The Effect of Polymorphisms in DNA Repair Genes and Carcinogen Metabolizers on Leukocyte Telomere Length: A Cohort of Healthy Spanish Smokers.

INTRODUCTION: Smoking implies exposure to carcinogenic agents that causes DNA damage, which could be suspected to enhance telomere attrition. To protect and deal with DNA damage, cells possess mechanisms that repair and neutralize harmful substances. Polymorphisms altering DNA repair capacity or carcinogen metabolism may lead to synergistic effects with tobacco carcinogen-induced shorter telomere length independently of cancer interaction. The aim of this study was to explore the association between leukocyte telomere length (LTL) and several genetic polymorphisms in DNA repair genes and carcinogen metabolizers in a cohort of healthy smokers. METHODS: We evaluated the effect of six genetic polymorphisms in cytochrome P1A1 (Ile462Val), XRCC1 (Arg399Gln), APEX1 (Asp148Glu), XRCC3 (Thr241Met), and XPD (Asp312Asn; Lys751Gln) on LTL in a cohort of 145 healthy smokers in addition to smoking habits. RESULTS: Logistic regression analysis showed an association between XRCC1 399Gln allele and shorter telomere length (OR = 5.03, 95% CI = 1.08% to 23.36%). There were not association between the rest of polymorphisms analyzed and LTL. CONCLUSIONS: Continuous exposure to tobacco could overwhelm the DNA repair machinery, making the effect of the polymorphisms that reduce repair capacity more pronounced. Analyzing the function of smoking-induced DNA-repair genes and LTL is an important goal in order to identify therapeutic targets to treat smoking-induced diseases.

Effects of cigarette smoking and nicotine metabolite ratio on leukocyte telomere length.

Studies of the effects of smoking on leukocyte telomere length (LTL) using cigarettes smoked per day or pack years smoked (PYS) present limitations. Reported high levels of smoking may not increase toxin exposure levels proportionally. Nicotine metabolism ratio (NMR) predicts total cigarette puff volume and overall exposure based on total N-nitrosamines, is highly reproducible and independent of time since the last cigarette. We hypothesized that smokers with higher NMRs will exhibit increased total puff volume, reflecting efforts to extract more nicotine from their cigarettes and increasing toxin exposure. In addition, higher levels of smoking could cause a gross damage in LTL. The urinary cotinine, 3-OH cotinine and nicotine levels of 147 smokers were analyzed using a LC/MS system Triple-Q6410. LTL and CYP2A6 genotype was determined by PCR in blood samples. We found a significant association between NMR and CYP2A6 genotype. Reduction in LTL was seen in relation to accumulated tobacco consumption and years smoking when we adjusted for age and gender. However, there were no significant differences between NMR values and LTL. In our study the higher exposure was associated with lower number of PYS. Smokers with reduced cigarette consumption may exhibit compensatory smoking behavior that results in no reduced tobacco toxin exposure. Our results suggest that lifetime accumulated smoking exposure could cause a gross damage in LTL rather than NMR or PYS. Nevertheless, a combination of smoking topography (NMR) and consumption (PYS) measures may provide useful information about smoking effects on health outcomes.

Are SNP-Smoking Association Studies Needed in Controls? DNA Repair Gene Polymorphisms and Smoking Intensity.

Variations in tobacco-related cancers, incidence and prevalence reflect differences in tobacco consumption in addition to genetic factors. Besides, genes related to lung cancer risk could be related to smoking behavior. Polymorphisms altering DNA repair capacity may lead to synergistic effects with tobacco carcinogen-induced lung cancer risk. Common problems in genetic association studies, such as presence of gene-by-environment (G x E) correlation in the population, may reduce the validity of these designs. The main purpose of this study was to evaluate the independence assumption for selected SNPs and smoking behaviour in a cohort of 320 healthy Spanish smokers. We found an association between the wild type alleles of XRCC3 Thr241Met or KLC3 Lys751Gln and greater smoking intensity (OR = 12.98, 95% CI = 2.86-58.82 and OR=16.90, 95% CI=2.09-142.8; respectively). Although preliminary, the results of our study provide evidence that genetic variations in DNA-repair genes may influence both smoking habits and the development of lung cancer. Population-specific G x E studies should be carried out when genetic and environmental factors interact to cause the disease.

