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Loss-of-function of alpha thalassemia/mental retardation syndrome X-linked (ATRX) protein leads to a phenotype called alternative lengthening of telomeres (ALT) in some tumors. High-grade astrocytomas comprise a heterogeneous group of central nervous system tumors. We examined a large cohort of adult (91) and pediatric (n=88) high-grade astrocytomas as well as lower grade forms (n=35) for immunohistochemical loss of ATRX protein expression and the presence of ALT using telomere-specific fluorescence in situ hybridization, with further correlation to other known genetic alterations. We found that in pediatric high-grade astrocytomas, 29.6% of tumors were positive for ALT and 24.5% were immunonegative for the ATRX protein, these two alterations being highly associated with one another (P<0.0001). In adult high-grade astrocytomas, 26.4% of tumors were similarly positive for ALT, including 80% of ATRX protein immunonegative cases (P<0.0001). Similar frequencies were found in 11 adult low-grade astrocytomas, whereas all 24 pilocytic astrocytomas were negative for ALT. We did not find any significant correlations between isocitrate dehydrogenase status and either ALT positivity or ATRX protein expression in our adult high-grade astrocytomas. In both cohorts, however, the ALT positive high-grade astrocytomas showed more frequent amplification of the platelet-derived growth factor receptor alpha gene (PDGFRA; 45% and 50%, respectively) than the ALT negative counterparts (18% and 26%; P=0.03 for each). In summary, our data show that the ALT and ATRX protein alterations are common in both pediatric and adult high-grade astrocytomas, often with associated PDGFRA gene amplification.

High-grade astrocytomas (HGAs), corresponding to World Health Organization grades III (anaplastic astrocytoma) and IV (glioblastoma; GBM), are biologically aggressive, and their molecular classification is increasingly relevant to clinical management. PDGFRA amplification is common in HGAs, although its prognostic significance remains unclear. Using fluorescence in situ hybridization (FISH), the most sensitive technique for detecting PDGFRA copy number gains, we determined PDGFRA amplification status in 123 pediatric and 263 adult HGAs. A range of PDGFRA FISH patterns were identified and cases were scored as non-amplified (normal and polysomy) or amplified (low-level and high-level). PDGFRA amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors. Amplification was not prognostic in pediatric HGAs. In adult tumors diagnosed initially as GBM, the presence of combined PDGFRA amplification and isocitrate dehydrogenase 1 (IDH1)(R132H) mutation was a significant independent prognostic factor (P = 0.01). In HGAs, PDGFRA amplification is common and can manifest as high-level and focal or low-level amplifications. Our data indicate that the latter is more prevalent than previously reported with copy number averaging techniques. To our knowledge, this is the largest survey of PDGFRA status in adult and pediatric HGAs and suggests PDGFRA amplification increases with grade and is associated with a less favorable prognosis in IDH1 mutant de novo GBMs., (© 2013 International Society of Neuropathology.)

Background: The impact of repeated surgical resection on the survivorship of patients with malignant astrocytomas is an issue of some controversy in the medical literature., Objectives: To clarify this issue through a retrospective analysis of treatment outcomes in a brain tumor clinic., Methods: The patient records from the Brain Tumor Clinic at Hahnemann University Hospital for the period 1988 to 2000 were reviewed. From these, 112 cases of glioblastoma multiforme and 50 cases of anaplastic astrocytoma were chosen for analysis., Results: The group of patients with glioblastomas showed a median survival of 415 days. When analyzed as subgroups based on the number of surgical resections, the median survival was 393 days in the group with biopsy only, 380 days in the group with one surgical resection, and 548 days in the group with two or three resections. Using the Kaplan-Meier method to generate survival plots and the log rank test to compare groups, repeat debulking was found to be a significant predictor of survival (P = 0.173). The group of patients with anaplastic astrocytomas showed a median survival of 1,311 days. When analyzed by subgroups, the patients with biopsy only had a median survival of 544 days, those with one debulking 1,589 days and those with two or three debulkings 1,421 days. There was a trend toward increased survival with debulking and the log rank test again showed statistical significance (P = 0.1998)., Conclusions: This study indicates that repeated surgical resections offer increased survival for both glioblastomas and anaplastic astrocytomas.