Quantification of Tumor Malignancy with MRI

描述(申请人提供)：胶质瘤，最常见的原发脑肿瘤，是已知的最具侵袭性和致命性的肿瘤之一。尽管多年来对其他肿瘤的研究和治疗取得了重大进展，但胶质瘤仍然难以治愈，预后黯淡，大多数患者在确诊后两年内死亡。然而，最近引入的抗血管生成药物与传统的细胞毒性药物联合使用，导致了多年来首次显著延长预期寿命。然而，这些疗法的最佳使用和改进疗法的发展需要一种非侵入性的疗效监测手段。血管生成和浸润性是胶质瘤生物学的两个关键且相互关联的方面，它们在很大程度上决定了胶质瘤的侵袭性。恶性胶质瘤的特征是肿瘤细胞渗入正常大脑。肿瘤细胞最初沿着存在前血管渗透，并在此过程中将星形细胞从内皮细胞中夺走。血管内皮细胞的凋亡导致血管内陷、缺氧、肿瘤坏死，最终导致血管生成。因此，肿瘤血管是肿瘤生长的积极参与者，血管增殖程度是决定星形细胞瘤组织学分级的重要参数。此外，肿瘤的侵袭性和血管生成是紧密耦合的过程，强烈的血管生成与肿瘤细胞的浸润相吻合。相反，最近的研究表明，抑制血管生成促进了渗透。因此，浸润和血管生成是肿瘤生长的关键组成部分，在对肿瘤进行分级和监测治疗效果时，必须对两者进行评估。我们建议使用磁共振灌注成像和弥散成像分别监测血管生成和浸润情况。动态磁化率加权对比增强磁共振成像(DSC MRI)将用于测量相对脑血容量(RCBV)和血管通透性表面积乘积(PS)。扩散峰张量(DKT)MRI是扩散张量成像的扩展，将用于测量轴突密度的标志物--径向峰度(KR)。我们的基本假设是，rCBV和PS的值增加表明血管生成，而KR的值降低表明胶质瘤细胞向正常外观白质(NAWM)渗透。因此，成功的治疗将伴随着rCBV和PS的降低以及KR的增加。这些技术将用于评估贝伐单抗(一种抗血管生成药物)和传统细胞毒药物的联合治疗患者。血流灌注和扩散参数的变化将与治疗结果相关。

DESCRIPTION (provided by applicant): Gliomas, the most common primary brain tumor, are one of the most aggressive and fatal neoplasms known. Despite years of research and major advances in the treatment of other tumors, gliomas remain refractory and prognosis is bleak, with most patients dying within two years of diagnosis. However, the recent introduction of antiangiogenic drugs used in combination with conventional cytotoxic drugs has resulted in the first significant increases in life expectancy in many years. However, optimum use of these treatments and the development of improved ones require a non-invasive means of monitoring efficacy. Angiogenesis and infiltration are two key and linked aspects of glioma biology that largely determine the aggressiveness of gliomas. Malignant gliomas are characterized by infiltration of tumor cells into the normal brain. Tumor cells initially infiltrate along preexistig vessels and in the process prize astrocytic cells away from the endothelial cells. Apoptosis of endothelial cells then leads to vascular involution, hypoxia, tumor necrosis and finally angiogenesis. Tumor vessels are thus an active participant in tumor growth, and the degree of vascular proliferation is an important parameter in determining the histological grade of astrocytomas. Moreover, tumor invasiveness and angiogenesis are tightly coupled processes, with intense angiogenesis coinciding with tumor cell infiltration. Conversely, recent studies suggest that suppressing angiogenesis promotes infiltration. Infiltration and angiogenesis are thus key components of tumor growth and both must be assessed when grading tumors and monitoring treatment efficacy. We propose using perfusion and diffusion MRI to monitor angiogenesis and infiltration respectively. Dynamic, susceptibility-weighted contrast-enhanced MRI (DSC MRI) will be used to measure relative cerebral blood volume (rCBV) and the vascular permeability-surface area product (PS). Diffusion kurtosis tensor (DKT) MRI, an extension of diffusion tensor imaging, will be used to measure radial kurtosis (KR), a marker of axonal density. Our underlying hypothesis is that increased values of rCBV and PS indicate angiogenesis, and that decreased values of KR indicate infiltration of glioma cells into normal appearing white matter (NAWM). Hence successful treatment will be accompanied by decreases in rCBV and PS and increases in KR. These techniques will be used to assess patients treated with combinations of bevacizumab (an antiangiogenic) and conventional cytotoxic drugs. Changes in perfusion and diffusion parameters will be correlated with treatment outcome.