RESUMEN
OBJECTIVES: Lung cancer is the most fatal cancer in the developed world due to presence of metastases at time of diagnosis. The aim of this study is to examine DNA hypermethylation in sputum compared to sputum cytology for the diagnosis of lung cancer. A novel risk analysis is introduced, using the distinction between diagnostic and risk markers. METHODS: Two independent sets were randomly composed from a prospectively collected sputum bank (Set 1: n = 98 lung cancer patients, n = 90 controls; Set 2: n = 60 lung cancer patients, n = 445 controls). Sputum cytology was performed for all samples. The following DNA hypermethylation markers were tested in both sets: RASSF1A, APC and cytoglobin (CYGB). Two statistical analyses were conducted: multivariate logistic regression and a risk classification model based on post-test probabilities. RESULTS: In multivariate analysis, RASSF1A was the best of the three markers in discriminating lung cancer cases from controls in both sets (sensitivity 41-52%, specificity 94-96%). The risk model showed that 36% of lung cancer patients were defined as "high risk" (≥ 60% chance on lung cancer) based on RASSF1A hypermethylation in Set 1. The model was reproducible in Set 2. Risk markers (APC, CYGB) have less diagnostic value. Sensitivity of cytology for lung cancer diagnosis was 22%. RASSF1A hypermethylation yielded a sensitivity of 45%. The combined sensitivity for RASSF1A with cytological diagnosis increased to 52% with similar specificity (94%). CONCLUSION: In a diagnostic setting, hypermethylation analysis in sputum is possible when a diagnostic marker is used. However, risk markers are insufficient for this purpose.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/diagnóstico , Metilación de ADN , Neoplasias Pulmonares/diagnóstico , Proteínas Supresoras de Tumor/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Anciano , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Estudios de Casos y Controles , Citoglobina , Detección Precoz del Cáncer , Femenino , Globinas/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Análisis Multivariante , Curva ROC , Riesgo , Esputo/metabolismoRESUMEN
INTRODUCTION: Circulating plasma DNA is present in a considerably higher concentration in lung cancer patients than in controls. Conflicting data are reported about circulating DNA as a prognostic factor. The aim of this study was to prospectively analyse the relationship of circulating plasma DNA with overall survival (OS) of previously untreated non-small cell lung cancer (NSCLC) patients. METHODS: 46 untreated NSCLC patients and 21 controls with a follow-up time of 6.5 years were analyzed. Quantification of baseline circulating plasma DNA was performed by a real-time quantitative polymerase chain reaction (qPCR) targeting the human beta-globin gene. Survival analysis was performed using the Kaplan-Meier method and compared with a Cox-regression analysis. RESULTS: The median DNA concentration of the patients who died (87%) was significantly higher compared to the patients that survived at the end of follow-up (55ng/ml versus 23ng/ml, p=0.02). In patients with higher DNA concentration overall survival was significantly worse. In this study no relation of DNA concentration with tumour characteristics, age, gender or pulmonary inflammatory conditions was found. CONCLUSION: In this study a high circulating plasma DNA concentration at time of diagnosis in NSCLC patients was a prognostic factor for poorer survival. Circulating DNA may be used as a non-invasive biomarker to refine the prognostic profile in NSCLC patients.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , ADN/sangre , Neoplasias Pulmonares/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Carcinoma de Pulmón de Células no Pequeñas/terapia , ADN de Neoplasias/sangre , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/fisiopatología , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
BACKGROUND: Despite its proven efficacy, transbronchial needle aspiration (TBNA) remains an underutilized technique for sampling enlarged mediastinal lymph nodes in the staging of lung cancer. Previous investigators have reported on TBNA experience, but without mentioning individual learning curves related to lymph node size in pulmonologists experienced in bronchoscopy. OBJECTIVES: The aim of this study was to evaluate the TBNA learning curve in a group of pulmonologists already experienced in bronchoscopy, and to relate their yields to lymph node size and location. METHODS: Data on TBNA yield and related lymph node size were collected retrospectively for five individual pulmonologists. RESULTS: The diagnostic yield of five pulmonologists who started to perform TBNA was evaluated over the first 32 months. TBNA was performed on 138 lymph nodes in 119 patients. The overall diagnostic yield was 77% (range 67-91%). The average diagnostic yield increased from 77% at the start of the learning curve to 82% after 32 months of experience. It was related to lymph node size, but not to lymph node location. The average lymph node size was 22 mm. CONCLUSIONS: Satisfactory results were obtained immediately after introduction of TBNA in the bronchoscopy workup. There is no significant TBNA learning curve. The diagnostic yield was related to lymph node size but not to lymph node location.
