Neuroprotection of Radiosensitive Juvenile Mice by Ultra-High Dose Rate FLASH Irradiation
Neuroprotection of Radiosensitive Juvenile Mice by Ultra-High Dose Rate FLASH Irradiation
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DOI：
10.3390/cancers12061671
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发表时间：
2020-06-01
期刊：
影响因子：
5.2
通讯作者：
Limoli, Charles L.
中科院分区：
文献类型：
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作者：
Alaghband, Yasaman;Cheeks, Samantha N.;Limoli, Charles L.
高精度治疗的提供和成像技术的重大进展极大地提高了放射治疗的耐受性；然而，选择性地保留正常组织和减少放射毒性引起的神经认知副作用仍然是儿童脑肿瘤患者面临的重大问题。髓母细胞瘤(MB)是儿童中最常见的一种原发脑癌，虽然其总体存活率仍然很高(80%)，但终生神经毒性副作用很常见，并对患者的生活质量产生不利影响。为了避免这些临床并发症，我们研究了超高剂量率闪光放射治疗(Flash-RT)保护对辐射敏感的幼年小鼠大脑免受正常组织毒性的能力。与常规剂量率(Conv)照射相比，闪光RT可以改善辐射所致的多个独立行为范式的认知功能障碍，保护发育中和成熟的神经元，减少小胶质细胞增生，限制生长激素水平的下降。这种保护性的“闪光效应”是显著的，特别是因为类似的8GyConv-RT全脑剂量导致行为表现的多个指数(物体在更新的位置、新物体识别、恐惧消退、明暗盒子、社交)、未成熟(Doublecortin(+))和成熟(Neun(+))神经元的数量减少，以及增加神经炎症和不良反应，这是闪光-RT没有发现的。我们的数据表明，一种潜在的创新治疗方式能够避免(如果不能预防)与长期治疗相关的许多副作用，这些副作用破坏了髓母细胞瘤幸存者的长期认知和情感健康。
Major advances in high precision treatment delivery and imaging have greatly improved the tolerance of radiotherapy (RT); however, the selective sparing of normal tissue and the reduction of neurocognitive side effects from radiation-induced toxicities remain significant problems for pediatric patients with brain tumors. While the overall survival of pediatric patients afflicted with medulloblastoma (MB), the most common type primary brain cancer in children, remains high (>= 80%), lifelong neurotoxic side-effects are commonplace and adversely impact patients' quality of life. To circumvent these clinical complications, we have investigated the capability of ultra-high dose rate FLASH-radiotherapy (FLASH-RT) to protect the radiosensitive juvenile mouse brain from normal tissue toxicities. Compared to conventional dose rate (CONV) irradiation, FLASH-RT was found to ameliorate radiation-induced cognitive dysfunction in multiple independent behavioral paradigms, preserve developing and mature neurons, minimize microgliosis and limit the reduction of the plasmatic level of growth hormone. The protective "FLASH effect" was pronounced, especially since a similar whole brain dose of 8 Gy delivered with CONV-RT caused marked reductions in multiple indices of behavioral performance (objects in updated location, novel object recognition, fear extinction, light-dark box, social interaction), reductions in the number of immature (doublecortin(+)) and mature (NeuN(+)) neurons and increased neuroinflammation, adverse effects that were not found with FLASH-RT. Our data point to a potentially innovative treatment modality that is able to spare, if not prevent, many of the side effects associated with long-term treatment that disrupt the long-term cognitive and emotional well-being of medulloblastoma survivors.