Ultra-high Dose Research Articles

Demonstration of ultra-high dose rate electron irradiation at FLASHlabatPITZ.

The Photo Injector Test facility at DESY in Zeuthen (PITZ) is building up an R&D platform, known as FLASHlab@PITZ, for systematically studying the FLASH effect in cancer treatment with its high-brightness electron beams, which can provide a uniquely large dose parameter range for radiation experiments. In this paper, we demonstrate the capabilities by experiments with a reduced parameter range on a startup beamline and study the potential performance of the full beamline by simulations. To measure the dose, Gafchromic films are installed both in front of and after the samples; Monte Carlo simulations are conducted to predict the dose distribution during beam preparation and help understand the dose distribution inside the sample. Plasmid DNA is irradiated under various doses at conventional and ultra-high dose rate (UHDR) to study the DNA damage by radiations. Start-to-end simulations are performed to verify the performance of the full beamline. On the startup beamline, reproducible irradiation has been established with optimized electron beams and the delivered dose distributions have been measured with Gafchromic films and compared to FLUKA simulations. The functionality of this setup has been further demonstrated in biochemical experiments at conventional dose rate of 0.05 Gy/s and UHDR of several 105 Gy/s and a varying dose up to 60 Gy, with the UHDR experiments finished within a single RF pulse (less than 1 millisecond); the observed conformation yields of the irradiated plasmid DNA revealed its dose-dependent radiation damage. The upgrade to the full FLASHlab@PITZ beamline is justified by simulations with homogeneous radiation fields generated by both pencil beam scanning (PBS) and scattering beams. With the demonstration of ultra-high dose rate irradiation and the simulated performance of the new beamline, FLASHlab@PITZ will serve as a powerful platform for studying the FLASH effects in cancer treatment.

Electron beam monitoring of a modified conventional medical accelerator with a portable current transformer system traceable to primary electrical standards.

Ultra-high dose rate radiotherapy (UHDR) delivers therapeutic doses at rates >40Gy/s in a fraction of a second, aiming to enhance the therapeutic ratio through the FLASH effect. The substantial increase in UHDR beam current poses serious challenges for conventional active dosimeters. Integrating current transformers (ICT) offer a nondestructive solution for accurate monitoring, enabling the type of fast transient readout that will be crucial for UHDR treatment verification. The aim of this study is to build and characterize a clinically deployable ICT system and to develop an accurate calibration methodology for absolute charge determination that is traceable to primary electrical standards. The ICT was constructed from a Super MuMetal® toroid, and its secondary winding was made from 50 Ω coaxial cable. A 3D-printed case with an internal conductive coating shields the toroid assembly from interference. The ICT readout involves a custom differential amplifier and a commercial flash analog-to-digital converter. The system was calibrated using a bespoke sub-µs current pulser in the range of (2 to 16) mA, which itself is traceable to electrical standards via an in-house built electrometer with a calibrated feedback capacitor. The performance of the ICT was evaluated as a milliampere-scale beam monitor against concurrent absorbed dose graphite calorimetry irradiation measurements acquired on a specially tuned medical accelerator for UHDR delivery. The ICT responses for nominal test pulses, generated by a function generator and a current pulser, exhibited accurate reproduction of rise and fall times within the 1ns sampling frequency. A systematic droop effect of 0.6(1)%/µs was observed but is accounted for through the calibration chain. The calibration of the current pulser exhibited a repeatability typically better than 0.05%, with a slowly-varying leakage that can be subtracted using a linear regression of the leakage current. The ICT charge calibration demonstrated a repeatability in the range of (0.5 to<0.05)% for charge per pulse values in the range of (0.5 to 50)nC, respectively. The ICT response showed a strong linear relationship (adj-R2=0.99997) to charge per pulse. The in-beam comparison with a graphite calorimeter demonstrated the effectiveness of the ICT as an online beam monitor, independent of pulse repetition frequency in the range of (25 to 200)Hz, reducing the mean excess (i.e., independent of accelerator output) calorimeter variation to 0.3% (0.1% standard error on the mean). This work demonstrates the feasibility of accurately calibrating the ICT in terms of absolute charge and applying it as a clinically deployable monitoring system of mA-scale electron beams delivered by a medical accelerator.

