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Background: FLASH radiation therapy (RT) offers a promising avenue for the broadening of the therapeutic index. However, to leverage the full potential of FLASH in the clinical setting, an improved understanding of the biological principles involved is critical. This requires the availability of specialized equipment optimized for the delivery of conventional (CONV) and ultra‐high dose rate (UHDR) irradiation for preclinical studies. One method to conduct such preclinical radiobiological research involves adapting a clinical linear accelerator configured to deliver both CONV and UHDR irradiation. Purpose: We characterized the dosimetric properties of a clinical linear accelerator configured to deliver ultra‐high dose rate irradiation to two anatomic sites in mice and for cell‐culture FLASH radiobiology experiments. Methods: Delivered doses of UHDR electron beams were controlled by a microcontroller and relay interfaced with the respiratory gating system. We also produced beam collimators with indexed stereotactic mouse positioning devices to provide anatomically specific preclinical treatments. Treatment delivery was monitored directly with an ionization chamber, and charge measurements were correlated with radiochromic film measurements at the entry surface of the mice. The setup for conventional dose rate irradiation utilized the same collimation system but at increased source‐to‐surface distance. Monte Carlo simulations and film dosimetry were used to characterize beam properties and dose distributions. Results: The mean electron beam energies before the flattening filter were 18.8 MeV (UHDR) and 17.7 MeV (CONV), with corresponding values at the mouse surface of 17.2 and 16.2 MeV. The charges measured with an external ion chamber were linearly correlated with the mouse entrance dose. The use of relay gating for pulse control initially led to a delivery failure rate of 20% (± 1 pulse); adjustments to account for the linac latency improved this rate to < 1/20. Beam field sizes for two anatomically specific mouse collimators (4 × 4 cm2 for whole‐abdomen and 1.5 × 1.5 cm2 for unilateral lung irradiation) were accurate within < 5% and had low radiation leakage (< 4%). Normalizing the dose at the center of the mouse (∼0.75 cm depth) produced UHDR and CONV doses to the irradiated volumes with > 95% agreement. Conclusion: We successfully configured a clinical linear accelerator for increased output and developed a robust preclinical platform for anatomically specific irradiation, with highly accurate and precise temporal and spatial dose delivery, for both CONV and UHDR irradiation applications. [ABSTRACT FROM AUTHOR]

Background: Reference dosimetry in ultra‐high dose rate (UHDR) beamlines is significantly hindered by limitations in conventional ionization chamber design. In particular, conventional chambers suffer from severe charge collection efficiency (CCE) degradation in high dose per pulse (DPP) beams. Purpose: The aim of this study was to optimize the design and performance of parallel plate ion chambers for use in UHDR dosimetry applications, and evaluate their potential as reference class chambers for calibration purposes. Three chamber designs were produced to determine the influence of the ion chamber response on electrode separation, field strength, and collection volume on the ion chamber response under UHDR and ultra‐high dose per pulse (UHDPP) conditions. Methods: Three chambers were designed and produced: the A11‐VAR (0.2–1.0 mm electrode gap, 20 mm diameter collector), the A11‐TPP (0.3 mm electrode gap, 20 mm diameter collector), and the A30 (0.3 mm electrode gap, 5.4 mm diameter collector). The chambers underwent full characterization using an UHDR 9 MeV electron beam with individually varied beam parameters of pulse repetition frequency (PRF, 10–120 Hz), pulse width (PW, 0.5–4 µs), and pulse amplitude (0.01–9 Gy/pulse). The response of the ion chambers was evaluated as a function of the DPP, PRF, PW, dose rate, electric field strength, and electrode gap. Results: The chamber response was found to be dependent on DPP and PW, and these dependencies were mitigated with larger electric field strengths and smaller electrode spacing. At a constant electric field strength, we measured a larger CCE as a function of DPP for ion chambers with a smaller electrode gap in the A11‐VAR. For ion chambers with identical electrode gap (A11‐TPP and A30), higher electric field strengths were found to yield better CCE at higher DPP. A PW dependence was observed at low electric field strengths (500 V/mm) for DPP values ranging from 1 to 5 Gy at PWs ranging from 0.5 to 4 µs, but at electric field strengths of 1000 V/mm and higher, these effects become negligible. Conclusion: This study confirmed that the CCE of ion chambers depends strongly on the electrode spacing and the electric field strength, and also on the DPP and the PW of the UHDR beam. A significant finding of this study is that although chamber performance does depend on PW, the effect on the CCE becomes negligible with reduced electrode spacing and increased electric field. A CCE of ≥95% was achieved for DPPs of up to 5 Gy with no observable dependence on PW using the A30 chamber, while still achieving an acceptable performance in conventional dose rate beams, opening up the possibility for this type of chamber to be used as a reference class chamber for calibration purposes of electron FLASH beamlines. [ABSTRACT FROM AUTHOR]

