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Background and Aims After the rediscovery of the normal tissue sparing FLASH effect of high dose rate radiation, research activities on this topic have been revived. But especially for protons, the portfolio of accelerators capable of performing studies at ultra-high dose rates is limited. Laser-plasma accelerators (LPA) can generate extremely intense proton bunches of many 10 MeV kinetic energy. In combination with dedicated dose delivery systems, LPA proton sources facilitate peak dose rates well above 10^8 Gy/s in a pulse structure regime complementary to conventional accelerators. Methods The reliable generation of proton spectra beyond 60 MeV at DRACO-PW [Ziegler et al, SciRep2021], combined with a dedicated energy selective pulsed magnet beam transport system [Brack et al, SciRep2020], allows tailored sample-specific dose distributions. Adapted on-shot dosimetry enables the required spectral monitoring of every proton bunch. Two irradiation series on volumetric biological samples were performed at DRACO-PW, accompanied by reference irradiations at the University Proton Therapy Dresden. Results The first small animal pilot study at a laser-driven proton source was conducted successfully. The mouse-ear tumor model’s requirements [Beyreuther et al, PLoS One2018] were fulfilled and verified at high precision (+/- 5%) concerning predefined dose value and conformity. Complementary, a study investigating dose-rate effects such as FLASH was performed irradiating zebrafish embryos with above 10^9 Gy/s. Conclusions We present a laser-based irradiation platform at the DRACO-PW facility that enables systematic radiobiological studies, laying the foundations for further studies at LPA sources exploring ultra-high dose-rate effects, such as FLASH, over previously unreachable parameter space.

Further development of proton therapy takes place largely through in-vivo experiments, which are subject to increasingly strict ethical and technical requirements. Proton irradiation of small animal organs demand for highly suitable experimental setups and intelligent protocols to mimic clinical workflows as closely as possible. This includes the possibility of on-beam imaging for precise positioning and treatment. To meet these requirements, proton radiography was integrated into an existing beam setup for mouse brain proton irradiation at the University Proton Therapy Dresden (UPTD). For the realization of the radiography a flat panel detector was installed on proton beam axis behind mouse position. Transmission imaging was achieved by increasing the proton energy significantly above that required for brain irradiation, i.e. the protons pass through the mouse and reach the detector with minimal dose deposition. The final workflow includes the acquisition of cone-beam computed tomography scans and planar X-ray images before the irradiation to receive anatomical information and perform a treatment planning. The hippocampus as target region for current mouse brain irradiation experiments can be determined by registration with mouse brain atlas data. Proton radiography is acquired with a scattered proton beam right before the irradiation, resulting in a radiograph, which can be registered to the X-ray image. Finally, the target volume can be aligned to the collimated proton beam for accurate brain irradiation, which was validated by immunohistochemical staining of DNA damage region. The setup for proton radiography and mouse brain irradiation, parameters influencing the radiography quality and experimental data will be presented.

Background and aims In FLASH radiotherapy (RT), a protective effect of healthy tissue was observed, while tumor control remains comparable to conventional RT[1]. One possible explanation is the oxygen depletion hypothesis, in which radiolysis of water/cytoplasma causes the production of radicals that then react with O2 dissolved in water. This would cause a reduction in O2, which results in a hypoxic target and thus a radio-protective effect. In a previous study[2], we measured O2 depletion in sealed water phantoms during irradiation at high dose rates (<300 Gy/s) for protons, carbon ions and photons. Methods In the study presented here, this experiment was conducted further to ultra-high dose rates (10^9 Gy/s) with protons at DRACO and electrons at ELBE, where also the impact of different pulse structures on O2 depletion was tested. In addition, various settings were tested in order to irradiate zebrafish embryos with FLASH while simultaneously measuring O2. Results and Conclusion We were able to confirm the results of the previous study even at ultra-high dose rates and with electrons and came to two conclusions: 1. not enough O2 was depleted at clinical doses to explain a FLASH effect based on radiation-induced hypoxia 2. the amount of O2 depleted per dose depends on dose rate, and higher dose rates deplete slightly less O2. Furthermore, it was possible to measure O2 depletion during zebrafish embryo irradiation making a simultaneous study of biological response and O2 depletion possible. [1]Favaudon, et al. (2014) https://doi.org/10.1126/scitranslmed.3008973 [2]Jansen, et al. (2021) https://doi.org/10.1002/mp.14917

Introduction: A prototype system for MR‐integrated proton therapy (MRiPT) with an in-beam MR scanner is currently under investigation at our facility. The commissioning thereof requires an accurate beam model, a 3D map of the full static magnetic field (MF) of the MR scanner and consideration of their interaction. This work describes measurements of the proton beam, the MF and beam modeling performed to set up a proton beam model for the MRiPT prototype system. Materials & Methods: Measurements of central proton beam spot sizes in air at 10 distances from the beam isocenter (between -15 and 54 cm) and integral depth-dose profiles (100 to 226.7 MeV) in water were obtained without MF using a scintillation detector and a water phantom with a Bragg peak chamber, respectively. A beam model was fitted to these measurements by utilizing an automated regularization-based optimization process. A 3D magnetic field map of the 0.33 T open MR scanner was acquired using spatially resolved Hall probe measurements. Results: In the absence of the MF, the optimized beam model reproduced the measured beam spot sizes in air with an error <0.5 mm for 100 – 226.7 MeV and depth dose curves in water with an error <0.1 g/cm² for 100 – 226.7 MeV. The magnetic field measuring approach delivers reproducible results with high accuracy and an uncertainty <±5 mT. Summary: A proton beam model for the MRiPT prototype system without MF was established and a high-precision method for mapping the 3D MF of the MR scanner was developed. The MF map and the beam model will be used to establish an experimental treatment planning system providing a correction algorithm accounting for the influence of the MF of the MR scanner on proton beams. Further investigations are necessary to validate the beam model in the presence of the MF.

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.

After the rediscovery of the normal tissue sparing effect of high dose rate radiation, i.e. the so-called FLASH effect, by Favaudon et al. in 2014, research activities on this topic have been revived and are flourishing ever since. Yet, the exact biological mechanism as well as the required boundary conditions and radiation qualities to reach said sparing remain mostly unclear. We present a laser-based irradiation platform at the Draco PW facility that enables systematic studies into the FLASH regime using proton peak dose rates of up to 10^9 Gy/s. Besides the PW class laser acceleration source, a key component is a pulsed high-field beamline to transport and shape the laser driven proton bunches spectrally and spatially in order to generate homogeneous dose distributions tailored to match the irradiation sample. Making use of the diverse capabilities of the laser driven irradiation platform a pilot experiment of highest complexity has been conducted – a systematic in-vivo tumor irradiation in a specifically developed mouse model. A plethora of online particle diagnostics, including Time-of-Flight, bulk scintillators and screens as well as ionization chambers, in conjunction with diagnostics for retrospective absolute dosimetry (radiochromic films) allowed for an unprecedented level of precision in mean dose delivery (±10 %) and dose homogeneity (±5 %) for the challenging beam qualities of a laser accelerator. The tailored detector suite is complemented by predictive simulations. The talk addresses how our interdisciplinary team overcame all hurdles from animal model development, over enhancing the laser and laser acceleration stability, to dose delivery and online dose monitoring. Results on radiation induced tumor growth delay by laser driven as well as conventionally accelerated proton beams are critically discussed.

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.

