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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.

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 system of laser-driven protons at the Draco PW using pulsed solenoids will be discussed. Its characterisation, technological development and improvement as well as the dosimetry suite as a vital part of the precise dose delivery will be addressed, while the presentation by U. Schramm covers recent experimental activities in detail. [1] T. Ziegler, et al., Proton beam quality enhancement by spectral phase control of a PW-class laser system, https://arxiv.org/abs/2007.11499 (2020) [2] Brack, et al., Spectral and spatial shaping of laser-driven proton beams using a pulsed high-field magnet beamline, SciRep, 10:9118, (2020) [3] Gotz M, et al., A new model for volume recombination in plane‐parallel chambers in pulsed fields of high dose‐per‐pulse. Phys Med Biol., 62: 8634, (2017)

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 higher pulse dose rate and 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 irradiation). Zebrafish embryos were irradiated with ~26 Gy either continuously at a dose rate of ~6.7 Gy/min (reference) or by 1441 electron pulses within 111 µs at a pulse dose rate of 109 Gy/s and a mean dose rate of 105Gy/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. The applied high pulse dose rate was confirmed as important beam parameter as well as the pivotal role of pO2 during irradiation.

In order to describe the volume recombination in a pulsed radiation field of high dose-per-pulse this study presents a numerical solution of a 1D transport model of the liberated charges in a plane-parallel ionization chamber. In addition, measurements were performed on an Advanced Markus ionization chamber in a pulsed electron beam to obtain suitable data to test the calculation. The experiment used radiation pulses of 4 μs duration and variable dose-per-pulse values up to about 1 Gy, as well as pulses of variable duration up to 308 [Formula: see text] at constant dose-per-pulse values between 85 mGy and 400 mGy. Those experimental data were compared to the developed numerical model and existing descriptions of volume recombination. At low collection voltages the observed dose-per-pulse dependence of volume recombination can be approximated by the existing theory using effective parameters. However, at high collection voltages large discrepancies are observed. The developed numerical model shows much better agreement with the observations and is able to replicate the observed behavior over the entire range of dose-per-pulse values and collection voltages. Using the developed numerical model, the differences between observation and existing theory are shown to be the result of a large fraction of the charge being collected as free electrons and the resultant distortion of the electric field inside the chamber. Furthermore, the numerical solution is able to calculate recombination losses for arbitrary pulse durations in good agreement with the experimental data, an aspect not covered by current theory. Overall, the presented numerical solution of the charge transport model should provide a more flexible tool to describe volume recombination for high dose-per-pulse values as well as for arbitrary pulse durations and repetition rates.

Purpose Gas-filled ionization chambers are the most important radiation detectors in radiotherapy. The collected charge at the electrodes does not represent the total released charge due to the unavoidable recombination processes. This needs to be considered for precise dose measurements. A quantitative description and correction of the recombination effects is established for two cases: continuous radiation exposure and pulsed radiation fields of single pulses with vanishing pulse duration. This work derives formulas for calculating the saturation correction for pulsed beams of nonvanishing pulse duration. Methods Recursive formulas are derived describing the spatio-temporal development of the charge density distributions in plane-parallel ionization chambers starting at neglected recombination. Pulse duration dependent effective chamber parameters are calculated, by comparing the coefficients of a series expansion for small recombination effects. These parameters are used afterward in the known formula for the saturation correction factor for pulsed irradiation with increased recombination effects which was established with the assumption of vanishing pulse duration. Results The formulas should be valid for pulse durations shorter than half the collection time of the chamber. They allow calculating the saturation correction factor for pulsed beams of nonvanishing pulse duration and arbitrary pulse dose, if chamber, beam, and filling gas parameters are known. The filling gas parameters could be determined from experimental data. The calculation results are in good agreement with already published experimental and simulated results for a Roos chamber. Conclusions The new formulas can be applied to determine the expected saturation correction for pulsed beams of different pulse duration and pulse dose including new beams at accelerators of new technologies. More experimental validation by using other chambers and an extension of the new formalism to pulse durations longer than half the collection time of the chamber is desired.

Background and purpose Motivated by first animal trials showing the normal tissue protecting effect of electron and photon Flash irradiation relative to conventional continuous beam delivery, the feasibility of proton Flash should be assessed. Materials and methods A setup and beam parameter settings for the treatment of zebrafish embryo with proton Flash and proton beam of conventional dose rate were established at the University Proton Therapy Dresden. Zebrafish embryos were treated with graded doses and the differential effect on embryonic survival and the induction of morphological malformations was followed for up to four days after irradiation. Results Beam parameters for the realization of proton Flash were set and tested with respect to controlled dose delivery to biological samples. The dose dependent embryonic survival data obtained for protons delivered as Flash and with a beam of conventional dose rate of 5 Gy/min show not significant influence of proton dose rate. Similarly, just a trend towards a protective effect of proton Flash was revealed for the induction of pericardial oedema as one type of acute radiation effect and spinal curvature as a developmental abnormality. Conclusion The feasibility of Flash proton irradiation was successfully shown, whereas more experiments are required to understand the absence of a clear protecting effect and therefore to figure out the limits and requirements for the Flash effect.

