DCE MRI Study for Breast Cancer.

描述（由申请人提供）：尽管最近发展了各种治疗方法，但乳腺癌仍然是妇女癌症死亡的第二大原因，也是45至55岁妇女死亡的主要原因。抗血管生成治疗方法已成为治疗癌症的重要手段。然而，这种针对个体患者的抗血管生成疗法的优化仍然没有解决。抗血管生成被认为可以暂时使异常的血管系统正常化，并矛盾地增加血流量，从而增加药物向肿瘤的输送。很大一部分患者对这种抗血管生成治疗没有反应，但尚不清楚这种失败是由于抗血管生成治疗未能使血管系统正常化还是由于细胞毒性杀死细胞的失败。因此，有必要评估血流量和细胞死亡，以阐明其机制并监测联合治疗的疗效。在这个建议中，我们将研究一个单一的MRI采集和分析，将允许评估两者。动态对比增强(DCE) - MRI已成为评估肿瘤微循环环境的有力工具。本文提出了一种新的DCE-MRI分析方法，该方法将组织均匀性模型的绝热近似与水交换模型（ATH-WX）相结合。该分析提供了灌注参数（流量、血管体积分数和血管渗透率-表面积积）和细胞结构参数（间质体积分数和细胞内水生命时间）的估计。研究的第一阶段由一系列实验组成，以测量肿瘤生长过程中ATH-WX模型参数与其他MRI和病理指标的相关性。在第二阶段，我们将测试所提出的用于检测早期治疗反应的ATH-WX模型，并将其与病理指标进行比较，以确定与治疗引起的病理变化最相关的ATH-WX参数。在第三阶段，我们计划应用ATH-WX模型来测量节拍化疗（MCT）的抗血管生成作用，其中使用常规细胞毒性药物来诱导抗血管生成和细胞毒性作用。总的来说，本研究收集的临床前实验数据将用于验证我们的主要假设，即提出的新方法（DCE-MRI与ATH-WX）可以同时提供抗血管生成和细胞毒性反应的定量测量。本课题的结论将为肿瘤微环境的定量测量提供一种经过彻底测试的无创MRI方法。本应用中提出的实验将为利用这种新型DCE-MRI方法通过及时改变无效的治疗方案来改善患者管理奠定重要的基石。由于MRI是现代医学中普遍使用的无创方法，因此在临床前环境中开发的方法可以很容易地转化为有效管理肿瘤治疗策略的临床工具。

DESCRIPTION (provided by applicant): Breast cancer remains the second leading cause of cancer death in women and the primary cause of death in women ages 45 to 55, despite recent development of various therapies. Anti-angiogenic treatment approaches have been used as important means of treating cancer. However, optimization of such anti-angiogenic therapies for individual patients remains unresolved. Anti-angiogenics are thought to temporarily normalize abnormal vasculature and paradoxically increase blood flow and hence drug delivery to tumors. A substantial proportion of patients do not respond to this anti-angiogenic therapy but it is unclear whether the failure is due to failure of the anti-angiogenic to normalize the vasculature or failure of the cytotoxic to kill cells. It is therefore necessary to assess both blood flow and cell death to elucidate the mechanism and to monitor the efficacy of combined treatments. In this proposal we will investigate a single MRI acquisition and analysis that will allow assessment of both. Dynamic contrast enhanced (DCE) - MRI has emerged as a powerful tool for assessing tumor microcirculation environment. In this proposal we introduce a novel analysis method for DCE-MRI that combines the adiabatic approximation of tissue homogeneity model with a water exchange model (ATH-WX). This analysis provides estimates of both perfusion parameters (flow, vascular volume fraction, and vascular permeability-surface area product) and cell structural parameters (interstitial volume fraction, and intracellular water life time). The first stage of the study is comprised of a series of experiments to measure the association of the ATH-WX model parameters with other MRI and pathology measures during tumor growth. In the second stage, we will test out the proposed ATH-WX model for detection of early treatment response and compare its measures with pathology, in order to determine the ATH-WX parameters that best correlate with pathological changes induced by the therapy. In the third stage, we plan to apply the ATH-WX model to measure the anti-angiogenic effects of metronomic chemotherapy (MCT) in which a conventional cytotoxic drug is used to induce both anti-angiogenic and cytotoxic effects. In overall, the preclinical experimental data collected in this study will be used to test our main hypothesis that the proposed novel method (DCE-MRI with ATH-WX) can provide quantitative measures of both anti-angiogenic and cytotoxic responses simultaneously. The conclusion of this project will deliver a thoroughly tested noninvasive MRI method for quantitative measurement of tumor microenvironment. The proposed experiments in this application will lay important stepping stones toward utilizing this novel DCE-MRI method to improve patient management by allowing timely changes to ineffective treatment regimens. Since MRI is a ubiquitous and noninvasive method commonly used in modern medicine, the developed method in preclinical environment can be easily translated into a clinical tool for effective management of tumor treatment strategies.