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Laser-plasma accelerators (LPAs) can deliver pico- to nanosecond long proton bunches, with ≥∼100 nC of charge dispersed over a broad energy spectrum. Increasing the repetition rates of today’s LPAs is a necessity for their practical application. This, however, creates a need for real-time proton bunch diagnostics. Scintillating screens are one detector solution, commonly applied in the field of electron LPAs for spatially resolved particle and radiation detection, yet their establishment for LPA proton detection is only slowly taking off. This is also due to the lack of available calibrations. In this paper, we present an absolute proton number calibration for the scintillating screen type DRZ High (Mitsubishi Chemical Corporation, Düsseldorf, Germany), one of the most sensitive screens according to calibrations for relativistic electrons and x-rays. For proton irradiation of the DRZ High screen, we find an increase in light yield of >60% compared to reference calibration data for relativistic electrons. The presented absolute light yield calibration shows an uncertainty of the proton number of 10% and can seamlessly be applied at other LPA facilities. Moreover, we investigate the scintillating screen light yield dependence on proton energy, since many types of scintillators (e.g., plastic, liquid, inorganic) show a reduced light yield for increased local energy deposition densities, an effect termed ionization quenching. The ionization quenching can reduce the light yield for low-energy protons by up to ∼20%. This work provides all necessary data for absolute spectral measurements of LPA protons with DRZ High scintillating screens, e.g., when these are used as detectors in the commonly available Thomson parabola spectrometers.

All necessary Data to recreate the published plots and images in the publication: "Absolute energy-dependent scintillating screen calibration for real-time detection of laser-accelerated proton bunches". Included are the raw scintillating screen images, the plotting data and Python Scripts used for calculations and plotting.

Purpose: A better knowledge of the dependence of the tissue sparing effect at ultra-high dose rate (UHDR) on physical beam parameters (dose, dose rate, radiation quality) would be helpful towards a mechanistic understanding of the FLASH effect and for its broader clinical translation. To address this, a comprehensive study on the normal tissue sparing at UHDR using the zebrafish embryo (ZFE) model irradiated with protons and electrons was conducted. Methods: 1 day old ZFE were irradiated over a wide dose range (15-95 Gy) in three different beams (proton entrance channel, proton spread out Bragg peak and 30 MeV electrons) at UHDR and reference dose rate. After irradiation the ZFE were incubated for 4 days and then analyzed for their development and morphological characteristics. Results: Dose-effect curves for four different biological endpoints of ZFE (pericardial edema, curved spine, embryo length and eye diameter) were obtained and a sparing effect was observed for all three beams. It was demonstrated that proton relative biological effectiveness and UHDR sparing are both relevant to consider in order to predict the resulting dose response. Dose dependent FLASH modifying factors (FMF) for ZFE, calculated based on the obtained dose-effect curves, were found to be compatible with rodent data from the literature. It was found that the UHDR sparing effect saturates at doses above ~50 Gy with an FMF of ~0.7-0.8. Only a moderate dependence of the tissue sparing effect in ZFE on the biological endpoint, but a strong dose rate dependence were observed. Conclusion: The ZFE model was shown to be a suitable high-throughput pre-clinical model for radiobiological studies on FLASH radiotherapy, providing results comparable to rodent models. The obtained results emphasize to further clarify the nature of the observed dose rate dependence.

Proton beam-induced convection in water triggered local MRI magnitude signal loss in combined imaging and irradiation experiments performed on a new research prototype in-beam low-field MRI proton radiotherapy device. In this study, the influence of convection on the MRI phase signal was tested. Both mechanical and thermal inhibition of convection in dedicated water phantoms resulted in the absence of MRI phase signatures, which were clearly visible under conditions were convection could develop. Moreover, a change in either convection velocity or Venc sequence motion sensitivity changed the observed phase contrast, confirming the convection-driven phase contrast mechanism.

Böhlen et al. [1] recently proposed a model that describes the magnitude of the normal tissue sparing Flash effect as a function of dose based on available in vivo data. The newly introduced flash modifying factor FMF translates doses applied at ultra-high dose rate to equivalent doses at conventional dose rate similar to the concept of relative biological effectiveness [1]. Primarily founded on rodent data, the model [1] includes only one study that demonstrated a dose-dependent Flash effect by length differences measured at 5 days-old zebrafish embryo (ZFE) after irradiation with electron doses of 5 – 12 Gy [2]. We studied this systematic overview about the available Flash data with great interest and acknowledged it as a very useful guidance for future Flash research. Coincidentally, we have just recently measured ZFE data in the high dose range (15 – 50 Gy) that appear to match very well with the existing rodent data. Comparable to our previous studies at the ELBE accelerator [3, 4], one day-old ZFE were irradiated using electron beams of reference (mean dose rate 0.11 Gy/s) and ultra-high dose rate (UHDR; mean dose rate 0.9×105 Gy/s) (Fig. 1a). Normal tissue toxicity was quantified by analyzing the length deficit of the 5 days-old embryos compared to unirradiated controls. Since the controls grew on average 30% from irradiation to analysis this is the maximum length deficit that can be caused by irradiation. The derived FMF values extend the available ZFE data [2] and cover in a single experiment almost the entire dose range applied in the rodent studies for different tissues. Comparable to the rodent data (Fig. 1b) the ZFE FMF increases with dose. The good agreement of our ZFE data with the rodent data [1] demonstrates the feasibility of the ZFE model for basic Flash effect studies, e.g., on the influence of physical beam parameters [3–6]. Hence, the ZFE model could be deployed as a high-throughput alternative to rodent studies at this translational level [5]

The main advantage proton beams offer over photon beams in radiation therapy of cancer patients is the dose maximum at their finite range, yielding a reduction in the dose deposited in healthy tissues surrounding the tumor. Since no direct method exists to measure the beam’s range during dose delivery, safety margins around the tumor are applied, compromising the dose conformality and reducing the targeting accuracy. Here, we demonstrate that online MRI can visualize the proton beam and reveal its range during irradiation of liquid-filled phantoms. A clear dependence on beam energy and current was found. These results stimulate research into novel MRI-detectable beam signatures and already find application in the geometric quality assurance for magnetic resonance-integrated proton therapy systems currently under development.

Laser plasma-based proton accelerators (LPA) can contribute to research of ultra-high dose rate radiobiology as they provide pulse dose rates unprecedented at medical proton sources. Yet, LPAs pose challenges regarding precise dosimetry due to the high pulse dose rates, but also due to the sources' lower spectral stability and pulsed operation mode. For in-vivo models, further challenges arise from the necessary small field dosimetry for volumetric dose distributions. In this work, we present a dosimetry and beam monitoring concept for in-vivo irradiations of small target volumes with LPA protons, solving aforementioned challenges. The volumetric dose distribution in a sample (mean dose value and lateral/depth dose inhomogeneity) is provided by combining two independent dose measurements using radiochromic films (dose-rate independent) and ionization chambers (dose-rate dependent), respectively. The unique feature of the dosimetric setup is beam monitoring with a transmission time-of-flight spectrometer to quantify spectral fluctuations of the irradiating proton pulses. The resulting changes in the depth dose profile during irradiation of an in-vivo sample are hence accessible and enable pulse-resolved depth dose correction for each dose measurement. A first successful small animal pilot study using an LPA proton source serves as a testcase for the presented dosimetry approach and proves its performance in a realistic setting.

