulated to record the radial track dimensions throughout the chemical stage from 1 ps to 1 μs. Using the track areas, the geometric probability of track overlap was calculated for various exposures and timescales. A sample of irradiations were then simulated in detail to compare any change in chemical yields for independently and instantaneously delivered tracks, and validate the analytic model. Main results. Track overlap for a clinical 2 Gy dose was negligible for biologically relevant timepoints for all energies. Overlap probability increased with time after irradiation, proton energy and dose, with a minimum 23 Gy dose required before significant track overlap occurred. Simulating chemical interactions confirmed these results with no change in radical yields seen up to 8 Gy for independently and instantaneously delivered tracks. Significance. These observations suggest that the spatial separation between incident protons is too large for physico-chemical inter-track interactions, regardless of the delivery time, indicating such interactions would not play a role in any potential changes in biological response between laser-accelerated and conventional proton therapy.

Results of a multicenter, randomized, phase 3 trial of trimodality therapy with I-125 brachytherapy, external beam radiation therapy, and long- versus short-term androgen deprivation therapy for localized high-risk prostate cancer (TRIP/TRIGU0907).

305 Background: The TRIP trial was a multicenter, phase 3 randomized investigation designed to determine whether 30 months of androgen deprivation therapy (ADT) was superior to 6 months of ADT when combined with brachytherapy and external beam radiotherapy (EBRT) for localized high-risk prostate cancer. Methods: The trial was done in 37 hospitals in Japan. Men between 40 to 79 years old with stage T2c-3a, or a prostate-specific antigen (PSA) >20 ng/ml or a Gleason score >7 received 6 months of ADT combined with I-125 brachytherapy at a prescription dose of 110 Gy, followed by EBRT of 45 Gy. Patients were randomly assigned either no further treatment (short arm) or 24 months of adjuvant ADT (long arm) after stratification. The primary endpoint was biochemical progression-free survival using the Phoenix definition of failure. Secondary endpoints included clinical progression, metastasis, salvage treatment, disease-specific survival, overall survival, and grade 3 or higher of adverse events. An intention-to-treat analysis was conducted with survival estimates determined using competing risk analyses. Results: Of 332 patients, 165 were randomized to the short and 167 to the long arm. The median follow-up periods were 9.43 and 9.24 years, respectively. 24 patients have died in each arm. The cumulative incidence for biochemical progression in the short vs. long arm were 10.4% (95% confidence interval [CI] 6.62-16.42) vs 9.5% (5.85-15.46) at 9 years, respectively (p=0.647). The cumulative incidences for clinical progression, distant metastases, salvage treatment, and disease-specific mortality events were not significantly different between the two arms. The overall survival rates of the short arm vs long arm were 87.2% (82.13-92.63%) and 85.9% (80.41-91.77%) at 9 years, respectively (p=0.914). Endocrine-related grade 3 morbidity for short arm vs long arm was 0.6% vs 1.8% (p=0.623), and radiation-related grade 3 morbidity was 1.2% vs 0.6% (p=0.622). Conclusions: In localized high-risk prostate cancer, TRIP did not demonstrate the superiority of 30 months vs. 6 months of ADT when combined with brachytherapy and EBRT. These data suggest that ultra-high radiation doses can be combined with a shorter course of ADT without compromising survival. Clinical trial information: UMIN000003992 .

Characterization of LiF:Mg,Ti thermoluminescence detectors in low-LET proton beams at ultra-high dose rates

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-100TM Microcubes, 1 mm × 1 mm × 1 mm) was packaged in matrices of 5 × 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.

The PTB water calorimeter for determining the absolute absorbed dose to water in ultra-high pulse dose rate electron beams

The PTB water calorimeter for determining the absolute absorbed dose to water in ultra-high pulse dose rate electron beams

Induction of DNA strand breaks and oxidative base damages in plasmid DNA by ultra-high dose rate proton irradiation

