Threshold Dose Rate Research Articles

Abstract A003: Influence of beam pauses, dose, and dose rate on the FLASH effect in two mouse models

Abstract Limited understanding of the FLASH effect poses a challenge in gauging the feasibility of translation to clinical practice with the available radiotherapy equipment. We aimed to examine the effect of pausing during treatment, whether due to multi-field treatments or technical difficulties, and if there is a minimum dose or dose rate threshold for FLASH. Experiments were conducted on two distinct beamlines with associated beam properties: (i)a preclinical beamline at University of Washington Medical Center (UWMC) delivering a 50 MeV proton beam in scattering mode, and (ii)a clinical beamline at Fred Hutchinson Proton Therapy Center (PTC), delivering 229 MeV protons with pencil beam scanning (PBS). After dose finding experiments, we delivered a total 14-16 Gy to the pelvis of BALB/c mice or 6-8 Gy to the pelvis of SCID mice in transmission mode (∼45-120 Gy/s FLASH, 0.5-1 Gy/s CONV), using survival as endpoint. Utilizing both beamlines, we demonstrated a FLASH effect for delivery without pauses at or above 45 Gy/s, improving survival from 45% to 83%. The addition of a 30 second- or 2-minute pause in delivery, resulting in 2 doses of 7-8Gy delivered at 45Gy/sec or higher, resulted in a reduction of the FLASH effect, with an overall survival of 67% with either pause length. This led to question if the reduced effectiveness was due to the pause in treatment or reaching a minimum dose threshold. We then chose to examine FLASH with single 6-8Gy exposures in SCID mice as they have a much higher radiosensitivity and enable us to study the same endpoint at lower dose. Interestingly, in SCID mice we did not see a FLASH effect at all, with no significantly different survival either at 8Gy (78-80% survival) or 6Gy (12-15% survival) between FLASH and CONV arms. This loss of the FLASH effect could be explained by several factors; first, we may have hit the minimum dose threshold, second, SCID mice have impaired DNA damage repair (DDR), and third, SCID mice lack a fully functional immune system. To tease this apart we are currently performing experiments to deplete T-cell populations in BALB/c mice with anti-CD4/CD8 antibodies prior to irradiation to reduce immune system functionality but maintain DDR. Results are forthcoming. We observed the FLASH effect for both scattering and scanning proton beams when the dose was delivered in a single irradiation at ≥45 Gy/s. Including a pause of 30 seconds or 2 minutes seems to attenuate the FLASH effect but does not fully negate it. This attenuation may be due to the pause itself or the existence of a minimum dose threshold. Additionally, we have observed a loss of the FLASH effect in SCID mice, but the cause of this remains unknown and under investigation. At present we are working to decouple the potential effects of DDR and immune response in the FLASH effect in SCID mice. Citation Format: Danielle P. Johnson Erickson, Sunan Cui, Ning Cao, Matt Ruth, Alec Morimoto, Benjamin A Shaver, Zacharias Seitz, Clemens Grassberger, Jatinder Saini, Tony Wong, Eric Ford, Ramesh Rengan, Jing Zeng, Marco Schwarz. Influence of beam pauses, dose, and dose rate on the FLASH effect in two mouse models. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr A003.

Possible existence of dose-rate threshold for mutation induction by chronic low-dose-rate gamma-rays.

To assess the biological effects of low-dose and low-dose-rate radiation, we established a sensitive assay system for detecting somatic mutations in hypoxanthine-phosphoribosyltransferase 1 (HPRT1) gene. In this study, we investigated the dose-rate effects of mutagenesis by gamma irradiation at dose-rates of 6.6, 20 and 200mGy d-1. We identified a potential inflection point in the gamma-induced mutant frequency, which ranged between 6.6 and 20mGy d-1. In addition, the mutant spectrum was not different from that of the non-irradiated control at all dose-rates. Compared with previous studies with low-concentration HTO exposure, mutant frequencies were similar, but mutant spectrum showed different trends, especially at high-dose-rates (200mGy d-1). These observations indicate the presence of potential mechanistic differences in mutagenic events between tritium beta and gamma-rays.

A microscopic oxygen transport model for ultra-high dose rate radiotherapy in vivo: The impact of physiological conditions on FLASH effect.

