Regional variation in lung and bronchus cancer survival in the US using mortality-to-incidence ratios.

Despite major achievements aimed at reducing smoking over the last 50 years in the U.S., lung cancer remains the leading cause of cancer death. This study used mortality-to-incidence rate ratios (MIR) calculated from 2008 to 2012 National Cancer Institute data to highlight state-level variations in relative lung and bronchus cancer survival. In an ad hoc sensitivity analysis, we calculated a correlation between our state-level MIRs and five-year 1-survival rates for states reporting incident lung and bronchus cancer cases (2004-2008) to the Surveillance, Epidemiology, and End Results (SEER) Program database. Differences were observed in state lung and bronchus cancer MIRs, with the highest MIR values (poor relative survival) in southern states and the lowest MIRs primarily in northeastern states. In our sensitivity analysis, state-level MIRs were highly correlated with 1-survival rates. Examining regional variation in survival using MIRs can be a useful tool for identifying areas of health disparities and conducting surveillance activities.

Poly (ADP-ribose) glycohydrolase silencing-mediated maintenance of H2A and downregulation of H2AK9me protect human bronchial epithelial cells from benzo(a)pyrene-induced carcinogenesis.

Poly (ADP-ribosylation) is a key post-translational modification (PTM), and poly (ADP-ribose) glycohydrolase (PARG) is the main enzyme that hydrolyzes poly (ADP-ribose) in eukaryotic organisms. Our previous findings suggested that knockdown of PARG attenuates benzo(a)pyrene (BaP) carcinogenesis. However, the mechanisms underlying PARG-mediated protective effects remain limited. In this study, the expression levels of histones were analyzed by Western blotting and immunofluorescence. Histone H2A levels were abnormally decreased by BaP-induced carcinogenesis, but were maintained by knockdown of PARG in the 16HBE human bronchial epithelial cell line. The interaction between poly (ADP-ribose) and H2A was confirmed by co-immunoprecipitation. PARG-related modifications in H2A were profiled by immune antibody enrichment coupled with mass spectrometry. H2AK5ac, H2AK9ac, H2AK13ac, H2A.ZK4K7K11ac, and H2AK9me were expressed in BaP-transformed 16HBE (BTC-16HBE) cells, but were not detectable in normal 16HBE or BaP-transformed 16HBE cells with knockdown of PARG (BTC-shPARG). Further verification by Western blotting indicated that H2AK9me was elevated in BTC-16HBE cells but decreased in BTC-shPARG cells. These findings suggest that knockdown of PARG protects against BaP-induced carcinogenesis in 16HBE cells by downregulating H2AK9me. Our in vivo studies confirmed that PARG silencing decreased H2AK9me levels, thereby countering the carcinogenic teratogenic effects induced by BaP.

Analysis of c-ErbB1/epidermal growth factor receptor and c-ErbB2/HER-2 expression in bronchial dysplasia: evaluation of potential targets for chemoprevention of lung cancer.

PURPOSE: Lung cancer is preceded by a premalignant phase during which intervention could decrease associated morbidity and mortality. Molecular characterization of factors involved in controlling progression of bronchial dysplasias will provide markers of premalignant change and identify targets for chemoprevention. EXPERIMENTAL DESIGN: Immunohistochemical analysis of epidermal growth factor receptor (EGFR; c-ErbB1/EGFR), HER-2/neu (c-ErbB2/HER-2), Ki-67, and minichromosome maintenance protein 2 (MCM2) expression in bronchial dysplasia was undertaken to characterize molecular alterations associated with the progression of these lesions in 268 bronchoscopically obtained biopsies from 134 subjects. RESULTS: Analysis of biopsies with the most severe diagnosis from each subject showed a linear relationship between increasing marker expression and severity of dysplastic change for EGFR (P < 0.001), Ki-67 (P < 0.001), and MCM2 (P = 0.001) but not HER-2 (P = 0.102). Increased expression of either EGFR or HER-2 was associated with increased levels of Ki-67 and MCM2 expression, and combined overexpression of these receptors was associated with the highest levels of proliferation, suggesting a synergistic effect. Finally, the lack of an associated trend toward increased EGFR expression when comparing the worst and best biopsies within each subject indicated a potential field effect in the induction of EGFR expression. CONCLUSIONS: The results suggest a prominent role for EGFR overexpression in the development and progression of bronchial dysplasia and provide rationale for exploring inhibition of EGFR signaling in lung cancer chemoprevention.

Cyclin D1 proteolysis: a retinoid chemoprevention signal in normal, immortalized, and transformed human bronchial epithelial cells.

