Gliomas, the most common primary brain tumor, are one of the most aggressive and fatal neoplasms known. Despite years of research and major advances in the treatment of other tumors, gliomas remain refractory and prognosis is bleak, with most patients dying within two years of diagnosis. However, the recent introduction of antiangiogenic drugs used in combination with conventional cytotoxic drugs has resulted in the first significant increases in life expectancy in many years. However, optimum use of these treatments and the development of improved ones require a non-invasive means of monitoring efficacy. Angiogenesis and infiltration are two key and linked aspects of glioma biology that largely determine the aggressiveness of gliomas. Malignant gliomas are characterized by infiltration of tumor cells into the normal brain. Tumor cells initially infiltrate along preexistig vessels and in the process prize astrocytic cells away from the endothelial cells. Apoptosis of endothelial cells then leads to vascular involution, hypoxia, tumor necrosis and finally angiogenesis. Tumor vessels are thus an active participant in tumor growth, and the degree of vascular proliferation is an important parameter in determining the histological grade of astrocytomas. Moreover, tumor invasiveness and angiogenesis are tightly coupled processes, with intense angiogenesis coinciding with tumor cell infiltration. Conversely, recent studies suggest that suppressing angiogenesis promotes infiltration. Infiltration and angiogenesis are thus key components of tumor growth and both must be assessed when grading tumors and monitoring treatment efficacy. We propose using perfusion and diffusion MRI to monitor angiogenesis and infiltration respectively. Dynamic, susceptibility-weighted contrast-enhanced MRI (DSC MRI) will be used to measure relative cerebral blood volume (rCBV) and the vascular permeability-surface area product (PS). Diffusion kurtosis tensor (DKT) MRI, an extension of diffusion tensor imaging, will be used to measure radial kurtosis (KR), a marker of axonal density. Our underlying hypothesis is that increased values of rCBV and PS indicate angiogenesis, and that decreased values of KR indicate infiltration of glioma cells into normal appearing white matter (NAWM). Hence successful treatment will be accompanied by decreases in rCBV and PS and increases in KR. These techniques will be used to assess patients treated with combinations of bevacizumab (an antiangiogenic) and conventional cytotoxic drugs. Changes in perfusion and diffusion parameters will be correlated with treatment outcome.
Gliomas are the most common primary brain tumor and are one of the most aggressive and lethal cancers known. The goal of this proposal is to develop new methods of monitoring glioma aggressiveness and proliferative potential that will promote both the optimum use of current treatments and the development of new ones.
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