Retrospective analysis of the impact of respiratory motion in treatment margins for frameless lung SBRT based on respiratory-correlated CBCT data-sets.

To investigate the impact of respiratory motion in the treatment margins for lung SBRT frameless treatments and to validate our treatment margins using 4D CBCT data analysis. Two hundred and twenty nine fractions with early stage NSCLC were retrospectively analyzed. All patients were treated in frameless and free breathing conditions. The treatment margins were calculated according to van Herk equation in Mid-Ventilation. For each fraction, three 4D CBCT scans, pre- and postcorrection, and posttreatment, were acquired to assess target baseline shift, target localization accuracy and intra-fraction motion errors. A bootstrap analysis was performed to assess the minimum number of patients required to define treatment margins. The retrospectively calculated target-baseline shift, target localization accuracy and intra-fraction motion errors agreed with the literature. The best tailored margins to our cohort of patients were retrospectively computed and resulted in agreement with already published data. The bootstrap analysis showed that fifteen patients were enough to assess treatment margins. The treatment margins applied to our patient's cohort resulted in good agreement with the retrospectively calculated margins based on 4D CBCT data. Moreover, the bootstrap analysis revealed to be a promising method to verify the reliability of the applied treatment margins for safe lung SBRT delivery

Effect of conventional and ultra-high dose rate "FLASH" irradiations on preclinical tumour models: A systematic analysis: Tumour response to CONV and UHDR irradiation.

When compared to conventional dose rate irradiation (CONV), ultra-high dose rate irradiation (UHDR) has shown superior normal tissue sparing. However, a clinically relevant widening of the therapeutic window by UHDR, termed "FLASH effect", also depends on the tumour toxicity obtained by UHDR. Based on a combined analysis of published literature, the current study re-examines the hypothesis of tumour isoefficacy for UHDR versus CONV and aims to identify potential knowledge gaps to inspire future in vivo studies. A systematic literature search identified publications assessing in vivo tumour responses comparing UHDR and CONV. Qualitative and quantitative analyses were performed, including combined analyses of tumour growth and survival data. We identified 66 data sets from 15 publications that compared UHDR and CONV for tumour efficacy. The median number of animals per group was 9 (range: 3-15) and the median follow-up period was 30.5 (range: 11-230) days after the first irradiation. Tumour growth assays were the predominant model used. Combined statistical analyses of tumour growth and survival data are consistent with UHDR isoefficacy compared to CONV. Only one study determined tumour-controlling dose (TCD <sub>50</sub> ) and reported statistically non-significant differences. The combined quantitative analyses of tumour responses support the assumption of UHDR isoefficacy compared to CONV. However, the comparisons are primarily based on heterogeneous tumour growth assays with limited numbers of animals and short follow-up, and most studies do not assess long-term tumour control probability. Therefore, the assays may be insensitive in resolving smaller response differences, such as responses of radio-resistant tumour sub-clones. Hence, tumour cure experiments, including additional TCD <sub>50</sub> experiments, are needed to confirm the assumption of isoeffectiveness in curative settings

Commissioning of an ultra-high dose rate pulsed electron beam medical LINAC for FLASH RT preclinical animal experiments and future clinical human protocols.

To present the acceptance and the commissioning, to define the reference dose, and to prepare the reference data for a quality assessment (QA) program of an ultra-high dose rate (UHDR) electron device in order to validate it for preclinical animal FLASH radiotherapy (FLASH RT) experiments and for FLASH RT clinical human protocols. The Mobetron <sup>®</sup> device was evaluated with electron beams of 9 MeV in conventional (CONV) mode and of 6 and 9 MeV in UHDR mode (nominal energy). The acceptance was performed according to the acceptance protocol of the company. The commissioning consisted of determining the short- and long-term stability of the device, the measurement of percent depth dose curves (PDDs) and profiles at two different positions (with two different dose per pulse regimen) and for different collimator sizes, and the evaluation of the variability of these parameters when changing the pulse width and pulse repetition frequency. Measurements were performed using a redundant and validated dosimetric strategy with alanine and radiochromic films, as well as Advanced Markus ionization chamber for some measurements. The acceptance tests were all within the tolerances of the company's acceptance protocol. The linearity with pulse width was within 1.5% in all cases. The pulse repetition frequency did not affect the delivered dose more than 2% in all cases but 90 Hz, for which the larger difference was 3.8%. The reference dosimetry showed a good agreement within the alanine and films with variations of 2.2% or less. The short-term (resp. long-term) stability was less than 1.0% (resp. 1.8%) and was the same in both CONV and UHDR modes. PDDs, profiles, and reference dosimetry were measured at two positions, providing data for two specific dose rates (about 9 Gy/pulse and 3 Gy/pulse). Maximal beam size was 4 and 6 cm at 90% isodose in the two positions tested. There was no difference between CONV and UHDR mode in the beam characteristics tested. The device is commissioned for FLASH RT preclinical biological experiments as well as FLASH RT clinical human protocols

Pion double charge exchange on 4He

The doubly differential cross sections for the $^4$He$(\pi^+,\pi^-) 4p$ reaction were calculated using both a two-nucleon sequential single charge exchange model and an intranuclear cascade code. Final state interactions between the two final protons which were the initial neutrons were included in both methods. At incident pion energies of 240 and 270 MeV the low-energy peak observed experimentally in the energy spectrum of the final pions can be understood only if the contribution of pion production is included. The calculated cross sections are compared with data.Comment: 25 pages, 9 figure

Technical note: Validation of an ultrahigh dose rate pulsed electron beam monitoring system using a current transformer for FLASH preclinical studies.

The Oriatron eRT6 is a linear accelerator (linac) used in FLASH preclinical studies able to reach dose rates ranging from conventional (CONV) up to ultrahigh (UHDR). This work describes the implementation of commercially available beam current transformers (BCTs) as online monitoring tools compatible with CONV and UHDR irradiations for preclinical FLASH studies. Two BCTs were used to measure the output of the Oriatron eRT6 linac. First, the correspondence between the set nominal beam parameters and those measured by the BCTs was checked. Then, we established the relationship between the total exit charge (measured by BCTs) and the absorbed dose to water. The influence of the pulse width (PW) and the pulse repetition frequency (PRF) at UHDR was characterized, as well as the short- and long-term stabilities of the relationship between the exit charge and the dose at CONV and UHDR. The BCTs were able to determine consistently the number of pulses, PW, and PRF. For fixed PW and pulse height, the exit charge measured from BCTs was correlated with the dose, and linear relationships were found with uncertainties of 0.5 % and 3 % in CONV and UHDR mode, respectively. Short- and long-term stabilities of the dose-to-charge ratio were below 1.6 %. We implemented commercially available BCTs and demonstrated their ability to act as online beam monitoring systems to support FLASH preclinical studies with CONV and UHDR irradiations. The implemented BCTs support dosimetric measurements, highlight variations among multiple measurements in a row, enable monitoring of the physics parameters used for irradiation, and are an important step for the safety of the clinical translation of FLASH radiation therapy