Search

Purpose: FLASH proton pencil beam scanning (p-PBS) showed a reduction in mouse skin toxicity and fibrosis when delivered as a single, uninterrupted, high-dose fraction. Clinical p-PBS treatment usually requires multiple beams to achieve good conformality, and these beams are separated by minutes to allow patient and equipment repositioning. We evaluate the impact of multibeam versus single-beam proton radiation on the FLASH sparing effect on skin toxicity., Methods and Materials: The right hind leg of 10-week-old female C57Bl/6j mice was irradiated using a Varian ProBeam proton beam scanning gantry system at conventional (1 Gy/s) or FLASH (100 Gy/s) average field dose rate. We scored the skin toxicity after different doses for 7 weeks. The treatment was delivered as 1, 2, or 3 equal beams with an interruption of 2 minutes. For each beam delivery, the equipment remained in the same position so that there was a full overlap of beams administered., Results: Single-beam delivery confirmed a benefit for p-PBS FLASH in this model at 30, 35, and 40 Gy. At 30 and 35 Gy, a single beam interruption of 2 minutes (2 × 15 Gy or 2 × 17.5 Gy) reduced the FLASH sparing effect, which remained significant (P < .001). However, 2 interruptions (3 × 10 Gy or 3 × 11.6 Gy) abrogated the normal tissue sparing effect., Conclusions: Our results indicate that the FLASH sparing effect in areas of beam overlap can be compromised by interruptions in delivery time. Time gap between overlapping beams and spatial arrangement of the delivered beams are important parameters for FLASH studies. The effect of multibeam needs to be studied on different organs of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Purpose: Knowledge of biological responses to proton therapy (PT) in comparison to X-ray remains in its infancy. Identification of PT specific molecular signals is an important opportunity for the discovery of biomarkers and synergistic drugs to advance clinical application. Since PT is used for the treatment of lymphoma, we report here transcriptomic responses of lymphoma cell lines to PT vs X-ray and identify potential therapeutic targets., Materials and Methods: Two lymphoma cell lines of human (BL41) and murine (J3D) origin were irradiated by X-ray and PT. Differential transcriptome regulation was quantified by RNA sequencing for each radiation type at 12 hours post irradiation. Gene-set enrichment analysis revealed deregulated molecular pathways and putative targets for lymphoma cell sensitization to PT., Results: Transcriptomic gene set enrichment analyses uncovered pathways that contribute to the unfolded protein response (UPR) and mitochondrial transport. Functional validation at multiple time points demonstrated increased UPR activation and decreased protein translation, perhaps due to increased oxidative stress and oxidative protein damage after PT. PPARgamma was identified as a potential regulator of the PT transcriptomic response. Inhibition of PPARgamma by two compounds, T0070907 and SR2595, sensitized lymphoma cells to PT., Conclusions: Proton vs X-ray radiation leads to the transcriptional regulation of a specific subset of genes in line with diminished protein translation and UPR activation that may be due to oxidative stress. This study demonstrates that different radiation qualities trigger distinct cellular responses in lymphoma cells, and identifies PPARgamma inhibition as a potential strategy for the sensitization of lymphoma to PT., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)