Objectives: For the integration of magnetic resonance imaging (MRI) into proton therapy (PT), a 0.22 T MRI was installed at the pencil beam scanning beam line at OncoRay. As a next step, dosimetry in the magnetic field has to be established. This work aims to study the influence of the static field (B0) of the MRI on ionisation chamber (IC) responses for proton beams through measurements and Monte Carlo (MC) simulations. Materials & methods: A Semiflex 0.3 and a PinPoint 3D IC were positioned in a water phantom placed in the MR imager isocenter. The absolute dose at five proton energies (70, 110, 150, 190, 226.7 MeV) was measured within the entrance plateau of the depth-dose curve using a 10×10 cm² homogeneous irradiation field. The correction factor kB→,M,Q was obtained by dividing the measured dose with/without B0. For the MC simulations, beam-commissioning data (depth-dose profiles in water, beam spot sizes in air) were used to create a MC beam model in TOPAS (1.5×105 particles). A 3D map of the scanner’s magnetic field (MF) was calculated with COMSOL and used in the simulations to mimic the experimental setup. Results: The MF correction factor kB→,M,Q showed systematic energy-dependent differences between dose readings with and without B0. For the Semiflex 0.3, kB→,M,Q was 0.9926, 0.9942, 0.9941, 0.9959 and 1.0036 for 70, 110, 150, 190 and 226.7 MeV, respectively. For the same energies, kB→,M,Q for the PinPoint 3D was 0.9920, 0.9931, 0.9938, 0.9952 and 0.9969. For all energies, the standard deviations of kB→,M,Q were smaller than 0.002 for both ICs. MC simulations of the Semiflex 0.3 response to 110 MeV showed no statistically significant B0 effect with kB→,M,Q of 0.997 (95% CI: 0.9893, 1.0049). Conclusion: Measurements showed a small but significant influence of the MRI scanner’s B0 field on the IC response, which was beam energy-dependent. Further investigations should clarify the necessity of dosimetric correction factors for the MR-integrated PT.

Introduction To date, proton therapy is hampered by the lack of reliable in-vivo real-time feedback on the beam range, profile and energy deposition. So far, no technique enables the determination of beam effects on images also showing anatomical information in 2D/3D with high temporal and spatial resolution. The aim of this study is to demonstrate the possibility of visualizing a stopping proton beam in water using MR imaging. Materials & methods An open 0.22 T MR scanner was combined with a static proton research beamline to acquire MR images during simultaneous proton beam irradiation. Proton beams with an energy of 190−225 MeV and current of 3−64 nA impinged centrally on a 20 cm PMMA range modulator and were stopped in a water-filled phantom placed inside a dedicated knee MR receiver coil. A variety of different MR pulse sequences including T1- and T2-weighted Spin Echo (SE), Turbo Spin Echo, spoiled and unspoiled T1-weighted Gradient Echo (GE), inversion recovery gradient echo (IRGE), FLASH, Scout and time-of-flight (TOF) Angio were used. For each sequence, coronal images were acquired both with and without irradiation. Results The unspoiled GE sequence exhibited a hyper-intense central line artefact that showed a beam energy and current dependent twist under irradiation. The spoiled GE, IRGE, FLASH, Scout and TOF Angio sequences showed hyper- or hypo-intense signatures in the images that varied with the expected range and mimicked the shape of a 2D dose profile. The intensity of the effects depends on the beam current. The beam range determined from the MR images agrees to the expected range within a few millimeters. No beam induced signal changes were observed in the SE sequences. Conclusion A stopping proton beam in liquid water can be visualized with MRI. The observed signatures are beam energy and range as well as beam current and dose dependent. The underlying physical principles and the transferability to non-liquid materials needs further investigation.

Further development of proton therapy takes place largely through in-vivo experiments, which are subject to increasingly strict ethical and technical requirements. Proton irradiation of small animal organs demand for highly suitable experimental setups and intelligent protocols to mimic clinical workflows as closely as possible. This includes the possibility of on-beam imaging for precise positioning and treatment. To meet these requirements, proton radiography was integrated into an existing beam setup for mouse brain proton irradiation at the University Proton Therapy Dresden (UPTD). For the realization of the radiography a flat panel detector was installed on proton beam axis behind mouse position. Transmission imaging was achieved by increasing the proton energy significantly above that required for brain irradiation, i.e. the protons pass through the mouse and reach the detector with minimal dose deposition. The final workflow includes the acquisition of cone-beam computed tomography scans and planar X-ray images before the irradiation to receive anatomical information and perform a treatment planning. The hippocampus as target region for current mouse brain irradiation experiments can be determined by registration with mouse brain atlas data. Proton radiography is acquired with a scattered proton beam right before the irradiation, resulting in a radiograph, which can be registered to the X-ray image. Finally, the target volume can be aligned to the collimated proton beam for accurate brain irradiation, which was validated by immunohistochemical staining of DNA damage region. The setup for proton radiography and mouse brain irradiation, parameters influencing the radiography quality and experimental data will be presented.

Objectives: For the integration of magnetic resonance imaging (MRI) into proton therapy (PT), a 0.22 T MRI was installed at the pencil beam scanning beam line at OncoRay. As a next step, dosimetry in the magnetic field has to be established. This work aims to study the influence of the static field (B0) of the MRI on ionisation chamber (IC) responses for proton beams through measurements and Monte Carlo (MC) simulations. Materials & methods: A Semiflex 0.3 and a PinPoint 3D IC were positioned in a water phantom placed in the MR imager isocenter. The absolute dose at five proton energies (70, 110, 150, 190, 226.7 MeV) was measured within the entrance plateau of the depth-dose curve using a 10×10 cm² homogeneous irradiation field. The correction factor kB→,M,Q was obtained by dividing the measured dose with/without B0. For the MC simulations, beam-commissioning data (depth-dose profiles in water, beam spot sizes in air) were used to create a MC beam model in TOPAS (1.5×105 particles). A 3D map of the scanner’s magnetic field (MF) was calculated with COMSOL and used in the simulations to mimic the experimental setup. Results: The MF correction factor kB→,M,Q showed systematic energy-dependent differences between dose readings with and without B0. For the Semiflex 0.3, kB→,M,Q was 0.9926, 0.9942, 0.9941, 0.9959 and 1.0036 for 70, 110, 150, 190 and 226.7 MeV, respectively. For the same energies, kB→,M,Q for the PinPoint 3D was 0.9920, 0.9931, 0.9938, 0.9952 and 0.9969. For all energies, the standard deviations of kB→,M,Q were smaller than 0.002 for both ICs. MC simulations of the Semiflex 0.3 response to 110 MeV showed no statistically significant B0 effect with kB→,M,Q of 0.997 (95% CI: 0.9893, 1.0049). Conclusion: Measurements showed a small but significant influence of the MRI scanner’s B0 field on the IC response, which was beam energy-dependent. Further investigations should clarify the necessity of dosimetric correction factors for the MR-integrated PT.

Clinical treatment with protons relies on the concept of relative biological effectiveness (RBE) to convert the absorbed dose into an RBE-weighted dose that equals the dose for radiotherapy with photons causing the same biological effect. Currently, in proton therapy a constant RBE of 1.1 is generically used. However, empirical data indicate that the RBE is not constant, but increases at the distal edge of the proton beam. This increase in RBE is of concern, as the clinical impact is still unresolved, and clinical studies demonstrating a clinical effect of an increased RBE are emerging. Within the European Particle Therapy Network (EPTN) work package 6 on radiobiology and RBE, a workshop was held in February 2020 in Manchester with one day of discussion dedicated to the impact of proton RBE in a clinical context. Current data on RBE effects, patient outcome and modelling from experimental as well as clinical studies were presented and discussed. Furthermore, representatives from European clinical proton therapy centres, who were involved in patient treatment, laid out their current clinical practice on how to consider the risk of a variable RBE in their centres. In line with the workshop, this work considers the actual impact of RBE issues on patient care in proton therapy by reviewing preclinical data on the relation between linear energy transfer (LET) and RBE, current clinical data sets on RBE effects in patients, and applied clinical strategies to manage RBE uncertainties. A better understanding of the variability in RBE would allow development of proton treatments which are safer and more effective.