Trends in dentomaxillofacial radiology.

Oral and maxillofacial diagnostic imaging is of paramount importance in dental clinical diagnosis, treatment planning, and follow-up procedures. Periapical radiographic examination and numerous panoramic systems are used in routine clinical dental practice. Cone beam CT is widely used and currently the method of choice in oral and maxillofacial implantology, endodontics, maxillofacial surgery, periodontics, degenerative temporomandibular joint disease, orthodontics, airway studies, sleep disorders, and forensic dentistry. Another innovative laboratory research tool that offers three-dimensional (3D) detailed high-resolution images of in vitro teeth and neighboring structures with submicrometric accuracy is microcomputed tomography. Ultra-high radiation doses, long scanning times, and high costs preclude its routine clinical use. In response to the high demand for a technique that could provide real-time images using a cost-effective, rapid, user-friendly, and portable technique without ionizing radiation, some authors proposed ultrasound imaging methods as an alternative to X-ray imaging techniques. Ultrasonography can be used in the dentomaxillofacial region for various diagnostic purposes such as salivary gland and superficial tissue examination. Recently, dedicated dental magnetic resonance imaging with appropriate software, hardware, sequences, and field of view tailored to fit dentomaxillofacial anatomy was introduced. Lately, 3D printing technologies and their application in dentistry has attracted attention. During 3D printing a given material is added in successive layers to create a 3D object. The application of this technology has the potential to decrease operation time and minimize operator bias and the possibility of procedural errors. Another hot topic regarding dentomaxillofacial radiology is artificial intelligence, which is a field related to computer science dedicated to developing systems or machines that can perform tasks traditionally associated with human intelligence. It is obvious that further investigation and research in the field of dentomaxillofacial radiology will make great contributions to diagnostic imaging for various dental specialties.

Pulse-by-pulse treatment planning and its application to generic observations of ultra-high dose rate (FLASH) radiotherapy with photons and protons.

The exact temporal characteristics of beam delivery affect the efficacy and outcome of ultra-high dose rate (UHDR or "FLASH") radiotherapy, mainly due to the influence of the beam pulse structure on mean dose rate. Single beams may also be delivered in separate treatment sessions to elevate mean dose rate. This paper therefore describes a model for pulse-by-pulse treatment planning and demonstrates its application by making some generic observations of the characteristics of FLASH radiotherapy with photons and protons.&#xD;&#xD;Approach. A beam delivery model was implemented into the AutoBeam (v6.3) inverse treatment planning system, so that the individual pulses of the delivery system could be explicitly described during optimisation. The delivery model was used to calculate distributions of time-averaged and dose-averaged mean dose rate and the dose modifying factor for FLASH was then determined and applied to dose calculated by a discrete ordinates Boltzmann solver. The method was applied to intensity-modulated radiation therapy (IMRT) with photons as well as to passive scattering and pencil beam scanning with protons for the case of a simple phantom geometry with a prescribed dose of 36 Gy in 3 fractions.&#xD;&#xD;Main results. Dose and dose rate are highest in the target region, so FLASH sparing is most pronounced around the planning target volume. When using a treatment session per beam, OAR sparing is possible more peripherally. The sparing with photons is higher than with protons because the dose to OAR is higher with photons.&#xD;&#xD;Significance. The framework provides an efficient method to determine the optimal technique for delivering clinical dose distributions using FLASH. The most sparing occurs close to the PTV for hypofractionated treatments.&#xD.