Background: Dosimetry in ultra‐high dose rate (UHDR) beamlines is significantly challenged by limitations in real‐time monitoring and accurate measurement of beam output, beam parameters, and delivered doses using conventional radiation detectors, which exhibit dependencies in ultra‐high dose‐rate (UHDR) and high dose‐per‐pulse (DPP) beamline conditions. Purpose: In this study, we characterized the response of the Exradin W2 plastic scintillator (Standard Imaging, Inc.), a water‐equivalent detector that provides measurements with a time resolution of 100 Hz, to determine its feasibility for use in UHDR electron beamlines. Methods: The W2 scintillator was exposed to an UHDR electron beam with different beam parameters by varying the pulse repetition frequency (PRF), pulse width (PW), and pulse amplitude settings of an electron UHDR linear accelerator system. The response of the W2 scintillator was evaluated as a function of the total integrated dose delivered, DPP, and mean and instantaneous dose rate. To account for detector radiation damage, the signal sensitivity (pC/Gy) of the W2 scintillator was measured and tracked as a function of dose history. Results: The W2 scintillator demonstrated mean dose rate independence and linearity as a function of integrated dose and DPP for DPP ≤ 1.5 Gy (R2 > 0.99) and PRF ≤ 90 Hz. At DPP > 1.5 Gy, nonlinear behavior and signal saturation in the blue and green signals as a function of DPP, PRF, and integrated dose became apparent. In the absence of Cerenkov correction, the W2 scintillator exhibited PW dependence, even at DPP values <1.5 Gy, with a difference of up to 31% and 54% in the measured blue and green signal for PWs ranging from 0.5 to 3.6 µs. The change in signal sensitivity of the W2 scintillator as a function of accumulated dose was approximately 4%/kGy and 0.3%/kGy for the measured blue and green signal responses, respectively, as a function of integrated dose history. Conclusion: The Exradin W2 scintillator can provide output measurements that are both dose rate independent and linear in response if the DPP is kept ≤1.5 Gy (corresponding to a mean dose rate up to 290 Gy/s in the used system), as long as proper calibration is performed to account for PW and changes in signal sensitivity as a function of accumulated dose. For DPP > 1.5 Gy, the W2 scintillator's response becomes nonlinear, likely due to limitations in the electrometer related to the high signal intensity. [ABSTRACT FROM AUTHOR]

Background: Dosimetry in ultra‐high dose rate (UHDR) electron beamlines poses a significant challenge owing to the limited usability of standard dosimeters in high dose and high dose‐per‐pulse (DPP) applications. Purpose: In this study, Al2O3:C nanoDot optically stimulated luminescent dosimeters (OSLDs), single‐use powder‐based LiF:Mg,Ti thermoluminescent dosimeters (TLDs), and Gafchromic EBT3 film were evaluated at extended dose ranges (up to 40 Gy) in conventional dose rate (CONV) and UHDR beamlines to determine their usability for calibration and dose verification in the setting of FLASH radiation therapy. Methods: OSLDs and TLDs were evaluated against established dose‐rate–independent Gafchromic EBT3 film with regard to the potential influence of mean dose rate, instantaneous dose rate, and DPP on signal response. The dosimeters were irradiated at CONV or UHDR conditions on a 9‐MeV electron beam. Under UHDR conditions, different settings of pulse repetition frequency (PRF), pulse width (PW), and pulse amplitude were used to characterize the individual dosimeters' response in order to isolate their potential dependencies on dose, dose rate, and DPP. Results: The OSLDs, TLDs, and Gafchromic EBT3 film were found to be suitable at a dose range of up to 40 Gy without any indication of saturation in signal. The response of OSLDs and TLDs in UHDR conditions were found to be independent of mean dose rate (up to 1440 Gy/s), instantaneous dose rate (up to 2 MGy/s), and DPP (up to 7 Gy), with uncertainties on par with nominal values established in CONV beamlines (± 4%). In cross‐comparing the response of OSLDs, TLDs and Gafchromic film at dose rates of 0.18–245 Gy/s, the coefficient of variation or relative standard deviation in the measured dose between the three dosimeters (inter‐dosimeter comparison) was found to be within 2%. Conclusions: We demonstrated the dynamic range of OSLDs, TLDs, and Gafchromic film to be suitable up to 40 Gy, and we developed a protocol that can be used to accurately translate the measured signal in each respective dosimeter to dose. OSLDs and powdered TLDs were shown to be viable for dosimetric measurement in UHDR beamlines, providing dose measurements with accuracies on par with Gafchromic EBT3 film and their concurrent use demonstrating a means for redundant dosimetry in UHDR conditions. [ABSTRACT FROM AUTHOR]