Ultra-high dose rate irradiation (≥40Gy/s, FLASH) has been shown to reduce normal tissue toxicity, while maintaining tumor control compared to conventional dose-rate radiotherapy. The radiolytic oxygen (O2) depletion (ROD) resulting from FLASH has been proposed to explain the normal tissue protection effect; however, in vivo experiments have not confirmed that FLASH induced global tissue hypoxia. Nonetheless, the experiments reported are based on volume-averaged measurement, which have inherent limitations in detecting microscopic phenomena, including the potential preservation of stem cells niches due to local FLASH-induced O2 depletion. Computational modeling offers a complementary approach to understand the ROD caused by FLASH at the microscopic level. We developed a comprehensive model to describe the spatial and temporal dynamics of O2 consumption and transport in response to irradiation in vivo. The change of oxygen enhancement ratio (OER) was used to quantify and investigate the FLASH effect as a function of physiological and radiation parameters at microscopic scale. We considered time-dependent O2 supply and consumption in a 3D cylindrical geometry, incorporating blood flow linking the O2 concentration ([O2]) in the capillary to that within the tissue through the Hill equation, radial and axial diffusion of O2, metabolic and zero-order radiolytic O2 consumption, and a pulsed radiation structure. Time-evolved distributions of [O2] were obtained by numerically solving perfusion-diffusion equations. The model enables the computation of dynamic O2 distribution and the relative change of OER (δROD) under various physiological and radiation conditions in vivo. Initial [O2] level and the subsequent changes during irradiation determined δROD distribution, which strongly depends on physiological parameters, i.e., intercapillary spacing, ultimately determining the tissue area with enhanced radioresistance. We observed that the δROD/FLASH effect is affected by and sensitive to the interplay effect among physiological and radiation parameters. It renders that the FLASH effect can be tissue environment dependent. The saturation of FLASH normal tissue protection upon dose and dose rate was shown. Beyond ∼60Gy/s, no significant decrease in radiosensitivity within tissue region was observed. In turn, for a given dose rate, the change of radiosensitivity became saturated after a certain dose level. Pulse structures with the same dose and instantaneous dose rate but with different delivery times were shown to have distinguishable δROD thus tissue sparing, suggesting the average dose rate could be a metric assessing the FLASH effect and demonstrating the capability of our model to support experimental findings. On a macroscopic scale, the modeling results align with the experimental findings in terms of dose and dose rate thresholds, and it also indicates that pulse structure can vary the FLASH effect. At the microscopic level, this model enables us to examine the spatially resolved FLASH effect based on physiological and irradiation parameters. Our model thus provides a complementary approach to experimental methods for understanding the underlying mechanism of FLASH radiotherapy. Our results show that physiological conditions can potentially determine the FLASH efficacy in tissue protection. The FLASH effect may be observed under optimal combination of physiological parameters, not limited to radiation conditions alone.

