Faculty Bibliography

Nonparaneoplastic glutamic acid decarboxylase antibody (GADAb)-related autoimmune encephalitis is a syndrome characterized by refractory seizures, progressive cognitive deficits, and psychiatric manifestations. The limbic subtype is well described, has characteristic affective and memory disturbances, and typical mesial temporal MRI abnormalities. We found only one single case report of the extralimbic subtype. We report clinical, radiological, and pathological findings of two additional cases with contrast-enhancing lesions. One of our cases presented as vasculitis, and the other imitated a tumor. Pathological evidence of both vasculitis and encephalitis has never been previously reported in any inflammatory condition affecting the brain. Our cases confirm prior reports that immune therapy can better control seizures associated with GADAb autoimmune encephalitis, and support the rationale for assaying for GADAb titers in patients with etiologically unclear extralimbic lesions and refractory epilepsy, independent of seizure types

Purpose: The role of invasion as a prognostic factor in high-grade gliomas (HGG) remains controversial. An apparent increase in invasiveness following anti-angiogenic therapy makes this question clinically relevant. The goal of this study is to assess survival differences in patients with newly diagnosed HGG who present with diffuse invasive disease compared to those who did not, but went on to develop diffuse invasive disease following bevacizumab therapy. Materials and Methods: Twenty-three patients presented as newly diagnosed diffuse invasive HGG. All patients underwent surgical resection with radiation therapy and temozolomide for one year. Progression-free survival (PFS) and overall survival (OS) were compared to a control of 58 patients with focal high-grade glioma who received similar therapy, but that included bevacizumab at 10 mg/kg given every two weeks. Results: The patient characteristics were similar in each group. The median PFS and OS for invasive HGG patients were 6 and 13 months and for the focal HGG patients, 11 and 24 months, respectively (P=0.092 and P=0.071). In the subgroup of invasive HGG that showed significant angiogenesis, the median PFS and OS were 3 and 9 months, respectively. 56% of the focal HGG patients recurred as diffuse invasive relapse. For patients with focal HGG who recurred as invasive disease, the median PFS and OS were 9 and 21 months respectively. Conclusions: Presence of diffuse invasive disease not accompanied by angiogenesis either prior to therapy or subsequent to anti-angiogenic therapy does not seem to have prognostic significance. However, invasion accompanied by angiogenesis in newly diagnosed HGG may confer a poor prognosis

OBJECTIVE: We describe a patient with seronegative autoimmune limbic encephalitis (SNALE) masquerading as glioma. Brain magnetic resonance imaging (MRI) abnormalities, distinctive pathological findings, and spontaneous remission are highlighted. BACKGROUND: There are 15 previously reported SNALE cases, 1 with pathology. MATERIALS AND METHODS: A 66-year-old man presented with prominent amnestic syndrome, progressive cognitive decline, and refractory complex partial seizures. RESULTS: Initial brain MRI suggested herpes limbic encephalitis. A 3-week course of intravenous acyclovir was ineffective. Cerebrospinal fluid analysis revealed no pleocytosis. Repeat brain MRI showed a left uncal-hippocampal, contrast-enhancing lesion with mass effect, which was resected. Pathology revealed perivascular and parenchymal mixed lymphocytic inflammatory infiltrates, microglial nodules, neuronophagia, microglial activation, astrocytosis, and lymphocyte emperipolesis within neurons. Thorough searches for infectious pathogens and autoantibodies were negative. Six weeks later, a new enhancing right mesial temporal lesion appeared, with increased seizure activity and further cognitive impairment. Although immune therapy was declined, spontaneous resolution of the new enhancing lesion, with full seizure control and significant cognitive improvement, occurred. CONCLUSIONS: SNALE may masquerade as glioma. Pathologic changes in our case of SNALE are distinctive. Spontaneous resolution of a focal SNALE lesion may potentially occur without immune therapy

Rhabdoid tumors (RT) are aggressive pediatric malignancies with poor prognosis. INI1/hSNF5 is a component of the chromatin remodeling SWI/SNF complex and a tumor suppressor deleted in RT. Previous microarray studies indicated that reintroduction of INI1/hSNF5 into RT cells leads to repression of a high degree of mitotic genes including Aurora Kinase A (Aurora A, STK6). Here, we found that INI1/SNF5 represses Aurora A transcription in a cell-type-specific manner. INI1-mediated repression was observed in RT and normal cells but not in non-RT cell lines. Chromatin immunoprecipitation (ChIP) assay indicated that INI1/hSNF5 associates with Aurora A promoter in RT and normal cells but not in non-RT cells. Real-time PCR and immunohistochemical analyses of primary human and mouse RTs harboring mutations in INI1/hSNF5 gene indicated that Aurora A was overexpressed/derepressed in these tumor cells, confirming that INI1/hSNF5 represses Aurora A in vivo. Knockdown of Aurora A impaired cell growth, induced mitotic arrest and aberrant nuclear division leading to decreased survival, and increased cell death and caspase 3/7-mediated apoptosis in RT cells (but not in normal cells). These results indicated that Aurora A is a direct downstream target of INI1/hSNF5-mediated repression in RT cells and that loss of INI1/hSNF5 leads to aberrant overexpression of Aurora A in these tumors, which is required for their survival. We propose that a high degree of Aurora A expression may play a role in aggressive behavior of RTs and that targeting expression or activity of this gene is a novel therapeutic strategy for these tumors. Cancer Res; 71(9); 3225-35. (c)2011 AACR

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

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

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

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