The University Proton Therapy facility in Dresden (UPTD), Germany, is equipped with an experimental room with a beamline providing a static pencil beam. High proton beam currents can be achieved at this beamline which makes it suitable for FLASH experiments. However, the established experimental setup uses only the entrance channel of the proton Bragg curve. In this work, a set of 3D-printed range modulators designed to generate spread out Bragg peaks (SOBPs) for radiobiological experiments at ultra-high dose rate at this beamline is described. A new method to optimize range modulators specifically for the case of a static pencil beam based on the central depth dose profile is introduced. Modulators for two different irradiation setups were produced and characterized experimentally by measurements of lateral and depth dose distributions using different detectors. In addition, Monte Carlo simulations were performed to assess profiles of the dose averaged linear energy transfer. These newly produced range modulators will allow future proton FLASH experiments in the SOBP at UPTD with two different experimental setups.

The recently observed FLASH effect provides normal tissue protection at a similar tumor treatment efficacy via ultra-high dose rate (UHDR) irradiation and promises great benefits for radiotherapy patients. Dedicated studies are now necessary to define a robust set of dose application parameters for FLASH radiotherapy and to identify underlying mechanisms. These studies require particle accelerators with variable temporal dose application characteristics for numerous radiation qualities, equipped for preclinical radiobiological research. Here we present the DRESDEN PLATFORM, a research hub for ultra-high dose rate radiobiology. By uniting clinical and research accelerators with radiobiology infrastructure and know-how, the DRESDEN PLATFORM offers a unique environment for studying the FLASH effect. We introduce its experimental capabilities and qualify the platform for systematic investigation of FLASH by presenting results from a concerted in vivo radiobiology study with zebrafish embryos. The comparative pre-clinical study was conducted across three accelerator facilities, including an advanced laser-driven proton source applied for FLASH-relevant in vivo irradiations for the first time. The data show a protective effect of UHDR irradiation up to 10^5 Gy/s and suggests consistency of the protective effect even at escalated dose rates of 10^9 Gy/s. With the first clinical FLASH studies underway, research facilities like the DRESDEN PLATFORM, addressing the open questions surrounding FLASH, are essential to accelerate FLASH’s translation into clinical practice.

Böhlen et al. [1] recently proposed a model that describes the magnitude of the normal tissue sparing Flash effect as a function of dose based on available in vivo data. The newly introduced flash modifying factor FMF translates doses applied at ultra-high dose rate to equivalent doses at conventional dose rate similar to the concept of relative biological effectiveness [1]. Primarily founded on rodent data, the model [1] includes only one study that demonstrated a dose-dependent Flash effect by length differences measured at 5 days-old zebrafish embryo (ZFE) after irradiation with electron doses of 5 – 12 Gy [2]. We studied this systematic overview about the available Flash data with great interest and acknowledged it as a very useful guidance for future Flash research. Coincidentally, we have just recently measured ZFE data in the high dose range (15 – 50 Gy) that appear to match very well with the existing rodent data. Comparable to our previous studies at the ELBE accelerator [3, 4], one day-old ZFE were irradiated using electron beams of reference (mean dose rate 0.11 Gy/s) and ultra-high dose rate (UHDR; mean dose rate 0.9×105 Gy/s) (Fig. 1a). Normal tissue toxicity was quantified by analyzing the length deficit of the 5 days-old embryos compared to unirradiated controls. Since the controls grew on average 30% from irradiation to analysis this is the maximum length deficit that can be caused by irradiation. The derived FMF values extend the available ZFE data [2] and cover in a single experiment almost the entire dose range applied in the rodent studies for different tissues. Comparable to the rodent data (Fig. 1b) the ZFE FMF increases with dose. The good agreement of our ZFE data with the rodent data [1] demonstrates the feasibility of the ZFE model for basic Flash effect studies, e.g., on the influence of physical beam parameters [3–6]. Hence, the ZFE model could be deployed as a high-throughput alternative to rodent studies at this translational level [5]

Laser-plasma accelerated (LPA) proton bunches are now prepared and provided for research fields ranging from ultra-high dose rate radiobiology to material science and probing of extreme states of matter. Yet, the capabilities to fully characterize the spectrally and angularly broad LPA bunches lag behind the rapidly evolving applications. The Optical Cone beam TOmograph for Proton Online Dosimetry - short OCTOPOD - translates the angularly resolved spectral characterization of LPA proton bunches into the spatially resolved detection of the volumetric dose distribution deposited in a liquid scintillator. Up to 24 multi-pinhole arrays record projections of the volumetric scintillation light distribution and allow for tomographic reconstruction of the volumetric dose deposition pattern, from which proton spectra may be retrieved in arbitrary directions by spectral deconvolution. Applying the OCTOPOD at a cyclotron, we show the reliable retrieval of various spatial dose deposition patterns and detector sensitivity over a broad dose range from less than 1 Gy to more than 100 Gy, as required for LPA proton bunch characterization. With a dedicated vacuum housing, the OCTOPOD was installed at a LPA proton source, providing real-time data on proton acceleration performance for various laser-target interaction parameters and attesting the system optimal performance in the harsh laser plasma environment.

Objective. Local magnetic resonance (MR) signal loss was previously observed during proton beam irradiation of free-floating water phantoms at ambient temperature using a research prototype in- beam magnetic resonance imaging (MRI) scanner. The emergence of this MR signal loss was hypothesised to be dependent on beam-induced convection. The aim of this study was therefore to unravel whether physical conditions allowing the development of convection must prevail for the beam-induced MRI signatures to emerge. Approach. The convection dependence of MRI magnitude signal-based proton beam visualisation was investigated in combined irradiation and imaging experiments using a gradient echo (GE)-based time-of-flight (ToF) angiography pulse sequence, which was first tested for its suitability for proton beam visualisation in free-floating water phantoms at ambient temperature. Subsequently, buoyant convection was selectively suppressed in water phantoms using either mechanical barriers or temperature control of water expansivity. The underlying contrast mechanism was further assessed using sagittal imaging and variation of T1 relaxation time-weighting. Main results. In the absence of convection-driven water flow, weak beam- induced MR signal changes occurred, whereas strong changes did occur when convection was not mechanically or thermally inhibited. Moreover, the degree of signal loss was found to change with the variation of T1-weighting. Consequently, beam-induced MR signal loss in free-floating water phantoms at ambient temperature does not exclusively originate from buoyant convection, but is caused by local composite effects of beam-induced motion and radiation chemistry resulting in a local change in the water T1 relaxation time. Significance. The identification of ToF angiography sequence- based proton beam visualisation in water phantoms to result from composite effects of beam-induced motion and radiation chemistry represents the starting point for the future eluc