Utilidad clínica e impacto económico de la punción transbronquial convencional de adenopatías mediastínicas en el carcinoma broncogénico / Clinical Utility and Economic Impact of Conventional Transbronchial Needle Aspiration of Mediastinal Lymphadenopathies in Bronchogenic Carcinoma

OBJETIVOS: Analizar la utilidad clínica y el impacto económico de la punción transbronquial convencional (PTBC) en los pacientes con carcinoma broncogénico (CB) y adenopatías mediastínicas en la tomografía computarizada (TC) torácica. Analizar los factores predictores de punción válida. PACIENTES Y MÉTODOS: Estudio observacional retrospectivo entre 2006 y 2011 de todas las PTBC realizadas a pacientes con CB y adenopatías mediastínicas o hiliares accesibles a la técnica en la TC torácica. RESULTADOS: Se realizó PTBC sobre 267 adenopatías de 192 pacientes. En el 34,9% de los pacientes se pinchó más de una adenopatía. Se obtuvo punción válida en 153 pacientes (79,7%) y diagnóstica en 124 (64,6%). El análisis multivariante mostró que los factores que se asocian a la obtención de punción válida y diagnóstica son el diámetro de la adenopatía y el número de adenopatías pinchadas. La PTBC fue la única técnica endoscópica que permitió el diagnóstico de CB en 54 pacientes (28,1%). La PTBC evitó el 67,6% de las mediastinoscopias de estadificación. La prevalencia de afectación tumoral mediastínica fue del 74,4%, la sensibilidad de la PTBC del 86,2% y el valor predictivo negativo del 63,6%. Entre mediastinoscopias y otras técnicas diagnósticas evitadas, la PTBC ha supuesto un ahorro de 451,57 € por paciente estudiado. CONCLUSIONES: La PTBC es una técnica clínicamente útil y económicamente rentable en los pacientes con CB y adenopatías patológicas mediastínicas o hiliares, por lo que debería ser realizada como una técnica endoscópica más, de forma habitual, en estos pacientes

OBJECTIVES: To analyze the clinical utility and economic impact of conventional transbronchial needle aspiration (TBNA) in patients with diagnosis of bronchogenic carcinoma (BC) and mediastinal lymphadenopathies in thoracic computed tomography (CT). To assess the predictive factors of valid aspirations. PATIENTS AND METHODS: Retrospective observational study between 2006 and 2011 of all TBNA performed in patients with final diagnosis of BC and accessible hilar or mediastinal lymphadenopathies on thoracic CT. RESULTS: We performed TBNA on 267 lymphadenopathies of 192 patients. In 34.9% of patients, two or more lymph nodes were biopsied. Valid aspirations were obtained in 153 patients (79.7%) that were diagnostic in 124 (64.6%). Multivariate analysis showed that factors associated with valid or diagnostic results are the diameter of the lymph node and the number of lymph nodes explored. TBNA was the only endoscopic technique that provided the diagnosis of BC in 54 patients (28.1%). Staging mediastinoscopy was avoided in 67.6% of patients. The prevalence of mediastinal lymph node involvement was 74.4%, sensitivity of TBNA was 86.2% and negative predictive value was 63.6%. Including mediastinoscopy and other avoided diagnostic techniques, TBNA saved 451.57 € per patient. CONCLUSIONS: TBNA is a clinically useful, cost-effective technique in patients with BC and mediastinal or hilar lymphadenopathies. It should therefore be performed on a regular basis during diagnostic bronchoscopy of these patients

Clinical utility and economic impact of conventional transbronchial needle aspiration of mediastinal lymphadenopathies in bronchogenic carcinoma.

