Faculty Bibliography

Giant cell tumors (GCTs) and aneurysmal bone cysts (ABCs) are locally aggressive but benign lesions typically of the long bones of the extremities or spine and rarely involve the cranial vault or skull base. Although they are distinct entities pathologically and cytogenetically, GCTs can occur with secondary ABCs, which are likely reactive in nature. The reported cases have primarily involved bones of the extremities and, to our knowledge, there has been only one case of coexisting GCT and ABC of the calvarium or skull base. We describe a 27-year old woman who underwent complete resection of a GCT with secondary ABC of the left occipital bone and condyle. We discuss the significance of the co-occurrence of these lesions and their optimal management

BACKGROUND/PURPOSE: The prognostic value of defining subcategories of gliomas is still controversial. This study aims to determine the utility of relative cerebral blood volume (rCBV) in predicting clinical response in patients with low-grade glioma at multiple institutions. MATERIALS AND METHODS: Sixty-nine patients were studied with dynamic susceptibility contrast-enhanced perfusion MRI at two institutions. The pathologic diagnoses of the low-grade gliomas were 34 astrocytomas, 20 oligodendroglioma, 9 oligoastrocytomas, 1 ganglioglioma and 5 with indeterminate histology. Wilcoxon tests were used to compare patients in different response categories with respect to baseline rCBV. Kaplan-Meier curve and log-rank tests were used to predict the association of rCBV with time to progression. RESULTS: At both institutions, patients with an adverse event (progressive disease or death) had a significantly higher baseline rCBV than those without (complete response or stable disease) (p value=0.0138). The odds ratio for detecting an adverse event when using rCBV was 1.87 (95% confidence interval: 1.14-3.08). rCBV was significantly negatively associated with time to progression (p=0.005). The median time to progression among subjects with rCBV>1.75 was 365 days, while there was 95% confidence that the median time to progression was at least 889 days among subjects with rCBV<1.75. CONCLUSION: Our study suggests not only that rCBV measurements correlate well with time to progression or death, but also that the findings can be replicated across institutions, which supports the application of rCBV as an adjunct to pathology in predicting glioma biology

Abstract Previously, we reported that peripheral vaccination of mice with modified autologous tumor cells secreting granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with ionizing radiation to the whole brain cured 50% of mice using a syngeneic, intracranial model of murine high-grade glioma. Here, we tested the combination of radiotherapy (4 Gy x 2) with an immunotherapeutic approach using an anti-CD137 antibody directed to the co-stimulatory molecule CD137. The CD137 antibody has shown promise in generating effective antitumor responses in several animal models and has demonstrated a favorable toxicity profile in the clinic. The combination of radiation and anti-CD137 therapy resulted in complete tumor eradication and prolonged survival in six of nine (67%) mice with established brain tumors (P = 0.0009). Five of six (83%) long-term survivors in the combination group demonstrated antitumor immunity by rejecting challenge tumors. Antitumor immunity was associated with an increased number of tumor-infiltrating lymphocytes (TILs) in brain tumors and increased tumor-specific production of gammaIFN. In view of the finding that radiation enhanced the antitumor effect of anti-CD137 therapy, this approach should be studied further for clinical translation

BACKGROUND: Glioblastoma (GBM) is the most common and malignant primary intracranial human neoplasm. GBMs are characterized by the presence of extensive areas of necrosis and hypoxia. Hypoxia and its master regulator, hypoxia inducible factor 1 (HIF-1) play a key role in glioma invasion. RESULTS: To further elucidate the functional role of HIF-1alpha in glioma cell migration in vitro and in invasion in vivo, we used a shRNA approach to knock down HIF-1alpha expression complemented with genome-wide expression profiling, performed in both normoxic and hypoxic conditions. Our data show that knock down of HIF-1alpha in glioma cells significantly impairs their migration in vitro as well as their ability to invade into the brain parenchyma in vivo. Next, we assessed the role that HIF-1alpha plays in maintaining the characteristics of cancer stem cells (CSCs). By using the tumor sphere forming assay, we demonstrate that HIF-1alpha plays a role in the survival and self-renewal potential of CSCs. Finally, expression profiling experiments in glioma cells provided detailed insight into a broad range of specific biological pathways and processes downstream of HIF-1alpha. We discuss the role of these processes in the migratory and invasive properties, as well as the stem cell biology of glioblastomas CONCLUSIONS: Our data show that knock down of HIF-1alpha in human and murine glioma cells impairs their migration in vitro and their invasion in vivo. In addition, our data suggest that HIF-1alpha plays a role in the survival and self-renewal potential of CSCs and identify genes that might further elucidate the role of HIF-1alpha in tumor migration, invasion and stem cell biology

AIM: To evaluate circulating endothelial lineage cells (ELCs) as biomarkers of tumor neovascularization in patients with pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: ELCs were isolated from the peripheral blood of patients with PDAC (n=14) or controls (n=17) before and after tumor resection/surgery and quantified using flow cytometry. Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) were detected in tumor using immunohistochemistry and in plasma using an ELISA technique. RESULTS: Circulating ELC levels were increased in patients with PDAC compared to controls. After PDAC resection, ELC levels declined. ELC level increases were associated with cancer recurrence. VEGF and PlGF were identified in cancer cells and exocrine pancreas cells. Only PlGF was detected in tumor-associated inflammatory cells. Plasma levels of PlGF were higher in patients with PDAC compared to controls. CONCLUSION: Circulating ELCs are a potential biomarker of PDAC neovascularization, and PlGF may be an important target in treatment of PDAC

Hemangioblastomas frequently develop in patients with von Hippel-Lindau (VHL) disease, an autosomal dominant genetic disorder. The tumors are characterized by a dense network of blood capillaries, often in association with cysts. Although activation of receptor tyrosine kinase (RTK) signaling, including epidermal growth factor receptor (EGFR) has been implicated in the development of malignant brain tumors such as high-grade gliomas, little is known about the role of RTK signaling in hemangioblastomas. To address this issue, we examined hemangioblastoma tumor specimens using receptor tyrosine kinase (RTK) activation profiling and immunohistochemistry. Six human hemangioblastomas were analyzed with a phospho-RTK antibody array, revealing EGFR phosphorylation in all tumors. EGFR expression was confirmed by immunohistochemistry in all tumors analyzed and downstream effector pathway activation was demonstrated by positive staining for phospho-AKT. Our findings suggest that, in primary hemangioblastomas, RTK upregulation and signaling predominantly involves EGFR, providing an attractive molecular target for therapeutic intervention

OBJECTIVE:: The purpose of this study was to compare the dynamic susceptibility-weighted contrast-enhanced (DSC) magnetic resonance (MR) perfusion and MR imaging findings between hemangioblastomas and pilocytic astrocytoma (PA). METHODS:: We retrospectively identified 6 patients with hemangioblastomas and 8 patients with PAs who underwent MR imaging before resection. Using fluid-attenuated inversion-recovery imaging, we graded peritumoral edema as absent, minimal, mild, moderate, or severe. In addition, 3 patients with hemangioblastomas and 4 patients with PAs underwent DSC-MR imaging before resection. RESULTS:: We observed moderate to severe peritumoral edema in 6 patients with hemangioblastomas and none or minimal peritumoral edema in 8 patients with PAs. The mean relative cerebral blood volume was 7.7 (SD, 1.0) in patients with hemangioblastomas and 1.8 (SD, 1.8) in patients with PAs. CONCLUSIONS:: Our preliminary findings demonstrate significantly higher DSC-MR imaging relative cerebral blood volumes in patients with hemangioblastomas when compared with patients with PAs. In addition, moderate to severe peritumoral edema was associated with hemangioblastomas