Molecular subtyping reveals immune alterations associated with progression of bronchial premalignant lesions.

Bronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at risk for progression to cancer. Here we report the identification of four molecular subtypes of PMLs with distinct differences in epithelial and immune processes based on RNA-Seq profiling of endobronchial biopsies from high-risk smokers. The Proliferative subtype is enriched with bronchial dysplasia and exhibits up-regulation of metabolic and cell cycle pathways. A Proliferative subtype-associated gene signature identifies subjects with Proliferative PMLs from normal-appearing uninvolved large airway brushings with high specificity. In progressive/persistent Proliferative lesions expression of interferon signaling and antigen processing/presentation pathways decrease and immunofluorescence indicates a depletion of innate and adaptive immune cells compared with regressive lesions. Molecular biomarkers measured in PMLs or the uninvolved airway can enhance histopathological grading and suggest immunoprevention strategies for intercepting the progression of PMLs to lung cancer.

Class I HDACs are mediators of smoke carcinogen-induced stabilization of DNMT1 and serve as promising targets for chemoprevention of lung cancer.

DNA methylation is an early event in bronchial carcinogenesis and increased DNA methyltransferase (DNMT)1 protein expression is a crucial step in the oncogenic transformation of epithelia. Here, we investigate the role of class I histone deacetylases (HDAC) 1 to 3 in the stabilization of DNMT1 protein and as a potential therapeutic target for lung cancer chemoprevention. Long-term exposure of immortalized bronchial epithelial cells (HBEC-3KT) to low doses of tobacco-related carcinogens led to oncogenic transformation, increased HDAC expression, cell-cycle independent increased DNMT1 stability, and DNA hypermethylation. Overexpression of HDACs was associated with increased DNMT1 stability and knockdown of HDACs reduced DNMT1 protein levels and induced DNMT1 acetylation. This suggests a causal relationship among increased class I HDACs levels, upregulation of DNMT1 protein, and subsequent promoter hypermethylation. Targeting of class I HDACs with valproic acid (VPA) was associated with reduced HDAC expression and a profound reduction of DNMT1 protein level. Treatment of transformed bronchial epithelial cells with VPA resulted in reduced colony formation, demethylation of the aberrantly methylated SFRP2 promoter, and derepression of SFRP2 transcription. These data suggest that inhibition of HDAC activity may reverse or prevent carcinogen-induced transformation. Finally, immunohistochemistry on human lung cancer specimens revealed a significant increase in DNMT1, HDAC1, HDAC2, and HDAC3 expression, supporting our hypotheses that class I HDACs are mediators of DNMT1 stability. In summary, our study provides evidence for an important role of class I HDACs in controlling the stability of DNMT1 and suggests that HDAC inhibition could be an attractive approach for lung cancer chemoprevention.

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

[Preventing lung cancer]. / Prévenir le cancer du poumon.

Lung cancer is one cancer for which preventative measures can be most effective. Unfortunately the strategies developed, in particular in terms of smoking, whether with regard to primary prevention, treatment by healthcare professionals or regulations, are insufficient or poorly adapted.

[Epidemiology of lung cancer]. / Epidemiologie des Bronchialkarzinoms.

Lung cancer is by far the most common form of cancer worldwide and in Germany is now "only" still the commonest cause of death from cancer. The most important single risk factor is smoking but in selected population groups, for example in the professional area, other factors can also play a role which cannot be ignored and open up a corresponding potential for prevention. Effective early detection procedures are at present unknown. The most promising, however, is multislice computed tomography (MSCT) which for this reason is presently being tested for effectiveness in several large research projects. The results are not expected for some years. Until then the early detection of lung cancer with MSCT cannot be considered suitable for routine use but can only be justified within the framework of research studies.

Carcinoma broncogénico: alteraciones genéticas y abandono del tabaco / No disponible

No disponible

Intrapulmonary IFN-beta gene therapy using an adenoviral vector is highly effective in a murine orthotopic model of bronchogenic adenocarcinoma of the lung.