Purpose Radiation cancer therapy with ultra-high dose rate (UHDR) exposure, so-called FLASH radiotherapy, appears to reduce normal tissue damage without compromising tumor response to therapy. The aim of this study was to clarify whether a 59.5 MeV proton beam at an UHDR of 48.6 Gy/s could effectively reduce the DNA damage of pBR322 plasmid DNA in solution compared to the conventional dose rate (CONV) of 0.057 Gy/s. Materials and Methods A simple system, consisting of pBR322 plasmid DNA in 1× Tris-EDTA buffer, was initially employed for proton beam exposure. We then used formamidopyrimidine-DNA glycosylase (Fpg) enzymes. which convert oxidative base damages of oxidized purines to DNA strand breaks, to quantify DNA single strand breaks (SSBs) and double strand breaks (DSBs) by agarose gel electrophoresis. Results Our findings showed that the SSB induction rate (SSB per plasmid DNA/Gy) at UHDR and the induction of Fpg enzyme sensitive sites (ESS) were significantly reduced in UHDR compared to CONV. However, there was no significant difference in DSB induction and non-DSB cluster damages. Conclusions UHDR of a 59.5 MeV proton beam could reduce non-clustered, non-DSB damages, such as SSB and sparsely distributed ESS. However, this effect may not be significant in reducing lethal DNA damage that becomes apparent only in acute radiation effects of mammalian cells and in vivo studies.

Noise Considerations for Tomographic Reconstruction of Single-Projection Digital Holographic Interferometry-Based Radiation Dosimetry

Optical Calorimetry (OC) is a 2D Digital Holographic Interferometry (DHI)-based measurement technique with potential applications for the 3D dosimetry of ultra-high dose rate (FLASH) radiation therapy beams through tomographic reconstruction. This application requires accurate measurements of DHI signals in environments with low signal-to-noise ratios (SNRs) in order to accurately measure absorbed energy to a medium per unit mass (Dose). However, tomographic reconstruction accuracy is sensitive to noise in the measurements. In this study, a virtual model of an OC dosimeter was used to characterize and model major sources of noise within a DHI setup, allowing for the modelled noise sources to be selectively reduced. The tomographic reconstruction of the 3D dose distribution was achieved using the inverse Abel transform. Reducing the noise contribution from atmospheric turbulence and mechanical vibration by one half improved the central axis reconstruction error from 6.5% to 1.3% and 1.1%, respectively, and the mean dose difference from 2.9% to 0.4% and 0.3%, respectively. This indicates the potential of the tomographic DHI-based 3D OC dosimeter to reconstruct accurate 3D dose distributions from a single projection if the specified sources of noise can be reduced to acceptable levels. The used methodology is applicable to any application of tomographic DHI where reconstruction quality is highly sensitive to noise.

Absolute dosimetry for FLASH proton pencil beam scanning radiotherapy

A paradigm shift is occurring in clinical oncology exploiting the recent discovery that short pulses of ultra-high dose rate (UHDR) radiation—FLASH radiotherapy—can significantly spare healthy tissues whilst still being at least as effective in curing cancer as radiotherapy at conventional dose rates. These properties promise reduced post-treatment complications, whilst improving patient access to proton beam radiotherapy and reducing costs. However, accurate dosimetry at UHDR is extremely complicated. This work presents measurements performed with a primary-standard proton calorimeter and derivation of the required correction factors needed to determine absolute dose for FLASH proton beam radiotherapy with an uncertainty of 0.9% (1sigma), in line with that of conventional treatments. The establishment of a primary standard for FLASH proton radiotherapy improves accuracy and consistency of the dose delivered and is crucial for the safe implementation of clinical trials, and beyond, for this new treatment modality.

Introduction of Research Work on Laser Proton Acceleration and Its Application Carried out on Compact Laser–Plasma Accelerator at Peking University

Laser plasma acceleration has made remarkable progress in the last few decades, but it also faces many challenges. Although the high gradient is a great potential advantage, the beam quality of the laser accelerator has a certain gap, or it is different from that of traditional accelerators. Therefore, it is important to explore and utilize its own features. In this article, some recent research progress on laser proton acceleration and its irradiation application, which was carried out on the compact laser plasma accelerator (CLAPA) platform at Peking University, have been introduced. By combining a TW laser accelerator and a monoenergetic beamline, proton beams with energies of less than 10 MeV, an energy spread of less than 1%, and with several to tens of pC charge, have been stably produced and transported in CLAPA. The beamline is an object–image point analyzing system, which ensures the transmission efficiency and the energy selection accuracy for proton beams with large initial divergence angle and energy spread. A spread-out Bragg peak (SOBP) is produced with high precision beam control, which preliminarily proved the feasibility of the laser accelerator for radiotherapy. Some application experiments based on laser-accelerated proton beams have also been carried out, such as proton radiograph, preparation of graphene on SiC, ultra-high dose FLASH radiation of cancer cells, and ion-beam trace probes for plasma diagnosis. The above applications take advantage of the unique characteristics of laser-driven protons, such as a micron scale point source, an ultra-short pulse duration, a wide energy spectrum, etc. A new laser-driven proton therapy facility (CLAPA II) is being designed and is under construction at Peking University. The 100 MeV proton beams will be produced via laser–plasma interaction by using a 2-PW laser, which may promote the real-world applications of laser accelerators in malignant tumor treatment soon.

