Faculty Bibliography

Advanced MRI techniques, such as MR spectroscopy, diffusion and perfusion MR imaging can give important in vivo physiological and metabolic information, complementing morphologic findings from conventional MRI in the clinical setting. Combining perfusion MRI and MR spectroscopy can help in patients with brain masses in who the pre-operative differential diagnosis is unclear. This review demonstrates the use of dynamic, susceptibility weighted, contrast-enhanced MR imaging (DSC MRI) and magnetic resonance spectroscopic imaging (MRSI) to distinguish surgical from non-surgical lesions in the brain. There is overlap in the MRI appearance of many enhancing and ring-enhancing lesions such as gliomas, metastases, inflammatory lesions, demyelinating lesions, subacute ischemia, abscess and some AIDS related lesions. We review examples of histopathologically confirmed high-grade glioma, a middle cerebral artery territory infarct, a tumefactive demyelinating lesion and a metastasis for which conventional MR imaging (MRI) was non-specific and potentially misleading and demonstrate how DSC MRI and MRSI features were used to increase the specificity of neurodiagnosis. At several institutions, many patients routinely undergo MRI as well as MRSI and DSC MRI. Cerebral blood flow (CBF), mean transit time (MTT), and relative cerebral blood volume (rCBV) measurements are obtained from regions of maximal perfusion as determined from perfusion color overlay maps. Metabolite levels and ratios are determined for Choline (Cho), N-Acetyl Aspartate (NAA), Lactate and Lipids (LL). Metabolite levels are obtained by measuring the peak heights of each metabolite and the ratios are obtained from these measurements for Cho/Cr, Cho/NAA and NAA/Cr. Neurosurgical intervention carries substantial morbidity, mortality, financial and potential emotional cost to the patient and family. Making a pre-operative diagnosis allows the neurosurgeon to be confident in the choice of treatment plan for the patient and allays considerable patient anxiety. The utility of combining clinical findings with multi-parametric information from perfusion and spectroscopic MR imaging in differentiating surgical lesions from those which do not require surgical intervention is discussed

BACKGROUND AND PURPOSE: The measurement of relative cerebral blood volume (rCBV) and the volume transfer constant (K(trans)) by means of dynamic contrast-enhanced (DCE) perfusion MR imaging (pMRI) can be useful in characterizing brain tumors. The purpose of our study was to evaluate the utility of these measurements in differentiating typical meningiomas and atypical meningiomas. METHODS: Fifteen patients with pathologically confirmed typical meningiomas and seven with atypical meningiomas underwent conventional imaging and DCE pMRI before resection. rCBV measurements were calculated by using standard intravascular indicator dilution algorithms. K(trans) was calculated from the same DCE pMRI data by using a new pharmacokinetic modeling (PM) algorithm. Results were compared with pathologic findings. RESULTS: Mean rCBV was 8.02 +/- 4.74 in the 15 typical meningiomas and 10.50 +/- 2.1 in the seven atypical meningiomas. K(trans) was 0.0016 seconds(-1) +/- 0.0012 in the typical group and 0.0066 seconds(-1) +/- 0.0026 in the atypical group. The difference in K(trans) was statistically significant (P <.01, Student t test). Other parameters generated with the PM algorithm (plasma volume, volume of the extravascular extracellular space, and flux rate constant) were not significantly different between the two tumor types. CONCLUSION: DCE pMRI may have a role in the prospective characterization of meningiomas. Specifically, the measurement of K(trans) is of use in distinguishing atypical meningiomas from typical meningiomas

