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.
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.
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