A Potential Cause for Unexplained Radiation Toxicity in Proton Therapy

Rare but devastating neurological tissue injury by proton therapy is poorly understood. One consideration is that the transition from passively scattered to pencil beam scanning (PBS) proton radiotherapy over the past decade has affected dose rate. We analyzed clinical data acquired at two institutions on a correlation of voxel-wise dose rates and injury of brain tissue (institution 1) and the optic apparatus (institution 2). All radiation-induced toxicities were delineated (Brain/optic apparatus) on follow-up MRIs. A method to calculate dose rates for PBS plans has been implemented at two institutions independently. Institution 1 reports beam-by-beam time-averaged maximum dose rates per voxel (VMDR) using a 100 ms time interval. Data from four patients who incurred brain tissue injury was included. Dose rate volume histograms were prepared for the target, a 1 cm outer ring to the target, and the necrotic region itself. Prescription doses ranged from 30.6 to 60 Gy delivering either 1.8 or 2.0 Gy per fraction. Tissue injury was generally observed in the dose fall-off at the edge of the target. Additionally, we performed LET weighted dose calculation, robustness analysis, and Monte Carlo calculations. Institution 2 presents voxel-wise dose delivered above a selected dose rate threshold, considering values between 30 and 180 Gy/min. The analysis was performed for 2 cases with optical apparatus injuries and one matching non-toxicity case. Both injuries were observed in the chiasma. Patients received 50.4, 50.4 and 55.8 Gy (non-toxicity) in 1.8 Gy fractions. D1 for chiasma was 51.1, 47.2 and 54 Gy, respectively. Mean and (max) LET in chiasma were 4.02 (4.72), 2.49 (3.16) and 3.44 (4.56) keV/µm accordingly. Institution 1 finds distinct dose rate hot spots in the contoured injured brain regions. Mean VMDR values across all beams are lower in targets than in the 1 cm outer ring (80 Gy/min and 82.8 Gy/min, respectively) and elevated to 113 Gy/min for necrotic regions. Neither of the additional computations showed significant increase of dose in the affected areas. Institution 2 observes that chiasmas, which developed radiation injuries, were exposed to higher dose levels delivered at elevated dose rates (> 72 Gy/min) than the chiasma that did not show any radiation injury. D95 above 72 Gy/min for the two volumes identified as radiation injury was 0.25 and 0.12 Gy/fx, while D98 to chiasmas minus radiation injury or chiasma without any injury for the matching case was 0.06, 0.03 and 0 Gy/fx respectively. Using unique formulations to assess voxel-wise dose rates to brain and optic chiasm, two independent institutions observed that regions with elevated dose rates correlated with radiographic radiation injury. An extended retrospective study including a larger patient cohort with radiation-induced toxicity and asymptomatic patients is under way to confirm or refute the presented observations.

Proton Dosimetry Using Radiation-Induced Luminescence in Micrometer-Core Germanosilicate Optical Fibers

We investigated the radiation-induced luminescence of 62.5 μm, 10 μm and 3 μm germanosilicate single- and multi-mode telecom-grade optical fibers for use as high-resolution dosimeters at dose rates ranging between 5 Gy s <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">-1</sup> and 120 Gy s <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">-1</sup> using proton beams of varying currents and energies. Only one of the two single-mode fibers under investigation had a detectable light yield, with a dose rate threshold around 20 Gy s <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">-1</sup> . All tested multi-mode fibers showed a detectable response over the whole accessible dose rate range. All tested multi-mode fibers displayed a linear dose rate response when the proton beam energy was fixed. However, the slope of the response curve showed a strong dependence on the proton beam energy. Geometry and material differences, as well as radiation-induced attenuation effects have been ruled out as sources for the observed proton energy dependence of the dose rate response.

Modeling ultra-high dose rate electron and proton FLASH effect with the physicochemical approach

Objective. A physicochemical model built on the radiochemical kinetic theory was recently proposed in (Labarbe et al ) to explain the FLASH effect. We performed extensive simulations to scrutinize its applicability for oxygen depletion studies and FLASH-related experiments involving both proton and electron beams. Approach. Using the dose and beam delivery parameters for each FLASH experiment, we numerically solved the radiochemical rate equations comprised of a set of coupled nonlinear ordinary differential equations to obtain the area under the curve (AUC) of radical concentrations. Main results. The modeled differences in AUC induced by ultra-high dose rates appeared to correlate well with the FLASH effect. (i) For the whole brain irradiation of mice performed in (Montay-Gruel et al ), the threshold dose rate values for memory preservation coincided with those at which AUC started to decrease much less rapidly. (ii) For the proton pencil beam scanning FLASH of (Cunningham et al ), we found linear correlations between radicals’ AUC and the biological endpoints: TGF-β1, leg contracture and plasma level of cytokine IL-6. (iii) Compatible with the findings of the proton FLASH experiment in (Kim et al ), we found that radicals’ AUC at the entrance and mid-Spread-Out Bragg peak regions were highly similar. In addition, our model also predicted ratios of oxygen depletion G-values between normal and UHDR irradiation similar to those observed in (Cao et al ) and (El Khatib et al ). Significance. Collectively, our results suggest that the normal tissue sparing conferred by UHDR irradiation may be due to the lower degree of exposure to peroxyl and superoxide radicals. We also found that the differential effect of dose rate on the radicals’ AUC was less pronounced at lower initial oxygen levels, a trait that appears to align with the FLASH differential effect on normal versus tumor tissues.

