Prognostic value of MGMT promoter methylation in glioblastoma patients treated with temozolomide-based chemoradiation : a Portuguese multicentre study

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. The identification of novel molecular prognostic markers of GBM has recently been an area of great interest in neuro-oncology. The methylation status of the MGMT gene promoter is currently a promising molecular prognostic marker, but some controversial data have precluded its clinical use. We analyzed MGMT methylation by methylation-specific PCR in 90 GBM patients from four Portuguese hospitals, uniformly treated with radiotherapy combined with concomitant and adjuvant temozolomide (Stupp protocol). The Kaplan-Meier method was used to construct survival curves, and the log-rank test and a Cox-regression model were used to analyze patient survival. The methylation status of MGMT was successfully determined in 89% (80/90) of the tumors. The frequency of tumoral MGMT promoter methylation was 47.5%. The median overall survivals (OSs) were 16 months (95% CI 12.2-19.8) and 13 months (95% CI 13.3-18.7) for patients whose tumors had a methylated or unmethylated MGMT, respectively. Univariate and multivariate analyses did not show any statistically significant association between MGMT methylation status and patient OS (P=0.583 by the log-rank test; P=0.617 by the Cox-regression test) or progression-free survival (P=0.775 by the log-rank test; P=0.691 by the Cox-regression test). None of the patient clinical features were significantly correlated with survival. This is the first study to report the frequency of MGMT methylation among Portuguese GBM patients. Our data did not show statistically significant associations between MGMT promoter methylation and the outcome of GBM patients treated with temozolomide. Additional robust prospective studies are warranted to clarify whether the MGMT status should be used in clinical decisions.This project was sponsored, in part, by Schering-Ploug Farma (Portugal). B.M.C. and O.M. are recipients of fellowships from the Portuguese Science and Technology Foundation (SFRH/BPD/33612/2009 and SFRH/BD/36463/ 2007). The funding institutions had no role in the study design, data collection and analysis, interpretation of the results, the preparation of the manuscript, or the decision to submit the manuscript for publication

Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets

Background. Gliomas exhibit high glycolytic rates, and monocarboxylate transporters (MCTs) play a major role in the maintenance of the glycolytic metabolism through the proton-linked transmembrane transport of lactate. However, their role in gliomas is poorly studied. Thus, we aimed to characterize the expression of MCT1, MCT4, and their chaperone CD 147 and to assess the therapeutic impact of MCT inhibition in gliomas. Methods. MCTs and CD 147 expressions were characterized by immunohistochemistry in nonneoplastic brain and glioma samples. The effect of CHC (MCT inhibitor) and MCT1 silencing was assessed in in vitro and in vivo glioblastoma models. Results. MCT1, MCT4, and CD 147 were overexpressed in the plasma membrane of glioblastomas, compared with diffuse astrocytomas and nonneoplastic brain. CHC decreased glycolytic metabolism, migration, and invasion and induced cell death in U251 cells (more glycolytic) but only affected proliferation in SW1088 (more oxidative). The effectiveness of CHC in glioma cells appears to be dependent on MCT membrane expression. MCT1 downregulation showed similar effects on different glioma cells, supporting CHC as an MCT1 inhibitor. There was a synergistic effect when combining CHC with temozolomide treatment in U251 cells. In the CAM in vivo model, CHC decreased the size of tumors and the number of blood vessels formed. Conclusions. This is the most comprehensive study reporting the expression of MCTs and CD 147 in gliomas. The MCT1 inhibitor CHC exhibited anti-tumoral and anti-angiogenic activity in gliomas and, of importance, enhanced the effect of temozolomide. Thus, our results suggest that development of therapeutic approaches targeting MCT1 may be a promising strategy in glioblastoma treatment.Life and Health Sciences Research Institute, University of Minho, Portugal; Fundacao para a Ciencia e Tecnologia [SFRH/BI/33503/2008, SFRH/BPD/69479/2010, SFRH/BD/36463/2007]info:eu-repo/semantics/publishedVersio

Downregulation of RKIP Is Associated with Poor Outcome and Malignant Progression in Gliomas

Malignant gliomas are highly infiltrative and invasive tumors, which precludes the few treatment options available. Therefore, there is an urgent need to elucidate the molecular mechanisms underlying gliomas aggressive phenotype and poor prognosis. The Raf Kinase Inhibitory protein (RKIP), besides regulating important intracellular signaling cascades, was described to be associated with progression, metastasis and prognosis in several human neoplasms. Its role in the prognosis and tumourigenesis of gliomas remains unclear

Benign Osteoblastoma of the Sphenoid Bone

Osteoblastoma is an uncommon benign bone tumor that accounts for 1% of all primary bone tumors. Well documented in the spine and long bones, it is rarely found in the skull, namely in the sphenoid bone, with only five cases reported in the literature. We report a case of an 11-year-old girl with a histologically confirmed benign osteoblastoma in an unusual location and an atypical aspect on the imaging studies

Sarcoidose nasal e laríngea â Caso clínico

Resumo: Os autores apresentam um caso clínico de uma doente de 41 anos a quem foi efectuado o diagnóstico de sarcoidose com base em manifestações clínicas nasais e laríngeas. Os autores fazem uma breve revisão bibliográfica sobre as manifestações clínicas da sarcoidose em ORL, nomeadamente no que concerne ao diagnóstico, terapêutica e prognóstico desta entidade clínica. Abstract: The authors present the case of a 41-year -old woman with nasal and laryngeal involvement by sarcoidosis, review the literature and discuss the otolaryngologic manifestations, the diagnostic evaluation, treatment and prognostic of this entity. Palavras-chave: Sarcoidose, nasal, laringe, otorrinolaringologia, Key Words: Sarcoidosis, nasal, laryngeal, otolaryngologic manifestation

Sarcoidose nasal e laríngea: Caso clínico Nasal and laryngeal sarcoidosis: Case presentation

Os autores apresentam um caso clínico de uma doente de 41 anos a quem foi efectuado o diagnóstico de sarcoidose com base em manifestações clínicas nasais e laríngeas. Os autores fazem uma breve revisão bibliográfica sobre as manifestações clínicas da sarcoidose em ORL, nomeadamente no que concerne ao diagnóstico, terapêutica e prognóstico desta entidade clínica.The authors present the case of a 41-year-old woman with nasal and laryngeal involvement by sarcoidosis, review the literature and discuss the otolaryngologic manifestations, the diagnostic evaluation, treatment and prognostic of this entity