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

描述（由申请人提供）：总体目标是开发和验证标准和新型灌注加权MRI（PWI）和弥散加权MRI（DWI）生物标志物，以监测脑肿瘤患者治疗临床试验和标准治疗计划的治疗反应。这一目标解决了对更好的靶向治疗监测方法的迫切需求，对于靶向治疗，增加肿瘤体积的标准措施不再足够。将用于临床试验的两种PWI方法是基于Schmainda博士实验室多年的PWI研究。第一种更广泛的DSC（动态磁化率对比）方法提供了在预加载造影剂后获得的肿瘤rCBV（相对脑血容量）测量结果，并针对混淆的造影剂泄漏效应进行了校正。rCBV方法的多年比较研究表明，该算法是目前最准确的方法之一。第二种方法，虽然证明较少，但很有可能成为最全面的灌注解决方案。它包括使用双回波梯度回波（DEGES）螺旋方法，该方法仅使用单剂量造影剂即可同时收集DSC（动态磁化率对比）和DCE（动态对比增强）灌注数据，并结合了对泄漏效应的全面校正。此外，新开发的用于纵向监测的是rCBV图像的“标准化”，其中rCBV值被转换为标准测量尺度，因此在研究中保持更大的视觉和定量一致性。由于量化不再需要用户定义的参考R 0 I，因此主观误差最小化。这些发展显然有利于易于纳入临床试验和标准实践。近年来，越来越清楚的是，全面评估脑肿瘤反应还需要评估肿瘤细胞密度、死亡和侵袭，特别是在非增强肿瘤中。在这种情况下，我们的实验室已经付出了巨大的努力，证明了最近的几个出版物，开发和验证扩散方法来监测肿瘤的生长和侵袭。通过计算随时间推移的表观扩散系数（ADC）的变化，我们在非造影剂增强区域内创建了功能性扩散图（FDM）。我们发现ADC的变化提示细胞密度增加，这比标准造影剂增强MRI更能预测抗血管生成药物贝伐单抗的反应。虽然PWI和DWI在治疗监测方面都表现出了很大的前景，但缺乏定义其重测重复性的研究，这是在临床试验中使用这些技术所必需的，因此代表了目标1的重点。此外，早期结果表明，混合PWI/DWI图可能提供最完整的治疗反应评估，这一假设将在目标2中进行检验。最后，为了使优化的PWI/DWI技术和工作流程以稳健且具有成本效益的方式用于临床试验和标准实践， 目标3涉及开发一个商业化的集成图像分析平台，用于大规模多中心临床试验。总之，这一努力应导致一个强大的和准备使用先进的成像平台的先进成像评价的传统和靶向脑肿瘤治疗。这将导致更高的临床试验效率，从而实现更快的药物发现和转化，并改善患者的个性化护理。

DESCRIPTION (provided by applicant): 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 susceptibility 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 R0Is 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 lackng, 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.