Glioblastoma (GBM) remains one of the most challenging solid cancers to treat due to its highly proliferative, angiogenic and invasive nature. The small molecule CDK inhibitor, flavopiridol, has demonstrated antitumor activity in human xenograft models and is currently in clinical trials showing efficacy in patients with advanced disease. We have developed an experimental animal model using the murine glioma GL261 cells as a novel in vivo system to screen potential therapeutic agents for GBM. Results of in vitro testing demonstrate that flavopiridol has several relevant clinical characteristics such as its ability to: 1. inhibit cell growth; 2. inhibit cell migration; 3. decrease expression of cyclin D1, CDK4 and p21; 4. induce apoptosis in cells with high levels of p27 expression; and 5. decrease the expression of the anti-apoptotic protein Bcl-2. The mechanism by which flavopiridol induces apoptosis is mitochondrial-mediated. We demonstrate by electron microscopy and immunohistochemistry that drug treatment induces mitochondrial damage that was accompanied by the release of cytochrome c into the cytosol together with the translocation of apoptosis inducing factor (AIF) into the nucleus. This finding in murine glioma cells differs from the mechanism of flavopiridolinduced cell death reported by us for human glioma cells (Alonso et al., Mol Cancer Ther 2003; 2:139) where drug treatment induced a caspase- and cytochrome c-independent pathway in the absence of detectable damage to mitochondria. In apoptotic human glioma cells only translocation of AIF into the nucleus occurred. Thus, the same drug kills different types of glioma cells by different mitochondrial-dependent pathways

The aim of this study was to develop an MRI protocol to evaluate the growth and vascularity of implanted GL261 mouse gliomas on a 7T microimaging system. Both conventional T(1)- and T(2)-weighted imaging and dynamic, contrast-enhanced T(2)*-weighted imaging were performed on 34 mice at different stages of tumor development. MRI measurements of relative cerebral blood volume (rCBV) were compared to histological assessments of microvascular density (MVD). Enhancement on postcontrast T(1)-weighted images was compared to histological assessments of Evan's blue extravasation. Conventional T(2)-weighted and postcontrast T(1)-weighted images demonstrated tumor growth characteristics consistent with previous descriptions of GL261 glioma. Furthermore, measurements of rCBV from MRI data were in good agreement with histological measurements of MVD from the same tumors. Postcontrast enhancement on T(1)-weighted images was observed at all stages of GL261 glioma progression, even before evidence of angiogenesis, indicating that the mechanism of conventional contrast enhancement in MRI does not require neovascularization. These results provide quantitative support for MRI approaches currently used to assess human brain tumors, and form the basis for future studies of angiogenesis in genetically engineered mouse brain tumor models. Magn Reson Med 49:848-855, 2003

Numerous studies examining the prognostic significance of p27KIP1 expression in human cancer have shown that decreased expression often is an independent prognostic factor associated with worse survival. However, the prognostic value of p27KIP1 expression in gliomas is less well established. To further address this issue, we evaluated the relationship between p27KIP1 protein expression in a series of 50 astrocytomas with clinicopathologic parameters including age, tumor grade, MIB-1 proliferation index, and patient survival using both Western blot analysis and immunohistochemistry. The level of p27KIP1 protein expression in 9 nonneoplastic brain tissue specimens served as a control. Sixteen high-grade astrocytomas were analyzed by Western blot, and 26 high-grade astrocytomas were analyzed by immunohistochemistry for levels of p27KIP1 protein expression. Regardless of the technique used to measure p27KIP1, approximately 50% of the high-grade tumors were low expressors and the other 50% were high expressors. Thus, expression of p27KIP1 was independent of tumor grade. Loss of p27KIP1 expression is often associated with an increase in proliferative activity. We measured the rate of tumor cell proliferation using MIB-1 immunostaining in 16 high-grade astrocytomas to determine whether there was an inverse correlation between p27KIP1 expression and proliferation. No correlation between p27KIP1 expression and MIB-1 labeling index or patient survival was found. Using immunohistochemistry, we noted that the staining pattern of p27KIP1 in glioblastomas was mainly in the pseudopalisading cells that outline areas of necrosis. Because p27KIP1 can be up-regulated by hypoxia, this staining pattern would be consistent with our observation that hypoxia-inducible factor 1alpha is expressed primarily in pseudopalisading tumor cells around necrotic zones. It has been shown that a high level of p27KIP1 prevents apoptosis in hypoxic cells. Thus, maintenance of high levels of p27KIP1 in gliomas could result from the hypoxic microenvironment present within the tumor. No correlation was found between p27KIP1 expression and any of the clinicopathologic parameters tested, including patient age and tumor grade, the 2 strongest predictors of survival among glioma patients