Faculty Bibliography

Prognosis of diffuse intrinsic pontine gliomas (DIPGs) remains poor. Failure has been predominantly local, with leptomeningeal dissemination (LD) occurring in 4-33% of patients in pre-MRI era series. Routine craniospinal imaging after initial treatment may reveal other relapse patterns relapse. Sixteen consecutive pediatric patients with DIPG treated between 2006 and 2009 were retrospectively reviewed. Treatment regimens, recurrence patterns, survival, and pathologic diagnosis were recorded. Fourteen patients received involved-field radiotherapy to 54 Gy, and two patients received craniospinal irradiation for LD at presentation. Neuraxis MRI was performed at diagnosis and at 4 month intervals following radiotherapy. Fifteen patients have had progression of disease (median progression-free survival 5.0 +/- 1.2 months), and 13 patients have died (median survival 9.0 +/- 1.4 months). Local failure occurred in 12 patients (75%). LD occurred in nine patients (56%). LD was present at diagnosis in three patients, after initial staging and treatment in six patients, and during autopsy in two patients. Median overall survival was 12.0 +/- 3.3 months without LD and 8.0 +/- 2.1 months with LD (P = 0.059, log rank test). Median progression-free survival was 9.5 +/- 3.9 months without LD and 3.0 +/- 2.1 months with LD (P = 0.012, log rank test). The high incidence of LD probably reflects liberal use of spine MRI surveillance. All patients should undergo routine craniospinal imaging at diagnosis and follow-up. Central nervous system prophylaxis should be considered in future clinical trials

Rhabdoid tumors (RTs) are rare, highly aggressive pediatric malignancies with poor prognosis and with no standard or effective treatment strategies. RTs are characterized by biallelic inactivation of the INI1 tumor suppressor gene. INI1 directly represses CCND1 and activates cyclin-dependent kinase (cdk) inhibitors p16(Ink4a) and p21(CIP). RTs are exquisitely dependent on cyclin D1 for genesis and survival. To facilitate translation of unique therapeutic strategies, we have used genetically engineered, Ini1(+/-) mice for therapeutic testing. We found that PET can be used to noninvasively and accurately detect primary tumors in Ini1(+/-) mice. In a PET-guided longitudinal study, we found that treating Ini1(+/-) mice bearing primary tumors with the pan-cdk inhibitor flavopiridol resulted in complete and stable regression of some tumors. Other tumors showed resistance to flavopiridol, and one of the resistant tumors overexpressed cyclin D1, more than flavopiridol-sensitive cells. The concentration of flavopiridol used was not sufficient to down-modulate the high level of cyclin D1 and failed to induce cell death in the resistant cells. Furthermore, FISH and PCR analyses indicated that there is aneuploidy and increased CCND1 copy number in resistant cells. These studies indicate that resistance to flavopiridol may be correlated to elevated cyclin D1 levels. Our studies also indicate that Ini1(+/-) mice are valuable tools for testing unique therapeutic strategies and for understanding mechanisms of drug resistance in tumors that arise owing to loss of Ini1, which is essential for developing effective treatment strategies against these aggressive tumors

