Quantifying Human Lung Tissue Dose Response Relationship

描述（由申请人提供）：本提案的目的是肺是一个非常放射敏感的器官。急性和早期辐射毒性效应让位于慢性晚期效应，即进行性组织纤维化和肺炎，这些效应在放射治疗后3-6个月优先发生，并在整个生命过程中逐渐升级。我们的测定是一种用于在体内定量正常肺组织的辐射剂量响应关系的方法，其基于容易获得的和非侵入性的体积计算机断层扫描（CT）成像，并且因此适用于人类受试者和辐射损伤的动物模型。在临床上，我们率先使用高剂量立体定向放射治疗来治疗肺的小转移瘤;使得有可能向靶和紧邻组织提供非常高的辐射剂量场（超过50 Gy），并且远离靶部位的剂量场下降。使用这些治疗剂量，实现了高的局部控制率，使我们能够对患者进行数年的随访。治疗后6个月在这些患者中获得的体积CT扫描显示了与治疗期间的高剂量区域对应的纤维化病灶区域，并且在远处部位没有可观察到的长期损伤。在这些患者中，我们能够应用图像配准技术和每个目标周围的3D剂量场的知识，以逐像素的方式量化正常肺组织的完整辐射剂量响应关系。我们的论点是，这种方法可以用来量化的变化，由于特定的代理或干预的调节作用的放射生物学反应。我们现在已经在临床上验证了血液中IL-1a循环水平的时间模式与可观察到的肺组织反应的时间过程之间的相关性，这种相关性是通过先前在动物模型中的工作预测的。未来，系列血液炎症分子测量与临床反应标志物之间的对应关系将由我们部门的辐射医学对策中心的持续进展指导。我们的假设是，我们的检测将使我们能够第一次定制预防和治疗策略，以定量组织反应指标。我们的建议包括在动物模型中进行分级肺照射实验，以验证并将我们的成像结果与细胞和组织放射生物学的先验知识联系起来。

DESCRIPTION (provided by applicant): The aim of this proposal is lungs are a very radiosensitive organ. Acute and early radiation toxicity effects give way to chronic late-effects of progressive tissue fibrosis and pneumonitis that take precedence 3-6 months post-radiation therapy and appear to escalate throughout life. Our assay is a method for quantifying in-vivo the radiation dose response relationship of normal lung tissue that is based on readily available and non-invasive volumetric computed tomography (CT) imaging and is therefore applicable both to human subjects and in animal models of radiation injury. In the clinic we have pioneered the use of high-dose stereotactic radiation therapy to treat small metastatic tumors of the lung; making it possible to deliver a very high radiation dose field (in excess of 50Gy) to the target and immediately adjacent tissue, and a fall-off in the dose field away from the target site. With these curative doses, a high rate of local control is achieved, allowing us to follow our patients for several years. Volumetric CT scans acquired in these patients six months post-treatment reveal a focal region of fibrosis corresponding to the high-dose region during therapy, and no observable long-term damage in distant sites. In these patients we are able to apply image registration techniques and knowledge of the 3D dose field around each target to quantify, on a pixel-by-pixel basis, the complete radiation dose response relationship of normal lung tissue. Our contention is that this method can be used to quantify changes in the radiobiologic response due to the moderating effects of specific agents or interventions. We have now validated clinically a correlation between temporal patterns of circulating levels of IL-1a in the blood and the time course of observable lung tissue response, a correlation predicted by prior work in animal models Future correspondences between serial blood inflammatory molecule measurements and clinical markers of response will be guided by the continued advances from our department's Center for Medical Countermeasures Against Radiation. Our hypothesis is that our assay will enable us for the first time to tailor preventive and treatment strategies to quantitative tissue reaction metrics. Our proposal includes graded lung irradiation experiments in animal models to validate and link our imaging results to prior knowledge of cellular and tissue radiobiology.