Heavy concrete shielding properties for carbon therapy

As medical facilities are usually built at urban areas, special concrete aggregates and evaluation methods are needed to optimize the design of concrete walls by balancing density, thickness, material composition, cost, and other factors. Carbon treatment rooms require a high radiation shielding requirement, as the neutron yield from carbon therapy is much higher than the neutron yield of protons. In this case study, the maximum carbon energy is 430 MeV/u and the maximum current is 0.27 nA from a hybrid particle therapy system. Hospital or facility construction should consider this requirement to design a special heavy concrete. In this work, magnetite is adopted as the major aggregate. Density is determined mainly by the major aggregate content of magnetite, and a heavy concrete test block was constructed for structural tests. The compressive strength is 35.7 MPa. The density ranges from 3.65 g/cm3 to 4.14 g/cm3, and the iron mass content ranges from 53.78% to 60.38% from the 12 cored sample measurements. It was found that there is a linear relationship between density and iron content, and mixing impurities should be the major reason leading to the nonuniform element and density distribution. The effect of this nonuniformity on radiation shielding properties for a carbon treatment room is investigated by three groups of Monte Carlo simulations. Higher density dominates to reduce shielding thickness. However, a higher content of high-Z elements will weaken the shielding strength, especially at a lower dose rate threshold and vice versa. The weakened side effect of a high iron content on the shielding property is obvious at 2.5 μSv/h. Therefore, we should not blindly pursue high Z content in engineering. If the thickness is constrained to 2 m, then the density can be reduced to 3.3 g/cm3, which will save cost by reducing the magnetite composition with 50.44% iron content. If a higher density of 3.9 g/cm3 with 57.65% iron content is selected for construction, then the thickness of the wall can be reduced to 174.2 cm, which will save space for equipment installation.

Trade-off in healthy tissue sparing of FLASH and fractionation in stereotactic proton therapy of lung lesions with transmission beams.

Besides a dose-rate threshold of 40-100Gy/s, the FLASH effect may require a dose>3.5-7Gy. Even in hypofractioned treatments, with all beams delivered in each fraction (ABEF), most healthy tissue is irradiated to a lower fraction dose. This can be circumvented by single-beam-per-fraction (SBPF) delivery, with a loss of healthy tissue sparing by fractionation. We investigated the trade-off between FLASH and loss of fractionation in SBPF stereotactic proton therapy of lung cancer and determined break-even FLASH-enhancement ratios (FERs). Treatment plans for 12 patients were generated. GTV delineations were available and a 5mm GTV-PTV margin was applied. Equiangular arrangements of 3, 5, 7, and 9 244MeV proton transmission beams were used. To facilitate SBPF, the number of fractions was equal to the number of beams. Iso-effective fractionation schedules with a single field uniform dose prescription were used: D95%,PTV=100%Dpres per beam. All plans were evaluated in terms of dose to lung and conformity of dose to target of FLASH-enhanced biologically equivalent dose (EQD2). Compared to ABEF, SBPF resulted in a median increase of EQD2mean to healthy lung of 56%, 58%, 55% and 54% in plans with 3, 5, 7 and 9 fractions respectively and of 236%, 78%, 50% and 41% in V100% EQD2, quantifying conformity. This can be compensated for by FERs of at least 1.28, 1.32, 1.30 and 1.23 respectively for EQD2mean and 1.29, 1.18, 1.28 and 1.15 for V100%,EQD2. A FLASH effect outweighing the loss of fractionation in SBPF may be achieved in stereotactic lung treatments. The trade-off with fractionation depends on the conditions under which the FLASH effect occurs. Better understanding of the underlying biology and the impact of delivery conditions is needed.

Use of single-energy proton pencil beam scanning Bragg peak for intensity-modulated proton therapy FLASH treatment planning in liver-hypofractionated radiation therapy.