S714 Purpose/Objective(s): Transforming growth factor-beta (TGFbeta) is a pleotropic cytokine in the tumor microenvironment that can promote malignant behaviors, including invasion and motility. Glioblastomas produce abundant TGFbeta, are routinely treated with radiation, and have a very poor prognosis. A role for TGFbeta in the DNA damage response has recently been discovered in which TGFb inhibition in vitro and in vivo compromises ATM-kinase activity induced by ionizing radiation (Cancer Research 66:10861-68; 62:5627-31). These data suggest that TGFbeta could protect cancer cells from the cytotoxic effects of radiation by promoting ATM dependent responses; if so, TGFbeta inhibitors, which are in clinical trials, might increase therapeutic response to radiation. Materials/Methods: We used the murine glioblastoma cell line, GL261, to test the effects of TGFbeta inhibition by LY364947 (a small molecule inhibitor of the TGFbeta type I receptor kinase) on proliferation, radiosensitivity, and neurosphere-forming capacity. Experiments were performed in triplicate and differences tested by ANOVA. Results: GL261 cells produce 0.9 ng/mL per 106 cells of total TGFbeta in media conditioned for 24 hr, the majority of which is latent TGFb2. They also respond to exogenous TGFbeta1 with an increase in Smad2 phosphorylation. Despite intact TGFb receptor kinase activity, GL261 cells displayed no growth modulation response to exogenous TGFbeta1 (0.5-2ng/mL) treatment or to inhibition by LY364947 (400nM). Nonetheless, inhibition of TGFbeta with LY364947 for 24 hours prior to radiation treatment significantly increased GL261 radiosensitivity in the clonogenic assay (p<0.001), with a 1.25 dose enhancement ratio at 10% surviving fraction. This correlated with a significant 55% decrease in H2AX foci following radiation treatment with 2Gy (p<0.0001). Irradiation of GL261 cells with 2Gy also decreased primary neurosphere-forming capacity by 28% (p<0.001, ANOVA), but had no effect on secondary neurosphere formation. Treatment with LY364947 alone had no effect on neurosphere formation. In contrast, treatment for 24 hours prior to irradiation decreased the primary neurosphere-forming capacity of irradiated GL261 cells by an additional 47% (p<0.001) and decreased secondary neurosphere formation by 68% (p<0.001). Conclusions: Given the radiosensitization and specifically the response of the neurosphere assay, which is thought to measure the glioma initiating cell population, our results suggest that inhibition of TGFb in combination with radiation represents a promising therapeutic strategy. By targeting the putative stem cells long term benefit of TGFb inhibition in glioblastoma may be achieved compared to poor response rates seen with the standard regimen of chemotherapy and radiotherapy

Neurocysticercosis (NCC) is the most common parasitic infection of the CNS. Surgical intervention is often required to treat for hydrocephalus with neuroendoscopy emerging as a logical alternative to craniotomies. While cranial NCC cases have increased in the United States, spinal NCC incidences have remained relatively low. We report a case of trapped fourth ventricle and myelopathy from both concomitant cranial and spinal NCC. This patient exhibited a subacute thoracic myelopathy and acute deterioration from a trapped fourth ventricle (TFV) from aqueductal and fourth ventricular outflow occlusion. She underwent urgent posterior fossa exploration. A fourth ventricular lesion consistent with NCC was removed from the distal aqueduct and the aqueduct was opened via aqueductoplasty with a ventricular catheter and balloon dilatation. She improved following surgery without extraoccular dysfunction. Intraoperative visualization and postoperative MRI flow-studies confirmed patency of the aqueduct and there was complete resolution of her fourth ventricle dilatation. With antiparasitic and corticosteroid therapy, her myelopathy has slowly improved over 9 months of follow-up

BACKGROUND: The role of endogenous neural stem cell progenitors in recovery from intracranial hemorrhage remains to be elucidated. Proliferation of such stem cells in the subventricular zone has been described in rodent models of experimental intracranial hemorrhage. Administration of a sonic hedgehog agonist at the time of hemorrhage was hypothesized to increase the quantity of such precursor cells. METHODS: Two groups of pigs were subjected to injection of autologous blood into the right frontal lobe. One group was also injected at the same site with a sonic hedgehog agonist at the time of the hemorrhage to stimulate cell growth, and the other was given a vehicle control. The pigs received intravenous BrdU for 5 days postoperatively to label replicating cells, and then were sacrificed at intervals up to 21 days. RESULTS: Pigs in the hemorrhage only group demonstrated increased and more persistent BrdU staining in the subventricular zone relative to pigs in the group that received sonic hedgehog agonist. The latter group demonstrated increased BrdU activity in non-neural lineage cells in the area of the hemorrhage. CONCLUSION: Sonic hedgehog agonist did not induce subventricular zone neural stem cell progenitor division after experimental intracranial hemorrhage in a pig model

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

BACKGROUND AND IMPORTANCE: We report the first case of synchronous choroid plexus papilloma of the fourth ventricle and myxopapillary ependymoma of the filum terminale. Both are papillary World Health Organization grade I tumors known to disseminate via cerebrospinal fluid pathways. CLINICAL PRESENTATION: A 65-year-old man presented with an incidental mass in the fourth ventricle found on a computed tomography scan of the head after a motor vehicle collision and an intradural mass of the filum terminale. The patient underwent resection of the fourth ventricle mass. After pathological diagnosis of a choroid plexus papilloma, the patient underwent resection of the spinal cord tumor. CONCLUSION: This case underscores the need for separate pathological diagnosis in a patient with an intradural spine lesion in the context of a benign intracranial lesion. We detail a panel of immunohistochemical markers essential for distinguishing the 2 papillary neuroectodermal tumors recovered in this case

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