Prospects for the sulfur-containing amino acids medicines usage for trimethylamine-N-oxide biosynthesis modulation in humans

The aim: to identify prospects for the sulfur-containing amino acids medicines usage for trimethylamine oxide (TMAO) biosynthesis modulation in humans. Intestinal microbiome and its metabolic products are currently widely discussed as a new therapeutic target for the treatment of cardiovascular, neurological and metabolic diseases. The effect of the intestinal microbiome on human health is unconditional. Its metabolites, including trimethylamine (TMA), TMAO and plasma amino acids, play an important role in the mechanisms of many diseases. The synthesis of TMAO directly depends on such factors as diet, intestinal microbiome status, genetic characteristics of the human body (activity and type of hepatic flavin monooxygenase). At the same time, all these factors are also able to affect the metabolism of sulfur-containing amino acids in the human body. Conversely, sulfur-containing amino acids are able to simulate the state of the intestinal microbiome and the activity of hepatic flavin monooxygenase. Today many sulfur-containing amino acid drugs are widely used in therapeutic practice (taurine, methionine, glutathione), including for the cardiovascular and metabolic diseases treatment. Their effect on the state of the intestinal microbiome and its metabolites is still unexplored. There are currently no strong clinical studies for the use of amino acid preparations to reduce plasma TMAO levels, although this perspective is interesting. The possibility of using taurine is questionable as it affects the state of the intestinal microbiome in ultra-high doses (more than 3 g/day), which can cause side effects. Glutathione drugs have low bioavailability due to its physical and chemical properties, and therefore have not become widespread in therapeutic practice. Drugs that activate glutathione synthesis – for example, selenium derivatives, glutoredoxins, some heat shock proteins (HPS70) actions are not studied in vivo enough. Unfortunately, methionine preparations, on the other hand, increase plasma TMAO levels. Conclusions. Despite the deep pathogenetic affinity of sulfur-containing amino acids and TMAO synthesis, the prospect of using these amino acids drugs to reduce TMAO synthesis is questionable. The problem of reducing the synthesis of TMAO in the human body remains unsolved and requires further search for promising pathogenetically drugs for its correction.

Ultra-high Dose-rate Carbon-ion Scanning Beam With a Compact Medical Synchrotron Contributing to Further Development of FLASH Irradiation.

The focus of this report is establishing an irradiation arrangement to realize an ultra-high dose-rate (uHDR; FLASH) of scanned carbon-ion irradiation possible with a compact commonly available medical synchrotron. Following adjustments to the operation it became possible to extract ≥1.0×109 carbon ions at 208.3 MeV/u (86 mm in range) per 100 ms. The design takes the utmost care to prevent damage to monitors, particularly in the nozzle, achieved by the uHDR beam not passing through this part of the apparatus. Doses were adjusted by extraction times, using a function generator. After one scan by the carbon-ion beam it became possible to create a field within the extraction time. The Advanced Markus chamber (AMC) and Gafchromic film are then able to measure the absolute dose and field size at a plateau depth, with the operating voltage of the chamber at 400 V at the uHDR for the AMC. The beam scanning utilizing this uHDR irradiation could be confirmed at a dose of 6.5±0.08 Gy (±3% homogeneous) at this volume over at least 16×16 mm2 corresponding to a dose-rate of 92.3 Gy/s (±1.3%). The dose was ca. 0.7, 1.5, 2.9, and 5.4 Gy depending on dose-rate and field size, with the rate of killed cells increasing with the irradiation dose. The compact medical synchrotron achieved FLASH dose-rates of >40 Gy/s at different dose levels and in useful field sizes for research with the apparatus and arrangement developed here.

Effects of Flash Radiotherapy on Blood Lymphocytes in Humans and Small Laboratory Animals.

