Genetic variants of vascular endothelial growth factor predict risk and survival of gliomas

The vascular endothelial growth factor regulates angiogenesis that is increased in glioma. VEGF polymorphisms are thought to modulate vascular endothelial growth factor plasma levels and therefore may be implicated in glioma risk. We aimed to clarify the role of VEGF and von Willebrand factor polymorphisms in glioma susceptibility and prognosis. A case-control study of 126 glioma patients and 180 cancer-free controls was performed. Using Sequenom MassARRAY platform, 11 VEGF and 1 VWF polymorphisms were genotyped. Unconditional multivariate logistic regression models were used to calculate odds ratios and 95% confidence intervals. The associations between polymorphisms and survival were evaluated using a Cox regression model. Bonferroni's adjustment was used to correct for multiple testing. The VEGF polymorphism rs833061 was strongly associated with increased risk for glioma (odds ratio = 164.85) and glioblastoma (odds ratio = 155.66), confirmed after Bonferroni correction. Also, the VEGF polymorphisms rs3024994, rs2010963, and particularly the homozygous carriers of rs1005230 were associated with a worse prognosis for glioma and glioblastoma. Our data support a role of VEGF and VWF polymorphisms as glioma biomarkers, with additional potential relevance for molecular stratification of patients for anti-angiogenic therapies.FCT -Fundação para a Ciência e a Tecnologia(NORTE-01-0145-FEDER-000013)info:eu-repo/semantics/publishedVersio

Impact of EGFR genetic variants on glioma risk and patient outcome

B.M. Costa and M. Viana-Pereira contributed equally to this work; The authors thank the Immunochemotherapy Department of Hospital S. Marcos, and Clinica Laboratorial Dr. Edgar Botelho Moniz, S. Tirso, Portugal, for their helpful assistance in the management of controlsBACKGROUND: The epidermal growth factor receptor (EGFR) regulates important cellular processes and is frequently implicated in human tumors. Three EGFR polymorphisms have been described as having a transcriptional regulatory function: two single-nucleotide polymorphisms in the essential promoter region, -216G/T and -191C/A, and a polymorphic (CA)(n) microsatellite sequence in intron 1. We aimed to elucidate the roles of these EGFR polymorphisms in glioma susceptibility and prognosis. METHODS: We conducted a case-control study with 196 patients with glioma and 168 cancer-free controls. Unconditional multivariate logistic regression models were used to calculate ORs and 95% confidence intervals. A Cox regression model was used to evaluate associations with patient survival. False-positive report probabilities were also assessed. RESULTS: None of the EGFR -216G/T variants was significantly associated with glioma risk. The -191C/A genotype was associated with higher risk for glioma when the (CA)(n) alleles were classified as short for ≤16 or ≤17 repeats. Independently of the (CA)(n) repeat cutoff point used, shorter (CA)(n) repeat variants were significantly associated with increased risk for glioma, particularly glioblastoma and oligodendroglioma. In all tested models with different (CA)(n) cutoff points, only -191C/A genotype was consistently associated with improved survival of patients with glioblastoma. CONCLUSIONS: Our findings implicate EGFR -191C/A and the (CA)(n) repeat polymorphisms as risk factors for gliomas, and suggest -191C/A as a prognostic marker in glioblastoma. Impact: Our data support a role of these EGFR polymorphisms in determining glioma susceptibility, with potential relevance for molecularly based stratification of patients with glioblastoma for individualized therapies.Schering-Plough Farma, PortugalFundação para a Ciência e a Tecnologia (FCT) - SFRH/BPD/33612/2009; SFRH/BD/29145/200

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

Impact of TGF-ß1 -509C/T and 869T/C polymorphisms on glioma risk and patient prognosis