Flash proton radiation therapy via a stochastic three-operator splitting method

Abstract The inverse radiation therapy planning problem is crucial in achieving tumoricidal doses while minimizing radiation-induced normal-tissue toxicity. Compared to conventional radiation therapy (with conventional dose rates), flash proton radiation therapy (with ultra-high dose rates) can provide additional normal tissue sparing. However, this groundbreaking advancement in radiation oncology introduces a challenging nonconvex and nonsmooth optimization problem. In this paper, we propose a stochastic three-operator splitting (STOS) algorithm to address the flash proton radiation therapy problem. We establish the convergence and convergence rates of the STOS algorithm under the nonconvex framework for both unbiased gradient estimators and variance-reduced gradient estimators. These stochastic gradient estimators include the most popular ones, such as SGD, SAGA, SARAH, and SAG, among others. Experimental results demonstrate that the flash proton radiation therapy plans obtained by the STOS algorithm can effectively kill tumors while better protecting normal tissues.

Discordance in acute gastrointestinal toxicity between synchrotron-based proton and linac-based electron ultra-high dose rate irradiation.

Proton FLASH has been investigated using cyclotron and synchrocyclotron beamlines but not synchrotron beamlines. We evaluated the impact of dose rate (ultra-high [UHDR] vs. conventional [CONV]) and beam configuration (shoot-through [ST] vs. spread-out-Bragg-peak [SOBP]) on acute radiation-induced gastrointestinal toxicity (RIGIT) in mice. We also compared RIGIT between synchrotron-based protons and linac-based electrons with matched mean dose rates. We administered abdominal irradiation (12-14 Gy single fraction) to female C57BL/6J mice with an 87 MeV synchrotron-based proton beamline (2 cm diameter field size as a lateral beam). Dose rates were 0.2 Gy/s (S-T pCONV), 0.3 Gy/s (SOBP pCONV), 150 Gy/s (S-T pFLASH), and 230 Gy/s (SOBP pFLASH). RIGIT was assessed by the jejunal regenerating crypt assay and survival. We also compared responses to proton [pFLASH and pCONV] with responses to electron CONV (eCONV, 0.4 Gy/s) and electron FLASH (eFLASH, 188-205 Gy/s). The number of regenerating jejunal crypts at each matched dose was lowest for pFLASH (similar between S-T and SOBP), greater and similar between pCONV (S-T and SOBP) and eCONV, and greatest for eFLASH. Correspondingly, mice that received pFLASH SOBP had the lowest survival rates (50% at 50 days), followed by pFLASH S-T (80%), and pCONV SOBP (90%), but 100% of mice receiving pCONV S-T survived (log-rank P = 0.047 for the four groups). Our findings are consistent with an increase in RIGIT after synchrotron-based pFLASH versus pCONV. This negative proton-specific FLASH effect versus linac-based electron irradiation underscores the importance of understanding the physical and biological factors that will allow safe and effective clinical translation.

Fast spot order optimization to increase dose rates in scanned particle therapy FLASH treatments

The advent of ultra-high dose rate irradiation, known as FLASH radiation therapy, has shown promising potential in reducing toxicity while maintaining tumor control. However, the clinical translation of these benefits necessitates efficient treatment planning strategies. This study introduces a novel approach to optimize proton therapy for FLASH effects using traveling salesperson problem (TSP) heuristics. We applied these heuristics to optimize the arrangement of proton spots in treatment plans for 26 prostate cancer patients, comparing the performance against conventional sorting methods and global optimization techniques. Our results demonstrate that TSP-based heuristics significantly enhance FLASH coverage to the same extent as the global optimization technique, but with computation times reduced from hours to a few seconds. This approach offers a practical and scalable solution for enhancing the effectiveness of FLASH therapy, paving the way for more effective and personalized cancer treatments. Future work will focus on further optimizing run times and validating these methods in clinical settings.

Probing Spatiotemporal Effects of Intertrack Recombination with a New Implementation of Simultaneous Multiple Tracks in TRAX-CHEM.