Purpose: The low sensitivity and limitation to water phantoms of convection-dependent MRI magnitude signal-based proton beam visualization hinder its in-vivo applicability in MR-integrated proton beam therapy. The purpose of the present study was therefore to assess possible contrast mechanisms for MRI phase signal-based proton beam visualization that can potentially be exploited to enhance the sensitivity of the method and extend its applicability to tissue materials. Methods: To assess whether proton beam-induced magnetic field perturbations, changes in material susceptibility or convection result in detectable changes in the MRI phase signal, water phantom characteristics, experiment timing and imaging parameters were varied in combined irradiation and imaging experiments using a time-of-flight angiography pulse sequence on a prototype in-beam MRI scanner. Velocity encoding was used to further probe and quantify beam-induced convection. Results: MRI phase signal-based proton beam visualization proved feasible. The observed phase difference contrast was evoked by beam-induced buoyant convection with flow velocities in the mm/s range. Proton beam-induced magnetic field perturbations or changes in magnetic susceptibility did not influence the MRI phase signal. Velocity encoding was identified as a means to further enhance the detection sensitivity. Conclusion: Because the MRI phase difference contrast observed during proton beam irradiation of water phantoms is caused by beam-induced convection, this method will unlikely be transferable to tightly compartmentalized tissue wherein flow effects are restricted. Strongly velocity encoded pulse sequences, however, were identified as promising candidates for the future development of MRI- based methods for water phantom-based geometric quality assurance in MR-integrated proton beam therapy.

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

The data set comprises raw data, processed data and detector data for the OCTOPOD detector applied for characterization of proton bunches at a proton cyclotron and a laser-driven proton accelerator.

Source data, scripts and parts of figures to generate the figures in publication

The data set comprises raw data, processed data and detector data for the miniSCIDOM detector applied for characterization of proton bunches at a proton cyclotron and a laser-driven proton accelerator.

Background and Aims The Flash effect, i.e. the radiobiological observation of normal tissue sparing but efficient tumor killing by ultra-high dose rate (UHDR) irradiation, promise great benefits for cancer patient treatment. The translation process of the Flash effect should be accompanied by systematic studies on the necessary beam parameters for each clinical applied radiation. Using the zebrafish embryo model, the influence of partial oxygen level (https://doi.org/10.1016/j.radonc.2021.02.003), electron pulse structure and dose were studied thoroughly. To investigate a similar range of proton beam parameters UHDR experiments at different accelerators, but under comparable conditions, are required. Methods To cover a broad range of proton dose rates, experiments have been prepared at the University Proton Therapy Dresden (UPTD) and at the Draco laser accelerator (Helmholtz-Zentrum Dresden-Rossendorf) providing quasi-continuous and single-shot proton beam delivery in the range of 0.12 to 10^9 Gy/s. To fulfil the requirements of the model, i.e., irradiating a sufficiently high number of embryos at low oxygen level, dedicated setups were established that also allow for the online measurement of oxygen partial pressure and cope with the geometric restrictions of the respective accelerator. Results A comparison experiment at UPTD reveal a significant protecting Flash effect in both setups for zebrafish embryo treated with 300 Gy/s relative to conventional proton dose rate. Moreover, a higher protection of the embryos was indicated comparing the embryo length after irradiation with 10^9 Gy/s and conventional proton dose rate, respectively. Conclusions Experimental setups have been established that allow for systematic proton dose rate studies using the zebrafish embryo model at the clinical cyclotron of UPTD and at the Draco laser accelerator. Therewith, the experimental possibilities at the Dresden platform for UHDR radiobiology are extended providing electron and prot

Background and Aims A prominent explanation of the FLASH effect is the oxygen depletion hypothesis, in which the radiolysis of water or cytoplasm produces radicals that react with the O2 dissolved in the water or cytoplasm. This would result in an oxygen depletion leading to a hypoxic target and hence radiation protection effect based on the Oxygen Enhancement Ratio. The presented study aims to investigate the impact of beam pulse structure on oxygen depletion and its correlation with biological endpoints. Methods O2 depletion was measured using 30 MeV electron irradiation on a sealed water target. Read-out was performed using TROXSP5 sensors. The beam pulse structure was altered to assess 4 different regimes of average and beam pulse dose rate. At clinical doses, not enough O2 was consumed to explain a FLASH effect due to radiation-induced hypoxia. The amount of O2 depleted per dose depends on the dose rate, and slightly less O2 is removed at higher dose rates, suggesting radical-radical reactions as a possible mechanism of the FLASH effect. Furthermore, our results regarding the pulse structures showed that the average dose rate seems to dominate the pulse dose rate in terms of radical production and O2 depletion. The direct comparison of the depletion measurements presented here with biological experiments on zebrafish embryos from another study also showed that there was a strong correlation between O2 depletion and biological radiation response (FIG 1). The results emphasize that the FLASH effect in biological tissues is likely to be explained by decreased effective radical production at high dose rates. Conclusions In the tested beam parameters, the mean dose rate has the most pronounced effect on O2 depletion. Depletion measurements showed a clear correlation with biological data, from which FLASH effects can be largely explained by changes in radical production.

Purpose/Objective In a previous experiment at the HZDR research electron accelerator ELBE high mean dose rates of 105 Gy/s in combination with partial oxygen pressure below 5 mmHg protect zebrafish embryo from radiation damage compared to continuous reference irradiation (mean dose rate of 0.11 Gy/s) and higher oxygen pressure (Pawelke et al. Radiother Oncol 2021). However, the influence of beam pulse structure on the radiation response remains unanswered and should be resolved in an upcoming experiment. Material/Methods In addition to the Flash and the reference regime, the ELBE accelerator was used to mimic the pulse structure of a clinical electron linac delivering a dose of 28 Gy by 5 pulses at a frequency of 250 Hz. For comparison, a fourth regime of similar mean dose rate, but continuous beam (280 Gy/s) mimicking FLASH irradiation at a isochronous proton cyclotron (Beyreuther et al. Radiother Oncol 2019) was applied. Wild type zebrafish embryo (24 hpf) were irradiated and the radiation induced malformation were studied during the four day follow up for all four regimes. Zebrafish embryo irradiation was performed under low oxygen pressure and the depletion of depletion during irradiation was measured online. Results Compared to the reference regime a protecting Flash effect was found the three other pulse regimes for endpoints, except embryo survival. Analysing the radiation induced malformation more detailed significant correlations to mean and pulse dose rate are revealed. Surprisingly, the beam delivery in macro pulses (Linac regime) reduces the Flash effect relative to delivery at the same pulse dose rate but in a single pulse. Conclusion. The ELBE electron accelerator can be applied to study the influence of beam dose rate and pulse structure on the Flash effect by varying both parameters over several orders of magnitude. Hence, ELBE is an ideal tool for systematic studies on optimal electron beam parameters for Flash, including pulse structures that are r

