背景:与常规剂量率放疗(CONV-RT)相比,超高剂量率放疗(FLASH-RT)通过最小化正常组织毒性而不损害抗肿瘤疗效,从而改善了治疗指数。探讨FLASH-RT对人小儿髓母细胞瘤脑肿瘤的转化潜能,我们使用放射敏感性幼年小鼠模型评估长期神经系统不良结局.
方法:暴露于低分割(2×10Gy,FLASH-RT或CONV-RT)全脑照射和未照射的对照进行了行为测试,以确定治疗后四个月的认知状态。在照射后6个月处死动物,并分析组织的神经和脑血管减少。
结果:在6个月的随访中分析了FLASH-RT对神经系统的影响。FLASH-RT改善了CONV-RT引起的神经认知功能下降,并在电生理(长期增强)上保留了突触可塑性和完整性,多个大脑区域的分子(突触素)和结构(巴松/荷马-1布顿)水平。FLASH-RT的益处还与减少神经炎症(活化的小胶质细胞)和保留脑血管结构有关。通过维持水通道蛋白-4水平和最小化小胶质细胞共定位到血管。
结论:与CONV-RT相比,低分割的FLASH-RT在对辐射敏感的幼年小鼠大脑中提供了显着且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,并强调了其解决儿科脑肿瘤幸存者长期面临的并发症的潜力。虽然在实现临床翻译之前必须谨慎行事,目前的研究结果记录了FLASH-RT从突触到认知和微脉管系统的显着益处。
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.