Among the most investigated hypotheses for a radiobiological explanation of the mechanism behind the FLASH effect in ultra-high dose rate radiotherapy, intertrack recombination between particle tracks arriving at a close spatiotemporal distance has been suggested. In the present work, we examine these conditions for different beam qualities and energies, defining the limits of both space and time where a non-negligible chemical effect is expected. To this purpose the TRAX-CHEM chemical track structure Monte Carlo code has been extended to handle several particle tracks at the same time, separated by pre-defined spatial and temporal distances. We analyzed the yields of different radicals as compared to the non-interacting track conditions and we evaluated the difference. We find a negligible role of intertrack for spatial distances larger than 1 μm, while for temporal distances up to μs, a non-negligible interaction is observed especially at higher LET. In addition, we emphasize the non-monotonic behavior of some relative yield as a function of the time separation, in particular of H2O2, due to the onset of a different reaction involving solvated electrons besides well-known OH· recombination.

Ultra‑high dose rate (FLASH) treatment: A novel radiotherapy modality (Review).

Ultra-high dose rate radiotherapy defined as FLASH radiotherapy is a potential technology to improve local tumor therapeutic gain ratio. It relies on linear accelerator capable of delivering large doses in a single microsecond pulse (>40 Gy/sec). This therapy would lead to sparing of normal tissue which has been termed the FLASH effect. As significant reduction of radiation-induced toxicity, a greater dose of FLASH radiotherapy could be administered in tumor region. Some evidences prove the relation between FLASH effect and oxygen. Yet, the underlying physicochemical and biological mechanism remain to be fully demonstrated. The current hypotheses that may explain the normal and tumor tissue different response were We summarized and the future direction of study and clinic implementation was proposed.

Exploring the Metabolic Impact of FLASH Radiotherapy.

FLASH radiotherapy (FLASH RT) is an innovative modality in cancer treatment that delivers ultrahigh dose rates (UHDRs), distinguishing it from conventional radiotherapy (CRT). FLASH RT has demonstrated the potential to enhance the therapeutic window by reducing radiation-induced damage to normal tissues while maintaining tumor control, a phenomenon termed the FLASH effect. Despite promising outcomes, the precise mechanisms underlying the FLASH effect remain elusive and are a focal point of current research. This review explores the metabolic and cellular responses to FLASH RT compared to CRT, with particular focus on the differential impacts on normal and tumor tissues. Key findings suggest that FLASH RT may mitigate damage in healthy tissues via altered reactive oxygen species (ROS) dynamics, which attenuate downstream oxidative damage. Studies indicate the FLASH RT influences iron metabolism and lipid peroxidation pathways differently than CRT. Additionally, various studies indicate that FLASH RT promotes the preservation of mitochondrial integrity and function, which helps maintain apoptotic pathways in normal tissues, attenuating damage. Current knowledge of the metabolic influences following FLASH RT highlights its potential to minimize toxicity in normal tissues, while also emphasizing the need for further studies in biologically relevant, complex systems to better understand its clinical potential. By targeting distinct metabolic pathways, FLASH RT could represent a transformative advance in RT, ultimately improving the therapeutic window for cancer treatment.

Respiratory-gated micro-computed tomography imaging to measure radiation-induced lung injuries in mice following ultra-high dose-rate and conventional dose-rate radiation therapy.

