Department of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA.
School of Health Sciences, Purdue University, 550 Stadium Mall Drive, Hampton Hall 1263A, West Lafayette, IN, 47907-2051, USA.
Radiat Oncol. 2021 Feb 6;16(1):30. doi: 10.1186/s13014-021-01753-1.
Radiation-induced brain injury is a common concern for survivors of adult and pediatric brain cancer. Pre-clinically, rodent models are the standard approach to evaluate mechanisms of injury and test new therapeutics for this condition. However, these rodent models fail to recapitulate the radiological and histological characteristics of the clinical disease.
Here we describe a hemispheric mini-pig model of radiation-induced brain injury generated with a clinical 6 MV photon irradiator and evaluated with a clinical 3T MRI. Two pairs of Yucatan mini-pigs each received either 15 Gy or 25 Gy to the left brain hemisphere. Quality of intensity modulated radiation therapy treatment plans was evaluated retrospectively with parameters reported according to ICRU guidelines. The pigs were observed weekly to check for any outright signs of neurological impairment. The pigs underwent anatomical MRI examination before irradiation and up to 6 months post-irradiation. Immediately after the last imaging time point, the pigs were euthanized and their brains were collected for histopathological assessment.
Analysis of the dose volume histograms showed that 93% of the prescribed dose was delivered to at least 93% of the target volume in the left hemisphere. Organs at risk excluded from the target volume received doses below clinical safety thresholds. For the pigs that received a 25 Gy dose, progressive neurological impairment was observed starting at 2 months post-irradiation leading to the need for euthanasia by 3-4 months. On MRI, these two animals presented with diffuse white matter pathology consistent with the human disease that progressed to outright radiation necrosis and severe brain swelling. Histology was consistent with the final MRI evaluation. The pigs that received a 15 Gy dose appeared normal all the way to 6 months post-irradiation with no obvious neurological impairment or lesions on MRI or histopathology.
Based on our results, a mini-pig model of radiation-induced brain injury is feasible though some optimization is still needed. The mini-pig model produced lesions on MRI that are consistent with the human disease and which are not seen in rodent models. Our data shows that the ideal radiation dose for this model likely lies between 15 and 25 Gy.
辐射诱导脑损伤是成人和儿童脑癌幸存者常见的问题。在临床前阶段，啮齿动物模型是评估损伤机制和测试该疾病新疗法的标准方法。然而，这些啮齿动物模型未能重现临床疾病的放射学和组织学特征。
在这里，我们描述了一种使用临床 6 MV 光子辐照器生成的辐射诱导脑损伤的半脑小型猪模型，并使用临床 3T MRI 进行了评估。两对尤卡坦小型猪每只接受左脑半球 15 Gy 或 25 Gy 的照射。通过根据 ICRU 指南报告的参数，回顾性评估强度调制放射治疗计划的质量。每周观察猪，以检查是否有任何明显的神经功能障碍迹象。在照射前和照射后 6 个月进行猪的解剖 MRI 检查。在最后一次成像时间点后，立即对猪进行安乐死，并收集其大脑进行组织病理学评估。
剂量体积直方图的分析表明，在左半球，93%的处方剂量至少输送到 93%的靶体积。从靶体积中排除的危险器官接受的剂量低于临床安全阈值。对于接受 25 Gy 剂量的猪，从照射后 2 个月开始观察到进行性神经功能障碍，导致 3-4 个月需要安乐死。在 MRI 上，这两只动物表现出弥漫性白质病变，与人类疾病一致，进展为明确的放射性坏死和严重的脑肿胀。组织学与最终 MRI 评估一致。接受 15 Gy 剂量的猪在照射后 6 个月内一直正常，没有明显的神经功能障碍或 MRI 或组织病理学上的病变。
根据我们的结果，辐射诱导脑损伤的小型猪模型是可行的，但仍需要进行一些优化。小型猪模型产生的 MRI 病变与人类疾病一致，而在啮齿动物模型中则未见。我们的数据表明，该模型的理想辐射剂量可能在 15 至 25 Gy 之间。