On-line image guidance using magnetic resonance (MR) imaging is expected to improve the targeting accuracy of proton therapy. However, to date no combined system exists. In this study, for the first time a low-field open MR scanner was integrated with a static proton research beam line to test the feasibility of simultaneous irradiation and imaging. The field-of-view of the MR scanner was aligned with the beam by taking into account the Lorentz force induced beam deflection. Various imaging sequences for extremities were performed on a healthy volunteer and on a patient with a soft-tissue sarcoma of the upper arm, both with the proton beam line switched off. T 1-weighted spin echo images of a tissue-mimicking phantom were acquired without beam, with energised beam line magnets and during proton irradiation. Beam profiles were acquired for the MR scanner's static magnetic field alone and in combination with the dynamic gradient fields during the acquisition of different imaging sequences. It was shown that MR imaging is feasible in the electromagnetically contaminated environment of a proton therapy facility. The observed quality of the anatomical MR images was rated to be sufficient for target volume definition and positioning. The tissue-mimicking phantom showed no visible beam-induced image degradation. The beam profiles depicted no influence due to the dynamic gradient fields of the imaging sequences. This study proves that simultaneous irradiation and in-beam MR imaging is technically feasible with a low-field MR scanner integrated with a static proton research beam line.

Regarding the long-term goal to develop and establish laser-based particle accelerators for a future radiotherapeutic treatment of cancer, the radiobiological consequences of the characteristic short intense particle pulses with ultra-high peak dose rate, but low repetition rate of laser-driven beams have to be investigated. This work presents in vitro experiments performed at the radiation source ELBE (Electron Linac for beams with high Brilliance and low Emittance). This accelerator delivered 20-MeV electron pulses with ultra-high pulse dose rate of 10(10) Gy/min either at the low pulse frequency analogue to previous cell experiments with laser-driven electrons or at high frequency for minimizing the prolonged dose delivery and to perform comparison irradiation with a quasi-continuous electron beam analogue to a clinically used linear accelerator. The influence of the different electron beam pulse structures on the radiobiological response of the normal tissue cell line 184A1 and two primary fibroblasts was investigated regarding clonogenic survival and the number of DNA double-strand breaks that remain 24 h after irradiation. Thereby, no considerable differences in radiation response were revealed both for biological endpoints and for all probed cell cultures. These results provide evidence that the radiobiological effectiveness of the pulsed electron beams is not affected by the ultra-high pulse dose rates alone.

Author(s): Brack, Florian-Emanuel; Kroll, Florian; Gaus, Lennart; Bernert, Constantin; Beyreuther, Elke; Cowan, Thomas E; Karsch, Leonhard; Kraft, Stephan; Kunz-Schughart, Leoni A; Lessmann, Elisabeth; Metzkes-Ng, Josefine; Obst-Huebl, Lieselotte; Pawelke, Jorg; Rehwald, Martin; Schlenvoigt, Hans-Peter; Schramm, Ulrich; Sobiella, Manfred; Szabo, Emilia Rita; Ziegler, Tim; Zeil, Karl | Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Purpose: In order to take full advantage of proton radiotherapy, the biological effect of protons in normal and tumor tissue should be investigated and understood in detail. The ongoing discussion on variable relative biological effectiveness along the proton depth dose distribution (eg, Paganetti 2015), and also the administration of concomitant treatments, demands dedicated in vitro trials that prepare the translation into the clinics. Therefore, a setup for radiobiological studies and the corresponding dosimetry should be established that enables in vitro experiments at a horizontal proton beam and a clinical 6 MV photon linear accelerator (Linac) as reference. Methods: The experimental proton beam at the University Proton Therapy Dresden is characterized by high beam availability and reliability throughout the day in parallel to patient treatment. For cell irradiation, a homogeneous 10 × 10 cm2 proton field with an optional spread-out Bragg-peak can be formed. A water-filled phantom was installed that allows for precise positioning of different sample geometries along the proton path. Results: Depth-dose profiles within the phantom and dose homogeneity over different cell samples were characterized for the proton beam and the photon reference source. A daily quality assurance protocol was implemented that provides absolute dose information required for significant and reproducible in vitro experiments. Cell survival test experiments were performed to demonstrate the feasibility of such experiments. Conclusion: In the experimental room of the University Proton Therapy Dresden, clinically relevant conditions for proton in vitro experiments have been realized. The established cell phantom and dosimetry facilitate irradiation in an aqueous environment and are transferable to other proton, photon and ion beam facilities. Precise positioning and easy exchange of cell samples, monitor unit-based dose delivery, and high beam availability allow for systematic in vitro experiments. The close vicinity to the radiotherapy and radiobiology departments provides access to clinical linacs and the interdisciplinary basis for further translational steps.

