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This prospective population-based study on a group of 132 resected IDH-wildtype (IDH-wt) glioblastoma (GBM) patients assesses the prognostic and predictive value of selected genetic biomarkers and clinical factors for GBM as well as the dependence of these values on the applied therapeutic modalities. The patients were treated in our hospital between June 2006 and June 2015. Clinical data and tumor samples were analyzed to determine the frequencies of TP53, MDM2, EGFR, RB1, BCR, and CCND1 gene aberrations and the duplication/deletion statuses of the 9p21.3, 1p36.3, 19q13.32, and 10p11.1 chromosome regions. Cut-off values distinguishing low (LCN) and high (HCN) copy number status for each marker were defined. Additionally, MGMT promoter methylation and IDH1/2 mutation status were investigated retrospectively. Young age, female gender, Karnofsky scores (KS) above 80, chemoradiotherapy, TP53 HCN, and CCND1 HCN were identified as positive prognostic factors, and smoking was identified as a negative prognostic factor. Cox proportional regression models of the chemoradiotherapy patient group revealed TP53 HCN and CCND1 HCN to be positive prognostic factors for both progression-free survival and overall survival. These results confirmed the influence of key clinical factors (age, KS, adjuvant oncotherapy, and smoking) on survival in GBM IDH-wt patients and demonstrated the prognostic and/or predictive importance of CCND1, MDM2, and 22q12.2 aberrations.

Background: Astrocytoma is the most prevalent form of primary brain cancer categorized into four histological grades by the World Health Organization. Investigation into individual grades of astrocytoma by previous studies has provided some insight into dysregulation of regulatory networks associated with increasing astrocytoma grades. However, further understanding of key mechanisms that distinguish different astrocytoma grades is required to facilitate targeted therapies., Methods: In this study, we utilized a large cohort of publicly available RNA sequencing data from patients with diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III), primary glioblastoma (grade IV), secondary glioblastoma (grade IV), recurrent glioblastoma (grade IV), and normal brain samples to identify genetic similarities and differences between these grades using bioinformatics applications., Results: Our analysis revealed a distinct gene expression pattern between grade II astrocytoma and grade IV glioblastoma (GBM). We also identified genes that were exclusively expressed in each of the astrocytoma grades. Furthermore, we identified known and novel genes involved in key pathways in our study. Gene set enrichment analysis revealed a distinct expression pattern of transcriptional regulators in primary GBM. Further investigation into molecular processes showed that the genes involved in cell proliferation and invasion were shared across all subtypes of astrocytoma. Also, the number of genes involved in metastasis, regulation of cell proliferation, and apoptosis increased with tumor grade., Conclusions: We confirmed existing findings and shed light on some important genes and molecular processes that will improve our understanding of glioma biology.

Aim: The aim of this study was to compare resection and biopsy of glioblastoma (GBM) in eloquent brain areas (EBA)., Methods: This was a prospective evaluation of 38 patients with GBM in EBA. 22 were treated by surgical resection and 16 by biopsy. Preoperative KPS, neurological status and size of lesion on MRI were assessed. One week and three months postoperatively KPS, neurological status and Performance Status (PS) WHO were evaluated. Extent of resection (EOR) and overall survival (OS) were described. Overall mean age of the patients was 64.3 years, the mean lesion size in the resection group was 47.7 mm and in the biopsy group 51.0 mm., Results: Worsening or development of permanent neurological deficits 3 months after surgery were significantly lower in the resection group (23%), than the biopsy group (94%). In the resection group the median pre and postoperative KPS three months after surgery was 80.0. In the biopsy group the median pre and postoperative KPS was 68.1 one week after the procedure. In the resection group, 3 months after surgery, the median PS was 1, in the biopsy group one week after surgery the median PS was 2. The difference was statistically insignificant. The mean OS after resection was 12.2 months, and after biopsy 3.5 months. The difference was highly statistically significant. The mean EOR was 90%., Conclusion: This is the first prospective study, to our knowledge, that compares the results of resection and biopsy of primary GBM in EBA. For patients in good clinical condition with tumors in or near EBA, recommended is as radical resection of GBM as possible.

Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis and progression of malignant brain tumors. Given the significance of tumor microenvironment in general, and the established role of paracrine VEGF signaling in glioblastoma (GBM) biology in particular, we explored the potential autocrine control of human astrocytoma behavior by VEGF. Using a range of cell and molecular biology approaches to study a panel of astrocytoma (grade III and IV/GBM)-derived cell lines and a series of clinical specimens from low- and high-grade astrocytomas, we show that co-expression of VEGF and VEGF receptors (VEGFRs) occurs commonly in astrocytoma cells. We found VEGF secretion and VEGF-induced biological effects (modulation of cell cycle progression and enhanced viability of glioblastoma cells) to function in an autocrine manner. Morevover, we demonstrated that the autocrine VEGF signaling is mediated via VEGFR2 (KDR), and involves co-activation of the c-Raf/MAPK, PI3K/Akt and PLC/PKC pathways. Blockade of VEGFR2 by the selective inhibitor (SU1498) abrogated the VEGF-mediated enhancement of astrocytoma cell growth and viability under unperturbed culture conditions. In addition, such interference with VEGF-VEGFR2 signaling potentiated the ionizing radiation-induced tumor cell death. In clinical specimens, both VEGFRs and VEGF were co-expressed in astroglial tumor cells, and higher VEGF expression correlated with tumor progression, thereby supporting the relevance of functional VEGF-VEGFR signaling in vivo. Overall, our results are consistent with a potential autocrine role of the VEGF-VEGFR2 (KDR) interplay as a factor contributing to malignant astrocytoma growth and radioresistance, thereby supporting the candidacy of this signaling cascade as a therapeutic target, possibly in combination with radiotherapy.