Ultra-high dose-rate radiotherapy (FLASH-RT) shows the potential to eliminate tumors while sparing healthy tissues. To investigate radiation-induced lung damage, we used in vivo respiratory-gated micro-computed tomography (micro-CT) to monitor mice that received photon FLASH-RT or conventional RT on the FLASH irradiation research station at TRIUMF. Thirty healthy male C57BL/6 mice received baseline micro-CT scans followed by radiation therapy targeting the thorax. Treatments administered included no irradiation, 10-MV photon FLASH-RT, and 10-MV conventional RT with either 15 or 30Gy prescribed dose. Follow-up micro-CT scans were obtained up to 24 weeks post-irradiation, and histology was obtained at the experimental endpoint. Lung volume and CT number were measured during peak inspiration and end-expiration and used to calculate the functional residual capacity (FRC) and tidal volume ( ). Radiation pneumonitis was observed sporadically in micro-CT images at 9 and 12 weeks post-irradiation. Fibrosis was observed in the endpoint images and confirmed with histology. Compared with the 15-Gy treatment groups and unirradiated controls, the micro-CT images for 30-Gy FLASH-RT showed differences during peak inspiration, with a significant reduction in , whereas the 30-Gy conventional RT showed differences during end-expiration, with a significant difference in FRC from 15Gy. Between 12 weeks and the endpoint, the 30-Gy conventional RT group exhibited the largest reduction in lung volume. Respiratory-gated micro-CT imaging was sensitive to radiation pneumonitis and fibrosis. Significant differences were seen in functional metrics measured at the endpoint for FRC (both 30-Gy groups) and (30-Gy FLASH-RT) compared with the control.

FLASH radiotherapy: mechanisms, nanotherapeutic strategy and future development.

Ultra-high dose-rate (FLASH) radiotherapy serves as an ideal procedure to treat tumors efficiently without harming normal tissues and has demonstrated satisfactory antitumor effects in multiple animal tumor models. However, the biological mechanisms of FLASH radiotherapy have not yet been fully elucidated, and the small number of devices delivering FLASH dose rate has limited its wide application. This review summarizes the possible biological mechanisms and antitumor effects of FLASH radiotherapy, its application in nanotherapeutic strategy, as well as its challenges and future development. Furthermore, some valuable guidance for promoting the progress of FLASH radiotherapy in nanotherapeutic strategies are provided.

X-ray-based ultra-high dose rate FLASH radiotherapy mitigates acute radiation-induced hippocampal injury and inflammation

X-ray-based ultra-high dose rate FLASH radiotherapy mitigates acute radiation-induced hippocampal injury and inflammation

Ultra-high dose rate (FLASH) carbon ion irradiation inhibited immune suppressive protein expression on Pan02 cell line.

Recently, ultra-high dose rate (> 40Gy/s, uHDR; FLASH) radiation therapy (RT) has attracted interest, because the FLASH effect that is, while a cell-killing effect on cancer cells remains, the damage to normal tissue could be spared has been reported. This study aimed to compare the immune-related protein expression on cancer cells after γ-ray, conventionally used dose rate (Conv) carbon ion (C-ion), and uHDR C-ion. B16F10 murine melanoma and Pan02 murine pancreas cancer were irradiated with γ-ray at Osaka University and with C-ion at Osaka HIMAK. The dose rates at 1.16Gy/s for Conv and 380Gy/s for uHDR irradiation. The expressed calreticulin (CRT), major histocompatibility complex class (MHC)-I, and programmed cell death 1 ligand (PD-L1) were evaluated by flow cytometry. Western blotting and PCR were utilized to evaluate endoplasmic reticulum (ER) stress, DNA damage, and its repair pathway. CRT, MHC-I on B16F10 was also increased by irradiation, while only C-ion increased MHC-I on Pan02. Notably, PD-L1 on B16F10 was increased after irradiation with both γ-ray and C-ion, while uHDR C-ion suppressed the expression of PD-L1 on Pan02. The present study indicated that uHDR C-ion has a different impact on the repair pathway of DNA damage and ER than the Conv C-ion. This is the first study to show the immune-related protein expressions on cancer cells after uHDR C-ion irradiation.

Characterization of an Inorganic Powder-Based Scintillation Detector Under a UHDR Electron Beam.

