Tyler V Kay, Anna L Price, Markus Sprenger, Victoria J P Radosova, Andrew Thompson, Eric L Martin, Denise Dunn, Victor Popov, Stepan Mikhailov, Zachary J Reitman, Ying K Wu, Scott R Floyd, Mark Oldham
{"title":"用新型高能电子束研究大鼠脑器官型模型中的FLASH效应。","authors":"Tyler V Kay, Anna L Price, Markus Sprenger, Victoria J P Radosova, Andrew Thompson, Eric L Martin, Denise Dunn, Victor Popov, Stepan Mikhailov, Zachary J Reitman, Ying K Wu, Scott R Floyd, Mark Oldham","doi":"10.1016/j.ijrobp.2025.09.057","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Ultra-high dose rate (FLASH) radiation therapy is reported to reduce normal tissue toxicity while maintaining tumor control, however mechanism(s) remain obscure. To study FLASH mechanisms in brain tissue, we developed a novel experimental platform featuring a specialized high-energy electron linear accelerator, HIGS (High Intensity Gamma Ray Source), paired with an organotypic ex vivo brain metastasis model.</p><p><strong>Methods: </strong>We varied inter-pulse spacing to modulate the mean dose rate (MDR) of our unique 35 MeV electron beam, while maintaining extremely high instantaneous dose rate (IDR). We characterized dosimetry and targeting accuracy of the FLASH beam with film dosimetry. We combined this FLASH beam with an organotypic rat brain slice/breast carcinoma co-culture model of brain metastasis to assess effects on normal and neoplastic tissues. Live cell and bioluminescence imaging demonstrated cancer cell growth effects, while normal tissue responses and immune activation were assessed using live cell imaging, cytokine profiles, and confocal microscopy. We performed comparison experiments with 20 MeV electrons from a Varian clinical linear accelerator (VCLA) using conventional dose rates.</p><p><strong>Results: </strong>The highest IDR of the FLASH beam to date was 20.7 ± 0.6 MGy/s, with maximum MDR of 20.7 MGy/s delivered in one pulse of 1 µs duration. Beam targeting was accurate to < 1 mm and reproducible. HIGS-FLASH and VCLA dose rates equivalently decreased cell growth. HIGS-FLASH irradiation significantly increased TNFα and fractalkine levels and confocal microscopy revealed distinct changes in microglial morphology slices suggesting microglia activation.</p><p><strong>Conclusions: </strong>Our novel experimental platform produces extremely high dose rates and rapid normal/neoplastic tissue readouts for mechanistic research into the effects of FLASH radiation in the brain. HIGS-FLASH irradiation induces comparable cancer cell growth inhibition but differential effects on cytokines and microglial morphology, suggesting that acute innate immune responses may be involved in FLASH normal tissue effects in the brain.</p>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":" ","pages":""},"PeriodicalIF":6.5000,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Investigating the FLASH Effect in a Rat Brain Organotypic Model with a Novel High Energy Electron Beam.\",\"authors\":\"Tyler V Kay, Anna L Price, Markus Sprenger, Victoria J P Radosova, Andrew Thompson, Eric L Martin, Denise Dunn, Victor Popov, Stepan Mikhailov, Zachary J Reitman, Ying K Wu, Scott R Floyd, Mark Oldham\",\"doi\":\"10.1016/j.ijrobp.2025.09.057\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Ultra-high dose rate (FLASH) radiation therapy is reported to reduce normal tissue toxicity while maintaining tumor control, however mechanism(s) remain obscure. To study FLASH mechanisms in brain tissue, we developed a novel experimental platform featuring a specialized high-energy electron linear accelerator, HIGS (High Intensity Gamma Ray Source), paired with an organotypic ex vivo brain metastasis model.</p><p><strong>Methods: </strong>We varied inter-pulse spacing to modulate the mean dose rate (MDR) of our unique 35 MeV electron beam, while maintaining extremely high instantaneous dose rate (IDR). We characterized dosimetry and targeting accuracy of the FLASH beam with film dosimetry. We combined this FLASH beam with an organotypic rat brain slice/breast carcinoma co-culture model of brain metastasis to assess effects on normal and neoplastic tissues. Live cell and bioluminescence imaging demonstrated cancer cell growth effects, while normal tissue responses and immune activation were assessed using live cell imaging, cytokine profiles, and confocal microscopy. We performed comparison experiments with 20 MeV electrons from a Varian clinical linear accelerator (VCLA) using conventional dose rates.