Among the causes of death due to cancer, brain tumors are ranked second in the pediatric age group and fourth in middle-aged man. Despite the use of multimodality therapy, malignant gliomas are uniformly fatal; only 50 percent of patients survive one year from the time of diagnosis. These stark statistics underscore the urgent need for an early therapeutic assessment of therapeutic efficacy in these patients. A sensitive and early predictor of therapeutic outcome for patients would provide for improved care and the opportunity to individualize and adjust the treatment to each patient. The central hypothesis of this project is that the effectiveness of therapeutic interventions can be determined prior to tumor shrinkage using quantitative MR imaging and spectroscopic methods. In this proposal, the treatment of rat 9L brain tumors using chemotherapy, radiation, chemotherapy + radiation, and gene therapy will be accomplished and the effects on 1H MRS metabolites along with tumor perfusion and diffusion values explored during the course of therapy. In addition, a second proposed hypothesis is that the extent of tumor vascularization can be monitored by MRI/S methods and that the extent of tumor vascularization will affect therapeutic outcome. The effectiveness of MRI/S for assessing the treatment of brain tumors will be evaluated in three specific aims. MRI and 1H MRS data of tumors obtained during treatment will be compared with histopathology, autoradiography measurements of tumor perfusion and capillary permeability, animal survival, changes in tumor volumes, tumor growth rates, and cell kill to determine which specific or combined MR-observable parameter(s) can be utilized as surrogate markers for predicting therapeutic outcome. The effects of variations in the degree of tumor vascularization on the effects of tumor perfusion, diffusion and proton steady-state metabolite levels will also be investigated and how these differences effect brain tumor therapy. Overall, these studies will provide the foundation for evaluating the effectiveness of MRI/S for the early assessment of brain tumor therapeutic efficacy. These results are anticipated to provide the foundation for using these MR methods in animal studies and serve as the basis for translating and evaluating these approaches in the clinic.
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