A mathematical model, which describes the level of surviving lymphocytes in the blood after ultra-high (FLASH) and lower dose rates of partial-body irradiation, is developed. The model is represented by simple analytic formulae that involve a few parameters, namely, physiologic parameters (characteristics of the blood flow through the blood circulatory system and its irradiated part), a biophysical parameter (a characteristic of the blood lymphocytes radiosensitivity), and the physical parameters (characteristics of irradiation). The model predicts that the level of surviving blood lymphocytes increases as the dose rate increases and approaches the limiting level of (1 - vR), where vR is the fraction of the blood volume in the irradiated part of the blood circulatory system. The model also predicts that the level of surviving blood lymphocytes after the same exposure is higher for lower vR. It is found that FLASH irradiation in humans with doses of 10 to 40 Gy and with exposure times significantly less (<1 s) than the blood circulation time (∼60 s) leads to the maximal blood lymphocyte sparing. Simple formula, which determines effective dose rates for optimal blood lymphocyte sparing, is derived in the framework of the developed model. For the dose range specified above, the obtained modeling prediction of the range of effective dose rates for optimal blood lymphocyte sparing in humans (namely, N ≥40 Gy/s) coincides with the dose rate range in FLASH radiation therapy. It is revealed that the respective effective dose rates for mice are higher than those for humans (for the same dose range) due to the shorter blood circulation time in mice than in humans. Proceeding from the findings obtained in this paper, a hypothesis elucidating the mechanisms of the abscopal effect of FLASH radiation therapy (namely, an antitumor response on metastases located outside of irradiated part of a body) is proposed.

Development of a compact linear accelerator to generate ultrahigh dose rate high-energy X-rays for FLASH radiotherapy applications.

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 40Gy/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. A 1.65m 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. The BTW linac generated 300-mA-pulse-current 11 MeV electron beams with 29kW 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 80Gy/s at an SSD of 50cm and 45Gy/s at an SSD of 67.9cm, both at a 2.1cm depth of the water phantom. The FFF radiation fields at 50cm and 67.9cm SSD at a 2.1cm depth of the water phantom showed Gaussian-like distributions with 14.3 and 20cm full-width at half-maximum (FWHM) values, respectively. 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.

Characterization of Lab-on-Fiber-based dosimeters in ultra-high dose radiation fields

Next generation High Energy Physics (HEP) accelerators will require new devices and technologies capable of operating in extreme environments characterized by ultra-high radiation doses up to the MGy levels. To this aim, we report on an innovative Lab-On-Fiber (LOF) probe for the real-time dose monitoring. The proposed platform is based on a metallo-dielectric nanostructured grating made of gold and poly(methyl methacrylate) (PMMA) patterned on the termination of single mode fibers. The nanostructure has been judiciously designed to support a plasmonic resonance in the reflection spectrum occurring at near infrared wavelengths. Electron beam lithography was used for the fabrication of two LOF prototypes, which in turn, were exposed to X-rays with a total dose of 2.02 MGy and a dose rate of 88 kGy/h. Reflection spectra acquired during the irradiation revealed a clear dependence of the LOF resonance wavelength and depth on the absorbed dose, confirming the outcomes of our previous proton campaign. Morphological characterization of the irradiated samples showed that the main radiation induced effect is the reduction of the PMMA thickness (ranging between 26 % and 40 %), which in turn strongly affects the resonance behavior. Quantitative morphological measurements have been used to achieve a fair and objective correlation with our numerical modelling. Moreover, we investigated the effect of ultra-high doses of several radiation types, including X-rays, electrons and protons, on the thickness of PMMA nanolayers deposited on planar substrates. Experimental results revealed that the amount of absorbed dose (1.9–16.06 MGy) is the main parameter affecting the PMMA relative compaction (9.5–59.1 %), while the influence of the radiation type, dose rate and initial PMMA thickness can be considered negligible. Overall, these results pave the way to the development of radiation type independent PMMA assisted LOF dosimeters operating at MGy doses for the radiation monitoring in future HEP experiments.