Background and purpose In consequence of a previous study, where no protecting proton Flash effect was found for zebrafish embryos, potential reasons and requirements for inducing a Flash effect should be investigated with the beam pulse structure and the partial oxygen pressure (pO2) as relevant parameters. Materials and methods The experiments were performed at the research electron accelerator ELBE, whose variable pulse structure enables dose delivery as electron Flash and quasi-continuously (reference). Zebrafish embryos were irradiated with ~26 Gy either continuously with a dose rate of ~6.7 Gy/min or in one 111 µs long pulse with a pulse dose rate of 109 Gy/s and a mean dose rate of 105 Gy/s, respectively. Using the OxyLite system to measure the pO2 a low- (pO2 ≤ 5 mmHg) and a high-pO2 group were defined on basis of the oxygen depletion kinetics in sealed embryo samples. Results A protective Flash effect was seen for most endpoints ranging from 4 % less reduction in embryo length to about 20 – 25 % less embryos with spinal curvature and pericardial edema, relative to reference irradiation. The reduction of pO2 below atmospheric levels (148 mmHg) resulted in higher protection, which was however more pronounced in the low-pO2 group. Conclusion The Flash experiment at ELBE showed that the zebrafish embryo model is appropriate for studying the radiobiological response of high dose rate irradiation. Pulse dose and pulse dose rate as important beam parameters were confirmed as well as the pivotal role of pO2 during irradiation.

Background and purpose In consequence of a previous study, where no protecting proton Flash effect was found for zebrafish embryos, potential reasons and requirements for inducing a Flash effect should be investigated with the beam pulse structure and the partial oxygen pressure (pO2) as relevant parameters. Materials and methods The experiments were performed at the research electron accelerator ELBE, whose variable pulse structure enables dose delivery as electron Flash and quasi-continuously (reference). Zebrafish embryos were irradiated with ~26 Gy either continuously with a dose rate of ~6.7 Gy/min or in one 111 µs long pulse with a pulse dose rate of 109 Gy/s and a mean dose rate of 105 Gy/s, respectively. Using the OxyLite system to measure the pO2 a low- (pO2 ≤ 5 mmHg) and a high-pO2 group were defined on basis of the oxygen depletion kinetics in sealed embryo samples. Results A protective Flash effect was seen for most endpoints ranging from 4 % less reduction in embryo length to about 20 – 25 % less embryos with spinal curvature and pericardial edema, relative to reference irradiation. The reduction of pO2 below atmospheric levels (148 mmHg) resulted in higher protection, which was however more pronounced in the low-pO2 group. Conclusion The Flash experiment at ELBE showed that the zebrafish embryo model is appropriate for studying the radiobiological response of high dose rate irradiation. Pulse dose and pulse dose rate as important beam parameters were confirmed as well as the pivotal role of pO2 during irradiation.

Laser-driven proton pulse provide unique properties in terms of pulse structure (ns) and instantaneous dose rate (10^9 Gy/s) but - inherently broadband and highly divergent - pose a challenge to established beamline concepts on the path to application-adapted irradiation field formation, particularly for three-dimensional cases. We present the successful implementation and characterisation of a highly efficient and tuneable dual pulsed solenoid beamline at the Draco PW facility[1] to generate volumetric dose distribution tailored to specific applications[2]. The vast experimental scope and already successfully performed studies range from systematic volumetric in-vivo tumour irradiations in a dedicated mouse model (with a stable mean dose delivery of ±10 % and a spatial dose homogeneity of ±5 % over a cylindrical volume of 5 mm diameter and height) to high-dose-rate irradiations in the FLASH regime (using proton peak dose rates of up to 10^9 Gy/s with about 20 Gy/shot homogeneously over a cylindrical sample volume of 4.5 mm diameter and 3 mm height) as well as particle diagnostics commissioning (with a multitude of spatial and spectral dose distributions). The beamline setup is complemented by a complex beam monitoring and dosimetry detector suite adapted to the ultra-high dose rate pulses and is in its unique synergy and redundancy capable of %-level precision dose delivery to samples as required for systematic irradiation studies. In addition to established radiochromic film dosimetry, the detector suite includes saturation-corrected (transmission) ionisation chambers [3] as well as screen and bulk scintillator setups, partly with tomographic reconstruction capabilities for 3D dose distribution retrieval. Moreover, non-invasive, single-shot-capable online time-of-flight-based spectral characterisation of filtered proton pulses has proven a powerful tool for beam monitoring as well as dosimetric purposes. In this presentation the complex and versatile dose delivery

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.

After the rediscovery of the normal tissue sparing effect of high dose rate radiation, i.e. the so-called FLASH effect, by Favaudon et al. in 2014, research activities on this topic have been revived and are flourishing ever since. Yet, the exact biological mechanism as well as the required boundary conditions and radiation qualities to reach said sparing remain mostly unclear. We present a laser-based irradiation platform at the Draco PW facility that enables systematic studies into the FLASH regime using proton peak dose rates of up to 10^9 Gy/s. Besides the PW class laser acceleration source, a key component is a pulsed high-field beamline to transport and shape the laser driven proton bunches spectrally and spatially in order to generate homogeneous dose distributions tailored to match the irradiation sample. Making use of the diverse capabilities of the laser driven irradiation platform a pilot experiment of highest complexity has been conducted – a systematic in-vivo tumor irradiation in a specifically developed mouse model. A plethora of online particle diagnostics, including Time-of-Flight, bulk scintillators and screens as well as ionization chambers, in conjunction with diagnostics for retrospective absolute dosimetry (radiochromic films) allowed for an unprecedented level of precision in mean dose delivery (±10 %) and dose homogeneity (±5 %) for the challenging beam qualities of a laser accelerator. The tailored detector suite is complemented by predictive simulations. The talk addresses how our interdisciplinary team overcame all hurdles from animal model development, over enhancing the laser and laser acceleration stability, to dose delivery and online dose monitoring. Results on radiation induced tumor growth delay by laser driven as well as conventionally accelerated proton beams are critically discussed.