(1) Background: Ultra-high dose rate (UHDR) radiation therapy needs a reliable dosimetry solution and scintillation detectors are promising candidates. In this study, we characterized an inorganic powder-based scintillation detector under a 9 MeV UHDR electron beam. (2) Methods: A mixture of ZnS:Ag powder and optic glue was coupled to an 8 m Eska GH-4001-P polymethyl methacrylate (PMMA) optical fiber. We evaluated the dependence of the detector on dose per pulse (DPP), pulse repetition frequency (PRF), and pulse width (PW). Additionally, we determined the stability and the reproducibility of the detector. (3) Results: The signal ratio between the PMMA clear optical fiber and the ZnS:Ag scintillator was around 210. ZnS:Ag produced a signal yield 54 times greater than that of a BCF-12 plastic scintillator. Signal variation with PRF changes was under 0.5%. The signal was linear to the integrated dose up to the maximum deliverable dose, 180 Gy. The variation in signal was linear to the change in both PW and DPP. Regarding stability, the standard deviation of 10 consecutive irradiations was 0.83%. For the reproducibility, all daily measurements varied within ±1.5%. (4) Conclusions: These findings show that the ZnS:Ag detector can be used for accurate dosimetry with UHDR beams.

Standard requirements for clinical very high energy electron and ultra high dose rate medical devices

Very High-Energy Electrons (VHEE) present a promising innovation in radiation therapy (RT), particularly for the treatment of deep-seated tumors using Ultra High Dose Rate (UHDR) within the framework of FLASH-RT. VHEE offers significant advantages, such as improved tumor targeting, reduced treatment times, and potential utilization of the FLASH effect, which may minimize normal tissue toxicity. However, the lack of an international technical standard for VHEE systems, especially for UHDR applications, remains a critical challenge. Current standards for radiation therapy equipment, such as IEC 60601-2-1 and IEC 60601-2-64, do not encompass VHEE technology. This regulatory gap underscores the need for developing a structured international standard to ensure the basic safety and essential performance of VHEE medical devices. Addressing this challenge requires overcoming complex dose delivery issues, such as the interaction of multiple fields and beam conformality and incorporating novel techniques like broad beam or pencil beam scanning. Establishing comprehensive regulatory standards is essential to ensure patient safety, consistent treatment practices, and the successful clinical integration of VHEE systems. These standards must encompass design guidelines, radiation protection protocols, and integration with existing oncology practices. Collaborative research and development efforts are crucial to formulating evidence-based guidelines, fostering the safe and effective use of VHEE in clinical settings. By addressing these challenges, VHEE technology has the potential to revolutionize cancer therapy, particularly for deep-seated tumors, while enhancing therapeutic outcomes for patients.

A 2D detector array for relative dosimetry and beam steering for FLASH radiotherapy with electrons.

FLASH radiotherapy is an emerging treatment modality using ultra-high dose rate beams. Much effort has been made to develop suitable dosimeters for reference dosimetry, yet the spatial beam characteristics must also be characterized to enable computerized treatment planning, as well as quality control and service of a treatment delivery device. In conventional radiation therapy, this is commonly achieved by beam profile scans in a water phantom using a point detector. In ultra-high dose rate beams, the delivered dose needed for a set of beam profile scans may exceed the regulatory dose limit specified for a typical treatment room, or degrade components of the scanning system and scanning detector. Point detector scans also cannot quantify the pulse-to-pulse stability of a beam profile. Detector arrays can overcome these challenges, but to date, no detector arrays suitable for ultra-high dose rate beams are commercially available. The study presents the development and characterization of a two-dimensional detector array for measuring pulse-resolved spatial fluence distributions in real-time and temporal structure of intra-pulse dose rate of ultra-high pulsed dose rate (UHPDR) electron beams used in FLASH radiotherapy. The performance of the SunPoint 1 diode was evaluated by measuring the response of the EDGE Detector in a 20 MeV UHPDR electron beam with a dose per pulse of 0.04Gy - 6Gy at a pulse duration of 1µs or 1.9µs, and instantaneous dose rates of 0.040 - 3.2MGy·s-1. Based on the findings regarding a suitable signal acquisition technique, a PROFILER 2 detector array made of SunPoint 1 diodes was then modified by minimizing trace resistance, applying a reverse bias, and implementing an RC component to each diode to optimize the transfer of the collected charge during a pulse. The resultant "FLASH Profiler" was then tested in the same UHPDR electron beam. The FLASH Profiler exhibited a linear response within±3% deviation over the investigated dose per pulse range. The FLASH Profiler array showed good agreement with the absolute dose measured using a flashDiamond point detector and an integrating current transformer for dose-per-pulse values of up to 6Gy. The FLASH Profiler was able to measure lateral beam profiles in real-time and on a single-pulse basis. The ability to capture and display the profiles during steering of UHPDR beams was demonstrated. The SunPoint 1 diode was able to measure the pulse duration and the intra-pulse dose rate with a time resolution of 4ns. The FLASH Profiler could be used for characterizing UHPDR electron beams and facilitating quality control and beam steering service of electron FLASH irradiators.