Exploring the Limits: Degradation Behavior of Lead Halide Perovskite Films under Exposure to Ultrahigh Doses of γ Rays of Up to 10 MGy

Herein, we show that thin films of MAPbI3, FAPbI3, (CsMA)PbI3, and (CsMAFA)PbI3, where MA and FA are methylammonium and formamidinium cations, respectively, tolerate ultrahigh doses of γ rays approaching 10 MGy without significant changes in their absorption spectra. However, among the studied materials, FAPbI3 was the only one that did not form metallic lead due to its extreme radiation hardness. Infrared near-field optical microscopy revealed the radiation-induced depletion of organic cations from the grains of MAPbI3 and their accumulation at the grain boundaries, whereas FAPbI3 on the contrary lost FA cations from the grain boundaries. The multication (CsMAFA)PbI3 perovskite underwent a facile phase segregation to domains enriched with MA and FA cations, which is a principally new radiation-induced degradation pathway. Our findings suggest that the radiation hardness of the rationally designed perovskite semiconductors could go far beyond the impressive threshold of 10 MGy we set herein for FAPbI3 films, which opens many exciting opportunities for practical implementation of these materials.

Out-of-field measurements and simulations of a proton pencil beam in a wide range of dose rates using a Timepix3 detector: Dose rate, flux and LET

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.

Cellular irradiations with laser-driven carbon ions at ultra-high dose rates

Objective. Carbon is an ion species of significant radiobiological interest, particularly in view of its use in cancer radiotherapy, where its large Relative Biological Efficiency is often exploited to overcome radio resistance. A growing interest in highly pulsed carbon delivery has arisen in the context of the development of the FLASH radiotherapy approach, with recent studies carried out at dose rates of 40 Gy s−1. Laser acceleration methods, producing ultrashort ion bursts, can now enable the delivery of Gy-level doses of carbon ions at ultra-high dose rates (UHDRs), exceeding 109 Gy s−1. While studies at such extreme dose rate have been carried out so far using low LET particles such as electrons and protons, the radiobiology of high-LET, UHDR ions has not yet been explored. Here, we report the first application of laser-accelerated carbon ions generated by focussing 1020 W cm−2 intense lasers on 10–25 nm carbon targets, to irradiate radioresistant patient-derived Glioblastoma stem like cells (GSCs). Approach. We exposed GSCs to 1 Gy of 9.5 ± 0.5 MeV/n carbon ions delivered in a single ultra-short (∼400-picosecond) pulse, at a dose rate of 2 × 109 Gy s−1, generated using the ASTRA GEMINI laser of the Central Laser Facility at the Rutherford Appleton Laboratory, Didcot, Oxfordshire, UK. We quantified carbon ion-induced DNA double strand break (DSB) damage using the 53BP1 foci formation assay and used 225 kVp x-rays as a reference radiation. Main Results. Laser-accelerated carbon ions induced complex DNA DSB damage, as seen through persistent 53BP1 foci (11.5 ± 0.4 foci/cell/Gy) at 24 h and significantly larger foci (1.69 ± 0.07 μm2) than x-rays induced ones (0.63 ± 0.02 μm2). The relative foci induction value for laser-driven carbon ions relative to conventional x-rays was 3.2 ± 0.3 at 24 h post-irradiation also confirming the complex nature of the induced damage. Significance. Our study demonstrates the feasibility of radiobiology investigations at unprecedented dose rates using laser-accelerated high-LET carbon ions in clinically relevant models.

FLASH Radiotherapy for the Treatment of Symptomatic Bone Metastases (FAST-01): Protocol for the First Prospective Feasibility Study.

In preclinical studies, FLASH therapy, in which radiation delivered at ultrahigh dose rates of ≥40 Gy per second, has been shown to cause less injury to normal tissues than radiotherapy delivered at conventional dose rates. This paper describes the protocol for the first-in-human clinical investigation of proton FLASH therapy. FAST-01 is a prospective, single-center trial designed to assess the workflow feasibility, toxicity, and efficacy of FLASH therapy for the treatment of painful bone metastases in the extremities. Following informed consent, 10 subjects aged ≥18 years with up to 3 painful bone metastases in the extremities (excluding the feet, hands, and wrists) will be enrolled. A treatment field selected from a predefined library of plans with fixed field sizes (from 7.5 cm × 7.5 cm up to 7.5 cm × 20 cm) will be used for treatment. Subjects will receive 8 Gy of radiation in a single fraction-a well-established palliative regimen evaluated in prior investigations using conventional dose rate photon radiotherapy. A FLASH-enabled Varian ProBeam proton therapy unit will be used to deliver treatment to the target volume at a dose rate of ≥40 Gy per second, using the plateau (transmission) portion of the proton beam. After treatment, subjects will be assessed for pain response as well as any adverse effects of FLASH radiation. The primary end points include assessing the workflow feasibility and toxicity of FLASH treatment. The secondary end point is pain response at the treated site(s), as measured by patient-reported pain scores, the use of pain medication, and any flare in bone pain after treatment. The results will be compared to those reported historically for conventional dose rate photon radiotherapy, using the same radiation dose and fractionation. FAST-01 opened to enrollment on November 3, 2020. Initial results are expected to be published in 2022. The results of this investigation will contribute to further developing and optimizing the FLASH-enabled ProBeam proton therapy system workflow. The pain response and toxicity data acquired in our study will provide a greater understanding of FLASH treatment effects on tumor responses and normal tissue toxicities, and they will inform future FLASH trial designs. : ClinicalTrials.gov NCT04592887; http://clinicaltrials.gov/ct2/show/NCT04592887. DERR1-10.2196/41812.