The transmission proton FLASH technique delivers high doses to the normal tissue distal to the target, which is less conformal compared to the Bragg peak technique. To investigate FLASH radiotherapy (RT) planning using single-energy Bragg peak beams with a similar beam arrangement as clinical intensity-modulated proton therapy (IMPT) in a liver stereotactic body radiation therapy (SBRT) and to characterize the plan quality, dose sparing of organs-at-risk (OARs), and FLASH dose rate percentage. An in-house platform was developed to enable inverse IMPT-FLASH planning using single-energy Bragg peaks. A universal range shifter and range compensators were utilized to effectively align the Bragg peak to the distal edge of the target. Two different minimum MU settings of 400 and 800 MU/spot (Bragg-400 MU and Bragg-800 MU) plans were investigated on 10 consecutive hepatocellular carcinoma patients previously treated by IMPT-SBRT to evaluate the FLASH dose and dose rate coverage for OARs. The IMPT-FLASH using single-energy Bragg peaks delivered 50Gy in five fractions with similar or identical beam arrangement to the clinical IMPT-SBRT plans. NRG GI003 dose constraint metrics were used. Three dose rate calculation methods, including average dose rate (ADR), dose threshold dose rate (DTDR), and dose-ADR (DADR), were all studied. The novel spot map optimization can fulfill the inverse planning using single-energy Bragg peaks. All the Bragg peak FLASH plans achieved similar results for the liver-gross tumor volume (GTV) Dmean and heart , compared to SBRT-IMPT. The Bragg-800 MU plans resulted in 18.3% higher clinical target volume (CTV) compared with SBRT (p<0.05), and no significant difference was found between Bragg-400 MU and SBRT plans. For the CTV Dmax , SBRT plans resulted in 10.3% (p<0.01) less than Bragg-400 MU plans and 16.6% (p<0.01) less than Bragg-800 MU plans. The Bragg-800 MU plans generally achieved higher ADR, DADR, and DTDR dose rates than Bragg-400 MU plans, and DADR mostly led to the highest V40Gy/s compared to other dose rate calculation methods, whereas ADR led to the lowest. The lower dose rate portions in certain OARs are related to the lower dose deposited due to the farther distances from targets, especially in the penumbra of the beams. Single-energy Bragg peak IMPT-FLASH plans eliminate the exit dose in normal tissues, maintaining comparable dose metrics to the conventional IMPT-SBRT plans, while achieving a sufficient FLASH dose rate for liver cancers. This study demonstrates the feasibility of and sufficiently high dose rate when applying the Bragg peak FLASH treatment for a liver cancer hypofractionated FLASH therapy. The advancement of this novel method has the potential to optimize treatment for liver cancer patients.

Radiolysis-Driven Evolution of Gold Nanostructures - Model Verification by Scale Bridging In Situ Liquid-Phase Transmission Electron Microscopy and X-Ray Diffraction.

Utilizing ionizing radiation for in situ studies in liquid media enables unique insights into nanostructure formation dynamics. As radiolysis interferes with observations, kinetic simulations are employed to understand and exploit beam‐liquid interactions. By introducing an intuitive tool to simulate arbitrary kinetic models for radiation chemistry, it is demonstrated that these models provide a holistic understanding of reaction mechanisms. This is shown for irradiated HAuCl4 solutions allowing for quantitative prediction and tailoring of redox processes in liquid‐phase transmission electron microscopy (LP‐TEM). Moreover, it is demonstrated that kinetic modeling of radiation chemistry is applicable to investigations utilizing X‐rays such as X‐ray diffraction (XRD). This emphasizes that beam‐sample interactions must be considered during XRD in liquid media and shows that reaction kinetics do not provide a threshold dose rate for gold nucleation relevant to LP‐TEM and XRD. Furthermore, it is unveiled that oxidative etching of gold nanoparticles depends on both, precursor concentration, and dose rate. This dependency is exploited to probe the electron beam‐induced shift in Gibbs free energy landscape by analyzing critical radii of gold nanoparticles.

Ecologically relevant radiation exposure triggers elevated metabolic rate and nectar consumption in bumblebees