Dosimetric study of synchrotron rapid beam off control and skip spot function for high beam intensity proton therapy.

All Hitachi proton pencil beam scanning facilities currently use discrete spot scanning (DSS). Mayo Clinic Florida (MCF) is installing a Hitachi particle therapy system with advanced technologies, including fast scan speeds, high beam intensity, rapid beam off control (RBOC), a skip spot function, and proton pencil beam scanning using dose driven continuous scanning (DDCS). A potential concern of RBOC is the generation of a shoulder at the end of the normal spot delivery due to a flap spot (FS) with a flap dose (FD), which has been investigated for carbon synchrotron but not for proton delivery. While investigated, for instance, for Hitachi's installation at MCF, this methodology could be applicable for all future high intensity proton deliveries. No Hitachi proton facility currently uses the proposed RBOC. This study aimed to understand the dosimetric impact of proton FD at MCF by simulating the FS with a Hitachi proton machine in research mode, reflecting the higher proton intensities expected with RBOC at MCF. Experiments were conducted to simulate MCF RBOC at Kyoto Prefecture University of Medicine (KPUM) in research mode, reducing delay time (Td) from 1.5ms to 0.1ms. 5,000 contiguous spots were delivered on the central axis for proton energies of 70.2, 142.5, and 220.0MeV; at normal, high dose rate (HDR), and ultra-high dose rate (uHDR) intensities; and at vertical and horizontal gantry angles for different Td. Measurements were taken using a fast oscilloscope and the nozzle's spot position monitor (SPM) and dose monitor (DM). A model was developed to predict FD dependence on beam intensity and assess the dosimetric impact for prostate and brain treatment plans. Two simulation types were planned: a flap DSS plan with FS at every spot and a flap DDCS plan with FS only at the end of each layer. FD was observed for RBOC with Td=0.1ms, showing no gantry angle dependence. FD increased with higher delayed dose rate (DDR), that is, beam intensity. The planning study showed dose volume histogram deterioration with increased FD compared to the clinical plan, but it was only significant for uHDR intensities. Deterioration was marginal in flap DSS plans for the HDR intensities planned at MCF, and flap DDCS plans were even less sensitive than flap DSS plans. MCF is installing proton DDCS with higher beam intensities, a skip spot function, and fast beam-off control. The resulting FD had an insignificant impact on dose distribution for two patient plans with both DSS and DDCS at the anticipated MCF intensities. However, significant dependence was observed in the case of uHDR. A method to measure the position and dose of the FS during commissioning is described in addition to recommendations for regular QA and log-based proton patient-specific quality assurance.

Rapid Sterilization of Clinical Apheresis Blood Products using Ultra-High Dose Rate Radiation.