Dual beam-current transformer design for monitoring and reporting of electron ultra-high dose rate (FLASH) beam parameters.

To investigate the usefulness and effectiveness of a dual beam-current transformer (BCTs) design to monitor and record the beam dosimetry output and energy of pulsed electron FLASH (eFLASH) beams in real-time, and to inform on the usefulness of this design for future eFLASH beam control. Two BCTs are integrated into the head of a FLASH Mobetron system, one located after the primary scattering foil and the other downstream of the secondary scattering foil. The response of the BCTs was evaluated individually to monitor beam output as a function of dose, scattering conditions, and ability to capture physical beam parameters such as pulse width (PW), pulse repetition frequency (PRF), and dose per pulse (DPP), and in combination to determine beam energy using the ratio of the lower-to-upper BCT signal. A linear relationship was observed between the absorbed dose measured on Gafchromic film and the BCT signals for both the upper and lower BCT (R2 >0.99). A linear relationship was also observed in the BCT signals as a function of the number of pulses delivered regardless of the PW, DPP, or PRF (R2 >0.99). The lower-to-upper BCT ratio was found to correlate strongly with the energy of the eFLASH beam due to differential beam attenuation caused by the secondary scattering foil. The BCTs were also able to provide accurate information about the PW, PRF, energy, and DPP for each individual pulse delivered in real-time. The dual BCT system integrated within the FLASH Mobetron was shown to be a reliable monitoring system able to quantify accelerator performance and capture all essential physical beam parameters on a pulse-by-pulse basis, and the ratio between the two BCTs was strongly correlated with beam energy. The fast signal readout and processing enables the BCTs to provide real-time information on beam output and energy and is proposed as a system suitable for accurate beam monitoring and control of eFLASH beams.

Radiobiology experiments with a laser driven x-ray source: Exploring the UHDR regime

Laser Driven Plasma Accelerators (LDPA) can generate both characteristic and Bremsstrahlung x-rays in ultrashort bunches. Because of the high intensity of the laser pulses, these laser-induced x-ray sources can achieve peak dose rates compatible with the FLASH regime. At the Laser Laboratory for Acceleration and Applications (L2A2/USC), a setup for the irradiation of in vitro cell cultures with a laser-driven x-ray source has been developed. The suitability of this source for studying the influence of Ultra High Dose Rates (UHDR) on DNA damage has been proven through the irradiation of in vitro cell cultures.

A rigorous behavioral testing platform for the assessment of radiation-induced neurological outcomes.

Behavioral testing is a popular and reliable method of neurocognitive assessment of rodents but the lack of standard operating procedures has led to a high variation of protocols in use. Therefore, there exists a strong need to standardize protocols for a combined behavioral platform in order to maintain consistency across institutions and assist newcomers in the field. This paper provides details on the methodology of several behavioral tasks which have been validated in identifying radiation induced cognitive impairment as well as provide guidance on timescales and best practices. The cognitive assessments outlined here are optimized for rodent studies and either target learning and memory (open field task, object in updated location, novel object recognition, object in place, and temporal order) or mood and cognition (social interaction, elevated plus maze, light dark box, forced swim test, and fear extinction). We have utilized this platform successfully in evaluating cognitive injury induced by various radiation types, doses, fractionation schedules and also with ultra-high dose rate FLASH radiotherapy. Recommended materials and software are provided as well as advice on methods of data analysis. In this way a comprehensive behavioral platform is described with broad applicability to assess cognitive endpoints critical to therapeutic outcome.