Laser-driven proton pulse provide unique properties in terms of pulse structure (ns) and instantaneous dose rate (10^9 Gy/s) but - inherently broadband and highly divergent - pose a challenge to established beamline concepts on the path to application-adapted irradiation field formation, particularly for three-dimensional cases. We present the successful implementation and characterisation of a highly efficient and tuneable dual pulsed solenoid beamline at the Draco PW facility[1] to generate volumetric dose distribution tailored to specific applications[2]. The vast experimental scope and already successfully performed studies range from systematic volumetric in-vivo tumour irradiations in a dedicated mouse model (with a stable mean dose delivery of ±10 % and a spatial dose homogeneity of ±5 % over a cylindrical volume of 5 mm diameter and height) to high-dose-rate irradiations in the FLASH regime (using proton peak dose rates of up to 10^9 Gy/s with about 20 Gy/shot homogeneously over a cylindrical sample volume of 4.5 mm diameter and 3 mm height) as well as particle diagnostics commissioning (with a multitude of spatial and spectral dose distributions). The beamline setup is complemented by a complex beam monitoring and dosimetry detector suite adapted to the ultra-high dose rate pulses and is in its unique synergy and redundancy capable of %-level precision dose delivery to samples as required for systematic irradiation studies. In addition to established radiochromic film dosimetry, the detector suite includes saturation-corrected (transmission) ionisation chambers [3] as well as screen and bulk scintillator setups, partly with tomographic reconstruction capabilities for 3D dose distribution retrieval. Moreover, non-invasive, single-shot-capable online time-of-flight-based spectral characterisation of filtered proton pulses has proven a powerful tool for beam monitoring as well as dosimetric purposes. In this presentation the complex and versatile dose delivery

After the rediscovery of the normal tissue sparing effect of high dose rate radiation, i.e. the so-called FLASH effect, by Favaudon et al. in 2014, research activities on this topic have been revived and are flourishing ever since. Yet, the exact biological mechanism as well as the required boundary conditions and radiation qualities to reach said sparing remain mostly unclear. We present a laser-based irradiation platform at the Draco PW facility that enables systematic studies into the FLASH regime using proton peak dose rates of up to 10^9 Gy/s. Besides the PW class laser acceleration source, a key component is a pulsed high-field beamline to transport and shape the laser driven proton bunches spectrally and spatially in order to generate homogeneous dose distributions tailored to match the irradiation sample. Making use of the diverse capabilities of the laser driven irradiation platform a pilot experiment of highest complexity has been conducted – a systematic in-vivo tumor irradiation in a specifically developed mouse model. A plethora of online particle diagnostics, including Time-of-Flight, bulk scintillators and screens as well as ionization chambers, in conjunction with diagnostics for retrospective absolute dosimetry (radiochromic films) allowed for an unprecedented level of precision in mean dose delivery (±10 %) and dose homogeneity (±5 %) for the challenging beam qualities of a laser accelerator. The tailored detector suite is complemented by predictive simulations. The talk addresses how our interdisciplinary team overcame all hurdles from animal model development, over enhancing the laser and laser acceleration stability, to dose delivery and online dose monitoring. Results on radiation induced tumor growth delay by laser driven as well as conventionally accelerated proton beams are critically discussed.

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.

Background and Aims After the rediscovery of the normal tissue sparing FLASH effect of high dose rate radiation, research activities on this topic have been revived. But especially for protons, the portfolio of accelerators capable of performing studies at ultra-high dose rates is limited. Laser-plasma accelerators (LPA) can generate extremely intense proton bunches of many 10 MeV kinetic energy. In combination with dedicated dose delivery systems, LPA proton sources facilitate peak dose rates well above 10^8 Gy/s in a pulse structure regime complementary to conventional accelerators. Methods The reliable generation of proton spectra beyond 60 MeV at DRACO-PW [Ziegler et al, SciRep2021], combined with a dedicated energy selective pulsed magnet beam transport system [Brack et al, SciRep2020], allows tailored sample-specific dose distributions. Adapted on-shot dosimetry enables the required spectral monitoring of every proton bunch. Two irradiation series on volumetric biological samples were performed at DRACO-PW, accompanied by reference irradiations at the University Proton Therapy Dresden. Results The first small animal pilot study at a laser-driven proton source was conducted successfully. The mouse-ear tumor model’s requirements [Beyreuther et al, PLoS One2018] were fulfilled and verified at high precision (+/- 5%) concerning predefined dose value and conformity. Complementary, a study investigating dose-rate effects such as FLASH was performed irradiating zebrafish embryos with above 10^9 Gy/s. Conclusions We present a laser-based irradiation platform at the DRACO-PW facility that enables systematic radiobiological studies, laying the foundations for further studies at LPA sources exploring ultra-high dose-rate effects, such as FLASH, over previously unreachable parameter space.

Background and aims In FLASH radiotherapy (RT), a protective effect of healthy tissue was observed, while tumor control remains comparable to conventional RT[1]. One possible explanation is the oxygen depletion hypothesis, in which radiolysis of water/cytoplasma causes the production of radicals that then react with O2 dissolved in water. This would cause a reduction in O2, which results in a hypoxic target and thus a radio-protective effect. In a previous study[2], we measured O2 depletion in sealed water phantoms during irradiation at high dose rates (<300 Gy/s) for protons, carbon ions and photons. Methods In the study presented here, this experiment was conducted further to ultra-high dose rates (10^9 Gy/s) with protons at DRACO and electrons at ELBE, where also the impact of different pulse structures on O2 depletion was tested. In addition, various settings were tested in order to irradiate zebrafish embryos with FLASH while simultaneously measuring O2. Results and Conclusion We were able to confirm the results of the previous study even at ultra-high dose rates and with electrons and came to two conclusions: 1. not enough O2 was depleted at clinical doses to explain a FLASH effect based on radiation-induced hypoxia 2. the amount of O2 depleted per dose depends on dose rate, and higher dose rates deplete slightly less O2. Furthermore, it was possible to measure O2 depletion during zebrafish embryo irradiation making a simultaneous study of biological response and O2 depletion possible. [1]Favaudon, et al. (2014) https://doi.org/10.1126/scitranslmed.3008973 [2]Jansen, et al. (2021) https://doi.org/10.1002/mp.14917

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.

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 To date, proton therapy is hampered by the lack of reliable in-vivo real-time feedback on the beam range, profile and energy deposition. So far, no technique enables the determination of beam effects on images also showing anatomical information in 2D/3D with high temporal and spatial resolution. The aim of this study is to demonstrate the possibility of visualizing a stopping proton beam in water using MR imaging. Materials & methods An open 0.22 T MR scanner was combined with a static proton research beamline to acquire MR images during simultaneous proton beam irradiation. Proton beams with an energy of 190−225 MeV and current of 3−64 nA impinged centrally on a 20 cm PMMA range modulator and were stopped in a water-filled phantom placed inside a dedicated knee MR receiver coil. A variety of different MR pulse sequences including T1- and T2-weighted Spin Echo (SE), Turbo Spin Echo, spoiled and unspoiled T1-weighted Gradient Echo (GE), inversion recovery gradient echo (IRGE), FLASH, Scout and time-of-flight (TOF) Angio were used. For each sequence, coronal images were acquired both with and without irradiation. Results The unspoiled GE sequence exhibited a hyper-intense central line artefact that showed a beam energy and current dependent twist under irradiation. The spoiled GE, IRGE, FLASH, Scout and TOF Angio sequences showed hyper- or hypo-intense signatures in the images that varied with the expected range and mimicked the shape of a 2D dose profile. The intensity of the effects depends on the beam current. The beam range determined from the MR images agrees to the expected range within a few millimeters. No beam induced signal changes were observed in the SE sequences. Conclusion A stopping proton beam in liquid water can be visualized with MRI. The observed signatures are beam energy and range as well as beam current and dose dependent. The underlying physical principles and the transferability to non-liquid materials needs further investigation.

