Faculty Bibliography

We describe a lesion with the magnetic resonance imaging (MRI) characteristics of a glioblastoma mutiforme and demonstrate how perfusion MRI and proton MR spectroscopic imaging can be used to differentiate necrotizing cerebritis from what appeared to be a high-grade glioma. A 43-year-old woman presented to her physician complaining of progressive visual disturbance and headache for several weeks. Conventional MRI demonstrated a parietal peripherally enhancing mass with central necrosis and moderate to severe surrounding T2 hyperintensity, suggesting an infiltrating high-grade glioma. However, advanced imaging, including dynamic susceptibility contrast MRI (DSC MRI) and magnetic resonance spectroscopic imaging (MRSI), suggested a nonneoplastic lesion. The DSC MRI data demonstrated no hyperperfusion within the lesion and surrounding T2 signal abnormality, and the MRSI data showed overall decrease in metabolites in this region, except for lactate. Because of the aggressive appearance to the lesion and the patients' worsening symptoms, a biopsy was performed. The pathologic diagnosis was necrotizing cerebritis. After the commencement of steroid therapy, imaging findings and patient symptoms improved. This report will review the utility of advanced imaging for differentiating inflammatory from neoplastic appearing lesions on conventional imaging

Hypoxia and hypoxia-inducible factor-1 (HIF-1) play a critical role in glioblastoma multiforme (GBMs). CXCR4 is involved in angiogenesis and is upregulated by HIF-1alpha. CXCR4 is a chemokine receptor for stromal cell-derived factor-1 (SDF-1)alpha, also known as CXCL12. We hypothesized that CXCR4 would be upregulated by hypoxia in GBMs. First, we investigated the expression of HIF-1alpha and CXCR4 in GBMs. CXCR4 was consistently found colocalized with HIF-1alpha expression in pseudopalisading glioma cells around areas of necrosis. In addition, angiogenic tumor vessels were strongly positive for CXCR4. Next, we tested the in vitro effect of hypoxia and vascular endothelial growth factor (VEGF) on the expression of CXCR4 in glioma cell lines and in human brain microvascular endothelial cells (HBMECs). Exposure to hypoxia induced significant expression of CXCR4 and HIF-1alpha in glioma cells, whereas treatment with exogenous VEGF increased CXCR4 expression in HBMECs. We also transfected U87MG glioma cells with an HIF-1alpha construct and observed that CXCR4 was upregulated in these cells even in normoxic conditions. We then used a lentivirus-mediated shRNA expression vector directed against HIF-1alpha. When exposed to hypoxia, infected cells failed to show HIF-1alpha and CXCR4 upregulation. We performed migration assays under normoxic and hypoxic conditions in the presence or absence of AMD3100, a CXCR4 inhibitor. There was a significant increase in the migration of U87MG and LN308 glioma cells in hypoxic conditions, which was inhibited in the presence of AMD3100. These studies demonstrate the critical role played by hypoxia and CXCR4 in glioma cell migration. Based on these studies, we suggest that hypoxia regulates CXCR4 in GBMs at two levels. First, through HIF-1alpha in the pseudopalisading tumor cells themselves and, secondly, by the VEGF-stimulated angiogenic response in HBMECs. We believe this knowledge may lead to a potentially important two-pronged therapy against GBM progression using chemotherapy targeting CXCR4

BACKGROUND AND PURPOSE: Numerous different parameters measured by perfusion MR imaging can be used for characterizing gliomas. Parameters derived from 3 different analyses were correlated with histopathologically confirmed grade in gliomas to determine which parameters best predict tumor grade. METHODS: Seventy-four patients with gliomas underwent dynamic susceptibility contrast-enhanced MR imaging (DSC MR imaging). Data were analyzed by 3 different algorithms. Analysis 1 estimated relative cerebral blood volume (rCBV) by using a single compartment model. Analysis 2 estimated fractional plasma volume (V(p)) and vascular transfer constant (K(trans)) by using a 2-compartment pharmacokinetic model. Analysis 3 estimated absolute cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) by using a single compartment model and an automated arterial input function. The Mann-Whitney U test was used make pairwise comparisons. Binary logistic regression was used to assess whether rCBV, V(p), K(trans), CBV, CBF, and MTT can discriminate high- from low-grade tumors. RESULTS: rCBV was the best discriminator of tumor grade ype, followed by CBF, CBV, and K(trans). Spearman rank correlation factors were the following: rCBV = 0.812 (P < .0001), CBF = 0.677 (P < .0001), CBV = 0.604 (P < .0001), K(trans) = 0.457 (P < .0001), V(p) = 0.301 (P =.009), and MTT = 0.089 (P = .448). rCBV was the best single predictor, and K(trans) with rCBV was the best set of predictors of high-grade glioma. CONCLUSION: rCBV, CBF, CBV K(trans), and V(p) measurements correlated well with histopathologic grade. rCBV was the best predictor of glioma grade, and the combination of rCBV with K(trans) was the best set of metrics to predict glioma grade

PURPOSE: High-grade glioma treatment includes ionizing radiation therapy. The high invasiveness of glioma cells precludes their eradication and is responsible for the dismal prognosis. Recently, we reported the down-regulation of MHC class I (MHC-I) products in invading tumor cells in human and mouse GL261 gliomas. Here, we tested the hypothesis that whole-brain radiotherapy (WBRT) up-regulates MHC-I expression on GL261 tumors and enhances the effectiveness of immunotherapy. EXPERIMENTAL DESIGN: MHC-I molecule expression on GL261 cells was analyzed in vitro and in vivo by flow cytometry and immunohistochemistry, respectively. To test the response of established GL261 gliomas to treatment, mice with measurable (at CT imaging) brain tumors were randomly assigned to four groups receiving (a) no treatment, (b) WBRT in two fractions of 4 Gy, (c) vaccination with irradiated GL261 cells secreting granulocyte-macrophage colony-stimulating factor, or (d) WBRT and vaccination. Endpoints were tumor response and survival. RESULTS: An ionizing radiation dose of 4 Gy maximally up-regulated MHC-I molecules on GL261 cells in vitro. In vivo, WBRT induced the expression of the beta2-microglobulin light chain subunit of the MHC class I complex on glioma cells invading normal brain and increased CD4+ and CD8+ T cell infiltration. However, the survival advantage obtained with WBRT or vaccination alone was minimal. In contrast, WBRT in combination with vaccination increased long-term survival to 40% to 80%, compared with 0% to 10% in the other groups (P < 0.002). Surviving animals showed antitumor immunity by rejecting challenge tumors. CONCLUSION: Ionizing radiation can be successfully combined with peripheral vaccination for the treatment of established high-grade gliomas