Abstract: Glioblastoma multiforme (GBM) is the most common primary brain tumour, and the most aggressive in nature. The prognosis for patients with GBM remains poor, with a median survival time of only 1-2 years. The treatment failure relies on the development of resistance by tumour cells and the difficulty of ensuring that drugs effectively cross the dual blood brain barrier/blood brain tumour barrier. The advanced molecular and genetic knowledge has allowed to identify the mechanisms responsible for temozolomide resistance, which represents the standard of care in GBM, along with surgical resection and radiotherapy. Such resistance has motivated the researchers to investigate new avenues for GBM treatment intended to improve patient survival. In this review, we provide an overview of major obstacles to effective treatment of GBM, encompassing biological barriers, cancer stem cells, DNA repair mechanisms, deregulated signalling pathways and autophagy. New insights and potential therapy approaches for GBM are also discussed, emphasizing localized chemotherapy delivered directly to the brain, immunotherapy, gene therapy and nanoparticle-mediated brain drug delivery.

Abstract: OBJECTIVE: Ventricular opening during glioblastoma (GBM) resection is controversial. Sufficient evidence regarding its prognostic role is missing. We investigated the impact of ventricular opening on overall survival (OS), hydrocephalus development, and postoperative morbidity in patients with GBM. METHODS: Patients who underwent primary GBM resection between 2006 and 2013 were assessed retrospectively. Established predictors for overall survival (age, Karnofsky Performance Status, extent of resection, O-6-methylguanine-DNA methyltransferase promoter methylation status, isocitrate dehydrogenase mutation status) and further clinical data (postoperative status, further treatment, preoperative tumor volume, proximity to the ventricle) were included in univariate and multivariate analyses. RESULTS: Thirteen (5.7%) of 229 patients developed a hydrocephalus. Multivariate logistic regression showed that neither ventricular opening, tumor size, proximity to the ventricle, nor extent of resection were significant risk factors for hydrocephalus. Ventricular opening did not delay postoperative therapy and was not associated with neurological morbidity. Kaplan-Meier analysis demonstrated that patients who underwent ventricular opening (n = 114) exhibited a median OS of 14.3 months (12.9-16.5), whereas patients who did not undergo ventricular opening (n = 115) exhibited a median OS of 18.6 months (16.1-20.8). However, multivariate Cox regression (n = 134) did not confirm ventricular opening as an independent negative predictor of OS (risk ratio 1.09, P = 0.77). Instead, it showed that a greater preoperative tumor volume >22.8 cm3 was a negative predictor of OS (risk ratio 1.76, P = 0.02). CONCLUSIONS: Because extent of resection is a strong independent predictor of OS and ventricular opening is safe, neurosurgeons should consider ventricular opening to achieve maximal tumor resection.

Abstract: The present study analyzed outcomes of surgery followed by concomitant chemoradiotherapy (CCRT) with temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM) at a single institution. Outcomes were retrospectively reviewed in 252 consecutive patients with newly diagnosed GBM who underwent surgery followed by CCRT with TMZ at the authors' institution between 2005 and 2013. At initial operation, 126 (50.0%), 55 (21.8%), 45 (17.9%), and 26 (10.3%) patients underwent gross total resection (GTR), subtotal resection, partial resection (PR), and biopsy, respectively. Their median overall survival (OS) was 20.8 months (95% confidence interval [CI] 17.7-23.9 months) and their median progression-free survival was 12.7 months (95% CI 11.2-14.2 months). The O-methylguanine-DNA methyltransferase (MGMT) promoter was methylated in 78 (34.1%) of the 229 patients assayed, and an isocitrate dehydrogenase 1 mutation was detected in 7 (6.6%) of the 106 patients analyzed. Univariate analyses showed that patient age, involvement of eloquent areas, involvement of the subventricular zone, presence of leptomeningeal seeding, Karnofsky Performance Status, extent of resection (EOR), MGMT promoter methylation, and presence of an oligodendroglioma component were prognostic of OS. Multivariate analysis showed that age, involvement of eloquent areas, presence of leptomeningeal seeding, EOR, and MGMT promoter methylation were significantly predictive of survival. OS in patients with GBM who undergo surgery followed by CCRT with TMZ is enhanced by complete resection. Other factors significantly prognostic of OS include that age, involvement of eloquent areas, presence of leptomeningeal seeding, and MGMT promoter methylation.