Relative survival of patients with non-malignant central nervous system tumours: a descriptive study by the Austrian Brain Tumour Registry.

BACKGROUND: Unlike malignant primary central nervous system (CNS) tumours outcome data on non-malignant CNS tumours are scarce. For patients diagnosed from 1996 to 2002 5-year relative survival of only 85.0% has been reported. We investigated this rate in a contemporary patient cohort to update information on survival. METHODS: We followed a cohort of 3983 cases within the Austrian Brain Tumour Registry. All patients were newly diagnosed from 2005 to 2010 with a histologically confirmed non-malignant CNS tumour. Vital status, cause of death, and population life tables were obtained by 31 December 2011 to calculate relative survival. RESULTS: Overall 5-year relative survival was 96.1% (95% CI 95.1-97.1%), being significantly lower in tumours of borderline (90.2%, 87.2-92.7%) than benign behaviour (97.4%, 96.3-98.3%). Benign tumour survival ranged from 86.8 for neurofibroma to 99.7% for Schwannoma; for borderline tumours survival rates varied from 83.2 for haemangiopericytoma to 98.4% for myxopapillary ependymoma. Cause of death was directly attributed to the CNS tumour in 39.6%, followed by other cancer (20.4%) and cardiovascular disease (15.8%). CONCLUSION: The overall excess mortality in patients with non-malignant CNS tumours is 5.5%, indicating a significant improvement in survival over the last decade. Still, the remaining adverse impact on survival underpins the importance of systematic registration of these tumours.

FGF5 as an oncogenic factor in human glioblastoma multiforme: autocrine and paracrine activities.

Fibroblast growth factor 5 (FGF5) is widely expressed in embryonic but scarcely in adult tissues. Here we report simultaneous overexpression of FGF5 and its predominant high-affinity receptor (FGFR1 IIIc) in astrocytic brain tumour specimens (N=49) and cell cultures (N=49). The levels of both ligand and receptor increased with enhanced malignancy in vivo and in vitro. Furthermore, secreted FGF5 protein was generally present in the supernatants of glioblastoma (GBM) cells. siRNA-mediated FGF5 downmodulation reduced moderately but significantly GBM cell proliferation while recombinant FGF5 (rFGF5) increased this parameter preferentially in cell lines with low endogenous expression levels. Apoptosis induction by prolonged serum starvation was significantly prevented by rFGF5. Moreover, tumour cell migration was distinctly stimulated by rFGF5 but attenuated by FGF5 siRNA. Blockade of FGFR1-mediated signals by pharmacological FGFR inhibitors or a dominant-negative FGFR1 IIIc protein inhibited GBM cell proliferation and/or induced apoptotic cell death. Moreover, rFGF5 and supernatants of highly FGF5-positive GBM cell lines specifically stimulated proliferation, migration and tube formation of human umbilical vein endothelial cells. In summary, we demonstrate for the first time that FGF5 contributes to the malignant progression of human astrocytic brain tumours by both autocrine and paracrine effects.

Dynamics of chemosensitivity and chromosomal instability in recurrent glioblastoma.

Glioblastoma multiforme is characterised by invasive growth and frequent recurrence. Here, we have analysed chromosomal changes in comparison to tumour cell aggressiveness and chemosensitivity of three cell lines established from a primary tumour and consecutive recurrences (BTL1 to BTL3) of a long-term surviving glioblastoma patient together with paraffin-embedded materials of five further cases with recurrent disease. Following surgery, the BTL patient progressed under irradiation/ lomustine but responded to temozolomide after re-operation to temozolomide. The primary tumour -derived BTL1 cells showed chromosomal imbalances typical of highly aggressive glioblastomas. Interestingly, BTL2 cells established from the first recurrence developed under therapy showed signs of enhanced chromosomal instability. In contrast, BTL3 cells from the second recurrence resembled a less aggressive subclone of the primary tumour. Although BTL2 cells exhibited a highly aggressive phenotype, BTL3 cells were characterised by reduced proliferative and migratory potential. Despite persistent methylation of the O6-methylguanine-DNA methyltransferase promoter, BTL3 cells exhibited the highest temozolomide sensitivity. A comparable situation was found in two out of five glioblastoma patients, both characterised by enhanced survival time, who also relapsed after surgery/chemotherapy with less aggressive recurrences. Taken together, our data suggest that pretreated glioblastoma patients may relapse with highly chemosensitive tumours confirming the feasibility of temozolomide treatment even in case of repeated recurrence.

Overexpression of the human major vault protein in astrocytic brain tumor cells.

Evidence has shown that the major human vault protein (MVP), which is identical to lung resistance-related protein (LRP), may be causally involved in a special type of multidrug resistance (MDR). The purpose of this study was to investigate the expression and cellular localization of MVP in cells derived from brain tumors and other tumors of neuroectodermal origin. Using both established cell lines (n = 22) and primary explants (n = 30), we show that a distinct overexpression of the MVP gene at the mRNA (RT-PCR) and protein (Western blot) levels is a characteristic feature of cells derived from astrocytic brain tumors. Primary cultures obtained from meningioma specimens also expressed high MVP levels, in contrast to neuroblastoma and medulloblastoma cells, which rarely contained detectable amounts of MVP. Normal human astrocytes cultured in vitro expressed MVP, although at low amounts compared with most malignant cell types. Basal MVP expression correlated with resistance against diverse antineoplastic drugs including anthracyclins, cisplatin and etoposide. By Western blot, MVP was also detected in all tumor samples taken from 7 glioma and 3 meningioma patients. Taken together, these data suggest overexpression of MVP as one explanation for the low efficacy of chemotherapeutic treatment of astrocytic brain tumors.