Transforming growth factor beta (TGF-ß) plays an important role in carcinogenesis. Two polymorphisms in the TGF-ß1 gene (-509C/T and 869T/C) were described to influence susceptibility to gastric and breast cancers. The 869T/C polymorphism was also associated with overall survival in breast cancer patients. In the present study, we investigated the relevance of these TGF-ß1 polymorphism in glioma risk and prognosis. A case-control study that included 114 glioma patients and 138 cancer-free controls was performed. Single nucleotide polymorphisms (SNPs) were evaluated by polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP). Univariate and multivariate logistic regression analyses were used to calculate odds ratio (OR) and 95 % confidence intervals (95 % CI). The influence of TGF-ß1 -509C/T and 869T/C polymorphisms on glioma patient survival was evaluated by a Cox regression model adjusted for patients' age and sex and represented in Kaplan-Meier curves. Our results demonstrated that TGF-ß1 gene polymorphisms -509C/T and 869T/C are not significantly associated with glioma risk. Survival analyses showed that the homozygous -509TT genotype associates with longer overall survival of glioblastoma (GBM) patients when compared with patients carrying CC + CT genotypes (OR, 2.41; 95 % CI, 1.06-5.50; p = 0.036). In addition, the homozygous 869CC genotype is associated with increased overall survival of GBM patients when compared with 869TT + TC genotypes (OR, 2.62; 95 % CI, 1.11-6.17; p = 0.027). In conclusion, this study suggests that TGF-ß1 -509C/T and 869T/C polymorphisms are not significantly associated with risk for developing gliomas but may be relevant prognostic biomarkers in GBM patients.This work was supported by Fundação para a Ciência e Tecnologia, Portugal (PTDC/SAU-GMG/113795/2009 and SFRH/BPD/33612/2009 to B.M.C.; SFRH/BD/88121/2012 to J.V.C.; SFRH/BD/92786/2013 to C.S.G.; PTDC/SAU-ONC/115513/2009 to R.R.)

Variação do peso de doentes oncológicos em quimioterapia

Introdução: O cancro representa 13% da mortalidade mundial e em Portugal diagnosticam-se, anualmente, entre 40 a 45 mil novos casos de cancro. A quimioterapia é largamente utilizada como terapia do cancro, um estado nutricional adequado pode reduzir complicações do tratamento. Muitos autores estudaram a alteração do peso induzida pela quimioterapia mas, enquanto que alguns mencionam que ocorre um aumento do peso, outros afirmam que há perda de peso. Objectivo: Avaliar a variação do peso corporal de doentes oncológicos antes e depois de realizarem quimioterapia. Materiais e métodos: Um estudo longitudinal e retrospectivo foi realizado no Serviço de Oncologia do Hospital de São Marcos de Braga. Foram incluídos no estudo todos os doentes com qualquer tipo de cancro, com idade superior a 18 anos e que iniciaram quimioterapia pela primeira vez no período entre Janeiro de 2007 e Abril de 2008, totalizando 130 indivíduos. A data de nascimento, o tipo de quimioterapia, o tipo de cancro, o número de ciclos de quimioterapia, a altura, o peso antes de iniciar a quimioterapia e o peso entre sexto e o sétimo mês após o início da quimioterapia, foram os dados recolhidos através da análise dos processos clínicos Resultados/Discussão: Verificou-se que, em média, o peso corporal aumentou significativamente 2,13 Kg após seis meses de quimioterapia (p=0,004), aumentando também o IMC 0,79 kg/m2 (p=0,006). Este aumento de peso pode dever-se ao facto de a quimioterapia reduzir o tumor, o que leva a uma melhor deglutição e a um aumento da quantidade de alimentos ingeridos que favorece o aumento de peso

Pneumonia Organizativa Fibrinosa Aguda Induzida pelo Rituximab: Uma Entidade a (Re)conhecer

A pneumonia organizativa fibrinosa aguda é uma entidade histológica, incluída no grupo das doenças pulmonares intersticiais, com múltiplas etiologias, incluindo a toxicidade farmacológica. Os autores descrevem o caso de um homem de 73 anos, com diagnóstico de linfoma linfoplasmocítico, sob tratamento de manutenção com rituximab após quimioterapia. O doente desenvolveu um quadro clínico insidioso caracterizado por tosse não produtiva, dispneia e astenia. A integração dos aspetos imagiológicos e da histologia de biópsia pulmonar conduziram ao diagnóstico de pneumonia organizativa fibrinosa aguda. Após suspensão do fármaco e instituição de corticoterapia o doente apresentou evolução clínica e imagiológica favorável. Dada a utilização crescente de terapêuticas-alvo em oncologia, o presente caso pretende contribuir para o reconhecimento desta entidade como potencial evento adverso. Recebido: 07/06/2017 - Aceite: 30/08/201