</p><p><strong>Results: </strong>The highest IDR of the FLASH beam to date was 20.7 ± 0.6 MGy/s, with maximum MDR of 20.7 MGy/s delivered in one pulse of 1 µs duration. Beam targeting was accurate to < 1 mm and reproducible. HIGS-FLASH and VCLA dose rates equivalently decreased cell growth. HIGS-FLASH irradiation significantly increased TNFα and fractalkine levels and confocal microscopy revealed distinct changes in microglial morphology slices suggesting microglia activation.</p><p><strong>Conclusions: </strong>Our novel experimental platform produces extremely high dose rates and rapid normal/neoplastic tissue readouts for mechanistic research into the effects of FLASH radiation in the brain. 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Investigating the FLASH Effect in a Rat Brain Organotypic Model with a Novel High Energy Electron Beam.
Purpose: Ultra-high dose rate (FLASH) radiation therapy is reported to reduce normal tissue toxicity while maintaining tumor control, however mechanism(s) remain obscure. To study FLASH mechanisms in brain tissue, we developed a novel experimental platform featuring a specialized high-energy electron linear accelerator, HIGS (High Intensity Gamma Ray Source), paired with an organotypic ex vivo brain metastasis model.
Methods: We varied inter-pulse spacing to modulate the mean dose rate (MDR) of our unique 35 MeV electron beam, while maintaining extremely high instantaneous dose rate (IDR). We characterized dosimetry and targeting accuracy of the FLASH beam with film dosimetry. We combined this FLASH beam with an organotypic rat brain slice/breast carcinoma co-culture model of brain metastasis to assess effects on normal and neoplastic tissues. Live cell and bioluminescence imaging demonstrated cancer cell growth effects, while normal tissue responses and immune activation were assessed using live cell imaging, cytokine profiles, and confocal microscopy. We performed comparison experiments with 20 MeV electrons from a Varian clinical linear accelerator (VCLA) using conventional dose rates.
Results: The highest IDR of the FLASH beam to date was 20.7 ± 0.6 MGy/s, with maximum MDR of 20.7 MGy/s delivered in one pulse of 1 µs duration. Beam targeting was accurate to < 1 mm and reproducible. HIGS-FLASH and VCLA dose rates equivalently decreased cell growth. HIGS-FLASH irradiation significantly increased TNFα and fractalkine levels and confocal microscopy revealed distinct changes in microglial morphology slices suggesting microglia activation.
Conclusions: Our novel experimental platform produces extremely high dose rates and rapid normal/neoplastic tissue readouts for mechanistic research into the effects of FLASH radiation in the brain. HIGS-FLASH irradiation induces comparable cancer cell growth inhibition but differential effects on cytokines and microglial morphology, suggesting that acute innate immune responses may be involved in FLASH normal tissue effects in the brain.
期刊介绍:
International Journal of Radiation Oncology • Biology • Physics (IJROBP), known in the field as the Red Journal, publishes original laboratory and clinical investigations related to radiation oncology, radiation biology, medical physics, and both education and health policy as it relates to the field.
This journal has a particular interest in original contributions of the following types: prospective clinical trials, outcomes research, and large database interrogation. In addition, it seeks reports of high-impact innovations in single or combined modality treatment, tumor sensitization, normal tissue protection (including both precision avoidance and pharmacologic means), brachytherapy, particle irradiation, and cancer imaging. Technical advances related to dosimetry and conformal radiation treatment planning are of interest, as are basic science studies investigating tumor physiology and the molecular biology underlying cancer and normal tissue radiation response.