Introduction: A prototype system for MR‐integrated proton therapy (MRiPT) with an in-beam MR scanner is currently under investigation at our facility. The commissioning thereof requires an accurate beam model, a 3D map of the full static magnetic field (MF) of the MR scanner and consideration of their interaction. This work describes measurements of the proton beam, the MF and beam modeling performed to set up a proton beam model for the MRiPT prototype system. Materials & Methods: Measurements of central proton beam spot sizes in air at 10 distances from the beam isocenter (between -15 and 54 cm) and integral depth-dose profiles (100 to 226.7 MeV) in water were obtained without MF using a scintillation detector and a water phantom with a Bragg peak chamber, respectively. A beam model was fitted to these measurements by utilizing an automated regularization-based optimization process. A 3D magnetic field map of the 0.33 T open MR scanner was acquired using spatially resolved Hall probe measurements. Results: In the absence of the MF, the optimized beam model reproduced the measured beam spot sizes in air with an error <0.5 mm for 100 – 226.7 MeV and depth dose curves in water with an error <0.1 g/cm² for 100 – 226.7 MeV. The magnetic field measuring approach delivers reproducible results with high accuracy and an uncertainty <±5 mT. Summary: A proton beam model for the MRiPT prototype system without MF was established and a high-precision method for mapping the 3D MF of the MR scanner was developed. The MF map and the beam model will be used to establish an experimental treatment planning system providing a correction algorithm accounting for the influence of the MF of the MR scanner on proton beams. Further investigations are necessary to validate the beam model in the presence of the MF.

Primary data and data description to publication: Electron dose rate and oxygen depletion protect zebrafish embryos from radiation damage Abstract: Background and purpose In consequence of a previous study, where no protecting proton Flash effect was found for zebrafish embryos, potential reasons and requirements for inducing a Flash effect should be investigated with the beam pulse structure and the partial oxygen pressure (pO2) as relevant parameters. Materials and methods The experiments were performed at the research electron accelerator ELBE, whose variable pulse structure enables dose delivery as electron Flash and quasi-continuously (reference). Zebrafish embryos were irradiated with ~26 Gy either continuously with a dose rate of ~6.7 Gy/min or in one 111 µs long pulse with a pulse dose rate of 109 Gy/s and a mean dose rate of 105 Gy/s, respectively. Using the OxyLite system to measure the pO2 a low- (pO2 ≤ 5 mmHg) and a high-pO2 group were defined on basis of the oxygen depletion kinetics in sealed embryo samples. Results A protective Flash effect was seen for most endpoints ranging from 4 % less reduction in embryo length to about 20 – 25 % less embryos with spinal curvature and pericardial edema, relative to reference irradiation. The reduction of pO2 below atmospheric levels (148 mmHg) resulted in higher protection, which was however more pronounced in the low-pO2 group. Conclusion The Flash experiment at ELBE showed that the zebrafish embryo model is appropriate for studying the radiobiological response of high dose rate irradiation. Pulse dose and pulse dose rate as important beam parameters were confirmed as well as the pivotal role of pO2 during irradiation.

All source data and scripts for publication: "Tumor irradiation in mice with a laser-accelerated proton beam"

ntense laser-driven proton pulses, inherently broadband and highly divergent, pose a challenge to established beamline concepts on the path to application-adapted irradiation field formation, particularly for 3D. Here we experimentally show the successful implementation of a highly efficient (50% transmission) and tuneable dual pulsed solenoid setup to generate a homogeneous (laterally and in depth) volumetric dose distribution (cylindrical volume of 5 mm diameter and depth) at a single pulse dose of 0.7 Gy via multi-energy slice selection from the broad input spectrum. The experiments were conducted at the Petawatt beam of the Dresden Laser Acceleration Source Draco and were aided by a predictive simulation model verified by proton transport studies. With the characterised beamline we investigated manipulation and matching of lateral and depth dose profiles to various desired applications and targets. Using an adapted dose profile, we performed a first proof-of-technical-concept laser-driven proton irradiation of volumetric in-vitro tumour tissue (SAS spheroids) to demonstrate concurrent operation of laser accelerator, beam shaping, dosimetry and irradiation procedure of volumetric biological samples.

ntense laser-driven proton pulses, inherently broadband and highly divergent, pose a challenge to established beamline concepts on the path to application-adapted irradiation field formation, particularly for 3D. Here we experimentally show the successful implementation of a highly efficient (50% transmission) and tuneable dual pulsed solenoid setup to generate a homogeneous (laterally and in depth) volumetric dose distribution (cylindrical volume of 5 mm diameter and depth) at a single pulse dose of 0.7 Gy via multi-energy slice selection from the broad input spectrum. The experiments were conducted at the Petawatt beam of the Dresden Laser Acceleration Source Draco and were aided by a predictive simulation model verified by proton transport studies. With the characterised beamline we investigated manipulation and matching of lateral and depth dose profiles to various desired applications and targets. Using an adapted dose profile, we performed a first proof-of-technical-concept laser-driven proton irradiation of volumetric in-vitro tumour tissue (SAS spheroids) to demonstrate concurrent operation of laser accelerator, beam shaping, dosimetry and irradiation procedure of volumetric biological samples.

ntense laser-driven proton pulses, inherently broadband and highly divergent, pose a challenge to established beamline concepts on the path to application-adapted irradiation field formation, particularly for 3D. Here we experimentally show the successful implementation of a highly efficient (50% transmission) and tuneable dual pulsed solenoid setup to generate a homogeneous (laterally and in depth) volumetric dose distribution (cylindrical volume of 5 mm diameter and depth) at a single pulse dose of 0.7 Gy via multi-energy slice selection from the broad input spectrum. The experiments were conducted at the Petawatt beam of the Dresden Laser Acceleration Source Draco and were aided by a predictive simulation model verified by proton transport studies. With the characterised beamline we investigated manipulation and matching of lateral and depth dose profiles to various desired applications and targets. Using an adapted dose profile, we performed a first proof-of-technical-concept laser-driven proton irradiation of volumetric in-vitro tumour tissue (SAS spheroids) to demonstrate concurrent operation of laser accelerator, beam shaping, dosimetry and irradiation procedure of volumetric biological samples.

Particle therapy is a growing cancer treatment modality worldwide. However, there still remains a number of unanswered questions considering differences in the biological response between particles and photons. These questions, and probing of biological mechanisms in general, necessitate experimental investigation. The “Infrastructure in Proton International Research” (INSPIRE) project was created to provide an infrastructure for European research, unify research efforts on the topic of proton and ion therapy across Europe, and to facilitate the sharing of information and resources. This work highlights the radiobiological capabilities of the INSPIRE partners, providing details of physics (available particle types and energies), biology (sample preparation and post-irradiation analysis), and researcher access (the process of applying for beam time). The collection of information reported here is designed to provide researchers both in Europe and worldwide with the tools required to select the optimal center for their research needs. We also highlight areas of redundancy in capabilities and suggest areas for future investment.

Ongoing advances in both imaging and treatment for oncology purposes have seen a significant rise in the use of not only the individual imaging modalities, but also their combination in single systems such as PET-CT and PET-MRI when planning for advanced oncology treatment, the most demanding of which is proton therapy. This has identified issues in the availability of suitable materials upon which to support the patient undergoing imaging and treatment owing to the differing requirements for each of the techniques. Sandwich composites are often selected to solve this issue but there is little information regarding optimum materials for their cores. In this paper we present a range of materials which are suitable for such purposes and evaluate the performance for use in terms of PET signal attenuation, proton beam stopping, MRI signal shading and X-Ray CT visibility. We find that Extruded Polystyrene offers the best compromise for patient support and positioning structures across all modalities tested, allowing for significant savings in treatment planning time and delivering more efficient treatment with lower margins.

