Investigating the FLASH Effect in a Rat Brain Organotypic Model with a Novel High Energy Electron Beam.

IF 6.5 1区医学 Q1 ONCOLOGY

International Journal of Radiation Oncology Biology Physics Pub Date : 2025-10-10 DOI:10.1016/j.ijrobp.2025.09.057

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":"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":"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.","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":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Radiation Oncology Biology Physics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ijrobp.2025.09.057","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

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.

查看原文本刊更多论文

用新型高能电子束研究大鼠脑器官型模型中的FLASH效应。

目的：据报道，超高剂量率（FLASH）放射治疗在维持肿瘤控制的同时降低了正常组织的毒性，但其机制尚不清楚。为了研究FLASH在脑组织中的机制，我们开发了一个新的实验平台，该实验平台采用了专门的高能电子直线加速器HIGS（高强度伽马射线源），并与器官型体外脑转移模型配对。方法：通过改变脉冲间隔来调节35 MeV电子束的平均剂量率（MDR），同时保持极高的瞬时剂量率（IDR）。我们用薄膜剂量法对FLASH光束的剂量学和靶向精度进行了表征。我们将这种闪光束与器官型大鼠脑切片/乳腺癌脑转移共培养模型相结合，以评估对正常组织和肿瘤组织的影响。活细胞和生物发光成像显示了癌细胞的生长效应，而正常组织的反应和免疫激活则通过活细胞成像、细胞因子谱和共聚焦显微镜进行评估。我们使用常规剂量率对瓦里安临床直线加速器（VCLA）的20 MeV电子进行了比较实验。结果：迄今为止，FLASH光束的最高IDR为20.7±0.6 MGy/s，最大MDR为20.7 MGy/s，一个脉冲持续1µs。光束瞄准精度小于1毫米，可重复性好。HIGS-FLASH和VCLA剂量率同样降低了细胞生长。HIGS-FLASH照射显著增加TNFα和fractalkine水平，共聚焦显微镜显示小胶质细胞形态学切片发生明显变化，提示小胶质细胞活化。结论：我们的新实验平台可以产生极高的剂量率和快速的正常/肿瘤组织读数，用于研究FLASH辐射对大脑的影响。HIGS-FLASH辐照可诱导类似的癌细胞生长抑制，但对细胞因子和小胶质细胞形态的影响不同，这表明急性先天免疫反应可能参与了FLASH对大脑正常组织的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

International Journal of Radiation Oncology Biology Physics 医学-核医学

CiteScore

11.00

自引率

7.10%

发文量

2538

审稿时长

6.6 weeks

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.