PDF(Pubmed)
Abstract：
Radiation-induced late side effects such as cognitive decline and normal tissue complications can severely affect quality of life and outcome in long-term survivors of brain tumors. Proton therapy offers a favorable depth-dose deposition with the potential to spare tumor-surrounding normal tissue, thus potentially reducing such side effects. In this study, we describe a preclinical model to reveal underlying biological mechanisms caused by precise high-dose proton irradiation of a brain subvolume. We studied the dose- and time-dependent radiation response of mouse brain tissue, using a high-precision image-guided proton irradiation setup for small animals established at the University Proton Therapy Dresden (UPTD). The right hippocampal area of ten C57BL/6 and ten C3H/He mice was irradiated. Both strains contained four groups (nirradiated = 3, ncontrol = 1) treated with increasing doses (0 Gy, 45 Gy, 65 Gy or 85 Gy and 0 Gy, 40 Gy, 60 Gy or 80 Gy, respectively). Follow-up examinations were performed for up to six months, including longitudinal monitoring of general health status and regular contrast-enhanced magnetic resonance imaging (MRI) of mouse brains. These findings were related to comprehensive histological analysis. In all mice of the highest dose group, first symptoms of blood-brain barrier (BBB) damage appeared one week after irradiation, while a dose-dependent delay in onset was observed for lower doses. MRI contrast agent leakage occurred in the irradiated brain areas and was progressive in the higher dose groups. Mouse health status and survival corresponded to the extent of contrast agent leakage. Histological analysis revealed tissue changes such as vessel abnormalities, gliosis, and granule cell dispersion, which also partly affected the non-irradiated contralateral hippocampus in the higher dose groups. All observed effects depended strongly on the prescribed radiation dose and the outcome, i.e. survival, image changes, and tissue alterations, were very consistent within an experimental dose cohort. The derived dose-response model will determine endpoint-specific dose levels for future experiments and may support generating clinical hypotheses on brain toxicity after proton therapy.
摘要：
辐射引起的后期副作用，例如认知能力下降和正常组织并发症，会严重影响脑肿瘤长期幸存者的生活质量和预后。质子治疗提供了有利的深度剂量沉积，有可能避免肿瘤周围的正常组织，从而潜在地减少这种副作用。在这项研究中,我们描述了一个临床前模型，以揭示由精确的大剂量质子照射脑亚体积引起的潜在生物学机制。我们研究了小鼠脑组织的剂量和时间依赖性辐射反应，使用在德累斯顿质子治疗大学（UPTD）建立的高精度图像引导质子辐照装置为小动物。照射10只C57BL/6和10只C3H/He小鼠的右侧海马区。两种菌株均包含四组（nradiated=3，ncontrol=1），剂量增加（0Gy，45Gy,65Gy或85Gy和0Gy，40Gy,60Gy或80Gy，分别)。随访检查长达六个月，包括一般健康状况的纵向监测和小鼠大脑的定期对比增强磁共振成像（MRI）。这些发现与全面的组织学分析有关。在最高剂量组的所有小鼠中，首次出现血脑屏障(BBB)损伤的症状,而对于较低剂量观察到剂量依赖性的发作延迟。MRI造影剂泄漏发生在受照射的大脑区域，在高剂量组中是进行性的。小鼠健康状态和存活对应于造影剂泄漏的程度。组织学分析显示组织变化，如血管异常，胶质增生,和颗粒细胞分散，这也部分影响了高剂量组的未照射对侧海马。所有观察到的效果在很大程度上取决于规定的辐射剂量和结果，即生存，图像更改,和组织改变，在实验剂量队列中非常一致。推导出的剂量反应模型将确定用于未来实验的终点特异性剂量水平，并可能支持产生质子治疗后脑毒性的临床假设。