Given previous work showing that an adenoviral vector expressing IFN-beta (Ad.IFNbeta) was highly effective in eradicating i.p. mesothelioma tumors, the antitumor efficacy of this agent was evaluated in an orthotopic model of bronchogenic adenocarcinoma of the lung. These transgenic mice have a conditionally expressed, oncogenic K-rasG12D allele that can be activated by intratracheal administration of an adenovirus expressing Cre recombinase (Ad.Cre). K-rasG12D mutant mice were given Ad.Cre intranasally to activate the oncogene. Mice were then given 10(9) plaque-forming units of a control vector (Ad.LacZ) or Ad.IFNbeta intranasally 3 and 4 weeks later, a time when lung tumors had been established. Cells derived from K-ras-mutated lung tumors were also grown in the flanks of mice to study mechanisms of therapeutic responses. In two separate experiments, untreated tumor-bearing mice all died by day 57 (median survival, 49 days). Ad.LacZ-treated mice all died by day 71 (median survival, 65 days). In contrast, 90% to 100% of mice treated with Ad.IFNbeta were long-term survivors (>120 days; P < 0.001). In addition, immunity to re-challenge with tumor cells was induced. In vitro and flank tumor studies showed that Ad.IFNbeta induced direct tumor cell killing and that depleting natural killer or CD8+ T cells, but not CD4+ T cells, with antibodies attenuated the effect of Ad.IFNbeta. These studies, showing remarkable antitumor activity in this orthotopic lung cancer model, provide strong preclinical support for a trial of Ad.IFNbeta to treat human non-small cell lung cancer.

[Early lung cancer detection with low-dose CT: an update]. / Lungenkrebsfrüherkennung mit Low-dose-CT: ein Update.

Lung cancer is the leading cause of death from malignancy. Due to a lack of early symptoms patients usually undergo therapy at advanced tumor stages when prognosis is poor. Feasibility studies of low-dose spiral CT screening of heavy smokers have shown that many small, resectable lung cancers can be diagnosed at early stages using simple diagnostic algorithms based on size and attenuation of detected pulmonary nodules with a small proportion of invasive procedures for benign lesions. Preliminary results of repeat screening confirms small size and favourable stage distribution of detected cancers, using even simpler diagnostic algorithms: additional diagnostic procedures are only required in new or growing nodules whereas follow-up with low-dose CT is sufficient in nodules that appear unchanged to exclude slow growth. However, mortality reduction by lung cancer screening with low-dose CT has yet to be demonstrated. Several randomised controlled trials are under way to assess possible mortality reduction by comparison of mortalities in a screening group and a control group. It is hoped that through international cooperation data from these trials can be pooled to allow for statistically significant conclusions as early as possible.

Occupational and environmental causes of bronchogenic carcinoma.

Occupational and environmental carcinogens account for an important minority of cases of bronchogenic carcinoma. From a public health perspective, it is important to characterize occupational and environmental carcinogens and to define disease risk to reduce preventable lung cancer. From a clinician's perspective, it is important to distinguish individual cases of occupational lung cancer from nonoccupational cases, because cancer acquired from work may be compensable through worker's compensation claims and litigation. Important carcinogens include asbestos, radon daughters, diesel exhaust, and metals. Epidemiologic investigations identify excess cases of lung cancer in populations exposed to carcinogens. Experimental animal and ex vivo human research provide complementary information supporting causal relationships between exposure and carcinogenesis. Clinical challenges include proving that a given case of lung cancer is due to an occupational exposure. Research challenges include determining safe exposure thresholds. Only a small percentage of all chemicals used in industry have been extensively analyzed for their carcinogenic potential. Scientific and regulatory information about pulmonary occupational and environmental health and safety is available from several important agencies and organizations, including the Occupational Safety and Health Administration, the National Institute for Occupational Safety and Health, the International Agency for Research on Cancer, the American Lung Association, and the Environmental Protection Agency.

Tratamiento del carcinoma broncogénico de células no pqueñas localmente avanzado etapa III B, con énfasis en la cirugía / Treatment of locally advanced non-small-cell bronchogenic carcinoma, estage III-B, with emphasis on surgery

Desde la fundación de nuestro Departamento de Cirugía de Tórax el 1§ de octubre de 1993, hasta el 30 de septiembre de 2000, se internaron 988 enfermos con cáncer broncogénico; 616 fueron completamente estadificados, 42.04 por ciento eran etapa III B. En el mismo lapso se realizaron 81 resecciones pulmonares con propósitos curativos, 4 de ellas en enfermos III B; a uno más, con síndrome de vena cava superior se le practicó una derivación paliativa venoauricular. También se realizaron tratamientos intrabronquiales para obstrucciones centrales, 8 con láser y 7 con braquiterapia y 2 drenajes pericárdicos subxifoideos para derrames malignos de repetición. Se revisan los datos vigentes y recientes sobre el tratamiento de enfermos con cáncer broncogénico de células no pequeñas en etapa III B, con énfasis en la cirugía.

Molecular events in bronchogenic carcinoma and their implications for therapy.

