PATH-38. ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS

Abstract BACKGROUND Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component. METHODS We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway. RESULTS The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia. CONCLUSION Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation

Loss of PTEN Is Not Associated with Poor Survival in Newly Diagnosed Glioblastoma Patients of the Temozolomide Era

Introduction: Pre-temozolomide studies demonstrated that loss of the tumor suppressor gene PTEN held independent prognostic significance in GBM patients. We investigated whether loss of PTEN predicted shorter survival in the temozolomide era. The role of PTEN in the PI3K/Akt pathway is also reviewed. Methods: Patients with histologically proven newly diagnosed GBM were identified from a retrospective database between 2007 and 2010. Cox proportional hazards analysis was used to calculate the independent effects of PTEN expression, age

Very long-term survival of an older glioblastoma patient after treatment with cilengitide: a case report

Glioblastoma (GBM) is the most common malignant brain tumor. Less than 1% of patients survive longer than 10 years. A 77-year-old woman was diagnosed with MGMT-methylated GBM in 2009. The patient received cilengitide as part of the CENTRIC clinical trial in conjunction with standard radiation and chemotherapy. Though the study was halted in 2013, our patient received cilengitide until 2016 with no radiographic evidence of recurrence thus far. This is the oldest reported GBM patient with greater than 10-year survival. Her exceptional response may have been influenced by MGMT promoter methylation status and PTEN expression

Differentiation of Benign Angiomatous and Microcystic Meningiomas with Extensive Peritumoral Edema from High Grade Meningiomas with Aid of Diffusion Weighted MRI

Objective. To determine whether angiomatous and microcystic meningiomas which mimic high grade meningiomas based on extent of peritumoral edema can be reliably differentiated as low grade tumors using normalized apparent diffusion coefficient (ADC) values. Methods. Preoperative magnetic resonance imaging (MRI) of seventy patients with meningiomas was reviewed. Morphologically, the tumors were divided into 3 groups. Group 1 contained 12 pure microcystic, 3 pure angiomatoid and 7 mixed angiomatoid and microcystic tumors. Group 2 included World Health Organization (WHO) grade II and WHO grade III tumors, of which 28 were atypical and 9 were anaplastic meningiomas. Group 3 included WHO grade I tumors of morphology different than angiomatoid and microcystic. Peritumoral edema, normalized ADC, and cerebral blood volume (CBV) were obtained for all meningiomas. Results. Edema index of tumors in group 1 and group 2 was significantly higher than in group 3. Normalized ADC value in group 1 was higher than in group 2, but not statistically significant between groups 1 and 3. CBV values showed no significant group differences. Conclusion. A combination of peritumoral edema index and normalized ADC value is a novel approach to preoperative differentiation between true aggressive meningiomas and mimickers such as angiomatous and microcystic meningiomas

Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma

We report the immunopathological analysis of the brain and tumor of two patients who died of anti-NMDAR-associated encephalitis, and of the tumor of nine patients who recovered. Findings included prominent microgliosis and deposits of IgG with rare inflammatory infiltrates in the hippocampus, forebrain, basal ganglia, and spinal cord. Detection of cells expressing markers of cytotoxicity (TIA, granzyme B, perforin and Fas/Fas ligand) was extremely uncommon. All tumors showed NMDAR-expressing neurons and inflammatory infiltrates. All patients' NMDAR antibodies were IgG1, IgG2, or IgG3. No complement deposits were observed in any of the central nervous system regions examined. Overall, these findings coupled with recently reported in vitro data showing that antibodies downregulate the levels of NMDA receptors suggest that the antibody immune-response is more relevant than cytotoxic T-cell mechanisms in the pathogenesis of anti-NMDAR-associated encephalitis

Ankyrin facilitates intracellular trafficking of α1-Na+-K+-ATPase in polarized cells

Defects in ankyrin underlie many hereditary disorders involving the mislocalization of membrane proteins. Such phenotypes are usually attributed to ankyrin's role in stabilizing a plasma membrane scaffold, but this assumption may not be accurate. We found in Madin-Darby canine kidney cells and in other cultured cells that the 25-residue ankyrin-binding sequence of α1-Na+-K+-ATPase facilitates the entry of α1,β1-Na+-K+-ATPase into the secretory pathway and that replacement of the cytoplasmic domain of vesicular stomatitis virus G protein (VSV-G) with this ankyrin-binding sequence bestows ankyrin dependency on the endoplasmic reticulum (ER) to Golgi trafficking of VSV-G. Expression of the ankyrin-binding sequence of α1-Na+-K+-ATPase alone as a soluble cytosolic peptide acts in trans to selectively block ER to Golgi transport of both wild-type α1-Na+-K+-ATPase and a VSV-G fusion protein that includes the ankyrin-binding sequence, whereas the trafficking of other proteins remains unaffected. Similar phenotypes are also generated by small hairpin RNA-mediated knockdown of ankyrin R or the depletion of ankyrin in semipermeabilized cells. These data indicate that the adapter protein ankyrin acts not only at the plasma membrane but also early in the secretory pathway to facilitate the intracellular trafficking of α1-Na+-K+-ATPase and presumably other selected proteins. This novel ankyrin-dependent assembly pathway suggests a mechanism whereby hereditary disorders of ankyrin may be manifested as diseases of membrane protein ER retention or mislocalization

Adult Brainstem Glioblastoma Multiforme: Long-term Survivor

Abstract Adult, malignant brainstem gliomas are rare entities that often cause treatment conundrums due to the difficulty of surgical resection and, therefore, the absence of pathological diagnosis. This leads to a reliance on radiological imaging for diagnosis, which can often be unreliable. These shortcomings have made the treatment of brainstem gliomas challenging with unpredictable outcomes. The mainstay of treatment consists of chemotherapy and radiation; however, recurrence is inevitable. Predicting outcomes has been the major difficulty in treating these patients as adult malignant brainstem gliomas Grade II have a median survival between five to seven years while Grades III and IV are between 10-17 months (with some studies showing significantly longer survival in Grade III). Here, we present the case of a patient with the pathologic diagnosis of a right brachium pontis glioblastoma who had a remarkable survival of 73 months, whereas the expected median survival for these patients is 10-17 months