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Background: We evaluated Gamma Knife radiosurgery (GKRS) as a treatment option for patients with recurrent glioblastoma., Patients and Methods: 42 patients with histopathologically diagnosed recurrent grade IV tumor were treated with GKRS. All patients had undergone standard multimodal first-line treatment. The average time from diagnosis to GKRS was 17.0 months. The median target volume was 5.1 cm3. The median margin dose was 10 Gy and the median central dose 20 Gy. In a subset of patients, O6-methylguanine methyltransferase (MGMT) promoter methylation analysis by pyrosequencing was performed., Results: Most patients did not develop complications after GKRS. Time to radiological progression after initial GKRS was 4.4 months (95% CI: 3.1-5.7 months). Radiological progression mainly occurred beyond the GKRS-irradiated area. The median survival time after initial GKRS was 9.6 months (95% CI: 7.7-11.5 months). The median overall survival time from diagnosis was 25.6 months (95% CI: 21.8-29.3 months). Patients with MGMT promoter methylation survived significantly longer (33.4 months; 95% CI: 21.2-45.5 months) compared to patients without MGMT promoter methylation (16.0 months; 95% CI: 8.0-23.9 months)., Conclusion: GKRS seems to be a relatively safe salvage treatment option for recurrent glioblastoma for highly selected patients but must be seen as part of a multimodal treatment algorithm., (© 2016 S. Karger AG, Basel.)

No data exist on angiogenic patterns and their prognostic impact in human glioblastoma. Such data are relevant for translation of antiangiogenic therapies into clinical applications. Using immunohistochemistry for CD34, we assessed vascular patterns in 114 primary glioblastomas. Vascular patterns comprised unevenly distributed glomeruloid/garland-like/clustered bizarre vascular formations and evenly distributed delicate capillary-like microvessels ("classic" vascular pattern). The combination of low content of bizarre vascular formations and prominent classic vascular pattern (n=29) was an independent factor for longer survival (p=0.006, Cox regression), as well as postoperative high Karnofsky performance status (p=0.005). In patients with a prominent classic vascular pattern, there was no difference of MIB1 labeling index whereas microvessel density and apoptotic index (TUNEL) were significantly higher as compared to all other patients (p<0.05). In addition, diffuse expression of hypoxia-inducible factor (HIF)-1alpha and strong expression of vascular endothelial growth factor were more common (p<0.05, Chi-square test). FISH revealed loss of chromosomes 1p and 19q only in 1/7 long-time survivors with classic pattern. We conclude that vascular patterns in primary glioblastoma influence clinical outcome and associate with variable expression of angiogenic proteins. Our findings denote for the first time distinct angiogenic subtypes of human glioblastoma which may prove relevant for anti-angiogenic therapy approaches.

TP53 plays a key role in cellular response to DNA-damaging agents, and mutation of this gene, which is associated with immunohistochemically detectable p53 protein accumulation, may influence response to chemo- and radiotherapy. We investigated immunohistochemically the influence of p53 protein accumulation in 114 consecutive cases of primary glioblastoma treated by surgery and adjuvant radio- and chemotherapy. In addition, we determined cellular proliferation index using the antibody MIB-1 and apoptotic index of tumor cells using the TUNEL-assay. Twenty-nine patients (25.4%) were considered as positive with regard to p53 protein expression (>50% p53 immunostained tumor cells). Patients with p53 positive glioblastomas were significantly younger (mean age 54.4+/-2 years) than those with p53 negative tumors (mean age 61.4+/-1.1 years) (p=0.002, Mann-Whitney test). While no significant difference in apoptotic index was found, we observed a significantly higher MIB-1 labeling index (LI) in patients with p53 positive tumors (median LI: 36.4%) compared to p53 negative ones (median LI: 23.8%) (p=0.005, Mann-Whitney test). p53 protein expression was associated with significantly longer survival in univariate analysis (p=0.0399, log-rank test). In multivariate analysis of overall survival (Cox regression) only postoperative Karnofsky performance status remained as independent prognostic factor. We conclude that glioblastoma patients with immunohistochemically detectable p53 protein expression, who received adjuvant radio- and chemotherapy, have a significantly better overall survival, possibly due to increased sensitivity to this adjuvant treatment.

Assessment of tumour cell proliferation in glioblastoma (GB) has been a topic of considerable research interest over the past decade. However, the correlation of tumour proliferation and patient outcome has yielded controversial results. In this study, we examined immunohistochemically, using paraffin-embedded tissue, the expression of the proliferation-related markers DNA topoisomerase IIalpha (TIIalpha) and Ki-67 antigen in a cohort of 114 GB patients treated consecutively with surgery and radiochemotherapy, and correlated the expression with patient outcome. The TIIalpha labelling index (LI) ranged between 5.2 and 87.2% (median: 25.6%). Survival analysis disclosed an association between high TIIalpha expression levels and prolonged survival (P=0.040, log-rank test). TIIalpha expression correlates closely with Ki-67 labelling index (R=0.927, P<0.001), which itself is predictive of patient survival (P=0.044). However, in multivariate analysis, only the Karnofsky performance status remained predictive of patient survival. We conclude that high expression of TIIalpha and Ki-67 appears to be associated with a prolonged survival in our cohort of GB patients.