An intratumoral or peritumoral microbial intracranial abscess is an infrequent diagnosis. The development of this complication may not be preceded by apparent local or general infection in all cases. To identify this diagnosis by radiological (MRI) or laboratory investigations is very intricate. Nevertheless, the recommended life-saving strategy is early surgery with resolution of both the tumor and infection. If subsequent oncological treatment is required, it has to be adjusted for prevention of re-inflammation. The described patient suffered from an intracranial abscess superimposed on a Glioblastoma Multiforme. The confirmed etiological agent was Staphylococcus aureus. The suspected route of microbial migration and colonization in this tumor was bacteremia via agents from thrombophlebitis. The patient is in a good condition following surgery, antimicrobial treatment, and radiotherapy.

Proteins of STAT family belongs to the transcription factors. Through their binding to the DNA specific sites and consequent regulation of transcription of various genes, these signaling proteins play an important role in many cell functions. Recent studies demonstrated persistent activation of STATs and loss of their natural inhibitors SOCS and PIAS in various human cancers. There is also evidence that experimental pharmacologic or genetic modulation of their function mignt by a new approach in anticancer treatment. The aim of this study was in vitro assesment and analysis of expression of STATs, SOCS and PIAS in glioblastoma cell lines undergoing treatment by PPARgamma agonists/antagonists because PPARgamma and STATs are tightly regulated by an overlapping set of nuclear regulatory proteins. We further analysed immunohistochemical expression of these proteins in vivo, with its correlation to grading in various brain tumors. The results of in vitro study showed decreased expression of phosphorylated form of STAT3 and increase of its inhibitors SOCS3 and PIAS3 in glioblastoma cell lines after treatment with IC50 of PPARgamma agonist ciglitazone. In vivo study failed to reveal changes in STAT3 and SOCS3 expression in either low and high grade astrocytomas, however we detect lower expression of STAT2 in low grade astrocytomas when comparing with high grade astrocytomas and lower expression of STAT3 in ependymomas when comparing with anaplastic ones. The results showed existing relationship between STAT and PPARgamma signaling in glial tumors and further suppport expected important role of STATs in regulation of growth and differentiation in these tumors.

The nuclear receptors PPARs (peroxisome proliferator-activated receptors) are transcription factors activated by specific ligands. PPARs play an important role in carcinogenesis, inflammation, atherosclerosis, lipid metabolism and diabetes. There is evidence that activation of PPARs by specific ligands is able to suppress the growth of different types of human cancer by mechanisms including the growth arrest, apoptosis and induction of differentiation, although the detailed signalling pathways have not been completely elucidated to date. The aim of our study was to determine whether synthetic ligands of PPARalpha and PPARgamma could affect the viability, proliferation, differentiation, apoptosis and expression of some cell cycle related proteins in glial tumor cell lines. The study was performed on human glioblastoma cell lines U-87 MG, T98G, A172 and U-118 MG. Cell lines were treated by ligands of PPARalpha (bezafibrate, gemfibrozil) and PPARgamma (ciglitazone). MTT, flow cytometry, TUNEL assay and immunoblotting were used for detection of changes in cell viability, proliferation, differentiation and apoptosis. Bezafibrate, ciglitazone and gemfibrozil inhibited viability of glioblastoma cell lines. The synthetic ligands significantly reduced or induced the expression of cyclins, p27Kip1, p21Waf1/Cip1, MDM-2, Bcl-2, Bax, PARP, Caspase 3, androgen receptors, etc. and did not affect the expression of the differentiation marker GFAP. Flow cytometry confirmed arrest of the cell cycle although the detection of apoptosis was controversial. Apart from hypolipidemic and hypoglycaemic effects, PPAR ligands may also have significant cytostatic effects of potential use in anticancer treatment.

Immunohistochemically assessed p53 expression was correlated with overall survival in 20 patients with glioblastoma multiforme. Various epitopes of p53 molecule were detected using DO-1, DO-7, CM-1 and BP-12-53 antibodies, proliferative activity was estimated using anti-PCNA and anti-Ki-67 antibodies and assessment of glycosylation changes using lectin histochemistry completed the study. The results show a statistically significant correlation between DO-1 binding and survival. However, we failed to find any similar statistically significant relationship using other antibodies used in this study. Nor the intensity of proliferative activity show any correlation with either p53 expression or overall survival. Glycosylation in glioblastoma multiforme cells reflected unspecific changes in tumor cells regardless of any relationship to p53 expression. The findings do not provide clear evidence for the predictive value of p53 expression. On the other hand, relatively larger numbers of p53 immunonegative cases may indicate that other mechanisms are involved in the development of this tumor.