SummaryWe collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.

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In this paper, the authors present the case of a patient with multifocal intradural extramedullary ependymoma, and they review 18 previously reported cases. A 32-year-old man presented to the authors' institution with a 1-month history of partial medullary syndrome. Magnetic resonance imaging of the neuraxis revealed multifocal intradural extramedullary lesions at the bulbomedullary junction and C2–3, T5–11, L-2, L-4, L-5, and sacrum. Histological examination revealed a WHO Grade II ependymoma. The literature survey yielded 18 cases of ependymoma at the same location; none of them were multifocal at presentation. The authors analyzed the epidemiological, clinical, and surgical features of all 19 cases reported to date, including the present case. Patients' ages ranged from 24 to 69 years; 15 patients were women and 4 were men. The time elapsed from symptom onset to diagnosis ranged from 1 month to 8 years. Pain (in 13 patients) and medullary syndrome (in 12) were reported as the initial symptoms (information was not provided for 1 patient). Tumors were predominantly located in the thoracic spine (11), but they also occurred in the cervicothoracic (3), cervical (2), and lumbar (2) spine. The remaining tumor was multifocal. Solitary extramedullary tumors were found intraoperatively in 13 patients; 3 were described as exophytic and 3 as extramedullary with some degree of medullary invasion. Histological examination revealed 9 WHO Grade II tumors, 4 Grade III tumors, and 1 myxopapillary tumor. Data obtained for the remaining cases proved inconclusive. The clinical condition improved in 11 patients, remained stable in 2, and worsened (recurrence or progression) in 6. Of the 4 patients with Grade II tumors who presented with recurrence or neuraxis spreading, 3 had meningeal infiltration or adhesion to the pia mater, which does not rule out the possibility of neoplastic remnants in that area. Intradural extramedullary ependymomas are rare, they predominate in women in the 5th decade of life, and pain is the most frequent initial symptom. The extent of resection and the presence of meningeal infiltration seem to be key determinants of prognosis. The present case is the first intradural extramedullary ependymoma (with the exception of those occurring at the conus medullaris and terminal filum) with multiple lesions at presentation.

Purpose: The epidermal growth factor receptor (EGFR) is amplified and overexpressed in adult glioblastoma, with response to targeted inhibition dependent on the underlying biology of the disease. EGFR has thus far been considered to play a less important role in pediatric glioma, although extensive data are lacking. We have sought to clarify the role of EGFR in pediatric high-grade glioma (HGG). Experimental Design: We retrospectively studied a total of 90 archival pediatric HGG specimens for EGFR protein overexpression, gene amplification, and mutation and assessed the in vitro sensitivity of pediatric glioma cell line models to the small-molecule EGFR inhibitor erlotinib. Results: Amplification was detected in 11% of cases, with corresponding overexpression of the receptor. No kinase or extracellular domain mutations were observed; however, 6 of 35 (17%) cases harbored the EGFRvIII deletion, including two anaplastic oligodendrogliomas and a gliosarcoma overexpressing EGFRvIII in the absence of gene amplification and coexpressing platelet-derived growth factor receptor α. Pediatric glioblastoma cells transduced with wild-type or deletion mutant EGFRvIII were not rendered more sensitive to erlotinib despite expressing wild-type PTEN. Phosphorylated receptor tyrosine kinase profiling showed a specific activation of platelet-derived growth factor receptor α/β in EGFRvIII-transduced pediatric glioblastoma cells, and targeted coinhibition with erlotinib and imatinib leads to enhanced efficacy in this model. Conclusions: These data identify an elevated frequency of EGFR gene amplification and EGFRvIII mutation in pediatric HGG than previously recognized and show the likely necessity of targeting multiple genetic alterations in the tumors of these children. (Clin Cancer Res 2009;15(18):5753-61) Amplification, overexpression, and/or mutation of the epidermal growth factor receptor (EGFR) represent a compelling set of molecular genetic indicators for targeted therapy in adult glioblastoma. About 40% of glioblastomas show amplification of the EGFR gene locus, and about half of these tumors express a mutant receptor (EGFRvIII) that is constitutively active due to an in-frame truncation within the extracellular ligand-binding domain (1). In addition, novel missense mutations have been reported in the extracellular domain of tumors and cell lines (2), and recently, additional mutations have been described outside of these regions (e.g., in the transmembrane domains), although the significance of these is not yet clear (3).EGFRvIII is caused by deletion of exons 2 to 7, resulting in a protein that lacks a ligand-binding domain and is constitutively activated and is further resistant to down-regulation due to a low rate of receptor endocytosis (4). EGFRvIII has been shown

BackgroundGlioblastoma (GBM) confers a dismal prognosis despite advances in current therapy. Cancer-testis antigens (CTA) comprise families of tumor-associated antigens that are immunogenic in different cancers. The aim of this study was to determine the expression profile of a large number of CTA genes in GBM.MethodsWe selected, from 153 CTA genes, those genes potentially expressed in GBM. The expression pattern of 30 CTA was then evaluated by RT-PCR in a series of 48 GBM and 5 normal brain samples. The presence of CTCFL protein was also evaluated by immunohistochemical staining.ResultsAmong the genes with no expression in normal brain, ACTL8 (57%), OIP5 (54%), XAGE3 (44%) and CTCFL (15%) were frequently expressed in GBM, while over 85% of the tumors expressed at least 1 of these four CTA. Coexpression of two or more CTA occurred in 49% of cases. CTCFL protein expression was detected in 13% of the GBM and was negative in normal brain samples. GBM expressing 3-4 CTA was associated with significantly better overall survival (OS) rates (P = 0.017). By multivariate analysis, mRNA positivity for 3-4 CTA (P = 0.044), radiotherapy (P = 0.010) and chemotherapy (P = 0.001) were independent prognostic factors for OS.ConclusionsGBM frequently express ACTL8, OIP5, XAGE3 and CTCFL. A relatively high percentage of tumors expressed at least one of these four CTA, opening the perspective for their utility in antigen-specific immunotherapy. Furthermore, mRNA positivity for 3-4 CTA is an independent predictor of better OS for GBM patients.

Perfusion-weighted imaging is a feasible method of reducing the sampling error in the histopathological diagnosis of a presumed LGG, particularly by improving the selection of targets for stereotactic biopsy.

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This investigation analyzed the immunoexpression of FasL, Fas, cleaved caspase-8, and cleaved caspase-3 in glioblastomas. Formalin-fixed and paraffin-embedded glioblastoma tissues and control brain tissues from 97 patients were analyzed by tissue microarrays and immunohistochemistry. Patients with glioblastomas that were negative or weakly stained (<50% of cells positive) for cleaved caspase-8 had worse cancer-specific overall survival (median=8.5 months) than did patients with tumors that highly expressed cleaved caspase-8 (median=11.7 months; P=0.0325), independent of clinical variables. There was no association of other markers with survival, treatment, sex, age, tumor size, and primary site. Among the tumors, there were reasonable to good positive correlations between the expression of FasL and Fas (r=0.47) and between Fas and cleaved caspase-8 (r=0.41), and there were poor positive correlations between Fas and cleaved caspase-3 (r=0.26), FasL and cleaved caspase-8 (r=0.22), and cleaved caspase-8 and -3 (r=0.31). Our results suggest that Fas-Fas-ligand signal transduction could be inhibited, especially at the stage of caspase-8 activation, thereby establishing a major mechanism for evasion of apoptosis by these tumors. The absence or low expression of cleaved caspase-8 in the tumors was a negative prognostic indicator for patient survival.