UHDpulse - Metrology for advanced radiotherapy using particle beams with ultra-high pulse dose rates is a recently started European Joint Research Project with the aim to develop and improve dosimetry standards for FLASH radiotherapy, very high energy electron (VHEE) radiotherapy and laser-driven medical accelerators. This paper gives a short overview about the current state of developments of radiotherapy with FLASH electrons and protons, very high energy electrons as well as laser-driven particles and the related challenges in dosimetry due to the ultra-high dose rate during the short radiation pulses. We summarize the objectives and plans of the UHDpulse project and present the 16 participating partners with their skills and roles.

ntense laser-driven proton pulses, inherently broadband and highly divergent, pose a challenge to established beamline concepts on the path to application-adapted irradiation field formation, particularly for 3D. Here we experimentally show the successful implementation of a highly efficient (50% transmission) and tuneable dual pulsed solenoid setup to generate a homogeneous (laterally and in depth) volumetric dose distribution (cylindrical volume of 5 mm diameter and depth) at a single pulse dose of 0.7 Gy via multi-energy slice selection from the broad input spectrum. The experiments were conducted at the Petawatt beam of the Dresden Laser Acceleration Source Draco and were aided by a predictive simulation model verified by proton transport studies. With the characterised beamline we investigated manipulation and matching of lateral and depth dose profiles to various desired applications and targets. Using an adapted dose profile, we performed a first proof-of-technical-concept laser-driven proton irradiation of volumetric in-vitro tumour tissue (SAS spheroids) to demonstrate concurrent operation of laser accelerator, beam shaping, dosimetry and irradiation procedure of volumetric biological samples.

Purpose/Objective: The laser-driven ionizing (LDI) beams have unique property of ultra-high dose rate, ultra-short pulses and carry the potential toward special clinical application. Our aim was to establish an in vivo zebrafish model for radiobiological research on later LDI radiation. Material/methods: 24 hours post-fertilization (hpf) zebrafish (Danio rerio) embryos were irradiated at the University Proton Therapy Dresden with escalated doses (5, 10, 15, 20 and 30 Gy) at two positions along the proton depth-dose curve, at the plateau and at the middle of Spread Out Bragg Peak, and with reference 6 MV photon beams from a clinical linac (n=96 in each group). The experiment was 3 times repeated under the same conditions. On the 3th (96 hpf) and 4th (120 hpf) days after irradiation morphological malformations were documented (photo) and determined quantitatively. Two independent observers measured the length of the embryos, the degree of the yolk sac edema and the diameter of the eyes. Additionally, we have detected the DNA double-strand breaks immunohistochemically (gamma-H2AX foci) after 30 min of the irradiation at the two positions of the proton (mSOBP and plateau) and photon beams, at 5 Gy dose level. Results: Dose-dependent organ developmental deteriorations could be detected morphologically at >10 Gy dose levels. The length of the embryo and the size of the eyes reduced, while the yolk sac edema increased significantly in dose dependent degree after 10 Gy, 15 Gy, 20 Gy and 30 Gy irradiation, at both developmental stages. At 5 Gy dose irradiation we have found significant elevation in the number of DNA double-strand breaks, as compared to the unirradiated control groups. Furthermore, data showed that after proton irradiation the degree of the DNA damage was higher, as compared to the photon irradiation. Conclusion: We could establish a reliable quantitative morphological analysis of dose-dependent organ malformations using an in vivo vertebrate system. The zebr

The combination of the beneficial effects of high dose-rate Flash-RT and proton depth dose distribution promise the differential sparing of normal tissue under similar tumour treating efficacy. However, of the two published attempts [1,2] made at clinical proton facilities, one in vivo study on zebrafish embryo was not able to measure a Flash effect [2]. In the discussion of this experiment, the zebrafish model, a non-ideal pulse-time-regime and an uncertain oxygen level during irradiation were identified as potential explanations for the missing Flash effect. In order to investigate these parameters in detail an experiment was scheduled at the research electron accelerator ELBE at HZDR, because an electron Flash effect was already demonstrated for zebrafish embryo [3]. The highly variable pulse structure of ELBE enables to deliver the dose either in therapy like quasi-continuous (cw) beams or as electron Flash irradiation. Zebrafish embryo were irradiated with 40 Gy with pulse dose rates of 109 Gy/s and mean dose rates of 106 Gy/s in comparison to 0.1 Gy/s with cw irradiation. In addition to this, the Oxylite system was applied to measure and control oxygen depletion kinetics in sealed embryo samples. A protective Flash effect was seen for most endpoints ranging from 4 % less reduction in embryo length to about 20 – 25 % less embryo with spinal curvature and pericardial oedema, relative to cw-irradiation. The reduction of partial oxygen pressure below atmospheric levels results in higher protection, the more the lower the oxygen level. In conclusion, the Flash experiment at ELBE show that the zebrafish embryo model is appropriate for the study of the radiobiological response of high dose rate irradiation. A sufficiently pulse dose seems to be more important than pulse dose rate and the partial oxygen pressure during irradiation plays a pivotal role. [1] Diffenderfer et al.: https://doi.org/10.1016/j.ijrobp.2019.10.049 [2] Beyreuther et al.: https://doi.org/10.1016

The combination of the beneficial effects of high dose-rate Flash-RT and proton depth dose distribution promise the differential sparing of normal tissue under similar tumour treating efficacy. However, of the two published attempts [1,2] made at clinical proton facilities, one in vivo study on zebrafish embryo was not able to measure a Flash effect [2]. In the discussion of this experiment, the zebrafish model, a non-ideal pulse-time-regime and an uncertain oxygen level during irradiation were identified as potential explanations for the missing Flash effect. In order to investigate these parameters in detail an experiment was scheduled at the research electron accelerator ELBE at HZDR, because an electron Flash effect was already demonstrated for zebrafish embryo [3]. The highly variable pulse structure of ELBE enables to deliver the dose either in therapy like quasi-continuous (cw) beams or as electron Flash irradiation. Zebrafish embryo were irradiated with 40 Gy with pulse dose rates of 109 Gy/s and mean dose rates of 106 Gy/s in comparison to 0.1 Gy/s with cw irradiation. In addition to this, the Oxylite system was applied to measure and control oxygen depletion kinetics in sealed embryo samples. A protective Flash effect was seen for most endpoints ranging from 4 % less reduction in embryo length to about 20 – 25 % less embryo with spinal curvature and pericardial oedema, relative to cw-irradiation. The reduction of partial oxygen pressure below atmospheric levels results in higher protection, the more the lower the oxygen level. In conclusion, the Flash experiment at ELBE show that the zebrafish embryo model is appropriate for the study of the radiobiological response of high dose rate irradiation. A sufficiently pulse dose seems to be more important than pulse dose rate and the partial oxygen pressure during irradiation plays a pivotal role. [1] Diffenderfer et al.: https://doi.org/10.1016/j.ijrobp.2019.10.049 [2] Beyreuther et al.: https://doi.org/10.1016

ntense laser-driven proton pulses, inherently broadband and highly divergent, pose a challenge to established beamline concepts on the path to application-adapted irradiation field formation, particularly for 3D. Here we experimentally show the successful implementation of a highly efficient (50% transmission) and tuneable dual pulsed solenoid setup to generate a homogeneous (laterally and in depth) volumetric dose distribution (cylindrical volume of 5 mm diameter and depth) at a single pulse dose of 0.7 Gy via multi-energy slice selection from the broad input spectrum. The experiments were conducted at the Petawatt beam of the Dresden Laser Acceleration Source Draco and were aided by a predictive simulation model verified by proton transport studies. With the characterised beamline we investigated manipulation and matching of lateral and depth dose profiles to various desired applications and targets. Using an adapted dose profile, we performed a first proof-of-technical-concept laser-driven proton irradiation of volumetric in-vitro tumour tissue (SAS spheroids) to demonstrate concurrent operation of laser accelerator, beam shaping, dosimetry and irradiation procedure of volumetric biological samples.