In line with the long-term aim of establishing the laser-based particle acceleration for future medical application, the radiobiological consequences of the typical ultra-short pulses and ultra-high pulse dose rate can be investigated with electron delivery.The radiation source ELBE (Electron Linac for beams with high Brilliance and low Emittance) was used to mimic the quasi-continuous electron beam of a clinical linear accelerator (LINAC) for comparison with electron pulses at the ultra-high pulse dose rate of 10(10) Gy min(-1) either at the low frequency of a laser accelerator or at 13 MHz avoiding effects of prolonged dose delivery. The impact of pulse structure was analyzed by clonogenic survival assay and by the number of residual DNA double-strand breaks remaining 24 h after irradiation of two human squamous cell carcinoma lines of differing radiosensitivity.The radiation response of both cell lines was found to be independent from electron pulse structure for the two endpoints under investigation.The results reveal, that ultra-high pulse dose rates of 10(10) Gy min(-1) and the low repetition rate of laser accelerated electrons have no statistically significant influence (within the 95% confidence intervals) on the radiobiological effectiveness of megavoltage electrons.

Pulsed radiation fields, characterized by microsecond pulse duration and correspondingly high pulse dose rates, are increasingly used in therapeutic, diagnostic and research applications. Yet, dose rate meters which are used to monitor radiation protection areas or to inspect radiation shielding are mostly designed, characterized and tested for continuous fields and show severe deficiencies in highly pulsed fields. Despite general awareness of the problem, knowledge of the specific limitations of individual instruments is very limited, complicating reliable measurements. We present here the results of testing three commercial dose rate meters, the RamION ionization chamber, the LB 1236-H proportional counter and the 6150AD-b scintillation counter, for their response in pulsed radiation fields of varied pulse dose and duration. Of these three the RamION proved reliable, operating in a pulsed radiation field within its specifications, while the other two instruments were only able to measure very limited pulse doses and pulse dose rates reliably.

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.

Proton beams may provide superior dose-conformity in radiation therapy. However, the large sizes and costs limit the widespread use of proton therapy (PT). The recent progress in proton acceleration via high-power laser systems has made it a compelling alternative to conventional accelerators, as it could potentially reduce the overall size and cost of the PT facilities. However, the laser-accelerated beams exhibit different characteristics than conventionally accelerated beams, i.e. very intense proton bunches with large divergences and broad-energy spectra. For the application of laser-driven beams in PT, new solutions for beam transport, such as beam capture, integrated energy selection, beam shaping and delivery systems are required due to the specific beam parameters. The generation of these beams are limited by the low repetition rate of high-power lasers and this limitation would require alternative solutions for tumour irradiation which can efficiently utilize the available high proton fluence and broad-energy spectra per proton bunch to keep treatment times short. This demands new dose delivery system and irradiation field formation schemes. In this paper, we present a multi-functional light-weight and compact proton gantry design for laser-driven sources based on iron-less pulsed high-field magnets. This achromatic design includes improved beam capturing and energy selection systems, with a novel beam shaping and dose delivery system, so-called ELPIS. ELPIS system utilizes magnetic fields, instead of physical scatterers, for broadening the spot-size of broad-energetic beams while capable of simultaneously scanning them in lateral directions. To investigate the clinical feasibility of this gantry design, we conducted a treatment planning study with a 3D treatment planning system augmented for the pulsed beams with optimizable broad-energetic widths and selectable beam spot sizes. High quality treatment plans could be achieved with such unconventional beam parameters, deliverable via the presented gantry and ELPIS dose delivery system. The conventional PT gantries are huge and require large space for the gantry to rotate the beam around the patient, which could be reduced up to 4 times with the presented pulse powered gantry system. The further developments in the next generation petawatt laser systems and laser-targets are crucial to reach higher proton energies. However, if proton energies required for therapy applications are reached it could be possible in future to reduce the footprint of the PT facilities, without compromising on clinical standards.

In ionization chambers, not all released charge is collected due to the recombination of charge carriers. This effect is taken into account by the saturation correction factor kS. A physical description of the correction factor has been established for pulsed radiation. However, it is only accurate when the pulse length is short compared with the collection time of the ionization chamber. In this paper we develop a description of the saturation correction for radiation pulses of arbitrary length. For this, a system of partial differential equations is solved iteratively. The numerical solutions are verified experimentally for a Roos ionization chamber (PTW TM34001) exposed to a pulsed electron beam. The results of this iterative procedure describe the experimental data well. The calculations are also possible for beam structures which are experimentally hard to get and thereby contribute to a better understanding and correct description of the saturation correction at arbitrary pulse length. Among other things the pulse length dependent distributions of the charge carriers in the ionization chamber is calculated, inclusive of the transition to the conditions prevailing in the case of continuous irradiation. Furthermore is shown that the formula for kS established by Hochhauser and Balk is applicable even at arbitrary pulse length, if pulse duration dependent effective values are used for the parameters a and p. These effective values have been determined for the Roos chamber at pulse lengths up to 300 μs.