Quality of Life in Breast Cancer Patients: The Moderator Role of Family Stress

En pacientes con cáncer de mama, la calidad de vida se ha aso- ciado con la respuesta al tratamiento y la supervivencia global. Cien muje- res sometidas a tratamiento de quimioterapia para el cáncer de mama completaron cuestionarios incluyendo información demográfica y clínica, Cuestionario de Calidad de Vida EORTC, Escalas de Ansiedad y Depre- sión Hospitalaria, Escala de Imagen Corporal, Índice de Relaciones Fami- liares y el Test de Orientación Vital. Los resultados mostraron que un ma- yor optimismo y una mejor imagen corporal se asociaron con una mejor calidad de vida. La morbilidad psicológica predijo significativamente la ca- lidad de vida física y emocional, pero la recurrencia sólo predijo la calidad de vida física. El estrés familiar fue un moderador en la relación entre la morbilidad psicológica y la calidad de vida emocional, mostrando la nece- sidad de detectar e intervenir en el estrés familiar en pacientes con cáncer de mama. Los resultados pueden ayudar en el diseño de intervenciones pa- ra las mujeres con cáncer de mama con el fin de promover la calidad de vi- da.In breast cancer patients, quality of life has been associated with treatment response and overall survival. One hundred women undergoing chemotherapy treatment for breast cancer completed questionnaires in- cluding demographic and clinical information, the EORTC - Quality of Life Questionnaire, Hospital Anxiety and Depression Scales, Body Image Scale, Index of Family Relations and the Life Orientation Test. The results showed that higher optimism and better body image were associated with improved quality of life. Distress significantly predicted physical and emo- tional quality of life, but recurrence only predicted physical quality of life. Family stress was a moderator in the relationship between psychological distress and emotional quality of life, showing the need to screen and in- tervene on family stress in patients with breast cancer. The results may help in designing interventions for women with breast cancer in order to promote quality of life

Immunoglobulin genes implicated in glioma risk

Both genetic and environmental factors are thought to be causal in gliomagenesis. Several genes have been implicated in glioma development, but the putative role of a major immunity-related gene complex member, immunoglobulin heavy chain ? (IGHG) has not been evaluated. Prior observations that IGHG-encoded ? marker (GM) allotypes exhibit differential sensitivity to an immunoevasion strategy of cytomegalovirus, a pathogen implicated as a promoter of gliomagenesis, has lead us to hypothesize that these determinants are risk factors for glioma. To test this hypothesis, we genotyped the IGHG locus comprising the GM alleles, specifically GM alleles 3 and 17, of 120 glioma patients and 133 controls via TaqMan® genotyping assay. To assess the associations between GM genotypes and the risk of glioma, we applied an unconditional multivariate logistic regression analysis adjusted for potential confounding variables. In comparison to subjects who were homozygous for the GM 17 allele, the GM 3 homozygotes were over twice as likely, and the GM 3/17 heterozygotes were over three times as likely, to develop glioma. Similar results were achieved when analyzed by combining the data corresponding to alleles GM 3 and GM 3/17 in a dominant model. The GM 3/17 genotype and the combination of GM 3 and GM 3/17 were found to be further associated with over 3 times increased risk for high-grade astrocytoma (grades III-IV). Allele frequency analyses also showed an increased risk for gliomas and high-grade astrocytoma in association with GM 3. Our findings support the premise that the GM 3 allele may present risk for the development of glioma, possibly by modulating immunity to cytomegalovirus.This work was supported in part by the US. National Institute of Neurological Disorders and Stroke and by Fundacao a Ciencia e Tecnologia, Portugal (PTDC/SAU-ONC/115513/2009). The authors thank the Immunochemotherapy Department of Hospital S. Marcos, and Clinica Laboratorial Dr. Edgar Botelho Moniz, S. Tirso, Portugal, for their helpful assistance in the management of controls, and to Monica Ferreira from ICVS for her valuable assistance in the management of cases and controls