Despite advances in surgery, radiation and chemotherapy, the treatment of malignant brain tumors remains one of the most perplexing clinical areas with the fewest advances in treatment in the field of oncology. It is of central importance to determine treatment response or failure, for both patients and physicians. Currently, the effectiveness of therapy is monitored by MRI or CT scanning of the tumor, along with neurological assessment of the patient. These indicators are imperfect since changes in tumor volume can take months to appear on conventional imaging, and changes in neurological function are often unrelated to change in tumor growth and volume. Nevertheless, such measures of therapeutic response are currently relied upon to determine when a different treatment option should be pursued. The availability of earlier and more accurate predictive indicators of treatment response would have obvious benefit to individual patients, as well as to advancing the treatment of brain tumors generally by facilitating clinical trials of new agents. This application seeks to advance the use of quantitative MRI for the clinical evaluation of brain tumor patients by adding information related to cellular membrane integrity and vascular volume to the anatomical detail provided by conventional MRI. The proposal is based on promising recent MR data from rodent brain tumor models and preliminary studies of human brain tumors. These have shown that microscopic cellular changes occur in the tissue structure of brain tumors following successful treatment; moreover these occur before changes in tumor volume are manifest. Changes in tumor cellular structure were detected as an increase in the apparent mobility (diffusion) of water within the tumor tissue using a specialized diffusion-sensitive MRI acquisition and processing techniques. The observation of an increase in water diffusion is indicative of therapy-induced tumor necrosis that is manifest as cellular membrane breakdown and cell shrinkage. These events facilitate movement of water within an enlarged extracellular space. It is hypothesized the effectiveness of a treatment can be assessed before there is a reduction in tumor volume, because the rate of cellular breakdown and necrosis is relatively rapid compared with the process of resorption and removal of cellular debris. In addition, specialized MRI techniques allow the mapping tumor blood volume (TBV) and perfusion. We further hypothesize that treatment of brain tumors damages tumor vasculature, thereby decreasing vessel density and total blood volume within tumors responsive to therapy. We propose to initiate a clinical study to further test these hypotheses on brain tumor patients. Clinical and MRI data will be collected on 164 subjects accrued from two institutions, University of Michigan and University of Pittsburgh. Conventional MRI and quantitative images of diffusion, TBV and perfusion will be obtained in these patients prior to and following initiation of treatment with chemotherapy and/or irradiation. Changes in diffusion and blood flow parameters will be quantitated and correlated with later measurement of clinical outcomes via tumor volume change and patient survival in order to determine the predictive value of the quantitative MRI indicators.
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