We performed experiments with the Petawatt beam of the Dresden laser acceleration source Draco to investigate the feasibility of controlled volumetric tumour irradiations with laser-accelerated protons. Therefore, a beamline of two pulsed solenoid magnets was implemented to efficiently capture and shape the beam, which was then analysed by a comprehensive suite of detectors (ionization chamber, scintillator, radiochromic film, ..). We extensively studied how to manipulate and match lateral and depth dose profiles to the desired application and target. These were assisted by benchmark experiments at a conventional accelerator to further characterize the ion-optical properties of the solenoids and to investigate potential distortions of the transported proton beam. With the characterized beamline first proof-of-principle irradiation studies of volumetric normal and tumour tissue samples have been performed successfully. To advance to full scale irradiation experiments, a higher mean dose rate is necessary to deliver high absolute dose values via multiple bunches (dose control) in short times (~min). Current limitations are the low repetition rate of the beamline and its long cooldown times. Therefore, we developed a novel, actively cooled pulsed solenoid, to be implemented in the beamline, enabling complex irradiation studies with high repetition rates and consequently high mean dose rates.

We performed experiments with the Petawatt beam of the Dresden laser acceleration source Draco to investigate the feasibility of controlled volumetric tumour irradiations with laser-accelerated protons. Therefore, a beamline of two pulsed solenoid magnets was implemented to efficiently capture and shape the beam, which was then analysed by a comprehensive suite of detectors (ionization chamber, scintillator, radiochromic film, ..). We extensively studied how to manipulate and match lateral and depth dose profiles to the desired application and target. These were assisted by benchmark experiments at a conventional accelerator to further characterize the ion-optical properties of the solenoids and to investigate potential distortions of the transported proton beam. With the characterized beamline first proof-of-principle irradiation studies of volumetric normal and tumour tissue samples have been performed successfully. To advance to full scale irradiation experiments, a higher mean dose rate is necessary to deliver high absolute dose values via multiple bunches (dose control) in short times (~min). Current limitations are the low repetition rate of the beamline and its long cooldown times. Therefore, we developed a novel, actively cooled pulsed solenoid, to be implemented in the beamline, enabling complex irradiation studies with high repetition rates and consequently high mean dose rates.

Purpose: To determine the volume recombination at high dose-per-pulse in liquid ionization chambers (LIC) and to ascertain whether existing calculation methods verified in air-filled chambers may be used to calculate a correction factor. Methods: Two LICs, one filled with 2,2,4-trimethylpentane (isooctane) the other with tetramethylsilane (TMS), were irradiated in a pulsed, 20 MeV electron beam. Via reference measurements with a Faraday-cup the saturation correction for volume recombination was determined for dose-per-pulse values ranging from about 5 mGy to 1 Gy for both chambers at a pulse duration of 693 ns. In addition, the isooctane-chamber was irradiated with pulses of varying duration, ranging from 5 ps to 10 ms, at a dose-per-pulse of about 76.5 mGy. The dose-per-pulse dependent measurements were compared to calculations based on Boag’s models (with and without a free electron fraction) and the two-dose-rate method. The pulse duration dependent measurements were compared to a numerical calculation that iteratively calculates the charge transport and loss in a 1D model of an ionization chamber. Results: In TMS only Boag’s model with a free electron fraction is in good agreement with the experimental data. However, in isooctane good agreement is observed between the experimental data, the two-dose-rate method, Boag’s model including a free electron fraction and to a lesser extend also Boag’s model without a free-electron fraction. Furthermore, the pulse duration dependent data for isooctane is well described by the numerical model. Conclusion: With isooctane as an active medium a LIC could be directly used in a field with high dose-per-pulse utilizing the well established two-dose-rate method to correct for volume recombination. In addition, pulsed fields with variable pulse duration are easily modeled for this medium using a numerical calculation. Other media, as exemplified by the TMS-filled chamber, might require additional considerations, such as including

Purpose/Objective: The laser-driven ionizing (LDI) beams have unique property of ultra-high dose rate, ultra-short pulses and carry the potential toward special clinical application. Our aim was to establish an in vivo zebrafish model for radiobiological research on later LDI radiation. Material/methods: 24 hours post-fertilization (hpf) zebrafish (Danio rerio) embryos were irradiated at the University Proton Therapy Dresden with escalated doses (5, 10, 15, 20 and 30 Gy) at two positions along the proton depth-dose curve, at the plateau and at the middle of Spread Out Bragg Peak, and with reference 6 MV photon beams from a clinical linac (n=96 in each group). The experiment was 3 times repeated under the same conditions. On the 3th (96 hpf) and 4th (120 hpf) days after irradiation morphological malformations were documented (photo) and determined quantitatively. Two independent observers measured the length of the embryos, the degree of the yolk sac edema and the diameter of the eyes. Additionally, we have detected the DNA double-strand breaks immunohistochemically (gamma-H2AX foci) after 30 min of the irradiation at the two positions of the proton (mSOBP and plateau) and photon beams, at 5 Gy dose level. Results: Dose-dependent organ developmental deteriorations could be detected morphologically at >10 Gy dose levels. The length of the embryo and the size of the eyes reduced, while the yolk sac edema increased significantly in dose dependent degree after 10 Gy, 15 Gy, 20 Gy and 30 Gy irradiation, at both developmental stages. At 5 Gy dose irradiation we have found significant elevation in the number of DNA double-strand breaks, as compared to the unirradiated control groups. Furthermore, data showed that after proton irradiation the degree of the DNA damage was higher, as compared to the photon irradiation. Conclusion: We could establish a reliable quantitative morphological analysis of dose-dependent organ malformations using an in vivo vertebrate system. The zebr

Particle therapy (PT) as cancer treatment, using protons or heavier ions, can provide a more favourable dose distribution compared to x-rays. While the physical characteristics of particle radiation have been the aim of intense research, less focus has been placed on the actual biological responses arising from particle irradiation. One of the biggest challenges for proton radiobiology is the RBE, with an increasing concern that the clinically-applied generic RBE-value of 1.1 is an approximation, as RBE is a complex quantity, depending on both biological and physical parameters, such as dose, LET, cellular and tissue radiobiological characteristics, as well as the endpoints being studied. Most of the available RBE data derive from in vitro experiments, with very limited in vivo data available, especially in late-reacting tissues, which provide the main constraints and influence the quality of life endpoints in radiotherapy. There is a need for systematic, large-scale studies to thoroughly establish the biology of particle radiation in a number of different experimental models in order to refine biophysical mathematical models that can potentially be used to guide PT. The overall objective of the European Particle Therapy Network (EPTN) WP6 is to form a network of research and therapy facilities in order to coordinate and standardise the radiobiological experiments, to obtain more accurate predictive parameters than in the past. Coordinated research is required in order to obtain the most appropriate experimental data. The aim in this paper is to describe the available radiobiology infrastructure of the centers involved in EPTN WP6.