OBJECTIVES: To analyze the clinical utility and economic impact of conventional transbronchial needle aspiration (TBNA) in patients with diagnosis of bronchogenic carcinoma (BC) and mediastinal lymphadenopathies in thoracic computed tomography (CT). To assess the predictive factors of valid aspirations. PATIENTS AND METHODS: Retrospective observational study between 2006 and 2011 of all TBNA performed in patients with final diagnosis of BC and accessible hilar or mediastinal lymphadenopathies on thoracic CT. RESULTS: We performed TBNA on 267 lymphadenopathies of 192 patients. In 34.9% of patients, two or more lymph nodes were biopsied. Valid aspirations were obtained in 153 patients (79.7%) that were diagnostic in 124 (64.6%). Multivariate analysis showed that factors associated with valid or diagnostic results are the diameter of the lymph node and the number of lymph nodes explored. TBNA was the only endoscopic technique that provided the diagnosis of BC in 54 patients (28.1%). Staging mediastinoscopy was avoided in 67.6% of patients. The prevalence of mediastinal lymph node involvement was 74.4%, sensitivity of TBNA was 86.2% and negative predictive value was 63.6%. Including mediastinoscopy and other avoided diagnostic techniques, TBNA saved 451.57 € per patient. CONCLUSIONS: TBNA is a clinically useful, cost-effective technique in patients with BC and mediastinal or hilar lymphadenopathies. It should therefore be performed on a regular basis during diagnostic bronchoscopy of these patients.

Vascular endothelial growth factor (VEGF) serum levels are associated with survival in early stages of lung cancer patients.

AIM: Evaluate the serum vascular endothelial growth factor (VEGF) levels in the prognosis of lung cancer patients. METHODS: Fifty-four serum samples were analyzed for VEGF concentrations (79.3% nonsmall cell lung cancer (NSCLC) and 20.7% small cell lung cancer). RESULTS: Patients with serum VEGF-A levels higher than the mean of the patients studied (434.93 pg/mL) presented a shorter median survival time than those with lower levels (p =.04), as in patients with NSCLC tumors (p =.04) and in those with stages I-II (p <.05), and high serum VEGF-A levels. CONCLUSION: Elevated VEGF serum levels have a negative prognostic impact on survival in NSCLC and early stages of lung cancer patients.

Prognostic significance of the expression of vascular endothelial growth factors A, B, C, and D and their receptors R1, R2, and R3 in patients with nonsmall cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer death in the world. The objective of this study was to investigate the expression of vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) in patients with nonsmall cell lung cancer (NSCLC) and its correlation with the prognosis for patients with lung cancer. METHODS: The expression status of VEGFs and VEGFRs was examined in 48 nonconsecutive specimens of primary lung cancer by immunohistochemistry. Correlations between the expression of VEGFs and VEGFRs and clinicopathologic parameters were analyzed. RESULTS: Nineteen of 48 samples (39.6%) were moderately/highly immunoreactive for VEGF-A, 6 samples (12.5%) were reactive for VEGF-B, 14 samples (29.2%) were reactive for VEGF-C, 11 samples (22.9%) were reactive for VEGF-D, 20 samples (41.7%) were reactive for VEGFR1, 26 samples (54.2%) were reactive for VEGFR2, 20 samples (41.7%) were reactive for VEGFR3, and 19 samples (39.6%) were reactive for nuclear expression of VEGFR3. Patients with moderate/high VEGF-C, VEGFR1, and VEGFR2 expression had worse survival, whereas patients with moderate/high VEGF-D and nuclear VEGFR3 expression had better survival. After adjusting according to tumor stage, VEGF-B and VEGF-D expression had a significant correlation with worse survival in patients with stage I and II disease. Patients with stage III and IV disease who had VEGFR1 and VEGFR2 expression had worse survival, whereas the expression of VEGF-D was correlated significantly with better survival. Finally, stage, VEGF-D expression, and VEGFR1 expression were significantly independent prognostic predictors. CONCLUSIONS: The results of the current study indicated that the over-expression of VEGFs and VEGFRs plays an important role in the survival of patients with NSCLC. The inclusion of angiogenic factors in the standard pathologic study of lung cancer may improve the clinical evaluation of patients with NSCLC.

