Jia-Ling Ruan1, Carl Lee2, Shari Wouters3, Iain D C Tullis1, Mieke Verslegers4, Mohamed Mysara4, Chee Kin Then1, Sean C Smart1, Mark A Hill1, Ruth J Muschel1, Amato J Giaccia1, Borivoj Vojnovic1, Anne E Kiltie1, Kristoffer Petersson5. 1. MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, United Kingdom. 2. Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, United Kingdom. 3. Interdisciplinary Biosciences Group, Belgian Nuclear Research Center (SCK CEN), Mol, Belgium; Molecular Pathology Group, Cell Biology and Histology and Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute, Campus Drie Eiken, University of Antwerp, Antwerp, Belgium. 4. Interdisciplinary Biosciences Group, Belgian Nuclear Research Center (SCK CEN), Mol, Belgium. 5. MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, United Kingdom; Radiation Physics, Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden. Electronic address: kristoffer.petersson@oncology.ox.ac.uk.
Abstract
PURPOSE: Preclinical studies using ultra-high dose rate (FLASH) irradiation have demonstrated reduced normal tissue toxicity compared with conventional dose rate (CONV) irradiation, although this finding is not universal. We investigated the effect of temporal pulse structure and average dose rate of FLASH compared with CONV irradiation on acute intestinal toxicity. MATERIALS AND METHODS: Whole abdomens of C3H mice were irradiated with a single fraction to various doses, using a 6 MeV electron linear accelerator with single pulse FLASH (dose rate = 2-6 × 106 Gy/s) or conventional (CONV; 0.25 Gy/s) irradiation. At 3.75 days postirradiation, fresh feces were collected for 16S rRNA sequencing to assess changes in the gut microbiota. A Swiss roll-based crypt assay was used to quantify acute damage to the intestinal crypts to determine how tissue toxicity was affected by the different temporal pulse structures of FLASH delivery. RESULTS: We found statistically significant improvements in crypt survival for mice irradiated with FLASH at doses between 7.5 and 12.5 Gy, with a dose modifying factor of 1.1 for FLASH (7.5 Gy, P < .01; 10 Gy, P < .05; 12.5 Gy, P < .01). This sparing effect was lost when the delivery time was increased, either by increasing the number of irradiation pulses or by prolonging the time between 2 successive pulses. Sparing was observed for average dose rates of ≥280 Gy/s. Fecal microbiome analysis showed that FLASH irradiation caused fewer changes to the microbiota than CONV irradiation. CONCLUSIONS: This study demonstrates that FLASH irradiation can spare mouse small intestinal crypts and reduce changes in gut microbiome composition compared with CONV irradiation. The higher the average dose rate, the larger the FLASH effect, which is also influenced by temporal pulse structure of the delivery.
PURPOSE: Preclinical studies using ultra-high dose rate (FLASH) irradiation have demonstrated reduced normal tissue toxicity compared with conventional dose rate (CONV) irradiation, although this finding is not universal. We investigated the effect of temporal pulse structure and average dose rate of FLASH compared with CONV irradiation on acute intestinal toxicity. MATERIALS AND METHODS: Whole abdomens of C3H mice were irradiated with a single fraction to various doses, using a 6 MeV electron linear accelerator with single pulse FLASH (dose rate = 2-6 × 106 Gy/s) or conventional (CONV; 0.25 Gy/s) irradiation. At 3.75 days postirradiation, fresh feces were collected for 16S rRNA sequencing to assess changes in the gut microbiota. A Swiss roll-based crypt assay was used to quantify acute damage to the intestinal crypts to determine how tissue toxicity was affected by the different temporal pulse structures of FLASH delivery. RESULTS: We found statistically significant improvements in crypt survival for mice irradiated with FLASH at doses between 7.5 and 12.5 Gy, with a dose modifying factor of 1.1 for FLASH (7.5 Gy, P < .01; 10 Gy, P < .05; 12.5 Gy, P < .01). This sparing effect was lost when the delivery time was increased, either by increasing the number of irradiation pulses or by prolonging the time between 2 successive pulses. Sparing was observed for average dose rates of ≥280 Gy/s. Fecal microbiome analysis showed that FLASH irradiation caused fewer changes to the microbiota than CONV irradiation. CONCLUSIONS: This study demonstrates that FLASH irradiation can spare mouse small intestinal crypts and reduce changes in gut microbiome composition compared with CONV irradiation. The higher the average dose rate, the larger the FLASH effect, which is also influenced by temporal pulse structure of the delivery.
Authors: Elise Konradsson; Maja L Arendt; Kristine Bastholm Jensen; Betina Børresen; Anders E Hansen; Sven Bäck; Annemarie T Kristensen; Per Munck Af Rosenschöld; Crister Ceberg; Kristoffer Petersson Journal: Front Oncol Date: 2021-05-13 Impact factor: 6.244
Authors: Joshua T Eggold; Stephanie Chow; Stavros Melemenidis; Jinghui Wang; Suchitra Natarajan; Phoebe E Loo; Rakesh Manjappa; Vignesh Viswanathan; Elizabeth A Kidd; Edgar Engleman; Oliver Dorigo; Billy W Loo; Erinn B Rankin Journal: Mol Cancer Ther Date: 2021-12-05 Impact factor: 6.009