Abstract Exposure to radiation is a natural part of our environment. Yet, due to nuclear accidents such as at Chernobyl, some organisms are exposed to significantly elevated dose rates. Our understanding of the effects of radiation in the environment is limited, confounded by substantial interspecific differences in radio‐sensitivity and conflicting findings. Here we study radiation impacts on bumblebees in the laboratory using principles from life‐history theory, which assume organismal investment in fitness‐related traits is constrained by resource availability and resource allocation decisions. To investigate how chronic radiation might negatively affect life‐history traits, we tested whether exposure affects bumblebee energy budgets by studying resource acquisition (feeding) and resource use (metabolic rate). We monitored metabolic rate, movement and nectar intake of bumblebees before, during and after 10 days of radiation exposure. Subsequently, we monitored feeding and body mass across a dose rate gradient to investigate the dose rate threshold for these effects. We studied dose rates up to 200 μGy/hr: a range found today in some areas of the Chernobyl Exclusion Zone. Chronic low‐dose radiation affected bumblebee energy budgets. At 200 μGy/hr nectar consumption elevated by 56% relative to controls, metabolic CO2 production increased by 18%, and time spent active rose by 30%. Once radiation exposure stopped, feeding remained elevated but CO2 production and activity returned to baseline. Our analysis indicates that elevated metabolic rate was not driven by increased activity but was instead closely associated with feeding increases. Our data suggest bumblebee nectar consumption was affected across the 50–200 μGy/hr range. We show field‐realistic radiation exposure influences fundamental metabolic processes with potential to drive changes in many downstream life‐history traits. We hypothesise that radiation may trigger energetically costly repair mechanisms, increasing metabolic rate and nectar requirements. This change could have significant ecological consequences in contaminated landscapes, including Chernobyl. We demonstrate bumblebees are more sensitive to radiation than assumed by existing international frameworks for environmental radiological protection. Read the free Plain Language Summary for this article on the Journal blog.

Radiolysis and Radiation-Driven Dynamics of Boehmite Dissolution Observed by In Situ Liquid-Phase TEM.

Over the last several decades, there have been several studies examining the radiation stability of boehmite and other aluminum oxyhydroxides, yet less is known about the impact of radiation on boehmite dissolution. Here, we investigate radiation effects on the dissolution behavior of boehmite by employing liquid-phase transmission electron microscopy (LPTEM) and varying the electron flux on the samples consisting of either single nanoplatelets or aggregated stacks. We show that boehmite nanoplatelets projected along the [010] direction exhibit uniform dissolution with a strong dependence on the electron dose rate. For nanoplatelets that have undergone oriented aggregation, we show that the dissolution occurs preferentially at the particles at the ends of the stacks that are more accessible to bulk solution than at the others inside the aggregate. In addition, at higher dose rates, electrostatic repulsion and knock-on damage from the electron beam causes delamination of the stacks and dissolution at the interfaces between particles in the aggregate, indicating that there is a threshold dose rate for electron-beam enhancement of dissolution of boehmite aggregates.

Treatment planning for Flash radiotherapy: General aspects and applications to proton beams.

The increased radioresistence of healthy tissues when irradiated at very high dose rates (known as the Flash effect) is a radiobiological mechanism that is currently investigated to increase the therapeutic ratio of radiotherapy treatments. To maximize the benefits of the clinical application of Flash, a patient-specific balance between different properties of the dose distribution should be found, that is, Flash needs to be one of the variables considered in treatment planning. We investigated the Flash potential of three proton therapy planning and beam delivery techniques, each on a different anatomical region. Based on a set of beam delivery parameters, on hypotheses on the dose and dose rate thresholds needed for the Flash effect to occur, and on two definitions of Flash dose rate, we generated exemplary illustrations of the capabilities of current proton therapy equipment to generate Flash dose distributions. All techniques investigated could both produce dose distributions comparable with a conventional proton plan and reach the Flash regime, to an extent that was strongly dependent on the dose per fraction and the Flash dose threshold. The beam current, Flash dose rate threshold, and dose rate definition typically had a more moderate effect on the amount of Flash dose in normal tissue. A systematic estimation of the impact of Flash on different patient anatomies and treatment protocols is possible only if Flash-specific treatment planning features become readily available. Planning evaluation tools such as a voxel-based dose delivery time structure, and the inclusion in the optimization cost function of parameters directly associated with Flash (e.g., beam current, spot delivery sequence, and scanning speed), are needed to generate treatment plans that are taking full advantage of the potential benefits of the Flasheffect.

A quantitative FLASH effectiveness model to reveal potentials and pitfalls of high dose rate proton therapy.

