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Ultrahigh dose-rate FLASH radiation therapy has emerged as a modality that promises to reduce normal tissue toxicity while maintaining tumor control. Previous studies of gastrointestinal toxicity using passively scattered FLASH proton therapy (PRT) have, however, yielded mixed results, suggesting that the requirements for gastrointestinal sparing by FLASH are an open question. Furthermore, the more clinically relevant pencil beam scanned (PBS) FLASH PRT has not yet been assessed in this context, despite differences in the spatiotemporal dose-rate distributions compared with passively scattered PRT. Here, to our knowledge, we provide the first report on the effects of PBS FLASH PRT on acute gastrointestinal injury in mice after whole abdominal irradiation. Whole abdominal irradiation was performed on C57BL/6J mice using the entrance channel of the Bragg curve of a 250 MeV PBS proton beam at field-averaged dose rates of 0.6 Gy/s for conventional (CONV) and 80 to 100 Gy/s for FLASH PRT. A 2D strip ionization chamber array was used to measure the dose and dose rate for each mouse. Survival was assessed at 14 Gy. Intestines were harvested and processed as Swiss rolls for analysis using a novel artificial intelligence-based crypt assay to quantify crypt regeneration 4 days after irradiation. Survival was significantly reduced after 14 Gy FLASH PRT compared with CONV (P <.001). Our artificial intelligence-based crypt assays demonstrated no significant difference in intestinal crypts/cm or crypt depth between groups 4 days after irradiation. Furthermore, we found no significant difference in 5-ethynyl-2′-deoxyuridine+ cells/crypt or Olfactomedin4+ intestinal stem cells with FLASH relative to CONV PRT. Overall, our data demonstrate significantly impaired survival after abdominal PBS FLASH PRT without apparent differences in intestinal histology 4 days after irradiation. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the acute changes in leukocyte populations after focal irradiation and to assess the role of interleukin 6 (IL-6) in acute and late radiation injury.Methods and Materials: Mice were surgically implanted with a radiopaque marker on the surface of the small intestine. Mice were then imaged with cone beam computed tomography to locate the marker and irradiated with 18 Gy of 5 × 5 mm collimated x-rays onto the marked intestine using the Small Animal Radiation Research Platform. Intestinal sections and blood were harvested 1, 3.5, 7, and 14 days and 2 months postirradiation (post-IR) for histology and complete blood count, respectively. Immune cell populations were assessed by immunofluorescence in the acute phase. Collagen deposition was assessed 2 months post-IR. IL-6-/- intestinal sections were assessed post-IR for morphology, EdU, Ki67, and TUNEL in comparison to IL-6+/+ mice. Furthermore, a set of IL-6+/+ mice were treated with anti-IL-6R to assess the role of IL-6 in late intestinal injury.Results: Intestinal radiation damage peaked 14 days post-IR, and fibrosis had developed by 60 days post-IR. There was a marked infiltration of immune cells into the irradiated intestine, with increased neutrophils, macrophages, B-cells, and CD4+ T cells maintained from 3.5 to 14 days post-IR. CD8+ T cells were decreased from days 7 to 14 post-IR. Systemically, leukocytes were increased in the peripheral blood 14 days post-IR with anemia being maintained from 14 days to 2 months. IL-6 was significantly increased in the serum post-IR. IL-6-/- mice demonstrated worsened intestinal injury acutely post-IR. Moreover, anti-IL-6R-treated mice presented with worsened intestinal fibrosis 2 months post-IR.Conclusions: Focal irradiation of the intestine produced a significant increase in immune cells in the irradiated area and systemic inflammation and anemia. Blockade of IL-6 signaling was found to exacerbate acute intestinal injury and late intestinal injury after focal irradiation. [ABSTRACT FROM AUTHOR]