Dunham, Christopher P.

1502 Background: High-grade gliomas (HGG, WHO grades III-IV) are morphologically and genetically diverse, with survivals ranging from months to decades. Although WHO 2000 grading criteria are well established for pure astrocytomas [anaplastic astrocytoma (AA) and glioblastoma (GBM)], those for oligodendroglial neoplasms [anaplastic oligoastrocytoma (AOA) and oligodendroglioma (AO)] remain subjective, there being a debate regarding the existence of a grade IV variant based on the finding of necrosis, particularly with pseudopalisading (PPN). Methods: Overall survival of 916 adult (>20 yr) patients diagnosed between 1990 and 2005 with supratentorial HGG (77 AA, 481 GBM, 183 AOA, 175 AO) was analyzed by uni- (log-rank) and multivariate (Cox proportional hazards) models for significance of the following factors: microvascular proliferation, necrosis, patient age, surgery (stereotactic vs. open), location, primary vs. secondary tumor, year of diagnosis, and chromosome 1p and 19q losses by fluorescence in situ hybridization. Results: Necrosis was a statistically significant predictor of poor survival on multivariate analyses in AOA (P=0.035), but not in AO (log-rank P=0.048, Cox P=0.9), while PPN showed a trend towards significance on multivariate analysis only in AOA (P=0.096). Other independent predictors on multivariate analysis included age, grade, surgery type, and year of diagnosis for AA/GBM and age, primary tumor, and 1p/19q codeletion for both AOA and AO (P<0.05). Median survival for AOA patients whose tumors featured necrosis (20.7 mo) was significantly worse than their counterparts lacking necrosis (>104 mo); survival of the latter was more similar to that of AO (83.5 mo), whereas in the former it was better than GBM (10.5 mo) (log-rank P<0.0001). Conclusions: Stratification of oligoastrocytomas, but not of pure oligodendrogliomas, into grades III (AOA) and IV (GBM with oligodendroglial features) on the basis of necrosis is prognostically justified and is more accurate than the current approach of using a single anaplastic grade. These data provide impetus for the modification of present WHO criteria. No significant financial relationships to disclose.

Abstract Purpose: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs. Experimental Design: Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens. Results: aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P &lt; 0.05). Conclusions: Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients. Clin Cancer Res; 17(7); 1924–34. ©2011 AACR.

Purpose High-grade gliomas (HGGs; WHO grades 3-4) are highly diverse, with survival times ranging from months to years. WHO 2000 grading criteria for high-grade oligodendroglial neoplasms [anaplastic oligoastrocytoma (AOA) and anaplastic oligodendroglioma (AO)] remain subjective, and the existence of grade 4 variants is controversial. Patients and Methods Overall survival (OS) of 1,093 adult patients with a cerebral HGG newly diagnosed between 1990 and 2005 was analyzed by univariate and multivariate models for significance of the following factors: patient age, surgery type, year of diagnosis, endothelial proliferation, necrosis, oligodendroglial histology, treatment center, and chromosome 1p, 19q, 7p (EGFR), and 10q (PTEN) abnormalities by fluorescence in situ hybridization (FISH). Results Necrosis was a statistically significant predictor of poor OS on univariate and multivariate analyses in AOA but not in AO. Median OS for patients with necrotic AOA (22.8 months) was significantly worse than for patients with non-necrotic AOA (86.9 months; P < .0001) but was better than conventional glioblastomas (9.8 months; P < .0001). In addition to patient age, the following were significant independent prognostic factors (P ≤ .001): grade and surgery type for the entire HGG cohort; modified grade for AOA (3 v 4); and modified grade, 1p/19q codeletion status, and oligodendroglial histology for the 586 HGGs analyzed by FISH. Conclusion Stratification of AOA, but not of pure AO, into grades 3 and 4 on the basis of necrosis is prognostically justified and is more powerful than the current approach. Both routine histology and genetic testing provide independent, prognostically useful information.