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

描述(申请人提供)：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)和弥散加权磁共振成像(DWI)生物标记物，以监测脑瘤患者的治疗临床试验和标准护理治疗计划的治疗反应。这一目标解决了对监测靶向治疗的更好方法的迫切需要，对于这种情况，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)方法提供了在预先加载造影剂后获得的肿瘤rCBV(相对脑血容量)测量，并校正了混杂造影剂渗漏的影响。对rCBV方法的多年比较研究表明，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灌流解决方案。它包括使用双回波梯度回波(DEGES)螺旋方法，仅使用一剂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，并包含对泄漏影响的全面校正。此外，为了纵向监测的目的，新开发的是rCBV图像的“标准化”，其中rCBV值被转换为标准测量标尺，从而在研究中保持更大的视觉和定量一致性。主观误差最小，因为不再需要用户定义的参考R0I进行量化。这些发展显然有利于更容易地纳入临床试验和标准实践。近年来，越来越清楚的是，全面评估脑肿瘤的疗效还需要评估肿瘤细胞的密度、死亡和侵袭情况，尤其是在无强化的肿瘤中。在这种背景下，我们的实验室已经做出了巨大的努力，最近的几篇论文证明了这一点，开发和验证扩散方法来监测肿瘤的生长和侵袭。通过计算表观扩散系数(ADC)随时间的变化，我们在非造影剂增强区域内创建了功能扩散图(FDM)。我们发现，与标准造影剂增强MRI相比，ADC的变化提示细胞密度增加更能预测对抗血管生成药物贝伐单抗的反应。虽然PWI和DWI在治疗监测方面都显示出了巨大的希望，但定义它们在临床试验中使用这些技术所必需的测试-重测重复性的研究还很少，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中得到验证。最后，为了使优化的PWI/DWI技术和工作流程以稳健和经济有效的方式可用于临床试验和标准实践， 目标3涉及用于大规模多中心临床试验的商业综合图像分析平台的开发。总而言之，这一努力应该会产生一个强大的、随时可以使用的先进成像平台，用于对常规和靶向脑肿瘤治疗进行先进的成像评估。这将导致更高的临床试验效率，从而能够更快地发现和翻译药物，并改善对患者的个性化护理。

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.