El cáncer de pulmón en la mujer / Lung cancer in women

El cáncer de pulmón es la décima causa de muerte en el mundo, pero se estima que pasará a ocupar el quinto lugar en los próximos años. En España esta situación es aún peor, con un futuro poco alentador como consecuencia del cambio en el hábito tabáquico en las mujeres. Además de su incorporación masiva a un hábito de riesgo, las mujeres que fuman son más susceptibles que los varones a desarrollar cáncer de pulmón. Tras un diagnóstico de cáncer de pulmón, las mujeres tienen diferencias en el tipo histológico y, en términos generales, viven más que los varones. En relación con el tratamiento, las mujeres tienen mejores supervivencias tras cirugía en tumores localizados. También viven más tras quimioterapia en tumores de células peque- ñas y en los no microcíticos avanzados. Estos datos nos obligan a cambiar la creencia de que el cáncer de pulmón es una enfermedad que afecta principalmente al sexo masculino y a conocer las peculiaridades que puede presentar en las mujeres (AU)

Lung cancer is the tenth cause of death worldwide but is predicted to become the fifth cause in the next few years. In Spain, the situation is even worse, with changes in smoking patterns in women providing little cause for optimism. A large number of women in Spain smoke and female smokers are more likely to develop lung cancer than male smokers. After diagnosis, women show differences in histological type and generally live longer than men. Women show better survival after surgery in localized tumors, as well as after chemotherapy in advanced non-small cell tumors and in small cell tumors. These data indicate the need to change the belief that lung cancer affects mainly men and to determine the special characteristics of this disease in women (AU)

Situación epidemiológica y pronóstica del cáncer de pulmón en nuestro medio / Epidemiology of lung cancer in spain and forecast for the future

El cáncer de pulmón es una enfermedad en permanente crecimiento, es la primera causa de muerte de origen tumoral en los países desarrollados. Su asociación con el tabaco hace de ella una enfermedad potencialmente evitable, presenta un claro predominio en varones, pero con un alarmante incremento en mujeres. Su principal factor pronóstico es poder recibir un tratamiento quirúrgico con intentos curativos; sin embargo, la realidad nos dice que el diagnóstico se suele realizar en fases avanzadas de la enfermedad, cuando sólo un 20% de los casos puede ser intervenido. Con los tratamientos no quirúrgicos, basados en quimioterapia y radioterapia, no se han observado significativos avances en los últimos años. Presenta una pobre supervivencia a los 5 años, que en nuestro medio se encuentra en un escaso 7-12%. Deberemos intentar mejorar las medidas de prevención y su diagnóstico precoz para mejorar el pronóstico final de esta enfermedad

Lung cancer, a steadily growing problem, ranks as the first cause of tumor-related deaths in developed countries. The relation between lung cancer and smoking makes it a potentially avoidable disease. Found mainly in men, it has made alarming gains among women. The main prognostic factor is the possibility of receiving curative surgery; however, in real practice the diagnosis usually comes when the disease has reached an advanced stage, when only 20% can be treated surgically. Nonsurgical treatments based on chemo- and radiotherapy have not advanced appreciably in recent years, and 5-year survival is poor, estimated at only around 7% to 12% in Spain. Attempts must be made to improve preventive measures and early diagnosis in order to improve the prognosis for lung cancer patients

[The EpicliCP-2003 study: A multicenter epidemiological and clinical study of lung cancer in Spain]. / Estudio multicéntrico epidemiológico-clínico de cáncer de pulmón en España (estudio EpicliCP-2003).

OBJECTIVE: Mortality due to lung cancer in Spain is increasing continuously. The aim of the present study was to collect information on the hospital incidence of lung cancer, as well as information on clinical management, in different regions of Spain. MATERIAL AND METHODS: A prospective observational study of patients diagnosed with lung cancer in 2003 was carried out in 13 centers in 9 autonomous communities. Epidemiological, clinical, diagnostic, and therapeutic variables were assessed. RESULTS: Of a total population of 2,726,601 inhabitants (1 346 483 men and 1 380 118 women), 1064 male and 125 female lung cancer patients were included. The incidence standardized to the world population varied between 42.4/100,000 and 61.8/100,000 in men and between 1.5/100,000 and 8.6/100,000 in women. Overall, 51% were aged over 70 years, and 97.5% of the men and 32% of the women were smokers or ex-smokers. Cytologic or histologic confirmation was obtained for 93.1% of the cases (20.8% of which were small cell lung cancers and 79.2% were non-small cell lung cancers). The main initial symptoms were cough, chest pain, and weight loss. In 13.7%, lung cancer was suspected because of abnormal chest x-ray. The percentage with clinical TNM stages I and II ranged from 6.3% to 26.9%. The most common stage was stage IV in all centers. The percentage of patients undergoing surgery ranged from 2.5% to 20.6%, with a mean of 14.8% (19.9% of whom were patients with non-small cell lung cancer); 27% received palliative treatment only. CONCLUSIONS: The proportion of women suffering from lung cancer increased with respect to previous studies, with notable differences among regions. Despite diagnostic improvements, the percentage of patients undergoing surgery is low, though interregional variation is considerable.

