Department of Radiation Oncology, University of California, Irvine, CA 92697-2695, USA.
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
Neuro Oncol. 2023 May 4;25(5):927-939. doi: 10.1093/neuonc/noac248.
Ultrahigh dose-rate radiotherapy (FLASH-RT) affords improvements in the therapeutic index by minimizing normal tissue toxicities without compromising antitumor efficacy compared to conventional dose-rate radiotherapy (CONV-RT). To investigate the translational potential of FLASH-RT to a human pediatric medulloblastoma brain tumor, we used a radiosensitive juvenile mouse model to assess adverse long-term neurological outcomes.
Cohorts of 3-week-old male and female C57Bl/6 mice exposed to hypofractionated (2 × 10 Gy, FLASH-RT or CONV-RT) whole brain irradiation and unirradiated controls underwent behavioral testing to ascertain cognitive status four months posttreatment. Animals were sacrificed 6 months post-irradiation and tissues were analyzed for neurological and cerebrovascular decrements.
The neurological impact of FLASH-RT was analyzed over a 6-month follow-up. FLASH-RT ameliorated neurocognitive decrements induced by CONV-RT and preserved synaptic plasticity and integrity at the electrophysiological (long-term potentiation), molecular (synaptophysin), and structural (Bassoon/Homer-1 bouton) levels in multiple brain regions. The benefits of FLASH-RT were also linked to reduced neuroinflammation (activated microglia) and the preservation of the cerebrovascular structure, by maintaining aquaporin-4 levels and minimizing microglia colocalized to vessels.
Hypofractionated FLASH-RT affords significant and long-term normal tissue protection in the radiosensitive juvenile mouse brain when compared to CONV-RT. The capability of FLASH-RT to preserve critical cognitive outcomes and electrophysiological properties over 6-months is noteworthy and highlights its potential for resolving long-standing complications faced by pediatric brain tumor survivors. While care must be exercised before clinical translation is realized, present findings document the marked benefits of FLASH-RT that extend from synapse to cognition and the microvasculature.
超高剂量率放疗（FLASH-RT）通过最大限度地减少正常组织毒性，在不影响抗肿瘤疗效的情况下，与常规剂量率放疗（CONV-RT）相比，提高了治疗指数。为了研究 FLASH-RT 在人类小儿髓母细胞瘤脑肿瘤中的转化潜力，我们使用了一种对放射敏感的幼年小鼠模型来评估不良的长期神经学结局。
3 周龄雄性和雌性 C57Bl/6 小鼠接受分割（2×10 Gy，FLASH-RT 或 CONV-RT）全脑照射，未照射对照小鼠接受行为测试，以确定治疗后 4 个月的认知状态。动物在照射后 6 个月处死，分析神经和脑血管损伤。
分析了 FLASH-RT 的神经影响，随访时间为 6 个月。FLASH-RT 改善了 CONV-RT 引起的神经认知障碍，并在多个脑区保持了电生理（长时程增强）、分子（突触小蛋白）和结构（Bassoon/Homer-1 末梢）水平的突触可塑性和完整性。FLASH-RT 的益处还与减少神经炎症（激活的小胶质细胞）和维持水通道蛋白-4 水平以及最大限度地减少与血管共定位的小胶质细胞有关，从而保持脑血管结构。
与 CONV-RT 相比，在对放射敏感的幼年小鼠脑中，分割的 FLASH-RT 提供了显著的、长期的正常组织保护。FLASH-RT 在 6 个月内保持关键认知结果和电生理特性的能力值得注意，这突出了其解决小儿脑肿瘤幸存者长期并发症的潜力。虽然在实现临床转化之前必须谨慎行事，但目前的研究结果证明了 FLASH-RT 的显著益处，这些益处从突触延伸到认知和微血管。