BACKGROUND: Retinoids (derivatives of vitamin A) are reported to reduce the occurrence of some second primary cancers, including aerodigestive tract tumors. In contrast, beta-carotene does not reduce the occurrence of primary aerodigestive tract cancers. Mechanisms explaining these effective retinoid and ineffective carotenoid chemoprevention results are poorly defined. Recently, the all-trans-retinoic acid (RA)-induced proteolysis of cyclin D1 that leads to the arrest of cells in G1 phase of the cell cycle was described in human bronchial epithelial cells and is a promising candidate for such a mechanism. In this study, we have investigated this proteolysis as a common signal used by carotenoids or receptor-selective and receptor-nonselective retinoids. METHODS: We treated cultured normal human bronchial epithelial cells, immortalized human bronchial epithelial cells (BEAS-2B), and transformed human bronchial epithelial cells (BEAS-2BNNK) with receptor-selective or receptor-nonselective retinoids or with carotenoids and studied the effects on cell proliferation by means of tritiated thymidine incorporation and on cyclin D1 expression by means of immunoblot analysis. We also examined whether calpain inhibitor I, an inhibitor of the 26S proteasome degradation pathway, affected the decline (i.e., proteolysis) of cyclin D1. RESULTS: Receptor-nonselective retinoids were superior to the carotenoids studied in mediating the decline in cyclin D1 expression and in suppressing the growth of bronchial epithelial cells. Retinoids that activated retinoic acid receptor beta or retinoid X receptor pathways preferentially led to a decrease in the amount of cyclin D1 protein and a corresponding decline in growth. The retinoid-mediated degradation of cyclin D1 was blocked by cotreatment with calpain inhibitor I. CONCLUSIONS: Retinoid-dependent cyclin D1 proteolysis is a common chemoprevention signal in normal and neoplastic human bronchial epithelial cells. In contrast, carotenoids did not affect cyclin D1 expression. Thus, the degradation of cyclin D1 is a candidate intermediate marker for effective retinoid-mediated cancer chemoprevention in the aerodigestive tract.

Efficacy of bronchoscopic therapies for bronchial mucoepidermoid carcinoma in children: results from six patients.

AIMS AND BACKGROUND: Bronchial mucoepidermoid carcinoma is a rare disease in children, and lobectomy is traditionally considered as a first-line treatment. As the tumor is characterized by intraluminal growth, low malignancy and superficial infiltration of bronchial walls, bronchoscopic interventional therapy may provide an alternative treatment with favorable results. The aim of the study was to evaluate the efficacy and safety of bronchoscopic therapies for bronchial mucoepidermoid carcinoma in children. METHODS AND STUDY DESIGN: Clinical manifestations, multiple bronchoscopic interventions and outcomes in 6 children with bronchial mucoepidermoid carcinoma were retrospectively analyzed. RESULTS: The median age was 8.7 years (range 4 to 12 years). All the tumors were located in the lobar bronchus and were detected by computerized tomography. Diagnoses of low-grade mucoepidermoid carcinoma were made based on biopsies obtained via bronchoscopy. Five tumors were classified as intraluminal type and successfully eradicated by carbon dioxide cryotherapy and argon plasma coagulation under bronchoscopy. The other tumor in patient 3 was classified as the mixture type and could not be removed by a bronchoscopic, so left upper lobectomy was performed. For each patient, interventional procedures were conducted on the average for 6 times. No recurrence was detected by bronchoscopic inspections or computed tomography scans during follow-ups for 16-72 months. CONCLUSIONS: Multiple bronchoscopic procedures, as alternative treatments, are effective in removing bronchial mucoepidermoid carcinoma mucoepidermoid carcinoma in children without any major complications.

Increased phospho-AKT (Ser(473)) expression in bronchial dysplasia: implications for lung cancer prevention studies.

AKT, a downstream mediator of phosphatidylinositol 3'-kinase, is activated in non-small cell lung cancer (NSCLC), but we have not yet defined the stage of malignant transformation at which AKT is activated in the bronchial epithelium. We performed immunohistochemical analysis of activated AKT [phosphorylated (p)-AKT Ser(473)] in tissue specimens of normal bronchial epithelium, bronchial hyperplasia and squamous metaplasia ("reactive" epithelium), bronchial dysplasia, and NSCLC. Among NSCLC specimens, immunohistochemical findings were correlated with patient demographics, tumor stage, histology, and survival. We observed p-AKT expression in 12 of 44 (27.3%) normal bronchial biopsy specimens, 4 of 9 (44.4%) reactive epithelium specimens, 22 of 25 (88%) dysplastic specimens, and 25 of 76 (33%) NSCLC specimens. Among patients with resected early-stage or locally advanced NSCLC, p-AKT expression had no effect on tumor stage, histology, or survival. Of the histological groups examined, bronchial dysplasia specimens expressed p-AKT most frequently, supporting AKT activation as an early event in lung cancer progression. Given its role as a mediator of malignant transformation, p-AKT should be investigated as a potential target in future lung cancer prevention studies.

A newly recognized cause of wheezing: AIDS-related bronchial leiomyomas.

We present two human immunodeficiency virus-infected children who developed wheezing and radiological evidence of pulmonary air trapping due to intra- and peribronchial leiomyomas. At autopsy, leiomyomas were also found in their spleens, which to our knowledge, has never been reported. The smooth muscle tumors were strongly positive for the Epstein-Barr virus, as demonstrated by in situ hybridization to Epstein-Barr virus-encoded ribonucleic acid, confirming the findings of recent investigators and linking these tumors to the Epstein-Barr virus.