Recent oncological studies identified beneficial properties of radiation applied at ultra-high dose rates several orders of magnitude higher than the clinical standard of the order of Gy/min. Sources capable of providing these ultra-high dose rates are under investigation. Here, we show that a stable, compact laser-driven proton source with energies greater than 60 MeV enables radiobiological in vivo studies. We performed a pilot irradiation study on human tumors in a mouse model, showing the concerted preparation of mice and laser accelerator, the dose-controlled, tumor-conform irradiation using a laser-driven as well as a clinical reference proton source, and the radiobiological evaluation of irradiated and unirradiated mice for radiation-induced tumor growth delay. The prescribed homogeneous dose of 4 Gy was precisely delivered at the laser-driven source. The results demonstrate a complete laser-driven proton research platform for diverse user-specific small animal models, able to deliver tunable single-shot doses up to around 20 Gy to millimeter-scale volumes on nanosecond time scales, equivalent to around 1E9 Gy/s, spatially homogenized and tailored to the sample. The platform provides a unique infrastructure for translational research with protons at ultra-high dose rate.

Laser-plasma based proton accelerators as a novel accelerator technology have matured to a level at which laboratory-scale setups for the emerging topic of image-guided precision small animal irradiation studies come into reach [Bra2019]. Providing a high proton energy bandwidth [Sch2016] which is filtered in a tunable pulsed magnet beam transport, these accelerators enable flexibility in terms of scattering-free irradiation field formation [Mas2014, Mas2015]. Regarding temporal dose delivery, with single pulse doses reaching the Gy level at unprecedented peak dose rates of up to 1012 Gy/s [Sch2016], laser-plasma based proton accelerator setups can give access to the dose rate regime of FLASH [Fav2014, Voz2019]. The realization of a full-scale setup for image-guided precision radiobiological studies for small animals focusing on dose rate dependent effects is currently prepared at the PENELOPE laser-plasma based proton accelerator at HZDR and will be presented with a focus on the technological requirements and solutions for dose delivery at laser-plasma based sources. This development relies on our experience in performing dose-controlled radiobiological in vitro studies [Kra2010, Zei2013] and first in vivo irradiation experiments at the DRACO laser-plasma based proton accelerator at HZDR, where we have established a pulsed solenoid beamline for 3D irradiation field formation, yielding a (5 mm)³ homogeneous volumetric dose distribution at a Gy single pulse dose level [8]. [Bra2019] F.-E. Brack, F. Kroll, L. Gaus, C. Bernert, E. Beyreuther, T. E. Cowan, L. Karsch, S. D. Kraft, L. A. Kunz-Schughart, E. Lessmann, J. Metzkes-Ng, L. Obst-Hübl, J. Pawelke, M. Rehwald, H.-P. Schlenvoigt, U. Schramm, M. Sobiella, E. R. Szabó, T. Ziegler, K. Zeil, Spectral and spatial shaping of laser-driven proton beams using a pulsed high-field magnet beamline. arXiv:1910.08430 (2019) [Sch2016] J. Schreiber, P. Bolton, K. Parodi, “Hands-on” laser-driven ion acceleration: A primer for laser

Laser-driven plasma accelerators (LPA) are compact sources of ultra-short, intense proton pulses in the multi-10-MeV energy range. These unique parameters predestine LPAs as powerful tools for ultra-high dose rate radiobiology research. The sources’ capabilities were recently demonstrated in the first successful small animal pilot study on radiation-induced tumor growth delay in mice using an LPA proton source [1]. To promote further sophisticated radiobiological studies at LPAs, adapted approaches for primary LPA source characterization, beam monitoring and dosimeters are required. Here, most prominent challenges are LPA-inherent pulse-to-pulse fluctuation in terms of intensity as well as proton energy distribution, the ultra-high pulse dose rate and the harsh plasma environment, featuring a strong electromagnetic pulse (EMP) and an intense mixed radiation background. These conditions call for robust online monitoring solutions. We present the solutions for source-to-sample characterization implemented at the ALBUS-2S beamline [2] at the Draco Petawatt laser system [3] at Helmholtz-Zentrum Dresden-Rossendorf. These include firstly an online beam monitoring system based on a time-of-flight spectrometer (ToF BMS). A core feature of the ToF BMS method is a precise spectrum-based forward-calculation of the corresponding volumetric dose distribution via Monte-Carlo simulation. Secondly, a dosimetric system for volumetric mm-scale sample irradiations was conceptualized and tested during an in vivo irradiation study, showing a solution for precise dosimetric characterization of ultra-high dose rate pulses at the ~500 mGy pulse dose range. Lastly, with the OCTOPOD and MiniSCIDOM, two devices for online, single pulse characterization of volumetric dose distributions are presented, applicable for the primary LPA source and mm-scale dose distributions at the sample site, respectively. Both devices are based on volumetric scintillators as active detector material and rely on t

In-beam MRI has recently proven capable of visualising proton beams in liquid-filled phantoms based on beam-induced local MR signal amplitude loss. This holds promise for on- line beam range verification and dosimetric as well as geometric quality assurance for hybrid MRI-proton therapy systems currently under development. The purpose of this study was firstly to determine whether, in addition to MR signal amplitude loss, the MRI phase signal is affected by the proton beam and secondly, to test whether these changes in MRI signals are triggered by beam-induced convection.

We report technological developments at DRACO-PW to monitor and improve laser-plasma conditions resulting in a stable particle-source >60MeV, which in combination with our transport-beamline and high-quality dosimetry enabled first dose-controlled “in-vivo” studies with laser-driven protons.