PurposeIn ultrahigh dose rate radiotherapy, the FLASH effect can lead to substantially reduced healthy tissue damage without affecting tumor control. Although many studies show promising results, the underlying biological mechanisms and the relevant delivery parameters are still largely unknown. It is unclear, particularly for scanned proton therapy, how treatment plans could be optimized to maximally exploit this protective FLASH effect.Materials and MethodsTo investigate the potential of pencil beam scanned proton therapy for FLASH treatments, we present a phenomenological model, which is purely based on experimentally observed phenomena such as potential dose rate and dose thresholds, and which estimates the biologically effective dose during FLASH radiotherapy based on several parameters. We applied this model to a wide variety of patient geometries and proton treatment planning scenarios, including transmission and Bragg peak plans as well as single‐ and multifield plans. Moreover, we performed a sensitivity analysis to estimate the importance of each model parameter.ResultsOur results showed an increased plan‐specific FLASH effect for transmission compared with Bragg peak plans (19.7% vs. 4.0%) and for single‐field compared with multifield plans (14.7% vs. 3.7%), typically at the cost of increased integral dose compared to the clinical reference plan. Similar FLASH magnitudes were found across the different treatment sites, whereas the clinical benefits with respect to the clinical reference plan varied strongly. The sensitivity analysis revealed that the threshold dose as well as the dose per fraction strongly impacted the FLASH effect, whereas the persistence time only marginally affected FLASH. An intermediate dependence of the FLASH effect on the dose rate threshold was found.ConclusionsOur model provided a quantitative measure of the FLASH effect for various delivery and patient scenarios, supporting previous assumptions about potentially promising planning approaches for FLASH proton therapy. Positive clinical benefits compared to clinical plans were achieved using hypofractionated, single‐field transmission plans. The dose threshold was found to be an important factor, which may require more investigation.

A Novel Proton Pencil Beam Scanning FLASH RT Delivery Method Enables Optimal OAR Sparing and Ultra-High Dose Rate Delivery: A Comprehensive Dosimetry Study for Lung Tumors.

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

Carbon Nanotubes for Radiation-Tolerant Electronics.

Electronics for space applications have stringent requirements on both performance and radiation tolerance. The constant exposure to cosmic radiation damages and eventually destroys electronics, limiting the lifespan of all space-bound missions. Thus, as space missions grow increasingly ambitious in distance away from Earth, and therefore time in space, the electronics driving them must likewise grow increasingly radiation-tolerant. In this work, we show how carbon nanotube (CNT) field-effect transistors (CNFETs), a leading candidate for energy-efficient electronics, can be strategically engineered to simultaneously realize a robust radiation-tolerant technology. We demonstrate radiation-tolerant CNFETs by leveraging both extrinsic CNFET benefits owing to CNFET device geometries enabled by their low-temperature fabrication, as well as intrinsic CNFET benefits owing to CNTs' inherent material properties. By performing a comprehensive study and optimization of CNFET device geometries, we demonstrate record CNFET total ionizing dose (TID) tolerance (above 10 Mrad(Si)) and show transient upset testing on complementary metal-oxide-semiconductor (CMOS) CNFET-based 6T SRAM memories via X-ray prompt dose testing (threshold dose rate = 1.3 × 1010 rad(Si)/s). Taken together, this work demonstrates CNFETs' potential as a technology for next-generation space applications.

Probabilistic risk assessment of solar particle events considering the cost of countermeasures to reduce the aviation radiation dose

Cosmic-ray exposure to flight crews and passengers, which is called aviation radiation exposure, is an important topic in radiological protection, particularly for solar energetic particles (SEP). We therefore assessed the risks associated with the countermeasure costs to reduce SEP doses and dose rates for eight flight routes during five ground level enhancements (GLE). A four-dimensional dose-rate database developed by the Warning System for Aviation Exposure to Solar Energetic Particles, WASAVIES, was employed in the SEP dose evaluation. As for the cost estimation, we considered two countermeasures; one is the cancellation of the flight, and the other is the reduction of flight altitudes. Then, we estimated the annual occurrence frequency of significant GLE events that would bring the maximum flight route dose and dose rate over 1.0 mSv and 80 μSv/h, respectively, based on past records of GLE as well as historically large events observed by the cosmogenic nuclide concentrations in tree rings and ice cores. Our calculations suggest that GLE events of a magnitude sufficient to exceed the above dose and dose rate thresholds, requiring a change in flight conditions, occur once every 47 and 17 years, respectively, and their conservatively-estimated annual risks associated with the countermeasure costs are up to around 1.5 thousand USD in the cases of daily-operated long-distance flights.