Laser-accelerated electron pulses have been used to irradiate human tumors grown on mice’s ears during radiobiological experiments. These experiments have been carried out with the JETI laser system at the Institute of Optics and Quantum Electronics in Jena, Germany. To treat a total of more than 50 mice, a stable and reliable operation of the laser-electron accelerator with a dose rate exceeding 1 Gy/min was necessary. To achieve this, a sufficient number of electrons at energies in excess of 5 MeV had to be generated. The irradiation time for a single mouse was a few minutes. Furthermore, the particle pulses’ parameters needed to remain achievable for a time period of several weeks. Due to the online detection of the radiation dose, the unavoidable shot-to-shot fluctuations, currently still typical for laser-based particle accelerators, could be compensated. The results demonstrate that particle pulses generated with laser-based accelerators have the potential to be a future alternative for conventional particle accelerators used for the irradiation of tumors.

Proton beams are a promising tool for the improvement of radiotherapy of cancer, and compact laser-driven proton radiation (LDPR) is discussed as an alternative to established large-scale technology facilitating wider clinical use. Yet, clinical use of LDPR requires substantial development in reliable beam generation and transport, but also in dosimetric protocols as well as validation in radiobiological studies. Here, we present the first dose-controlled direct comparison of the radiobiological effectiveness of intense proton pulses from a laser-driven accelerator with conventionally generated continuous proton beams, demonstrating a first milestone in translational research. Controlled dose delivery, precisely online and offline monitored for each out of ∼4,000 pulses, resulted in an unprecedented relative dose uncertainty of below 10 %, using approaches scalable to the next translational step toward radiotherapy application.

Gas-filled ionization chambers are widely used radiation detectors in radiotherapy. A quantitative description and correction of the recombination effects exists for two cases, for continuous radiation exposure and for pulsed radiation fields with short single pulses. This work gives a derivation of a formula for pulsed beams with arbitrary pulse rate for which the prerequisites of the two existing descriptions are not fulfilled. Furthermore, an extension of the validity of the two known cases is investigated. The temporal evolution of idealized charge density distributions within a plane parallel chamber volume is described for pulsed beams of vanishing pulse duration and arbitrary pulse repetition rate. First, the radiation induced release, movement and collection of the charge carriers without recombination are considered. Then, charge recombination is calculated basing on these simplified charge distributions and the time dependent spatial overlap of positive and negative charge carrier distributions. Finally, a formula for the calculation of the saturation correction factor is derived by calculation and simplification of the first two terms of a Taylor expansion for small recombination. The new formula of saturation correction contains the two existing cases, descriptions for exposure by single pulses and continuous irradiation, as limiting cases. Furthermore, it is possible to determine the pulse rate range for which each of the three descriptions is applicable by comparing the dependencies of the new formula with the two existing cases. As long as the time between two pulses is lower than one third of the collection time of the chamber, the formalism for a continuous exposure can be used. The known description for single pulse irradiation is only valid if the repetition rate is less than 1.2 times the inverse collection time. For all other repetition rates in between the new formula should be used. The experimental determination by Jaffe diagrams can be applied for all repetition rates which are not single pulse irradiation but will result in a small deviation from the correct saturation correction value.

In this paper, a scintillator-based online beam profile detector for the characterization of laser-driven proton beams is presented. Using a pixelated matrix with varying absorber thicknesses, the proton beam is spatially resolved in two spatial dimensions and simultaneously energy-resolved. A thin plastic scintillator placed behind the absorber and read out by a CCD camera is used as the active detector material. The spatial detector resolution reaches down to ~4mm and up to 9 energy ranges can be resolved with an energy resolution of ~1 MeV above 8 MeV proton energy. With these detector design parameters, the spatial characteristics of the proton distribution and its cut-off energy can be analyzed online and on-shot under vacuum conditions. The paper discusses the detector design, its characterization and calibration at a conventional proton source as well as the first detector application at a laser-driven proton source.