A novel ion beam radiation therapy apparatus employing pulsed high magnetic field coils for transporting the ion beam has been proposed. In this paper a new pulsed current converter topology is introduced, which can be used as a pulsed power supply for the therapy apparatus. Thyristors are selected as the semiconductors used in the pulsed current converter. Since the planned operating point is outside of the typical range of the semiconductors, research has been done to predict their behavior during turn-off (the most critical phase of the pulse). A behavioral model has been derived and experimentally parametrized to predict the turn-off behavior and to optimize snubber design.

Purpose/Objective: The laser-driven ionizing (LDI) beams have unique property of ultra-high dose rate, ultra-short pulses and carry the potential toward special clinical application. Our aim was to establish an in vivo zebrafish model for radiobiological research on later LDI radiation. Material/methods: 24 hours post-fertilization (hpf) zebrafish (Danio rerio) embryos were irradiated at the University Proton Therapy Dresden with escalated doses (5, 10, 15, 20 and 30 Gy) at two positions along the proton depth-dose curve, at the plateau and at the middle of Spread Out Bragg Peak, and with reference 6 MV photon beams from a clinical linac (n=96 in each group). The experiment was 3 times repeated under the same conditions. On the 3th (96 hpf) and 4th (120 hpf) days after irradiation morphological malformations were documented (photo) and determined quantitatively. Two independent observers measured the length of the embryos, the degree of the yolk sac edema and the diameter of the eyes. Additionally, we have detected the DNA double-strand breaks immunohistochemically (gamma-H2AX foci) after 30 min of the irradiation at the two positions of the proton (mSOBP and plateau) and photon beams, at 5 Gy dose level. Results: Dose-dependent organ developmental deteriorations could be detected morphologically at >10 Gy dose levels. The length of the embryo and the size of the eyes reduced, while the yolk sac edema increased significantly in dose dependent degree after 10 Gy, 15 Gy, 20 Gy and 30 Gy irradiation, at both developmental stages. At 5 Gy dose irradiation we have found significant elevation in the number of DNA double-strand breaks, as compared to the unirradiated control groups. Furthermore, data showed that after proton irradiation the degree of the DNA damage was higher, as compared to the photon irradiation. Conclusion: We could establish a reliable quantitative morphological analysis of dose-dependent organ malformations using an in vivo vertebrate system. The zebr

Laser-driven particle acceleration may promise more compact and cost effective heavy charged particle (proton and heavier ions) radiotherapy facilities and also potentially offers treatment benefits like better irradiation of moving tumours. In contrast to conventional accelerators, laser accelerators deliver short, very intense ion bunches of low repetition rate, broad energy spectra and large divergences. In addition to laser particle accelerator development, laser-driven ion beam radiotherapy (LIBRT) demands new solutions for beam transport, dosimetric control and tumour conformal dose delivery along with full characterization of radiobiological effects. Laser-driven beams are already used for radiobiological studies with cells and small animals. For irradiation of extended tumour volumes in patients, a compact light-weight gantry based on pulsed, high-field magnets has been designed, enabling the capture and transport of divergent, broad energy bunches and including a novel beam shaping and dose delivery system. High quality treatment plans could be achieved based on the axial and lateral clustering method, deliverable via such a gantry. However, laser-driven bunch parameters are still far away from therapy requirements. Beside improvement in stability and reproducibility, a considerable increase of the maximum ion energy is necessary which is expected from the ongoing development of high-repetition petawatt-class lasers.

Purpose/Objective: The laser-driven ionizing (LDI) beams have unique property of ultra-high dose rate, ultra-short pulses and carry the potential toward special clinical application. Our aim was to establish an in vivo zebrafish model for radiobiological research on later LDI radiation. Material/methods: 24 hours post-fertilization (hpf) zebrafish (Danio rerio) embryos were irradiated at the University Proton Therapy Dresden with escalated doses (5, 10, 15, 20 and 30 Gy) at two positions along the proton depth-dose curve, at the plateau and at the middle of Spread Out Bragg Peak, and with reference 6 MV photon beams from a clinical linac (n=96 in each group). The experiment was 3 times repeated under the same conditions. On the 3th (96 hpf) and 4th (120 hpf) days after irradiation morphological malformations were documented (photo) and determined quantitatively. Two independent observers measured the length of the embryos, the degree of the yolk sac edema and the diameter of the eyes. Additionally, we have detected the DNA double-strand breaks immunohistochemically (gamma-H2AX foci) after 30 min of the irradiation at the two positions of the proton (mSOBP and plateau) and photon beams, at 5 Gy dose level. Results: Dose-dependent organ developmental deteriorations could be detected morphologically at >10 Gy dose levels. The length of the embryo and the size of the eyes reduced, while the yolk sac edema increased significantly in dose dependent degree after 10 Gy, 15 Gy, 20 Gy and 30 Gy irradiation, at both developmental stages. At 5 Gy dose irradiation we have found significant elevation in the number of DNA double-strand breaks, as compared to the unirradiated control groups. Furthermore, data showed that after proton irradiation the degree of the DNA damage was higher, as compared to the photon irradiation. Conclusion: We could establish a reliable quantitative morphological analysis of dose-dependent organ malformations using an in vivo vertebrate system. The zebr

Only few ten radiotherapy facilities worldwide provide ion beams, in spite of their physical advantage of better achievable tumor conformity of the dose compared to conventional photon beams. Since, mainly the large size and high costs hinder their wider spread, great efforts are ongoing to develop more compact ion therapy facilities. One promising approach for smaller facilities is the acceleration of ions on micrometre scale by high intensity lasers. Laser accelerators deliver pulsed beams with a low pulse repetition rate, but a high number of ions per pulse, broad energy spectra and high divergences. A clinical use of a laser based ion beam facility requires not only a laser accelerator providing beams of therapeutic quality, but also new approaches for beam transport, dosimetric control and tumor conformal dose delivery procedure together with the knowledge of the radiobiological effectiveness of laser-driven beams. Over the last decade research was mainly focused on protons and progress was achieved in all important challenges. Although currently the maximum proton energy is not yet high enough for patient irradiation, suggestions and solutions have been reported for compact beam transport and dose delivery procedures, respectively, as well as for precise dosimetric control. Radiobiological in vitro and in vivo studies show no indications of an altered biological effectiveness of laser-driven beams. Laser based facilities will hardly improve the availability of ion beams for patient treatment in the next decade. Nevertheless, there are possibilities for a need of laser based therapy facilities in future.

Only few ten radiotherapy facilities worldwide provide ion beams, in spite of their physical advantage of better achievable tumor conformity of the dose compared to conventional photon beams. Since, mainly the large size and high costs hinder their wider spread, great efforts are ongoing to develop more compact ion therapy facilities. One promising approach for smaller facilities is the acceleration of ions on micrometre scale by high intensity lasers. Laser accelerators deliver pulsed beams with a low pulse repetition rate, but a high number of ions per pulse, broad energy spectra and high divergences. A clinical use of a laser based ion beam facility requires not only a laser accelerator providing beams of therapeutic quality, but also new approaches for beam transport, dosimetric control and tumor conformal dose delivery procedure together with the knowledge of the radiobiological effectiveness of laser-driven beams. Over the last decade research was mainly focused on protons and progress was achieved in all important challenges. Although currently the maximum proton energy is not yet high enough for patient irradiation, suggestions and solutions have been reported for compact beam transport and dose delivery procedures, respectively, as well as for precise dosimetric control. Radiobiological in vitro and in vivo studies show no indications of an altered biological effectiveness of laser-driven beams. Laser based facilities will hardly improve the availability of ion beams for patient treatment in the next decade. Nevertheless, there are possibilities for a need of laser based therapy facilities in future.