Quantitative (Perfusion and Diffusion) MRI Biomarkers to Measure Glioma Response

摘要：总体目标是开发和验证标准和新型的灌注加权磁共振成像。 (PWI)和弥散加权磁共振(DWI)生物标记物监测治疗反应的临床治疗 脑肿瘤患者的试验和标准护理治疗计划。这一目标解决了一个紧迫的需求 关于监测靶向治疗的更好方法，对于增加肿瘤体积的标准措施是 更长时间就足够了。将用于临床试验的两种PWI方法是基于多年的 在施马因达博士的实验室里进行的PWI研究。第一个更广泛的DSC(动态吸入性 对比剂)方法提供了肿瘤rCBV(相对脑血容量)测量后获得的前 对比剂的负荷和混杂的对比剂泄漏效果进行校正。多年对比 对rCBV方法的研究表明，该算法是目前可用的最准确的方法之一。 第二种方法虽然较少得到证实，但很有可能成为最全面的方法 灌注液。它包括使用双回波梯度回波(DEGES)螺旋方法，该方法 支持同时收集DSC(动态磁化率对比)和DCE(动态 增强对比剂)仅使用单剂量造影剂的灌注数据 对渗漏影响进行综合纠正。此外，新开发的目的是纵向 监测是rCBV图像的“标准化”，rCBV值被转换为标准 测量规模，因此在研究过程中保持了更大的视觉和数量一致性。主观性 由于不再需要用户定义的参考ROI进行量化，因此将误差降至最低。这些 发展显然有利于将其纳入临床试验和标准实践。 近年来，越来越清楚的是，全面评估脑肿瘤的反应也 需要评估肿瘤细胞密度、死亡和侵袭性，特别是在无强化的肿瘤中。在这 在此背景下，我们的实验室做出了巨大的努力，最近的几份出版物证明了这一点，以开发和 验证扩散方法以监测肿瘤的生长和侵袭。通过计算表观上的变化 扩散系数(ADC)，我们已经创建了非对比度内的泛函扩散图(FDM) 助剂增强区。我们发现，提示细胞密度增加的ADC变化更多 比标准造影剂增强MRI更能预测抗血管生成药物贝伐单抗的反应。 虽然PWI和DWI都显示出在治疗监测方面的巨大希望，但定义其 在临床试验中使用这些技术所必需的测试-再测试的可重复性是缺乏的，因此 代表目标1的重点。此外，早期结果表明，混合PWI/DWI映射可能会提供 对治疗反应的最完整的评估，这一假设将在目标2中进行检验。最后，为了 以强大且经济高效的方式提供优化的PWI/DWI技术和工作流程 临床试验和标准实践，目标3涉及商业综合图像分析的开发 大型多中心临床试验平台。 总而言之，这一努力应该会产生一个强大的、随时可以使用的高级成像平台 对常规和靶向脑肿瘤治疗的高级成像评估。这应该会导致 更高的临床试验效率，实现更快的药物发现和翻译，并改进个性化 照顾病人。

ABSTRACT: The overall goal is to develop and validate both standard and novel perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI) biomarkers to monitor treatment response for both therapeutic clinical trials and standard of care treatment plans for patients with brain tumors. This goal addresses an urgent need for better ways to monitor targeted therapies, for which standard measures of enhancing tumor volumes are no longer sufficient. The two PWI methods that will be characterized for clinical trials are based on many years of PWI research in Dr Schmainda's laboratory. The first more wide-spread DSC (dynamic suceptibility contrast) approach provides tumor rCBV (relative cerebral blood volume) measurements obtained after a pre- load of contrast agent and corrected for confounding contrast agent leakage effects. A multi-year comparison study of rCBV methods suggests that this algorithm is one of the most accurate approaches currently available. The second approach, while less-proven has high-potential to become the most comprehensive perfusion solution. It consists of using a dual-echo gradient-echo (DEGES) spiral method, which enables the simultaneous collection of both DSC (dynamic susceptibility contrast) and DCE (dynamic contrast enhanced) perfusion data using only a single dose of contrast agent and incorporates comprehensive correction for leakage effects. Also, newly developed for purposes of longitudinal monitoring is the "standardization" of rCBV images where rCBV values are transformed to a standard measurement scale so greater visual and quantitative consistency is maintained across studies. Subjective errors are minimized since user-defined reference ROIs are no longer needed for quantification. These developments are clearly beneficial for ease of incorporation into clinical trials and standard practice. In recent years it has become increasingly clear that the full evaluation of brain tumor response also requires the assessment of tumor cell density, death and invasion, especially in non-enhancing tumors. In this context, our laboratory has put forth great effort, evidenced by several recent publications, to develop and validate diffusion methods to monitor tumor growth and invasion. By computing changes in the apparent diffusion coefficient (ADC) across time, we have created functional diffusion maps (fDM) within non-contrast- agent-enhancing regions. We have found that changes in ADC suggestive of increased cell density were more predictive of response to the anti-angiogenic drug, bevacizumab, than standard contrast-agent enhanced MRI. While both PWI and DWI have demonstrated great promise for treatment monitoring, studies defining their test-retest repeatability, necessary for use of these techniques in clinical trials, are lacking, and thus represent the focus of Aim 1. In addition, early results suggest that hybrid PWI/DWI maps will likely provide the most complete assessment of treatment response, a hypothesis that will be tested in Aim 2. Finally, in order to make the optimized PWI/DWI technology and workflow available in a robust and cost-effective manner for clinical trials and standard practice, Aim 3 involves the development of a commercial integrated image analysis platform for use in large-scale multi-center clinical trials. Taken together this effort should result in a robust and ready to use advanced imaging platform for the advanced imaging evaluation of both conventional and targeted brain tumor therapies. This should lead to greater clinical trial efficiency enabling more rapid drug discovery and translation and improved individualized care for patients.