No abstract available

Purpose: The use of laser accelerators in radiation therapy can perhaps increase the low number of proton and ion therapy facilities in some years due to the low investment costs and small size. The laser-based acceleration technology leads to a very high peak dose rate of about 10{sup 11} Gy/s. A first dosimetric task is the evaluation of dose rate dependence of clinical dosimeters and other detectors. Methods: The measurements were done at ELBE, a superconductive linear electron accelerator which generates electron pulses with 5 ps length at 20 MeV. The different dose rates are reached by adjusting the number of electrons in one beam pulse. Three clinical dosimeters (TLD, OSL, and EBT radiochromic films) were irradiated with four different dose rates and nearly the same dose. A faraday cup, an integrating current transformer, and an ionization chamber were used to control the particle flux on the dosimeters. Furthermore two diamond detectors were tested. Results: The dosimeters are dose rate independent up to 410{sup 9} Gy/s within 2% (OSL and TLD) and up to 1510{sup 9} Gy/s within 5% (EBT films). The diamond detectors show strong dose rate dependence. Conclusions: TLD, OSL dosimeters, and EBT films are suitable for pulsedmore » beams with a very high pulse dose rate like laser accelerated particle beams.« less

Laser particle acceleration/Laser radiotherapy/Cell response to electrons/Pulsed irradiation. The notable progress in laser particle acceleration techn ology promises potential medical application in cancer therapy through compact and cost effective laser devices that are suitable for already existing clinics. Previously, consequences on the radiobiological response by laser driven particle beams characterised by an ultra high peak dose rate have to be inves tigated. Therefore, tumour and non-malignant cells were irradiated with pulsed laser accelerated electrons at the JETI facility for the comparison with continuous electrons of a conventional therapy LINAC. Dose res ponse curves were measured for the biological endpoints clonogenic survival and residual DNA double strand breaks. The overall results show no significant differences in radiobiological response for in vitro cell experiments between laser accelerated pulsed and clinical used electron beams. These first systematic in vitro cell response studies with precise dosimetry to laser driven electron beams represent a first s tep toward the long term aim of the application of laser accelerated particles in radiotherapy.

The dosimetric characterization of laser-accelerated electrons applied for the worldwide first systematic radiobiological in vitro cell irradiation will be presented. The laser-accelerated electron beam at the JeTi laser system has been optimized, monitored and controlled in terms of dose homogeneity, stability and absolute dose delivery. A combination of different dosimetric components were used to provide both an online beam as well as dose monitoring and a precise absolute dosimetry. In detail, the electron beam was controlled and monitored by means of an ionization chamber and an in-house produced Faraday cup for a defined delivery of the prescribed dose. Moreover, the precise absolute dose delivered to each cell sample was determined by an radiochromic EBT film positioned in front of the cell sample. Furthermore, the energy spectrum of the laser-accelerated electron beam was determined. As presented in a previous work of the authors, also for laser-accelerated protons a precise dosimetric characterization was performed that enabled initial radiobiological cell irradiation experiments with laser-accelerated protons. Therefore, a precise dosimetric characterization, optimization and control of laser-accelerated and therefore ultra-short pulsed, intense particle beams for both electrons and protons is possible, allowing radiobiological experiments and meeting all necessary requirements like homogeneity, stability and precise dose delivery. In order to fulfill the much higher dosimetric requirements for clinical application, several improvements concerning, i.e., particle energy and spectral shaping as well as patient safety are necessary.

Zusammenfassung In gasgefullten Ionisationskammern als Strahlungsdetektoren tritt beim Sammeln der Ladungstrager ein Rekombinationseffekt auf. Dieser Effekt muss in der Dosimetrie durch den Sattigungskorrektionsfaktor k S berucksichtigt werden. Die physikalische Beschreibung des Sattigungsfaktors fur gepulste Strahlung nach Boag, Hochhauser und Balk ist bekannt und bestatigt. Jedoch gilt sie nur unter der Annahme, dass die Pulsdauer gegenuber der Sammelzeit der Ionisationskammer kurz ist. In dieser Arbeit wird zunachst die Sattigungskorrektion bei Pulsdauern von 4 μ s in Abhangigkeit von der Pulsdosis experimentell untersucht, wobei sich die Theorie von Boag, Hochhauser und Balk bei Pulsdosen bis zu ca. 230 mGy erneut bestatigt. Bei langeren Pulsdauern nimmt der Korrektionsfaktor jedoch ab und erreicht bei ca. 200 μ s Pulsdauer 75% des fur kurze Pulse geltenden Wertes. Dieser verminderte Rekombinationseinfluss wird durch die Reaktionskinetik der Ionenrekombination als Reaktion zweiter Ordnung gedeutet. Dieser Effekt ist fur klinische Linearbeschleuniger mit typischen Pulsdauern von 4 μ s fur Pulsdosen bis zu ca. 120 mGy bei PTW Roos-Kammern vernachlassigbar.

An integrated dosimetry and cell irradiation system (IDOCIS) with laser-accelerated proton beams was developed, characterized, calibrated and successfully used for systematic in vitro experiments. Due to the broad exponentially shaped energy spectrum, the low-energy range of the protons (

Hyperon production in the threshold region was studied in the reaction pp → K + Λ p using the time-of-flight spectrometer COSY-TOF. Exclusive data, covering the full phase-space, were taken at the three different beam momenta of p beam = 2.95 , 3.20 and 3.30 GeV/c, corresponding to excess energies of e = 204 , 285 and 316 MeV, respectively. Total cross-sections were deduced for the three beam momenta to be 23.9 ± 0.8 ± 2.0 μb , 28.4 ± 1.3 ± 2.2 μb and 35.0 ± 1.3 ± 3.0 μb . Differential observables including Dalitz plots were obtained. The analysis of the Dalitz plots reveals a strong influence of the N ( 1650 ) -resonance at p beam = 2.95 GeV / c , whereas for the higher momenta an increasing relative contribution of the N ( 1710 ) - and/or of the N ( 1720 ) -resonance was observed. In addition, the pΛ-final-state interaction turned out to have a significant influence on the Dalitz plot distribution.