Lung cancer patients suffer a 15% overall survival despite advances in chemotherapy, radiation therapy and surgery. This unacceptably low survival rate is due to the usual finding of advanced disease at diagnosis. Detecting preneoplastic lesions and determining which invasive lesions are prone to metastasize or recur can be formidable tasks. Understanding the molecular events that occur during the multistep process of bronchogenic carcinogenesis may make these tasks more surmountable. Approaches leading to identification of patients susceptible to cancer formation include detection of poor metabolizers of carcinogens, those unable to repair genetic alterations, those with activated oncogenes or inactivated tumor suppressor genes, and those at risk of poor outcomes. Detection may be achieved at the cellular, chromosomal, genetic, or protein level. Novel therapies can then be developed that prevent tumor initiation into and promotion through the multistep carcinogenesis pathway, conversion from preneoplastic into invasive malignancies, and progression into metastasis or recurrences. Therapeutic success of chemoprevention can be followed by changes in molecular marker levels. Blockade of activated tumor-promoting oncogenes or replacement of inactivated tumor-suppressing or apoptosis-promoting genes can be achieved by gene therapy. Development of these novel molecular diagnostic and therapeutic strategies could result in prevention of cancer formation or at least prolongation of disease-free survival.

Screening for asymptomatic early bronchogenic carcinoma with low dose CT of the chest.

BACKGROUND: Survival of patients with lung carcinoma is very poor, particularly for patients with advanced disease. There are no early clinical symptoms, and screening with chest radiography has not been recommended. Computed tomography (CT) is superior to radiography for detection of pulmonary nodules but usually is associated with relatively high radiation exposure. Recently, accuracy of low dose CT has been shown to be similar to conventional dose CT. The goal of the current study was to assess the findings of low dose CT of the chest in heavy smokers. METHODS: More than 700 heavy smokers (> 20 pack years; age: > 40 years) underwent unenhanced low dose CT of the chest. Detected nodules were classified according to their density (soft tissue, calcified, fat) and size (< 6 mm, 6-10 mm, > 10 mm). In nodules larger than 10 mm with no CT features to suggest a benign lesion, histology was obtained. RESULTS: In approximately 40% of smokers, nodules smaller than or equal to 10 mm were detected. None was resected. In less than 3% of individuals, lesions larger than 10 mm were detected; 8 were bronchogenic carcinoma. All eight carcinomas were resectable. Lesions for which no histology was obtained were followed with low dose CT. CONCLUSIONS: Low dose CT detected 8 bronchogenic carcinomas in more than 700 heavy smokers. All eight were resectable. Pulmonary nodules measuring up to 10 mm were found in 40% of smokers. The significance of these small lesions has remained unclear.

[Chemoprevention of bronchogenic carcinoma]. / Chemoprevence bronchogenního karcinomu.

Lung cancer is the leading cause of cancer-related deaths in many developed countries. Understanding its carcinogenesis is critical for the development of rational approaches to cancer prevention. The concept of chemoprevention is based on the idea that the diffuse injury of the respiratory epithelium results from chronic carcinogen exposure. Chemoprevention agents should reverse or suppress the development of premalignant and malignant changes by different mechanisms. In the future, the clinical application to risk groups of patients could lead to substantially decreased frequency of the lung cancer. The results of ongoing trials are eagerly awaited.

[Neuropsychological effects of preventive CNS irradiation in adult tumor patients]. / Neuropsychologische Effekte der prophylaktischen ZNS-Bestrahlung bei erwachsenen Tumorpatienten.

Prophylactic cranial irradiation (PCI) has led to marked prolongation of survival, but also to intellectual and neuropsychological retardation in children with ALL. PCI has also been conducted in adult patients with small-cell bronchial carcinoma in the stage of minimal disease or with breast cancer. There are no studies assessing cognitive or other neuropsychological consequences of PCI in adult cancer patients. We report on a longitudinal prospective study of the effects of PCI on five major neuropsychological domains (intelligence, concentration, attention, memory and psychomotor performance). We report on our ongoing study, in which up to now 11 patients with small-cell lung cancer undergoing PCI have been investigated. Patients are assessed immediately before therapy started as well as 4 weeks and 3 months after onset of PCI. The used instruments are Standard Progressive Matrices (SPM), d2 Concentration Test, Minimental State, Verbal Learning Test and Psychomotor Tests (Steadiness, Aiming, Tapping, Tracking, Pursuit Rotor Test). Although our sample is small, results indicate that there is no evidence for a decrease in neuropsychological abilities in adults after three months. This is in contrast to the observed results after PCI in children. As compared to baseline measures, differences in memory, intelligence, concentration and attention were marginal over time. Moreover the progress of motor performance skills showed no clear tendency.