Apheresis platelets products and plasma are essential for medical interventions, but both still have inherent risks associated with contamination and viral transmission. Platelet products are vulnerable to bacterial contamination due to storage conditions, while plasma requires extensive screening to minimize virus transmission risks. Here we investigate rapid irradiation to sterilizing doses for bacteria and viruses as an innovative pathogen reduction technology. We configured a clinical linear accelerator to deliver ultra-high dose rate (6 kGy/min) irradiation to platelet and plasma blood components. Platelet aliquots spiked with 10 5 CFU of E.coli were irradiated with 0.1-20 kGy, followed by E.coli growth and platelet count assays. COVID Convalescent Plasma (CCP) aliquots were irradiated at a virus-sterilizing dose of 25 kGy and subsequently, RBD- specific antibody binding was assessed. 1 kGy irradiation of bacteria-spiked platelets reduced E.coli growth by 2.7- log without significant change of platelet count, and 5 kGy or higher produced complete growth suppression. The estimated sterilization (6-log bacterial reduction) dose was 2.3 kGy, corresponding to 31% platelet count reduction. A 25 kGy virus sterilizing dose to CCP produced a 9.2% average drop of RBD-specific IgG binding. This study shows proof-of-concept of a novel rapid blood sterilization technique using a clinical linear accelerator. Promising platelet counts and CCP antibody binding were maintained at bacteria and virus sterilizing doses, respectively. This represents a potential point-of-care blood product sterilization solution. If additional studies corroborate these findings, this may be a practical method for ensuring blood products safety. 1 kGy irradiation of bacteria-spiked platelets reduced E.coli growth by 2.7-log without significant change of platelet count, and 5 kGy or higher produced complete growth suppression. The estimated sterilization (6-log bacterial reduction) dose was 2.3 kGy, corresponding to 31% platelet count reduction.A 25 kGy virus sterilizing dose to CCP produced a 9.2% average drop of RBD- specific IgG binding.

Pulsed beam monitoring for electron FLASH.

Safe implementation and translation of FLASH radiotherapy to the clinic requirehs development of beam monitoring devices capable of high temporal resolution with wide dynamic ranges. Ideal detectors should be able to monitor LINAC pulses, withstand high doses and dose rates, and provide information about the beam output, energy/range, and profile. Two novel detectors have been designed and tested for ultra-high dose-rate (UHDR) monitoring: a multilayer nano-structured 3-layer high-energy-current (HEC3) detector, and a segmented large area, 4-section flat (S4) detector with the goal of exploring their properties for a future combined design. A Novalis-TX LINAC was converted to produce a 10 MeV electron-FLASH beam. Pulses were monitored using both HEC3 and S4 detectors. The HEC3 detector structure consisted of three electrode layers separated by a nanoporous aerogel (Aero): Al(50µm)-Aero(100µm)-Ta(10µm)-Aero(100µm)-Al(50µm). The S4 structure was comprised of three layers: Cu(100nm)-air(1mm)-Al(100nm) with contact potential for charge collection. Both detectors are self-powered as they do not require an external voltage bias for charge collection. The beam was also characterized using a photodiode, Gafchromic EBT-XD Film, OSLDs, and an Advanced Markus Chamber. The electron-FLASH beam displayed a Gaussian-like profile with 15cm FWHM at isocenter. Electron-FLASH dose rates up to an average of 260Gy/s were measured on the surface of a solid water phantom at isocenter with an instantaneous dose rate of 1.8×105Gy/s and a dose per pulse of up to 1Gy/pulse. Both HEC3 and S4 detectors could record individual pulses for repetition rates of 360Hz with a 4 µs pulse-width. The HEC3 detector signal increased linearly with dose, MU, number of pulses, and dose rate up to 850Gy/s with no loss of functionality at high doses or dose rates. The S4 detector showed linearity with MU and number of pulses at each of the four channels independently showing potential for spatial information and steering but lacked dose rate independence. Two novel detectors, HEC3 and S4, successfully measured electron-FLASH pulses and hence can be considered capable of electron-FLASH beam monitoring in different capacities. HEC3 detector technology is suitable for monitoring high-dose and UHDR beams with high temporal resolution required for pulse counting. We envision the combination of the HEC3 internal structure with the S4 piece-wise design for real-time monitoring of the temporal structure, spatial profiles, energy, and dosimetric properties of UHDR beams.