Purpose: In recent years, laser-based acceleration of charged particles has rapidly progressed and medical applications, e.g., in radiotherapy, might become feasible in the coming decade. Requirements are monoenergetic particle beams with long-term stable and reproducible properties as well as sufficient particle intensities and a controlled delivery of prescribed doses at the treatment site. Although conventional and laser-based particle accelerators will administer the same dose to the patient, their different time structures could result in different radiobiological properties. Therefore, the biological response to the ultrashort pulse durations and the resulting high peak dose rates of these particle beams have to be investigated. The technical prerequisites, i.e., a suitable cellirradiation setup and the precise dosimetric characterization of a laser-based particle accelerator, have to be realized in order to prepare systematic cellirradiation experiments. Methods: The Jena titanium:sapphire laser system (JETI) was customized in preparation for cellirradiation experiments with laser-accelerated electrons. The delivered electron beam was optimized with regard to its spectrum, diameter, dose rate, and dose homogeneity. A custom-designed beam and dose monitoring system, consisting of a Roos ionization chamber, a Faraday cup, and EBT-1 dosimetry films, enables real-time monitoring of irradiation experiments and precise determination of the dose delivered to the cells. Finally, as proof-of-principle experiment cell samples were irradiated using this setup. Results: Laser-accelerated electron beams, appropriate forin vitro radiobiological experiments, were generated with a laser shot frequency of 2.5 Hz and a pulse length of 80 fs. After laser acceleration in the helium gas jet, the electrons were filtered by a magnet, released from the vacuum target chamber, and propagated in air for a distance of 220 mm. Within this distance a lead collimator (aperture of 35 mm) was introduced, leading, along with the optimized setup, to a beam diameter of 35 mm, sufficient for the irradiation of common cell culture vessels. The corresponding maximum dose inhomogeneity over the beam spot was less than 10% for all irradiated samples. At cell position, the electrons posses a mean kinetic energy of 13.6 MeV, a bunch length of about 5 ps (FWHM), and a mean pulse dose of 1.6 mGy/bunch. Cross correlations show clear linear dependencies for the online recorded accumulated bunch charges, pulse doses, and pulse numbers on absolute doses determined with EBT-1 films. Hence, the established monitoring system is suitable for beam control and a dedicated dose delivery. Additionally, reasonable day-to-day stable and reproducible properties of the electron beam were achieved. Conclusions: Basic technical prerequisites for future cellirradiation experiments with ultrashort pulsed laser-accelerated electrons were established at the JETI laser system. The implemented online control system is suitable to compensate beam intensity fluctuations and the achieved accuracy of dose delivery to the cells is sufficient for radiobiological cell experiments. Hence, systematicin vitrocellirradiation experiments can be performed, being the first step toward clinical application of laser-accelerated particles. Further steps, including the transfer of the established methods to experiments on higher biological systems or to other laser-based particle accelerators, will be prepared.

A systematic study of the production of omega-mesons in proton-proton-collisions was carried out in a kinematically complete experiment at three excess energies(epsilon= 92, 128, 173MeV). Both protons were detected using the large-acceptance COSY-TOF spectrometer at an external beam line at the Cooler Synchrotron COSY at Forschungszentrum J\"ulich. The total cross section, angular distributions of both omega-mesons and protons were measured and presented in various reference frames such as the overall CMS, helicity and Jackson frame. In addition, the orientation of the omega-spin and invariant mass spectra were determined. We observe omega-production to take place dominantly in Ss and Sp final states at epsilon = 92, 128 MeV and, additionally, in Sd at epsilon= 173 MeV. No obvious indication of resonant omega-production via N^*-resonances was found, as proton angular distributions are almost isotropic and invariant mass spectra are compatible with phase space distributions. A dominant role of ^3P_1 and ^1S_0 initial partial waves for omega-production was concluded from the orientation of the decay plane of the omega-meson. Although the Jackson angle distributions in the omega-p-Jackson frame are anisotropic we argue that this is not an indication of a resonance but rather a kinematical effect reflecting the anisotropy of the omega angular distribution. The helicity angle distribution in the omega-p-helicity frame shows an anisotropy which probably reflects effects of the omega angular momenta in the final state; this observable may be, in addition to the orientation of the omega decay plane, the most sensitive one to judge the validity of theoretical descriptions of the production process.