Ion chambers are required for calibration and reference dosimetry applications in radiation therapy (RT). However, exposure of ion chambers in ultra‐high dose rate (UHDR) conditions pertinent to FLASH‐RT leads to severe saturation and ion recombination, which limits their performance and usability. The purpose of this study was to comprehensively evaluate a set of commonly used commercially available ion chambers in RT, all with different design characteristics, and use this information to produce a prototype ion chamber with improved performance in UHDR conditions as a first step toward ion chambers specific for FLASH‐RT. The Advanced Markus and Exradin A10, A26, and A20 ion chambers were evaluated. The chambers were placed in a water tank, at a depth of 2 cm, and exposed to an UHDR electron beam at different pulse repetition frequency (PRF), pulse width (PW), and pulse amplitude settings on an IntraOp Mobetron. Ion chamber responses were investigated for the various beam parameter settings to isolate their dependence on integrated dose, mean dose rate and instantaneous dose rate, dose‐per‐pulse (DPP), and their design features such as chamber type, bias voltage, and collection volume. Furthermore, a thin parallel‐plate (TPP) prototype ion chamber with reduced collector plate separation and volume was constructed and equally evaluated as the other chambers. The charge collection efficiency of the investigated ion chambers decreased with increasing DPP, whereas the mean dose rate did not affect the response of the chambers (± 1%). The dependence of the chamber response on DPP was found to be solely related to the total dose within the pulse, and not on mean dose rate, PW, or instantaneous dose rate within the ranges investigated. The polarity correction factor (Ppol) values of the TPP prototype, A10, and Advanced Markus chambers were found to be independent of DPP and dose rate (± 2%), while the A20 and A26 chambers yielded significantly larger variations and dependencies under the same conditions. Ion chamber performance evaluated under different irradiation conditions of an UHDR electron beam revealed a strong dependence on DPP and a negligible dependence on the mean and instantaneous dose rates. These results suggest that modifications to ion chambers design to improve their usability in UHDR beamlines should focus on minimizing DPP effects, with emphasis on optimizing the electric field strength, through the construction of smaller electrode separation and larger bias voltages. This was confirmed through the production and evaluation of a prototype ion chamber specifically designed with these characteristics. [ABSTRACT FROM AUTHOR]

Simple Summary: The ability of ultra-high dose rate FLASH radiation therapy (RT) to reduce normal tissue toxicity without affecting tumor response relative to conventional dose rate radiation therapy could fundamentally change the way we treat cancer. However, this field is still in its early stages, and the magnitude of the sparing effect between treatment centers differs greatly for reasons as yet unknown, which has put the robustness of the effect into question. In this study, we show that when similar irradiation beam parameter settings are used, the induced sparing effect is robust and reproducible across institutions. These settings should serve as a reference for further optimization of the FLASH effect. FLASH radiation therapy (RT) is a promising new paradigm in radiation oncology. However, a major question that remains is the robustness and reproducibility of the FLASH effect when different irradiators are used on animals or patients with different genetic backgrounds, diets, and microbiomes, all of which can influence the effects of radiation on normal tissues. To address questions of rigor and reproducibility across different centers, we analyzed independent data sets from The University of Texas MD Anderson Cancer Center and from Lausanne University (CHUV). Both centers investigated acute effects after total abdominal irradiation to C57BL/6 animals delivered by the FLASH Mobetron system. The two centers used similar beam parameters but otherwise conducted the studies independently. The FLASH-enabled animal survival and intestinal crypt regeneration after irradiation were comparable between the two centers. These findings, together with previously published data using a converted linear accelerator, show that a robust and reproducible FLASH effect can be induced as long as the same set of irradiation parameters are used. [ABSTRACT FROM AUTHOR]