Estudio multicéntrico epidemiológico-clínico de cáncer de pulmón en España (estudio EpicliCP-2003) / The EpicliCP-2003 Study: a multicenter epidemiological and clinical study of lung cancer in Spain

Objetivo: La mortalidad por cáncer de pulmón en España aumenta ininterrumpidamente. El objetivo del presente estudio ha sido conocer su incidencia hospitalaria, así como otros datos de manejo clínico, en varias regiones españolas. Material y métodos: Se ha realizado un estudio prospectivo observacional de los pacientes diagnosticados de cáncer de pulmón en 2003 en 13 centros de 9 comunidades autónomas. Se evaluaron variables epidemiológicas, clínicas, diagnósticas y terapéuticas. Resultados: Se han registrado 1.064 varones y 125 mujeres correspondientes a una población total de 2.726.601 habitantes (1.346.483 varones y 1.380.118 mujeres). Las tasas estandarizadas según población mundial variaron entre 42,4 y 61,8/100.000 en varones y entre 1,5 y 8,6/100.000 en mujeres. El 51% tenía más de 70 años. El 97,5% de los varones y el 32% de las mujeres eran fumadores o ex fumadores. Se obtuvo confirmación citohistológica en el 93,1% de los casos (un 20,8% microcíticos y un 79,2% no microcíticos). Los síntomas iniciales predominantes fueron tos, dolor torácico y pérdida de peso. En el 13,7% el diagnóstico se sospechó sólo por anormalidad radiológica. La proporción de estadios TNM clínicos I y II varió entre el 6,3 y el 26,9%. El estadio IV fue el más común en todos los centros. La tasa de intervenciones varió entre el 2,5 y el 20,6%; el promedio fue del 14,8% (un 19,9% del total de no microcíticos). El 27,0% sólo recibió medidas paliativas. Conclusiones: Entre los casos de cáncer de pulmón aumenta la proporción de mujeres con respecto a estudios previos, con notables diferencias interregionales. Pese a las mejoras diagnósticas, la tasa de intervenciones, muy variable entre diferentes centros, es muy baja

Objective: Mortality due to lung cancer in Spain is increasing continuously. The aim of the present study was to collect information on the hospital incidence of lung cancer, as well as information on clinical management, in different regions of Spain. Material and methods: A prospective observational study of patients diagnosed with lung cancer in 2003 was carried out in 13 centers in 9 autonomous communities. Epidemiological, clinical, diagnostic, and therapeutic variables were assessed. Results: Of a total population of 2 726 601 inhabitants (1 346 483 men and 1 380 118 women), 1064 male and 125 female lung cancer patients were included. The incidence standardized to the world population varied between 42.4/100 000 and 61.8/100 000 in men and between 1.5/100 000 and 8.6/100 000 in women. Overall, 51% were aged over 70 years, and 97.5% of the men and 32% of the women were smokers or ex-smokers. Cytologic or histologic confirmation was obtained for 93.1% of the cases (20.8% of which were small cell lung cancers and 79.2% were non-small cell lung cancers). The main initial symptoms were cough, chest pain, and weight loss. In 13.7%, lung cancer was suspected because of abnormal chest x-ray. The percentage with clinical TNM stages I and II ranged from 6.3% to 26.9%. The most common stage was stage IV in all centers. The percentage of patients undergoing surgery ranged from 2.5% to 20.6%, with a mean of 14.8% (19.9% of whom were patients with non-small cell lung cancer); 27% received palliative treatment only. Conclusions: The proportion of women suffering from lung cancer increased with respect to previous studies, with notable differences among regions. Despite diagnostic improvements, the percentage of patients undergoing surgery is low, though interregional variation is considerable