Detecting Ground Level Enhancements Using Soil Moisture Sensor Networks

AbstractGround level enhancements (GLEs) are space weather events that pose a potential hazard to the aviation environment through single event effects in avionics and increased dose to passengers and crew. The existing ground level neutron monitoring network provides continuous and well‐characterized measurements of the radiation environment. However, there are only a few dozen active stations worldwide, and there has not been a UK‐based station for several decades. Much smaller neutron detectors are increasingly deployed throughout the world with the purpose of using secondary neutrons from cosmic rays to monitor local soil moisture conditions (COSMOS). Space weather signals from GLEs and Forbush decreases have been identified in COSMOS data. Monte Carlo simulations of atmospheric radiation propagation show that a single COSMOS detector is sufficient to detect the signal of a medium‐strength (10%–100% increase above background) GLE at high statistical significance, including at fine temporal resolution. Use of fine temporal resolution would also provide a capability to detect Terrestrial Gamma Ray Flashes (via secondary neutrons) which are produced by certain lightning discharges and which can provide a hazard to aircraft, particularly in tropical regions. We also show how the COsmic‐ray Soil Moisture Observing System‐UK detector network could be used to provide warnings at the International Civil Aviation Organization “Moderate” and “Severe” dose rate thresholds at aviation altitudes, and how multiple‐detector hubs situated at strategic UK locations could detect a small GLE at high statistical significance and infer crucial information on the nature of the primary spectrum.

Induction of somatic mutations by low concentrations of tritiated water (HTO): evidence for the possible existence of a dose-rate threshold.

Tritium is a low energy beta emitter and is discharged into the aquatic environment primarily in the form of tritiated water (HTO) from nuclear power plants or from nuclear fuel reprocessing plants. Although the biological effects of HTO exposures at significant doses or dose rates have been extensively studied, there are few reports concerning the biological effects of HTO exposures at very low dose rates. In the present study using a hyper-sensitive assay system, we investigated the dose rate effect of HTO on the induction of mutations. Confluent cell populations were exposed to HTO for a total dose of 0.2 Gy at dose rates between 4.9 mGy/day and 192 mGy/day by incubating cells in medium containing HTO. HTO-induced mutant frequencies and mutation spectra were then investigated. A significant inflection point for both the mutant frequency and mutation spectra was found between 11 mGy/day and 21.6 mGy/day. Mutation spectra analysis revealed that a mechanistic change in the nature of the mutation events occurred around 11 mGy/day. The present observations and published experimental results from oral administrations of HTO to mice suggest that a threshold dose-rate for HTO exposures might exist between 11 mGy/day and 21.6 mGy/day where the nature of the mutation events induced by HTO becomes similar to those seen in spontaneous events.

Threshold dose rates for the cytogenetic effects in crested hairgrass populations from the Semipalatinsk nuclear test site, Kazakhstan

An assessment of cytogenetic effects in crested hairgrass (Koeleria gracilis Pers.) populations was carried out within the Semipalatinsk nuclear test site (Kazakhstan) where combat radioactive substances were tested in 1953–1957. Current levels of radioactive contamination within this site are varied by orders of magnitude, while soil characteristics and heavy metal pollution are similar. The main contribution to the absorbed by plants doses at this site was caused by incorporated 90Sr. The frequency of cytogenetic alterations in crested hairgrass was investigated in a wide range of doses (10−4–13 Gy/growing season) at 100 sampling points. For the first time in the field conditions the shape of the cytogenetic effects - dose rate relationship was evaluated with acceptable accuracy and found to be nonlinear. The frequency of aberrant cells remained practically unchanged up to 49 µGy/h. Exceeding the threshold dose rate lead to a steep increase in the aberrant cells frequency from less than 2% up to 16%. The main contribution to the cytogenetic effects was made by double bridges and fragments. Breakpoints for other types of cytogenetic alterations were also evaluated (7 µGy/h for single fragments and bridges; 74 for double fragments and bridges; 81 for mitotic abnormalities).