Introduction Combining MR imaging and beam delivery for image guided precision radiotherapy was already introduced clinically with hybrid MR-linac systems. For proton therapy, given the conformal treatment method as well as the sensitivity to changes in patient anatomy, a hybrid MR and proton therapy device might be even more beneficial. In Dresden, a clinical demonstrator prototype, consisting of an 0.32 T open MR scanner and a horizontal pencil beam scanning beamline was installed. From a medical phyics perspective, the establishment of reliable dosimetry methods is a prerequisite for further pre-clinical and clinical studies. In MR guided proton therapy (MRgPT), the primary treatment beam itself is influenced by the magnetic field of the scanner. We investigated whether the response of the dosimetry detector depends on the detector orientation with respect to the magnetic field lines. In this work we focused on potential effects of the 0.32 T magnetic field on commercially available ionization detectors. For photons, considerable orientation effects have been reported. Given the influence of the magnetic field on the particle trajectories, potential orientation effects could have a considerable influence on dosimetric measurements. Material & Methods Experiments were performed at the experimental room of the University Proton Therapy Dresden with and without the prototype MRgPT system positioned 58.2 cm downstream of the beam iso-center of the beam line. Four thimble type ionization detectors, a Farmer, a Semiflex, a PinPoint and a PinPoint 3D detector were positioned at 2 cm water-equivalent depth and irradiated using 10 x 15 cm² homogeneous proton fields. Lateral field shifts due to the vertical magnetic field were compensated for. Irradiations were performed for 3 nominal proton energies (100, 150 and 220 MeV) and repeated with the same set-up at 0.32 T (with MR scanner) and 0 T (MR scanner removed). Chambers were positioned in horizontal, vertical and 15° til

MRI-based proton beam visualisation in water has proven feasible in exploratory irradiation experiments performed on a first research prototype in-beam MRI system. Beam-induced convection was hypothesised to be implicated into MR signal loss observed within the beam volume. In this study, this hypothesis was tested in liquid water-filled phantoms by suppression of convection-induced motion using mechanical barriers and temperature control of water expansivity. In absence of convection-induced motion, no beam-induced signal changes occurred, supporting the hypothesis that convection triggers local MR signal loss during proton beam irradiation. The elucidation of the exact mechanism of convection-induced signal loss requires further investigation.

MRI-based proton beam visualisation in water has proven feasible in exploratory irradiation experiments performed on a first research prototype in-beam MRI system. Beam-induced convection was hypothesised to be implicated into MR signal loss observed within the beam volume. In this study, this hypothesis was tested in liquid water-filled phantoms by suppression of convection-induced motion using mechanical barriers and temperature control of water expansivity. In absence of convection-induced motion, no beam-induced signal changes occurred, supporting the hypothesis that convection triggers local MR signal loss during proton beam irradiation. The elucidation of the exact mechanism of convection-induced signal loss requires further investigation.

Background and purpose Continuing recent experiments at the research electron accelerator ELBE at the Helmholtz-Zentrum Dresden-Rossendorf the influence of beam pulse time structure on the Flash effect should be investigated in a zebrafish embryo model. Materials and methods The pulse structures of an isochronous and a synchrocyclotron were mimicked at ELBE with mean dose rates of 287 Gy/s and 177 Gy/s and pulse dose rates of 106 Gy/s and 109 Gy/s, respectively; and a macro pulsing for the latter. For comparison, a maximum (mean dose rate 2.5 x 105 Gy/s, pulse dose rate ~109 Gy/s) and a reference (mean dose rate of ~8 Gy/min) regime were applied. Radiation induced changes were assessed in zebrafish embryos over four days post irradiation. Results A significant protecting Flash effect with a clear dependence on mean dose rate was revealed for almost all endpoints and all electron pulse regimes relative to the reference. The macro pulse dependent prolongation of treatment time of the synchrotron-like regime reduce the protecting effect compared to the maximum regime delivered at same pulse but higher mean dose rate. The protecting Flash effect of the cyclotron-like regime was confirmed at a clinical isochronous proton cyclotron comparing the effects induced by 300 Gy/s relative to conventional proton beam delivery. Conclusion The mean dose rate or treatment time are more important than pulse dose rate for the extent of the normal tissue protecting Flash effect.

Background and purpose Continuing recent experiments at the research electron accelerator ELBE at the Helmholtz-Zentrum Dresden-Rossendorf the influence of beam pulse time structure on the Flash effect should be investigated in a zebrafish embryo model. Materials and methods The pulse structures of an isochronous and a synchrocyclotron were mimicked at ELBE with mean dose rates of 287 Gy/s and 177 Gy/s and pulse dose rates of 106 Gy/s and 109 Gy/s, respectively; and a macro pulsing for the latter. For comparison, a maximum (mean dose rate 2.5 x 105 Gy/s, pulse dose rate ~109 Gy/s) and a reference (mean dose rate of ~8 Gy/min) regime were applied. Radiation induced changes were assessed in zebrafish embryos over four days post irradiation. Results A significant protecting Flash effect with a clear dependence on mean dose rate was revealed for almost all endpoints and all electron pulse regimes relative to the reference. The macro pulse dependent prolongation of treatment time of the synchrotron-like regime reduce the protecting effect compared to the maximum regime delivered at same pulse but higher mean dose rate. The protecting Flash effect of the cyclotron-like regime was confirmed at a clinical isochronous proton cyclotron comparing the effects induced by 300 Gy/s relative to conventional proton beam delivery. Conclusion The mean dose rate or treatment time are more important than pulse dose rate for the extent of the normal tissue protecting Flash effect.

Background: Clinical data suggest that the relative biological effectiveness (RBE) in proton therapy (PT) varies with linear energy transfer (LET). However, LET calculations are neither standardized nor available in clinical routine. Here, the status of LET calculations among European PT institutions and their comparability are assessed and a consensus for harmonized LET reporting is presented. Materials and methods: Eight European PT institutions used suitable treatment planning systems with their centre-specific beam model to create treatment plans in a water phantom covering different field arrangements and fulfilling commonly agreed dose objectives. They employed their locally established LET simulation environments and procedures to determine the corresponding LET distributions. Dose distributions D1.1 and DRBE assuming constant and variable RBE, respectively, and LET were compared among the institutions. Inter-centre variability was assessed based on dose- and LET-volume-histogram parameters. Results: Treatment plans from six institutions fulfilled all clinical goals and were eligible for common analysis. D1.1 distributions in the target volume were comparable among PT institutions with variability <2.7%. However, corresponding LET values varied substantially between institutions for all field arrangements (≤57.1%), primarily due to differences in LET averaging technique and considered secondary particle spectra. Consequently, DRBE using nonharmonized LET calculations increased inter-centre dose variations substantially compared to D1.1 and significantly in mean dose to the target volume of perpendicular and opposing field arrangements (p<0.05). Harmonizing LET reporting (dose-averaging, all protons, LET to water) reduced the inter-centre variability in LET to the order of 10-15% within and outside the target volume for all beam arrangements. Consequentially, inter-institutional variability in DRBE decreased to that observed for D1.1 (p>0.05). Conclusion: Harm

Background and purpose: The relative biological effectiveness (RBE) varies along the treatment field. However, in clinical practice, a constant RBE of 1.1 is assumed, which can result in undesirable side effects. This study provides an accurate overview of current clinical practice for considering proton RBE in Europe. Materials and methods: A survey was devised and sent to all proton therapy centres in Europe that treat patients. The online questionnaire consisted of 39 questions addressing various aspects of RBE consider- ation in clinical practice, including treatment planning, patient follow-up and future demands. Results: All 25 proton therapy centres responded. All centres prescribed a constant RBE of 1.1, but also applied measures (except for one eye treatment centre) to counteract variable RBE effects such as avoid- ing beams stopping inside or in front of an organ at risk and putting restrictions on the minimum number and opening angle of incident beams for certain treatment sites. For the future, most centres (16) asked for more retrospective or prospective outcome studies investigating the potential effect of the effect of a variable RBE. To perform such studies, 18 centres asked for LET and RBE calculation and visualisation tools developed by treatment planning system vendors. Conclusion: All European proton centres are aware of RBE variability but comply with current guidelines of prescribing a constant RBE. However, they actively mitigate uncertainty and risk of side effects result- ing from increased RBE by applying measures and restrictions during treatment planning. To change RBE- related clinical guidelines in the future more clinical data on RBE are explicitly demanded.

