Dose and dose rate dependence of the tissue sparing effect at ultra-high dose rate studied for proton and electron beams using the zebrafish embryo model.

Purpose: A better characterization of the dependence of the tissue sparing effect at ultra-high dose rate (UHDR) on physical beam parameters (dose, dose rate, radiation quality) would be helpful towards a mechanistic understanding of the FLASH effect and for its broader clinical translation. To address this, a comprehensive study on the normal tissue sparing at UHDR using the zebrafish embryo (ZFE) model was conducted.

Methods: One-day-old ZFE were irradiated over a wide dose range (15-95 Gy) in three different beams (proton entrance channel, proton spread out Bragg peak and 30 MeV electrons) at UHDR and reference dose rate.

The DRESDEN PLATFORM is a research hub for ultra-high dose rate radiobiology.

The recently observed FLASH effect describes the observation of normal tissue protection by ultra-high dose rates (UHDR), or dose delivery in a fraction of a second, at similar tumor-killing efficacy of conventional dose delivery and promises great benefits for radiotherapy patients. Dedicated studies are now necessary to define a robust set of dose application parameters for FLASH radiotherapy and to identify underlying mechanisms. These studies require particle accelerators with variable temporal dose application characteristics for numerous radiation qualities, equipped for preclinical radiobiological research.

Beam pulse structure and dose rate as determinants for the flash effect observed in zebrafish embryo.

Background And Purpose: Continuing recent experiments at the research electron accelerator ELBE at the Helmholtz-Zentrum Dresden-Rossendorf the influence of beam pulse structure on the Flash effect was investigated.

Materials And Methods: The proton beam pulse structure of an isochronous cyclotron (UHDR) and a synchrocyclotron (UHDR) was mimicked at ELBE by quasi-continuous electron bunches at 13 MHz delivering mean dose rates of 287 Gy/s and 177 Gy/s and bunch dose rates of 10Gy/s and 10 Gy/s, respectively. For UHDR, 40 ms macro pulses at a frequency of 25 Hz superimposed the bunch delivery.

Electron dose rate and oxygen depletion protect zebrafish embryos from radiation damage.

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 (pO) 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.

Dose-dependent Changes After Proton and Photon Irradiation in a Zebrafish Model.

Background/aim: The importance of hadron therapy in the cancer management is growing. We aimed to refine the biological effect detection using a vertebrate model.

Materials And Methods: Embryos at 24 and 72 h postfertilization were irradiated at the entrance plateau and the mid spread-out Bragg peak of a 150 MeV proton beam and with reference photons.

Publisher Correction: Spectral and spatial shaping of laser-driven proton beams using a pulsed high-field magnet beamline.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Spectral and spatial shaping of laser-driven proton beams using a pulsed high-field magnet beamline.

Intense 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.

Feasibility of proton FLASH effect tested by zebrafish embryo irradiation.

Background And Purpose: Motivated by first animal trials showing the normal tissue protecting effect of electron and photon Flash irradiation, i.e. at mean dose rates of 100 Gy/s and higher, relative to conventional beam delivery over minutes the feasibility of proton Flash should be assessed.

Radiobiological effects and proton RBE determined by wildtype zebrafish embryos.

The increasing use of proton radiotherapy during the last decade and the rising number of long-term survivors has given rise to a vital discussion on potential effects on normal tissue. So far, deviations from clinically applied generic RBE (relative biological effectiveness) of 1.1 were only obtained by in vitro studies, whereas indications from in vivo trials and clinical studies are rare.

Radiobiological influence of megavoltage electron pulses of ultra-high pulse dose rate on normal tissue cells.

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.

Radiobiological response to ultra-short pulsed megavoltage electron beams of ultra-high pulse dose rate.

Purpose: 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.

Materials And Methods: 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.

Comparison study of in vivo dose response to laser-driven versus conventional electron beam.

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.

Radiobiological effectiveness of laser accelerated electrons in comparison to electron beams from a conventional linear accelerator.

The notable progress in laser particle acceleration technology 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 investigated. 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.

DNA double-strand break signalling: X-ray energy dependence of residual co-localised foci of gamma-H2AX and 53BP1.

Purpose: The application of ionising radiation for medical purposes requires the investigation of induced and persistent DNA damages, especially for soft X-rays that are assumed to be more effective than higher energy photons. Therefore, we examined the energy dependent time and dose response of residual DNA damage foci for soft X-rays in comparison to 200 kV photons.

Materials And Methods: DNA damage present in cell line 184A1 within 48 h after irradiations with 10 kV, 25 kV and 200 kV photons was analysed by immunochemical detection of co-localised gamma-H2AX (phosphorylated histone H2AX) and 53BP1 (tumour protein 53 binding protein) foci.

Relative biological effectiveness of 25 and 10 kV X-rays for the induction of chromosomal aberrations in two human mammary epithelial cell lines.

Administration of ionizing radiation for diagnostic purposes can be associated with a risk for the induction of tumors. Therefore, particularly with regard to general screening programs, e.g.

RBE of 10 kV X rays determined for the human mammary epithelial cell line MCF-12A.

The dependence of relative biological effectiveness (RBE) on photon energy is a topic of extensive discussions. The increasing amount of in vitro data in the low-energy region indicates this to be a complex dependence that is influenced by the end point and cell line studied. In the present investigation, the RBE of 10 kV X rays (W anode) was determined relative to 200 kV X rays (W anode, 0.

RBE of 25 kV X-rays for the survival and induction of micronuclei in the human mammary epithelial cell line MCF-12A.

The broad application of low energy X-rays below about 50 keV in radiation therapy and diagnostics and especially in mammography substantiates the precise determination of their relative biological effectiveness (RBE). A quality factor of 1 is stated for photons of all energies in the International Commission on Radiological Protection Recommendations. However, the RBE of low-energy X-rays compared to high-energy photons was found to be dependent on photon energy, cell line and endpoints studied, hence varying from less than one up to about four.