[Epidemiologic studies on the role of tobacco in various human cancers]. / Etudes épidémiologiques sur le rôle du tabac dans les différents cancers humains

The totality of epidemiological research over the last 25 years in the field of the relationship between tobacco consumption and the chance of developing certain cancers has demonstrated beyond reasonable doubt that the use of tobacco is implicated in the genesis of a certain number of cancers of the respiratory tract and the upper air and food passages. The most important relationship concerns carcinoma of the bronchus, currently the most frequently encountered in men, for which the incidence risk is directly related to the use of cigarettes and which rises with the amount smoked and with inhaling. Other possible aetiological factors, particularly occupational exposure to chemical and radio active agents, whilst interesting are none the less marginal. The ramifications of epidemiologic and experimental researchs lead us to envisage a multifactorial aetiology in which tobacco is a constant element. Avoidance of exposure would play a major role in prevention.

[Radon and primary bronchial cancer]. / Radon et cancer bronchique primitif.

Radon is a natural radioactive gas, with worldwide distribution, deriving from uranium decay products, which can be inhaled, weather in mining condition (extraction and management of uranium ores) or in domestic condition (in some high risk homes or geographic areas). The main epidemiologic studies on uranium mining workers have all confirmed an excess in relative risk of primary lung cancer. Epidemiologic studies on indoor exposure suggest a role of radon in the genesis of a certain number of primary lung cancer, although these results remain controversial and need to be confirmed. An overview of the main actual problems related to this bronchial carcinogen is presented in this paper.

[Our experience using autofluorescence bronchoscopy]. / Autofluoreszcens bronchoszkópiával szerzett tapasztalataink.

INTRODUCTION: Lung cancer is responsible for most cancer deaths in the world. The main reason for the poor prognosis is late diagnosis. Many patients could be successfully treated in early stage. AIMS: The authors performed 369 bronchological examination on 336 patients using autofluorescence bronchoscopy between 1998 and 2003 to detect preinvasive lesions and early forms of lung cancer. METHODS: Storz D-Light autofluorescence system has been used to perform the examinations. RESULTS: In one third of these patients invasive lung cancer developed during follow-up. Combining traditional white light and autofluorescence technique 50% more intraepithelial lesions have been observed and sensitivity has been increased by 69% compared to the lone use of white light bronchoscopy. CONCLUSIONS: Supported by most international studies these results emphasise that autofluorescence bronchoscopy has a major role in the early diagnosis of preinvasive bronchial lesions and may help in the prevention and early therapy of lung cancer.

[Prevention in pulmonology]. / Tüdógyógyászati prevenció.

In the fight against respiratory diseases the well established most effective strategy is their prevention. Mainly the field of screening-caring--so called the second and third levels in prevention--belongs to the competency of the pulmonology specialty, while the key-issue of primary prevention consisting of the reduction of environmental harm and health education is not--or at least not only--the responsibility of the health care system. In the light of national epidemiological data BCG vaccination of the new-born is necessary, however, the system of revaccination of school-age children needs revision. The system of chest screening by rtg nowadays is adapted to the local prevalence of tuberculosis; it is needed to concentrate to high-risk subjects. The effectivity of radiological screening now is recognised internationally and this perspective partly based on our national results. In the care of patients with chronic obstructive pulmonary diseases (COPD) the key-issue is the identification and regular follow-up, care of high-risk subjects with rapid decrease in lung function by effective screening. The most important issue in this work is smoking cessation. Of course, if we could prevent smoking addiction, we could significantly reduce the number of several other widespread diseases, not only lung cancer.

Surveillance for the detection of early lung cancer in patients with bronchial dysplasia.

BACKGROUND: The natural history of bronchial preinvasive lesions and the risk of developing lung cancer in patients with these lesions are not clear. Previous studies have treated severe dysplasia and carcinoma in situ (CIS) on the assumption that most will progress to invasive carcinoma. AIMS: To define the natural history of preinvasive lesions and assess lung cancer risk in patients with these lesions. HYPOTHESIS: Most preinvasive lesions will not progress to invasive carcinoma but patients with these lesions will be at high risk. METHODS: A cohort of patients with preinvasive lesions underwent fluorescence bronchoscopy every 4-12 months and computed tomography of the chest annually. The main end point was the development of invasive carcinoma. RESULTS: 22 patients with 53 lesions were followed up for 12-85 months. 11 cancers were diagnosed in 9 patients. Of the 36 high-grade lesions (severe dysplasia and CIS), 6 progressed to invasive cancers. 5 separate cancers developed at remote sites in patients with high-grade lesions. All cancers were N0M0 and curative treatment was given to 8 of the 9 patients. The cumulative risk of developing lung cancer in a patient with a high-grade lesion was 33% and 54% at 1 and 2 years, respectively. Of the 17 low-grade lesions, none progressed to invasive carcinoma. CONCLUSIONS: Although the risk of malignant progression of individual preinvasive lesions is relatively small, patients with high-grade lesions are at high risk of lung cancer. Surveillance facilitated early detection and treatment with curative intent in most patients.