Recent oncological studies identified beneficial properties of radiation applied at ultra-high dose rates several orders of magnitude higher than the clinical standard of the order of Gy/min. Sources capable of providing these ultra-high dose rates are under investigation. Here, we show that a stable, compact laser-driven proton source with energies greater than 60 MeV enables radiobiological in vivo studies. We performed a pilot irradiation study on human tumors in a mouse model, showing the concerted preparation of mice and laser accelerator, the dose-controlled, tumor-conform irradiation using a laser-driven as well as a clinical reference proton source, and the radiobiological evaluation of irradiated and unirradiated mice for radiation-induced tumor growth delay. The prescribed homogeneous dose of 4 Gy was precisely delivered at the laser-driven source. The results demonstrate a complete laser-driven proton research platform for diverse user-specific small animal models, able to deliver tunable single-shot doses up to around 20 Gy to millimeter-scale volumes on nanosecond time scales, equivalent to around 1E9 Gy/s, spatially homogenized and tailored to the sample. The platform provides a unique infrastructure for translational research with protons at ultra-high dose rate.

The influence of different average and bunch dose rates in electron beams on the FLASH effect was investigated. The present study measures O2 content in water at different beam pulse patterns and finds strong correlation with biological data, strengthening the hypothesis of radical-related mechanisms as a reason for the FLASH effect.

In-beam MRI has recently proven capable of visualising proton beams in liquid-filled phantoms based on beam-induced local MR signal amplitude loss. This holds promise for on- line beam range verification and dosimetric as well as geometric quality assurance for hybrid MRI-proton therapy systems currently under development. The purpose of this study was firstly to determine whether, in addition to MR signal amplitude loss, the MRI phase signal is affected by the proton beam and secondly, to test whether these changes in MRI signals are triggered by beam-induced convection.

MRI-based proton beam visualisation in water has proven feasible in exploratory irradiation experiments performed on a first research prototype in-beam MRI system. Beam-induced convection was hypothesised to be implicated into MR signal loss observed within the beam volume. In this study, this hypothesis was tested in liquid water-filled phantoms by suppression of convection-induced motion using mechanical barriers and temperature control of water expansivity. In absence of convection-induced motion, no beam-induced signal changes occurred, supporting the hypothesis that convection triggers local MR signal loss during proton beam irradiation. The elucidation of the exact mechanism of convection-induced signal loss requires further investigation.

Background and Aims A prominent explanation of the FLASH effect is the oxygen depletion hypothesis, in which the radiolysis of water or cytoplasm produces radicals that react with the O2 dissolved in the water or cytoplasm. This would result in an oxygen depletion leading to a hypoxic target and hence radiation protection effect based on the Oxygen Enhancement Ratio. The presented study aims to investigate the impact of beam pulse structure on oxygen depletion and its correlation with biological endpoints. Methods O2 depletion was measured using 30 MeV electron irradiation on a sealed water target. Read-out was performed using TROXSP5 sensors. The beam pulse structure was altered to assess 4 different regimes of average and beam pulse dose rate. At clinical doses, not enough O2 was consumed to explain a FLASH effect due to radiation-induced hypoxia. The amount of O2 depleted per dose depends on the dose rate, and slightly less O2 is removed at higher dose rates, suggesting radical-radical reactions as a possible mechanism of the FLASH effect. Furthermore, our results regarding the pulse structures showed that the average dose rate seems to dominate the pulse dose rate in terms of radical production and O2 depletion. The direct comparison of the depletion measurements presented here with biological experiments on zebrafish embryos from another study also showed that there was a strong correlation between O2 depletion and biological radiation response (FIG 1). The results emphasize that the FLASH effect in biological tissues is likely to be explained by decreased effective radical production at high dose rates. Conclusions In the tested beam parameters, the mean dose rate has the most pronounced effect on O2 depletion. Depletion measurements showed a clear correlation with biological data, from which FLASH effects can be largely explained by changes in radical production.

MRI-based proton beam visualisation in water has proven feasible in exploratory irradiation experiments performed on a first research prototype in-beam MRI system. Beam-induced convection was hypothesised to be implicated into MR signal loss observed within the beam volume. In this study, this hypothesis was tested in liquid water-filled phantoms by suppression of convection-induced motion using mechanical barriers and temperature control of water expansivity. In absence of convection-induced motion, no beam-induced signal changes occurred, supporting the hypothesis that convection triggers local MR signal loss during proton beam irradiation. The elucidation of the exact mechanism of convection-induced signal loss requires further investigation.

Background and Aims The Flash effect, i.e. the radiobiological observation of normal tissue sparing but efficient tumor killing by ultra-high dose rate (UHDR) irradiation, promise great benefits for cancer patient treatment. The translation process of the Flash effect should be accompanied by systematic studies on the necessary beam parameters for each clinical applied radiation. Using the zebrafish embryo model, the influence of partial oxygen level (https://doi.org/10.1016/j.radonc.2021.02.003), electron pulse structure and dose were studied thoroughly. To investigate a similar range of proton beam parameters UHDR experiments at different accelerators, but under comparable conditions, are required. Methods To cover a broad range of proton dose rates, experiments have been prepared at the University Proton Therapy Dresden (UPTD) and at the Draco laser accelerator (Helmholtz-Zentrum Dresden-Rossendorf) providing quasi-continuous and single-shot proton beam delivery in the range of 0.12 to 10^9 Gy/s. To fulfil the requirements of the model, i.e., irradiating a sufficiently high number of embryos at low oxygen level, dedicated setups were established that also allow for the online measurement of oxygen partial pressure and cope with the geometric restrictions of the respective accelerator. Results A comparison experiment at UPTD reveal a significant protecting Flash effect in both setups for zebrafish embryo treated with 300 Gy/s relative to conventional proton dose rate. Moreover, a higher protection of the embryos was indicated comparing the embryo length after irradiation with 10^9 Gy/s and conventional proton dose rate, respectively. Conclusions Experimental setups have been established that allow for systematic proton dose rate studies using the zebrafish embryo model at the clinical cyclotron of UPTD and at the Draco laser accelerator. Therewith, the experimental possibilities at the Dresden platform for UHDR radiobiology are extended providing electron and prot

