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

用于测量神经胶质瘤反应的定量（灌注和扩散）MRI 生物标志物

• 批准号: 9000135
• 负责人: KATHLEEN Marie SCHMAINDA
• 金额: $ 42.64万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-28 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9000135
• 关键词: Address; Algorithms; Angiogenesis Inhibitors; Brain Neoplasms; Cell Density; Cessation of life; Clinic; Clinical; Clinical Oncology; Clinical Trials; Collaborations; Collection; Computer software; Contrast Media; Data; Data Storage and Retrieval; Databases; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Dose; Evaluation; Extravasation; Glioblastoma; Glioma; Goals; Grant; Growth; Health; Hybrids; Image; Image Analysis; Laboratories; Lead; Magnetic Resonance Imaging; Maps; Measurement; Measures; Methods; Modification; Monitor; Multi-Institutional Clinical Trial; Patients; Perfusion; Perfusion Weighted MRI; Predisposition; Primary Brain Neoplasms; Principal Investigator; Process; Protocols documentation; Publications; Recurrence; Research; Software Tools; Standardization; Techniques; Technology; Testing; Therapeutic Clinical Trial; Time; Translating; Translations; Tumor Cell Invasion; Tumor Volume; Validation; Visual; Weight; Work; base; bevacizumab; cancer Biomedical Informatics Grid; cerebral blood volume; chemoradiation; contrast enhanced; cost; cost effective; data exchange; design; drug discovery; imaging biomarker; imaging modality; imaging platform; improved; neoplastic cell; novel; personalized care; predicting response; response; standard measure; standard of care; targeted treatment; time interval; treatment planning; treatment response; tumor; tumor growth

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.

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) 和扩散加权 MRI (DWI) 生物标志物，以监测脑肿瘤患者治疗性临床试验和标准护理治疗计划的治疗反应。这一目标解决了对更好的方法来监测靶向治疗的迫切需要，为此，增加肿瘤体积的标准措施已不再足够。将用于临床试验的两种 PWI 方法基于 Schmainda 博士实验室多年的 PWI 研究。第一个更广泛的 DSC（动态磁敏对比）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）测量值，并针对混杂的造影剂渗漏效应进行了校正。 rCBV 方法的多年比较研究表明，该算法是目前可用的最准确的方法之一。第二种方法虽然尚未得到证实，但很有潜力成为最全面的灌注解决方案。它采用双回波梯度回波 (DEGES) 螺旋方法，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，并结合渗漏效应的综合校正。此外，为了纵向监测而新开发的是 rCBV 图像的“标准化”，其中 rCBV 值被转换为标准测量尺度，以便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 R0I，因此主观误差被最小化。这些发展显然有利于轻松纳入临床试验和标准实践。近年来，越来越清楚的是，脑肿瘤反应的全面评估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。在这种背景下，我们的实验室付出了巨大的努力来开发和验证监测肿瘤生长和侵袭的扩散方法，最近的几篇出版物证明了这一点。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，表明细胞密度增加的 ADC 变化更能预测抗血管生成药物贝伐珠单抗的反应。虽然 PWI 和 DWI 在治疗监测方面都表现出了巨大的前景，但缺乏在临床试验中使用这些技术所必需的定义其重测重复性的研究，因此代表了目标 1 的重点。此外，早期结果表明，混合 PWI/DWI 图可能会提供最完整的治疗反应评估，这一假设将在目标 2 中得到检验。最后，为了优化 PWI/DWI 以稳健且具有成本效益的方式为临床试验和标准实践提供技术和工作流程， 目标 3 涉及开发用于大规模多中心临床试验的商业集成图像分析平台。总而言之，这项工作应该会产生一个强大且随时可用的先进成像平台，用于常规和靶向脑肿瘤治疗的高级成像评估。这应该会带来更高的临床试验效率，从而实现更快速的药物发现和转化，并改善对患者的个性化护理。