Surgeon experience in glioblastoma surgery of the elderly : a multicenter, retrospective cohort study

Purpose To assess the impact of individual surgeon experience on overall survival (OS), extent of resection (EOR) and surgery-related morbidity in elderly patients with glioblastoma (GBM), we performed a retrospective case-by-case analysis. Methods GBM patients aged≥65 years who underwent tumor resection at two academic centers were analyzed. The experience of each neurosurgeon was quantifed in three ways: (1) total number of previously performed glioma surgeries (lifetime experience); (2) number of surgeries performed in the previous fve years (medium-term experience) and (3) in the last two years (short-term experience). Surgeon experience data was correlated with survival (OS) and surrogate parameters for surgical quality (EOR, morbidity). Results 198 GBM patients (median age 73.0 years, median preoperative KPS 80, IDH-wildtype status 96.5%) were included. Median OS was 10.0 months (95% CI 8.0–12.0); median EOR was 89.4%. Surgery-related morbidity afected 19.7% patients. No correlations of lifetime surgeon experience with OS (P=.693), EOR (P=.693), and surgery-related morbidity (P=.435) were identifed. Adjuvant therapy was associated with improved OS (PConclusion Less experienced neurosurgeons achieve similar surgical results and outcome in elderly GBM patients within the setting of academic teaching hospitals. Adjuvant treatment and avoidance of surgery-related morbidity are crucial forgenerating a treatment beneft for this cohort.Peer reviewe

Chronic in vitro temozolomide treatment of human glioblastoma cell lines fails to induce resistance to the drug in vitro or in vivo but modifies gene expression.

info:eu-repo/semantics/nonPublishe

Inhibition of the sodium pump alpha-1 subunit in glioblastoma cells induce autophagy.

Abstract A35info:eu-repo/semantics/nonPublishe

Association between <i>MGMT</i> Enhancer Methylation and <i>MGMT</i> Promoter Methylation, MGMT Protein Expression, and Overall Survival in Glioblastoma

The repair protein O6-methylguanine-DNA methyltransferase (MGMT) is regulated epigenetically, mainly by the methylation of the MGMT promoter. MGMT promoter methylation status has emerged as a prognostic and predictive biomarker for patients with newly diagnosed glioblastoma (GBM). However, a strong negative correlation between MGMT promoter methylation and MGMT protein expression cannot be applied as a rule for all GBM patients. In order to investigate if the DNA methylation status of MGMT enhancers is associated with MGMT promoter methylation, MGMT expression, and the overall survival (OS) of GBM patients, we established assays based on high-resolution melting analysis and pyrosequencing for one intragenic and three intergenic MGMT enhancers. For CpGs in an enhancer located 560 kb upstream of the MGMT promoter, we found a significant negative correlation between the methylation status and MGMT protein levels of GBM samples expressing MGMT. The methylation status of CpGs in the intragenic enhancer (hs696) was strongly negatively correlated with MGMT promoter methylation and was significantly higher in MGMT-expressing GBM samples than in MGMT-non-expressing GBM samples. Moreover, low methylation of CpGs 01–03 and CpGs 09–13 was associated with the longer OS of the GBM patients. Our findings indicate an association between MGMT enhancer methylation and MGMT promoter methylation, MGMT protein expression, and/or OS

UNBS1450, a novel cardenolide that inhibits sodium pump alpha1 subunits which are overexpressed in glioblastomas.

Abstract 2672info:eu-repo/semantics/nonPublishe

Temozolomide displays anti-migratory effects in human glioblastoma cells through neuregulin down-regulation.

info:eu-repo/semantics/nonPublishe

Screening of anti-glioma effects induced by sigma-1 receptor ligands: potential new use for old anti-psychiatric medicines.