Purpose: The aim of this article is to investigate the energy dependence of the radiochromic film type, Gafchromic EBT-1, when scanned with a flatbed scanner for film readout. Methods: Dose response curves were determined for 12 different beam qualities ranging from a 10 kVp x-ray beam to a 15 MVp x-ray beam and include also two high energy electron beam qualities (6 and 18 MeV). The dose responses measured as net optical density (netOD) for the different beam qualities were normalized to the response of a reference beam quality (6 MVp). Results: A strong systematic energy dependence of the film response was found. The lower the effective beam energy, the less sensitive the EBT-1 films get. The maximum decrease in dose for the same film response between the 25 kVp and 6 MVp beam qualities was 44%. Additionally, a difference in energy dependence for different doses was discovered, meaning that higher doses show a smaller dependency on energy than lower doses. The maximum decrease in the normalized netOD was found to be 25% for a dose of 0.5 Gy relative to the normalized netOD for 10 Gy. Moreover, a scaling procedure is introduced, allowing the correction of the energy dependencemore » for the investigated beam qualities and also for comparable x-ray beam qualities within the energy range studied. Conclusions: A strong energy dependence for EBT-1 radiochromic films was found. The films were readout with a flatbed scanner. If the effective beam energy is known, the energy dependence can be corrected with the introduced scaling procedure. Further investigation of the influence of the spectral band of the readout device on energy dependence is needed to understand the reason for the different energy dependences found in this and previous works.« less

The quasifree reaction $np\to pp\pim$ was studied in a kinematically complete experiment by bombarding a liquid hydrogen target with a deuteron beam of momentum 1.85 GeV/c and analyzing the data along the lines of the spectator model. In addition to the three charged ejectiles the spectator proton was also detected in the large-acceptance time-of-flight spectrometer COSY-TOF. It was identified by its momentum and flight direction thus yielding access to the Fermi motion of the bound neutron and to the effective neutron 4-momentum vector $\mathbb{P}_n$ which differed from event to event. A range of almost 90 MeV excess energy above threshold was covered. Energy dependent angular distributions, invariant mass spectra as well as fully covered Dalitz plots were deduced. Sizeable $pp$ FSI effects were found as were contributions of $p$ and $d$ partial waves. The behavior of the elementary cross section $\sigma_{01}$ close to threshold is discussed in view of new cross section data. In comparison with existing literature data the results provide a sensitive test of the spectator model.

The p p → p K 0 Σ + reaction was investigated with the TOF spectrometer at COSY at 3.059 GeV / c incident beam momentum. The main objective was to clarify whether or not a narrow exotic S = + 1 resonance, the Θ + pentaquark, is populated at 1.53 GeV / c 2 in the p K 0 subsystem with a data sample of much higher statistical significance compared to the previously reported data in this channel. An analysis of these data does not confirm the existence of the Θ + pentaquark. This is expressed as an upper limit for the cross section σ ( p p → Σ + Θ + ) 0.15 μb at the 95% confidence level.

The long-term goal to integrate laser-based particle accelerators into radiotherapy clinics not only requires technological development of high-intensity lasers and new techniques for beam detection and dose delivery, but also characterization of the biological consequences of this new particle beam quality, i.e. ultra-short, ultra-intense pulses. In the present work, we describe successful in vivo experiments with laser-driven electron pulses by utilization of a small tumour model on the mouse ear for the human squamous cell carcinoma model FaDu. The already established in vitro irradiation technology at the laser system JETI was further enhanced for 3D tumour irradiation in vivo in terms of beam transport, beam monitoring, dose delivery and dosimetry in order to precisely apply a prescribed dose to each tumour in full-scale radiobiological experiments. Tumour growth delay was determined after irradiation with doses of 3 and 6 Gy by laser-accelerated electrons. Reference irradiation was performed with continuous electron beams at a clinical linear accelerator in order to both validate the dedicated dosimetry employed for laser-accelerated JETI electrons and above all review the biological results. No significant difference in radiation-induced tumour growth delay was revealed for the two investigated electron beams. These data provide evidence that the ultra-high dose rate generated by laser acceleration does not impact the biological effectiveness of the particles.

The recent advancements in the eld of laser-driven particle acceleration have made Laser driven Ion Beam Therapy (L-IBT) an attractive alternative to the conventional particle therapy facilities. To bring this emerging technology to clinical application we introduce the Broad Energy Assorted depth-Dose deposition (BEAD) scheme which makes ecient use of the large energy spread and high dose-per-pulse of Laser Accelerated Protons (LAP) and is capable of delivering homogeneous doses to tumors. Furthermore, as a key component of L-IBT solution we present a compact, iso-centric gantry design with 360° rotation capability with an Integrated Shot-to-shot Energy Selection System (ISESS), for efficient transport of LAP with large energy spread to the patient. We show that gantry size could be reduced by a factor of 2-3 compared to conventional gantry systems by utilizing pulsed, air-core magnets.

A plastic scintillator array of 3.4 m 2 total area for the detection of neutrons in medium-energy nucleon–nucleon reactions was constructed and built. Calibration procedures for the detector were developed which allow the monitoring of gain shifts by means of muons from the cosmic radiation. Experiments were performed in order to calibrate the efficiency simulations and study the performance of the detector using the d+t→α+n reaction at 14.7 MeV neutron energy and proton-induced deuteron breakup at 300 MeV .

Aim: Proton beams by their advantageous dose profile over conventional photon and electron beams may provide higher dose conformity and better healthy tissue sparing. But due to high costs and huge size of existing facilities, proton therapy is limited to few centers. A novel proton acceleration, on µm scale by ultra-intense lasers, promises compact accelerators and beam delivery systems. Unlike conventional proton beams, laser-accelerated proton (LAP) beam is characterized by short ultra-intense pulses with peak dose rates exceeding conventional values by ∼9 orders of magnitude but low repetition rate, broad energy spread and large divergence. They require completely new techniques of beam transport, dose delivery and quality assurance along with radiobiological characterization. Methods: The presented work is an ongoing joint translational research project of several institutions in Germany aiming to establish LAP therapy. In parallel to the development of high power laser systems and laser targets to generate stable and reproducible LAP beams, a dedicated radiation oncology focused research program is being followed. Results: Laser-based technology was established for cell and small animal irradiation. The high power laser system DRACO was setup and optimized for long-term stable proton acceleration. A dedicated fixed-beam transport system with integrated energy selection and field shaping as well as real time dose monitoring was established. The suitability and reliability of all components was proven in systematic radiobiological studies over months. No overall difference in the biological effectiveness between laser-accelerated and conventional beams was detected to date. For translation towards patient irradiation, increase of proton energy from ∼25 to ∼230 MeV by increasing the laser power from ∼100 TW to ∼1 PW is required and the development of PW laser is in progress. Furthermore, a compact 360° isocentric proton gantry was designed, based on novel light-weight high-field pulsed magnets. This gantry is ∼2.5x smaller than conventional proton gantries. The necessary pulsed magnets are being developed together with novel dose delivery strategy for LAP. Conclusions: LAP therapy is a promising alternative, yet require substantial development with a clinical prototype in some years. Supported by German BMBF, no. 03Z1N511. Disclosure: All authors have declared no conflicts of interest.

Clinical QA in teletherapy as well as the characterization of experimental radiation sources for future medical applications requires effective methods for measuring three-dimensional (3D) dose distributions generated in a water-equivalent medium. Current dosimeters based on ionization chambers, diodes, thermoluminescence detectors, radiochromic films, or polymer gels exhibit various drawbacks: High quality 3D dose determination is either very sophisticated and expensive or requires high amounts of effort and time for the preparation or read out. New detectors based on scintillator blocks in combination with optical tomography are studied, since they have the potential to facilitate the desired cost-effective, transportable, and long-term stable dosimetry system that is able to determine 3D dose distributions with high spatial resolution in a short time.A portable detector prototype was set up based on a plastic scintillator block and four digital cameras. During irradiation the scintillator emits light, which is detected by the fixed cameras. The light distribution is then reconstructed by optical tomography, using maximum-likelihood expectation maximization. The result of the reconstruction approximates the 3D dose distribution. First performance tests of the prototype using laser light were carried out. Irradiation experiments were performed with ionizing radiation, i.e., bremsstrahlung (6 to 21 MV), electrons (6 to 21 MeV), and protons (68 MeV), provided by clinical and research accelerators.Laser experiments show that the current imaging properties differ from the design specifications: The imaging scale of the optical systems is position dependent, ranging from 0.185 mm/pixel to 0.225 mm/pixel. Nevertheless, the developed dosimetry method is proven to be functional for electron and proton beams. Induced radiation doses of 50 mGy or more made 3D dose reconstructions possible. Taking the imaging properties into account, determined dose profiles are in agreement with reference measurements. An inherent drawback of the scintillator is the nonlinear light output for high stopping-power radiation due to the quenching effect. It impacts the depth dose curves measured with the dosimeter. For single Bragg peak distributions this leads to a peak to plateau ratio of 2.8 instead of 4.5 for the reference ionization chamber measurement. Furthermore, the transmission of the clinical bremsstrahlung beams through the scintillator leads to the saturation of one camera, making dose reconstructions in that case presently not feasible.It is shown that distributions of scintillation light generated by proton or electron beams can be reconstructed by the dosimetry system within minutes. The quenching apparent for proton irradiation, and the yet not precisely determined position dependency of the imaging scale, require further investigation and corrections. Upgrading the prototype with larger or inorganic scintillators would increase the detectable proton and electron energy range. The presented results show that the determination of 3D dose distributions using scintillator blocks and optical tomography is a promising dosimetry method.