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致命的成人原发性脑肿瘤。尽管有积极的治疗干预，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，这些肿瘤难以根除。这些恶性性质的严重程度可能因胶质瘤的不同组织学亚型而异。此外，个别肿瘤的病理特征可能具有异质性。因此，从活检肿瘤标本中获得的组织病理学分析可能不能充分代表所有肿瘤成分。将功能和代谢神经成像技术整合到导航外科手术方案中可能会改善活检的靶向性。本提案的长期目标是确定PET和MR联合成像策略是否可以识别和定位与成像结果相对应的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。本研究旨在：(1)利用新颖的软件平台，结合18F- FLT PET和DCE-MRI，确定在新诊断的高级别胶质瘤中逐体素量化增殖活性和微血管通透性的可行性；(2)利用图像引导的神经导航手术和术中增强MRI详细分析这些参数与局部组织学标志物之间的关系；(3)评估通过药代动力学建模方法获得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；(4)评估在参数图上增殖活性增加和减少的区域或微血管通透性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分子亚类和途径的背景下解释。目前，还没有准确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学表现之间的关系。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志物，将增殖估计与预后和临床结果联系起来。公共卫生相关性：恶性胶质瘤在外观和基因表达上都是异质肿瘤，并且都是致命的。结合代谢和功能成像策略，识别与不同分子表型相关的特征性影像学发现，可能提供预后信息，促进治疗计划，并提高我们对单个肿瘤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.