MRI-PET Guided Stereotactic Biopsy of High Grade Gliomas

描述(申请人提供)：恶性胶质瘤是最常见和最致命的成人原发脑肿瘤。尽管采取了积极的治疗措施，但由于其弥漫性浸润性生长模式和对化疗辅助治疗的频繁抵抗，这些肿瘤很难根除。这些恶性特征的严重程度在不同的胶质瘤组织亚型之间可能有所不同。此外，病理特征可能在单个肿瘤内分布不均。因此，从活检的肿瘤标本中得出的组织病理学分析可能不能充分反映所有的肿瘤成分。将功能和代谢神经成像技术整合到导航手术方案中可能会提高活检靶向治疗的效果。这项建议的长期目标是确定联合PET和MR成像策略是否能够在与成像结果相对应的部位识别和定位高级别胶质瘤的关键组织学和分子特征，改善预后评估，并作为治疗干预的生物标志物。该建议旨在：(1)使用新的软件平台，结合18F-Flt PET和DCE-MRI，确定在逐个体素的基础上对新诊断的高级别胶质瘤的增殖活性和微血管通透性进行量化的可行性；(2)通过图像引导的神经导航手术和术中增强MRI，确定这些参数与局部组织学标志物之间的详细关系；(3)评估通过药代动力学建模方法得出的参数图像是否与相应位置肿瘤细胞增殖的区域组织学分析在空间上相关；以及(4)评估参数图上增殖活性增强和微血管通透性降低的区域之间的基因表达差异是否定义了一致的差异转录组特征，以及这些差异是否可以在已知的GBM和通路的分子亚类的背景下解释。目前，还没有准确或可靠的方法来研究胶质瘤的组织学和分子特性与分子影像表现之间的关系。这项研究的成功将为更大规模的前瞻性研究奠定基础，评估18F-Flt增殖反应作为靶向治疗试验中的生物标记物，将增殖估计与预后和临床结果联系起来。公共卫生相关性：恶性胶质瘤是一种在外观和基因表达上都是异质性的肿瘤，并且都是致命的。结合代谢和功能成像策略识别特征性的成像结果，可以与不同的分子表型相关联，可以提供预后信息，促进治疗计划，并提高我们对单个肿瘤的分子和病理异质性的理解。

DESCRIPTION (provided by applicant): Malignant gliomas are the most common and lethal adult primary brain tumors. Despite aggressive therapeutic interventions, these tumors are difficult to eradicate due to their diffusely infiltrative growth pattern and frequent resistance to chemotherapeutic adjuvant therapy. The severity of these malignant properties may differ among various histologic subtypes of gliomas. In addition, pathologic features may be heterogeneously distributed within individual tumors. Therefore, histopathologic analyses derived from biopsied tumor specimens may not adequately represent all tumor components. The integration of functional and metabolic neuroimaging techniques into navigated surgical protocols may improve biopsy targeting efforts. The long-term objectives of this proposal are to determine whether combined PET and MR imaging strategies can identify and localize key histologic and molecular features of high-grade gliomas at sites corresponding to the imaging findings, improve prognostic assessments, and serve as biomarkers for treatment intervention. This proposal aims to: (1) determine the feasibility of quantifying proliferative activity and microvascular permeability within newly-diagnosed, high grade gliomas on a voxel-by-voxel basis using a novel software platform and combined 18F- FLT PET and DCE-MRI; (2) detail relationships between these parameters and histologic markers at a local level using image-guided neuronavigated surgery and contrast-enhanced intraoperative MRI; (3) assess whether parametric images, derived by pharmacokinetic modeling methods, spatially correlate with regional histologic assays of tumor cell proliferation at corresponding locations; and (4) evaluate whether differences in gene expression, seen between areas of increased and decreased proliferative activity or microvascular permeability on parametric maps, define consistent differential transcriptome signatures, and whether these are interpretable in the context of known molecular subclasses of GBM and pathways. Currently, there is no accurate or reliable method for investigating associations between the histologic and molecular properties of gliomas and molecular imaging findings. The success of this study will establish the groundwork for larger prospective studies assessing 18F-FLT proliferative response as a biomarker in trials of targeted therapy, relating estimates of proliferation with prognosis and clinical outcome. PUBLIC HEALTH RELEVANCE: Malignant gliomas are heterogeneous tumors in both appearance and gene expression, and are uniformly fatal. The identification of characteristic imaging findings using a combination of metabolic and functional imaging strategies, which can be linked to distinct molecular phenotypes, may offer prognostic information, facilitate treatment planning, and improve our understanding of the molecular and pathological heterogeneity within individual tumors.