Purpose: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

• Brain radiation impairs cognition, associated with neuronal degeneration and neuroinflammation. • Ultra-rapid FLASH produced reduced cognitive deficits vs. conventional delivery time. • Loss of hippocampal dendritic spines and neuroinflammation were less evident after FLASH. • These factors may mediate the improved therapeutic index of FLASH brain irradiation. To evaluate the impact of ultra-rapid FLASH mouse whole brain irradiation on hippocampal dendritic spines and neuroinflammation, factors associated with cognitive impairment after brain irradiation. We administered 30 Gy whole brain irradiation to C57BL6/J mice in sub-second (FLASH) vs. 240 s conventional delivery time keeping all other parameters constant, using a custom configured clinical linac. Ten weeks post-irradiation, we evaluated spatial and non-spatial object recognition using novel object location and object recognition testing. We measured dendritic spine density by tracing Golgi-stained hippocampal neurons and evaluated neuroinflammation by CD68 immunostaining, a marker of activated microglia, and expression of 10 pro-inflammatory cytokines using a multiplex immunoassay. At ten weeks post-irradiation, compared to unirradiated controls, conventional delivery time irradiation significantly impaired novel object location and recognition tasks whereas the same dose given in FLASH delivery did not. Conventional delivery time, but not FLASH, was associated with significant loss of dendritic spine density in hippocampal apical dendrites, with a similar non-significant trend in basal dendrites. Conventional delivery time was associated with significantly increased CD68-positive microglia compared to controls whereas FLASH was not. Conventional delivery time was associated with significant increases in 5 of 10 pro-inflammatory cytokines in the hippocampus (and non-significant increases in another 3), whereas FLASH was associated with smaller increases in only 3. Reduced cognitive impairment and associated neurodegeneration were observed with FLASH compared to conventional delivery time irradiation, potentially through decreased induction of neuroinflammation, suggesting a promising approach to increasing therapeutic index in radiation therapy of brain tumors. [ABSTRACT FROM AUTHOR]

• We established and validated scheme for UHDR intercomparisons. • We bring bring dosimetry consensus across participating institutions. • The method was tested and validated with high-energy electron beams between two centers and three different devices with CONV and UHDR. • The compatibility between the measured and expected doses show good agreement. • A first step towards dosimetric consensus for FLASH-RT. We describe a multicenter cross validation of ultra-high dose rate (UHDR) (>= 40 Gy/s) irradiation in order to bring a dosimetric consensus in absorbed dose to water. UHDR refers to dose rates over 100–1000 times those of conventional clinical beams. UHDR irradiations have been a topic of intense investigation as they have been reported to induce the FLASH effect in which normal tissues exhibit reduced toxicity relative to conventional dose rates. The need to establish optimal beam parameters capable of achieving the in vivo FLASH effect has become paramount. It is therefore necessary to validate and replicate dosimetry across multiple sites conducting UHDR studies with distinct beam configurations and experimental set-ups. Using a custom cuboid phantom with a cylindrical cavity (5 mm diameter by 10.4 mm length) designed to contain three type of dosimeters (thermoluminescent dosimeters (TLDs), alanine pellets, and Gafchromic films), irradiations were conducted at expected doses of 7.5 to 16 Gy delivered at UHDR or conventional dose rates using various electron beams at the Radiation Oncology Departments of the CHUV in Lausanne, Switzerland and Stanford University, CA. Data obtained between replicate experiments for all dosimeters were in excellent agreement (±3%). In general, films and TLDs were in closer agreement with each other, while alanine provided the closest match between the expected and measured dose, with certain caveats related to absolute reference dose. In conclusion, successful cross-validation of different electron beams operating under different energies and configurations lays the foundation for establishing dosimetric consensus for UHDR irradiation studies, and, if widely implemented, decrease uncertainty between different sites investigating the mechanistic basis of the FLASH effect. [ABSTRACT FROM AUTHOR]