NORMAL BRAIN RESPONSE AFTER GAMMA KNIFE IRRADIATION

局灶性间质内照射正被用于临床治疗 恶性脑瘤，通常遵循传统的远程治疗 协议。这种方法对某些类型的肿瘤有效，但 有可能对正常脑组织造成实质性损害。 另一种方法是使用聚焦高剂量外束 辐射，即放射外科，而不是高活度放射性同位素。 然而，放射外科的有害影响并不是很好。 研究过，缺乏关键的生物学信息，尤其是 关于剂量-体积关系以及焦点的程度 辐射损伤是可以修改的。这项建议主要集中在三个方面 正常脑组织对高剂量辐射反应的假说 焦点照射：1)辐射损伤的严重程度与 辐射组织的体积；2)微妙的变化 形态学/生理学可以预测由以下因素引起的最终组织破坏 放射外科；以及，3)放射外科的病理生理后果 在一定程度上是由多胺的存在和减少而引起的 组织多胺水平可能会缓和辐射诱导的程度 受伤。拟议的研究将涉及一种狗模型，并将很好地使用- 建立了非侵入性的方法来测量损伤的体积， 血管通透性(血到脑，k/i和脑到血，k/b， 转移常数)、局部脑血流量(RCBF)、平均通过时间 血液和血管容量的时间(四甲基偶氮唑蓝)。免疫组织化学方法将 用于细胞的定性和定量评价 照射后大脑的反应。具体目标是：1)确定 正常脑组织的形态和生理反应随时间的变化 单次放射外科治疗后恢复到正常体积的时间 脑；2)使用多个定量终点，以确定剂量 单次放射外科治疗后正常脑的反应特征 治疗，并量化指定剂量后的损伤程度 与受辐射的脑体积有关；3)在辐射方面- 诱导坏死，以确定是否以及在多大程度上剂量不均一 剂量分布的高剂量区影响剂量体积 关系；4)确定脑脊液多胺水平和/或 脑组织密度(CT数)、血流相关参数(rCBF、 Mtt，血管体积)或通透性(k/i和k/b)先于一般 组织分解，并可能是最终表达的有用预测因子 5)使用针对辐射损伤的免疫组织化学标记 巨噬细胞、血管内皮细胞、星形胶质细胞和细胞合成 DNA，以定性和定量地确定细胞反应 对正常脑组织进行局灶性照射；以及6)确定是否和 静脉输注α-二氟甲基鸟氨酸的程度 (DFMO)修改标准的形态和生理后果 放射外科治疗。

Focal interstitial irradiation is being used in the clinical management of malignant brain tumors and generally follows a conventional teletherapy protocol. This approach is effective against certain types of tumors, but has the potential for causing substantial damage to normal brain tissues. An alternative approach is to use focal high-dose external-beam irradiation, i.e., radiosurgery, instead of high activity radioisotopes. However, the deleterious effects of radiosurgery have not been well studied, and critical biological information is lacking, particularly regarding dose-volume relationships, and the extent to which focal radiation-induced injury can be modified. This proposal focuses on three hypotheses related to the response of normal brain tissue to high-dose focal irradiation: 1) the severity of radiation-induced damage is related to the volume of irradiated tissue; 2) subtle changes in morphology/physiology can predict the ultimate tissue breakdown caused by radiosurgery; and, 3) the pathophysiologic consequences of radiosurgery are mediated in part by the presence of polyamines, and reductions in tissue polyamine levels may moderate the extent of radiation-induced injury. The proposed study will involve a dog model and will use well- established noninvasive methodologies to measure volumes of injury, vascular permeability (blood-to-brain, k/i, and brain-to-blood, k/b, transfer constants), regional cerebral blood flow (rCBF), mean transit time (MTT) of blood and vascular volume. Immunohistochemical methods will be used for a qualitative and quantitative appraisal of the cellular response in irradiated brain. The specific aims are: 1) to determine the morphologic and physiologic responses of normal brain as a function of time after a single radiosurgical treatment to a defined volume of normal brain; 2) using multiple quantitative endpoints, to determine the dose response characteristics of normal brain after a single radiosurgical treatment, and quantify how the extent of injury after a specified dose relates to the volume of brain irradiated; 3) in terms of radiation- induced necrosis, to determine if and to what extend dose heterogeneity in the high dose region of the dose distribution affects the dose-volume relationship; 4) to determine if changes in CSF polyamine levels and/or brain tissue density (CT number), blood flow-related parameters (rCBF, MTT, vascular volume), or permeability (k/i and k/b) precede general tissue breakdown and may be useful predictors of the ultimate expression of radiation injury; 5) using immunohistochemical markers specific for macrophages, vascular endothelial cells, astrocytes and cells synthesizing DNA, to qualitatively and quantitatively determine the cellular response of normal brain tissue to focal irradiation; and 6) to determine if and to what extent an intravenous infusion of alpha-difluoromethylornithine (DFMO) modifies the morphologic and physiologic consequences of a standard radiosurgical treatment.