The recent rediscovery of the “Flash-effect” revived the interest in high dose-rate radiation effects throughout the radiobiology community, promising protection of normal tissue, while simultaneously not altering tumour control. Several preclinical and clinical studies are presently dedicated to electron FLASH with Linacs. However, the mechanisms of Flash is still unresolved albeit its clear impact in tissue sparing to radiation toxicity. For protons, the Flash effect was confirmed in a few animal experiments using the beam parameters available at clinical cyclotrons. Laser-driven proton accelerators offer the possibility to extend the range of proton beam parameters to higher dose rates enabling the investigation in vivo of high dose-rate effects for up to 10^9 Gy/s. The general applicability of these beams for radiobiological studies was proven with simple cellular models and zebrafish embryos. One-step further, systematic in vivo experiments were prepared with a proof-of-principle mouse irradiation campaign at the Draco laser accelerator and, for comparison, at the University Proton Therapy Dresden (UPTD). Moreover, to investigate the interplay of oxygen tension, oxygen consumption and proton dose rate in more detail, an experiment with zebrafish embryos was performed at both proton sources. At the conference, we will give an overview of our radiobiological experiments performed at both DRACO and Oncoray/UPTD, for different dose rates and varying oxygen pressures.

Introduction Combining MR imaging and beam delivery for image guided precision radiotherapy was already introduced clinically with hybrid MR-linac systems. For proton therapy, given the conformal treatment method as well as the sensitivity to changes in patient anatomy, a hybrid MR and proton therapy device might be even more beneficial. In Dresden, a clinical demonstrator prototype, consisting of an 0.32 T open MR scanner and a horizontal pencil beam scanning beamline was installed. From a medical phyics perspective, the establishment of reliable dosimetry methods is a prerequisite for further pre-clinical and clinical studies. In MR guided proton therapy (MRgPT), the primary treatment beam itself is influenced by the magnetic field of the scanner. We investigated whether the response of the dosimetry detector depends on the detector orientation with respect to the magnetic field lines. In this work we focused on potential effects of the 0.32 T magnetic field on commercially available ionization detectors. For photons, considerable orientation effects have been reported. Given the influence of the magnetic field on the particle trajectories, potential orientation effects could have a considerable influence on dosimetric measurements. Material & Methods Experiments were performed at the experimental room of the University Proton Therapy Dresden with and without the prototype MRgPT system positioned 58.2 cm downstream of the beam iso-center of the beam line. Four thimble type ionization detectors, a Farmer, a Semiflex, a PinPoint and a PinPoint 3D detector were positioned at 2 cm water-equivalent depth and irradiated using 10 x 15 cm² homogeneous proton fields. Lateral field shifts due to the vertical magnetic field were compensated for. Irradiations were performed for 3 nominal proton energies (100, 150 and 220 MeV) and repeated with the same set-up at 0.32 T (with MR scanner) and 0 T (MR scanner removed). Chambers were positioned in horizontal, vertical and 15° til

Purpose/Objective In a previous experiment at the HZDR research electron accelerator ELBE high mean dose rates of 105 Gy/s in combination with partial oxygen pressure below 5 mmHg protect zebrafish embryo from radiation damage compared to continuous reference irradiation (mean dose rate of 0.11 Gy/s) and higher oxygen pressure (Pawelke et al. Radiother Oncol 2021). However, the influence of beam pulse structure on the radiation response remains unanswered and should be resolved in an upcoming experiment. Material/Methods In addition to the Flash and the reference regime, the ELBE accelerator was used to mimic the pulse structure of a clinical electron linac delivering a dose of 28 Gy by 5 pulses at a frequency of 250 Hz. For comparison, a fourth regime of similar mean dose rate, but continuous beam (280 Gy/s) mimicking FLASH irradiation at a isochronous proton cyclotron (Beyreuther et al. Radiother Oncol 2019) was applied. Wild type zebrafish embryo (24 hpf) were irradiated and the radiation induced malformation were studied during the four day follow up for all four regimes. Zebrafish embryo irradiation was performed under low oxygen pressure and the depletion of depletion during irradiation was measured online. Results Compared to the reference regime a protecting Flash effect was found the three other pulse regimes for endpoints, except embryo survival. Analysing the radiation induced malformation more detailed significant correlations to mean and pulse dose rate are revealed. Surprisingly, the beam delivery in macro pulses (Linac regime) reduces the Flash effect relative to delivery at the same pulse dose rate but in a single pulse. Conclusion. The ELBE electron accelerator can be applied to study the influence of beam dose rate and pulse structure on the Flash effect by varying both parameters over several orders of magnitude. Hence, ELBE is an ideal tool for systematic studies on optimal electron beam parameters for Flash, including pulse structures that are r

Laser-plasma based proton accelerators as a novel accelerator technology have matured to a level at which laboratory-scale setups for the emerging topic of image-guided precision small animal irradiation studies come into reach [Bra2019]. Providing a high proton energy bandwidth [Sch2016] which is filtered in a tunable pulsed magnet beam transport, these accelerators enable flexibility in terms of scattering-free irradiation field formation [Mas2014, Mas2015]. Regarding temporal dose delivery, with single pulse doses reaching the Gy level at unprecedented peak dose rates of up to 1012 Gy/s [Sch2016], laser-plasma based proton accelerator setups can give access to the dose rate regime of FLASH [Fav2014, Voz2019]. The realization of a full-scale setup for image-guided precision radiobiological studies for small animals focusing on dose rate dependent effects is currently prepared at the PENELOPE laser-plasma based proton accelerator at HZDR and will be presented with a focus on the technological requirements and solutions for dose delivery at laser-plasma based sources. This development relies on our experience in performing dose-controlled radiobiological in vitro studies [Kra2010, Zei2013] and first in vivo irradiation experiments at the DRACO laser-plasma based proton accelerator at HZDR, where we have established a pulsed solenoid beamline for 3D irradiation field formation, yielding a (5 mm)³ homogeneous volumetric dose distribution at a Gy single pulse dose level [8]. [Bra2019] F.-E. Brack, F. Kroll, L. Gaus, C. Bernert, E. Beyreuther, T. E. Cowan, L. Karsch, S. D. Kraft, L. A. Kunz-Schughart, E. Lessmann, J. Metzkes-Ng, L. Obst-Hübl, J. Pawelke, M. Rehwald, H.-P. Schlenvoigt, U. Schramm, M. Sobiella, E. R. Szabó, T. Ziegler, K. Zeil, Spectral and spatial shaping of laser-driven proton beams using a pulsed high-field magnet beamline. arXiv:1910.08430 (2019) [Sch2016] J. Schreiber, P. Bolton, K. Parodi, “Hands-on” laser-driven ion acceleration: A primer for laser