The prognosis of glioblastoma (GBM) remains poor. Diffuse invasion of distant brain tissue by migrating cells from the primary tumour mass has already occurred at time of diagnosis. Anti-cancer effects of a selective sigma-1 agonist, 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), in glioblastoma were shown previously, leading to the present work where the effects on glioblastoma cells of 17 agonists or antagonists of sigma-1 receptors were studied, including currently marketed drugs fluvoxamine, dextromethorphan, donepezil, memantine and haloperidol. We first showed that established GBM cell lines, primary cultures and surgical specimens express sigma-1 receptors. In vitro analyses then focused on anti-proliferation and anti-migratory effects on human glioblastoma cell lines using quantitative videomicroscopy analyses. These cell monitoring assays revealed specific impacts on the mitotic cell process. Using an aggressive glioma model orthotopically grafted into the brains of immunocompromised mice, we showed that combining donepezil and temozolomide gave additive benefit in terms of long survivors as compared to temozolomide or donepezil alone. Clinical study is planned if further rodent dose-ranging studies of donepezil with temozolomide continue to show evidence of benefit in this model.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Temozolomide-induced modification of the CXC chemokine network in experimental gliomas

CXCL chemokines display important roles in glioblastoma (GBM) biology, including cell proliferation, death and migration features. While temozolomide (TMZ) represents the standard chemotherapeutic used to treat GBM patients, its role in CXCL networking in GBMs remains unexplored. The effects of short-term and long-term in vitro treatment with temozolomide on CXCL chemokine expression were characterized in human malignant glioma cell lines. U373 and T98G astroglioma and Hs683 oligodendroglioma cells were cultured for months in the presence of increasing concentrations of TMZ (up to 1 mM), and their whole genome profiles were analyzed along with a complete mapping of all CXCL chemokines and their respective receptor mRNAs. The study was extended to an additional established cell line and four primocultures. The in vitro results were compared with a clinical series of 156 human gliomas and 23 normal brain tissue samples. The expression and secretion of CXCL2, CXCL3 and CXCL8 following different TMZ treatments were determined in Hs683, U373 and T98G glioma cells. The long-term TMZ-treated astroglioma cells, but not the Hs683 oligodendroglioma cells, developed in vivo a certain level of resistance to TMZ, which correlated with the up- regulation of CXCL2, CXCL3 and CXCL8 expression in the U373 and T98G astroglioma cells. The transient down-regulation of CXCL2 in Hs683 glioma cells using siRNA markedly impaired their proliferation rate. In conclusion, TMZ affects the expression and secretion of CXCL2 (and, to a lesser extent, CXCL3 and CXCL8) in glioma cells, and CXCL2 directly impacts glioma cell biology. Copyright © 2011 Spandidos Publications Ltd. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.

Melanoma is a devastating skin cancer characterized by distinct biological subtypes. Besides frequent mutations in growth- and survival-promoting genes like BRAF and NRAS, melanomas additionally harbor complex non-random genomic alterations. Using an integrative approach, we have analysed genomic and gene expression changes in human melanoma cell lines (N=32) derived from primary tumors and various metastatic sites and investigated the relation to local growth aggressiveness as xenografts in immuno-compromised mice (N=22). Although the vast majority >90% of melanoma models harbored mutations in either BRAF or NRAS, significant differences in subcutaneous growth aggressiveness became obvious. Unsupervised clustering revealed that genomic alterations rather than gene expression data reflected this aggressive phenotype, while no association with histology, stage or metastatic site of the original melanoma was found. Genomic clustering allowed separation of melanoma models into two subgroups with differing local growth aggressiveness in vivo. Regarding genes expressed at significantly altered levels between these subgroups, a surprising correlation with the respective gene doses (>85% accordance) was found. Genes deregulated at the DNA and mRNA level included well-known cancer genes partly already linked to melanoma (RAS genes, PTEN, AURKA, MAPK inhibitors Sprouty/Spred), but also novel candidates like SIPA1 (a Rap1GAP). Pathway mining further supported deregulation of Rap1 signaling in the aggressive subgroup e.g. by additional repression of two Rap1GEFs. Accordingly, siRNA-mediated down-regulation of SIPA1 exerted significant effects on clonogenicity, adherence and migration in aggressive melanoma models. Together our data suggest that an aneuploidy-driven gene expression deregulation drives local aggressiveness in human melanoma.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe