Cancer ranks second as the cause of death from disease in the United States. Brain tumors rank second as the cause of cancer-related deaths in children and adults younger than 34 years old, and they affect adults of all ages. Primary malignant brain tumors are associated with the third highest cancer-related mortality rate and a disproportionate level of disability and morbidity. Accurate diagnosis and grading of brain tumors is critical to determining prognosis and therapy. The health related focus of this proposal is to reduce morbidity and mortality rates for patients with brain tumors through the development of a comprehensive magnetic resonance (MR) imaging (MRI)-based grading system that assesses tumor behavior and prognosis. We propose that comprehensive, quantitative, structural and non-anatomic MRI and proton MR spectroscopy (1H MRS) can provide surrogate markers of tumor malignancy permitting accurate preoperative grading of brain tumors, and potentially can offer independent prognostic information above and beyond the histopathologic phenotype. Our central hypothesis is that the malignant biologic behavior of primary brain tumors and the early stages of an aggressive growth phase are related to tumor angiogenesis, which can be measured quantitatively and non-invasively by using perfusion MRI (pMRI) methods. The overarching goal of this proposal is to apply a comprehensive, quantitative MRI method that will augment current methods of diagnosis and tumor grading, provide earlier evidence of treatment failure, identify surrogate markers of survival outcome, and aid in the development of novel therapies. The applicant's immediate goal is to acquire the knowledge and skills required to become an independent clinician-investigator focused on patient-oriented research through phased and well-designed, multidisciplinary, didactic training in the basic biology of brain tumors, in biostatistics and clinical study design, and in methods of optimizing pMRI and multidimensional 1H MRS.
Specific Aim 1 is to develop an imaging-based system for grading gliomas by using comprehensive MRI methods and to identify those MR variables that best predict tumor malignancy.
Specific Aim 2 is to validate MRI measurements of tumor angiogenesis and vascular permeability with histologic markers by directly correlating imaging and histologic results from biopsy samples obtained from the same anatomic location.
Specific Aim 3 is to predict treatment response and progression-free survival by using changes in perfusion and metabolic MRI variables before and after therapy in patients with newly diagnosed malignant glioma undergoing external-beam radiation therapy while participating in a clinical trial of adjuvant chemotherapy.
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