Recent oncological studies identified beneficial properties of radiation applied at ultra-high dose rates several orders of magnitude higher than the clinical standard of the order of Gy/min. Sources capable of providing these ultra-high dose rates are under investigation. Here, we show that a stable, compact laser-driven proton source with energies greater than 60 MeV enables radiobiological in vivo studies. We performed a pilot irradiation study on human tumors in a mouse model, showing the concerted preparation of mice and laser accelerator, the dose-controlled, tumor-conform irradiation using a laser-driven as well as a clinical reference proton source, and the radiobiological evaluation of irradiated and unirradiated mice for radiation-induced tumor growth delay. The prescribed homogeneous dose of 4 Gy was precisely delivered at the laser-driven source. The results demonstrate a complete laser-driven proton research platform for diverse user-specific small animal models, able to deliver tunable single-shot doses up to around 20 Gy to millimeter-scale volumes on nanosecond time scales, equivalent to around 1E9 Gy/s, spatially homogenized and tailored to the sample. The platform provides a unique infrastructure for translational research with protons at ultra-high dose rate.

We report technological developments at DRACO-PW to monitor and improve laser-plasma conditions resulting in a stable particle-source >60MeV, which in combination with our transport-beamline and high-quality dosimetry enabled first dose-controlled “in-vivo” studies with laser-driven protons.

Laser-driven plasma accelerators (LPA) are compact sources of ultra-short, intense proton pulses in the multi-10-MeV energy range. These unique parameters predestine LPAs as powerful tools for ultra-high dose rate radiobiology research. The sources’ capabilities were recently demonstrated in the first successful small animal pilot study on radiation-induced tumor growth delay in mice using an LPA proton source [1]. To promote further sophisticated radiobiological studies at LPAs, adapted approaches for primary LPA source characterization, beam monitoring and dosimeters are required. Here, most prominent challenges are LPA-inherent pulse-to-pulse fluctuation in terms of intensity as well as proton energy distribution, the ultra-high pulse dose rate and the harsh plasma environment, featuring a strong electromagnetic pulse (EMP) and an intense mixed radiation background. These conditions call for robust online monitoring solutions. We present the solutions for source-to-sample characterization implemented at the ALBUS-2S beamline [2] at the Draco Petawatt laser system [3] at Helmholtz-Zentrum Dresden-Rossendorf. These include firstly an online beam monitoring system based on a time-of-flight spectrometer (ToF BMS). A core feature of the ToF BMS method is a precise spectrum-based forward-calculation of the corresponding volumetric dose distribution via Monte-Carlo simulation. Secondly, a dosimetric system for volumetric mm-scale sample irradiations was conceptualized and tested during an in vivo irradiation study, showing a solution for precise dosimetric characterization of ultra-high dose rate pulses at the ~500 mGy pulse dose range. Lastly, with the OCTOPOD and MiniSCIDOM, two devices for online, single pulse characterization of volumetric dose distributions are presented, applicable for the primary LPA source and mm-scale dose distributions at the sample site, respectively. Both devices are based on volumetric scintillators as active detector material and rely on t

This dataset contains the raw and evaluated data of the paper plus the script for plotting the results.

Purpose/Objective In a previous experiment at the HZDR research electron accelerator ELBE high mean dose rates of 105 Gy/s in combination with partial oxygen pressure below 5 mmHg protect zebrafish embryo from radiation damage compared to continuous reference irradiation (mean dose rate of 0.11 Gy/s) and higher oxygen pressure (Pawelke et al. Radiother Oncol 2021). However, the influence of beam pulse structure on the radiation response remains unanswered and should be resolved in an upcoming experiment. Material/Methods In addition to the Flash and the reference regime, the ELBE accelerator was used to mimic the pulse structure of a clinical electron linac delivering a dose of 28 Gy by 5 pulses at a frequency of 250 Hz. For comparison, a fourth regime of similar mean dose rate, but continuous beam (280 Gy/s) mimicking FLASH irradiation at a isochronous proton cyclotron (Beyreuther et al. Radiother Oncol 2019) was applied. Wild type zebrafish embryo (24 hpf) were irradiated and the radiation induced malformation were studied during the four day follow up for all four regimes. Zebrafish embryo irradiation was performed under low oxygen pressure and the depletion of depletion during irradiation was measured online. Results Compared to the reference regime a protecting Flash effect was found the three other pulse regimes for endpoints, except embryo survival. Analysing the radiation induced malformation more detailed significant correlations to mean and pulse dose rate are revealed. Surprisingly, the beam delivery in macro pulses (Linac regime) reduces the Flash effect relative to delivery at the same pulse dose rate but in a single pulse. Conclusion. The ELBE electron accelerator can be applied to study the influence of beam dose rate and pulse structure on the Flash effect by varying both parameters over several orders of magnitude. Hence, ELBE is an ideal tool for systematic studies on optimal electron beam parameters for Flash, including pulse structures that are r

Source data for all figures of publication: "Tumor irradiation in mice with a laser-accelerated proton beam". The folder structure is adapted to match the figures in the publication.

Introduction In-beam MRI is expected to improve the targeting accuracy of proton therapy for moving target volumes providing real-time anatomical images and allowing the simultaneous visualisation of the therapeutic proton beam in liquid-filled phantoms [1,2]. The aim of this contribution is to provide an overview of our previous work on MRI-based proton beam visualisation. Materials & Methods A 0.22 T open MR scanner was positioned at a fixed horizontal proton research beamline in a clinical proton therapy facility. Water, ethanol, petroleum and mayonnaise phantoms were irradiated with nominal proton beam energies between 190 - 225 MeV at beam currents of 1 - 64 nA. A range of pulse sequences was used for the acquisition of a horizontal slice within the beam volume. Material, sequence, beam current and energy dependence of the beam signal were evaluated. Results The proton beam induces a beam current and energy dependent MRI signal in liquids of low viscosity. For fixed beam current setting, the beam range in water extracted from the MR images matches the expected residual range within a few millimetres. Gradient echo-based pulse sequences appear more sensitive to the beam-induced effect than spin echo-based sequences. Summary The method holds potential for on-line quality assurance for MR-integrated proton therapy. The underlying image contrast mechanism requires elucidation to enable the development of specifically tailored sequences with increased sensitivity for the beam-induced effect. Appendix 1 Figure 1: Beam current dependence of the 207 MeV beam signal in water acquired using a Time-of-Flight-Angiography sequence. Figure 2: Inversion Recovery-Gradient Echo images of water under irradiation at a beam current of 9 nA. The dotted lines indicate the expected proton ranges. References [1] Schellhammer SM. Technical feasibility of MR-integrated proton therapy: Beam deflection and image quality. Doctoral thesis, Technische Universität Dresden, 2019. [2] Gantz S.