Treatment outcomes in elderly with advanced-stage non-small cell lung cancer.

PURPOSE: Lung cancer remains the top cause of cancer morbidity and mortality in the world. Although the identification of epidermal growth factor receptor (EGFR) gene mutations could predict efficacy of tyrosine kinase inhibitor (TKI), testing for predictive biomarkers are not always possible due to tissue availability. The overall therapeutic decision remains a clinical one for a significant proportion of elderly patients with advanced stage lung cancer but no known EGFR mutation status. The purpose of this study was to compare the outcome of drug treatment modalities in progression-free survival (PFS) and overall survival (OS) for elderly with advanced-stage non-small cell lung cancer (NSCLC) and to identify clinical parameters that could predict treatment outcome. METHODS: Clinical records of patients aged 70 years or older with advanced-stage NSCLC who have received treatment were reviewed. A group of gender- and histology-matched subjects younger than age 70 years were identified as controls. RESULTS: Fifty-six elderly patients were included. The median age at diagnosis was 73 years; 60.7 % received only one line of treatment. Baseline performance status (PS) was the only predictor of improved PFS (p = 0.042) and OS (p = 0.002). There was no difference in survival between the upfront chemotherapy and the TKI groups CONCLUSIONS: In elderly with advanced-stage NSCLC without known EGFR mutation status, use of EGFR-TKI and chemotherapy resulted in comparable survival benefits. Age was not predictive of worse treatment outcome. The baseline PS should be taken into consideration in the therapeutic decision in elderly with NSCLC where the EGFR mutation status is not known.

EGFR array: uses in the detection of plasma EGFR mutations in non-small cell lung cancer patients.

INTRODUCTION: We aim to develop a simple and sensitive array-based method for the detection of epidermal growth factor receptor (EGFR) gene mutations in the plasma of non-small-cell lung cancer patients and determine its use in the follow-up of those on tyrosine-kinase inhibitor (TKI) therapy. METHOD: DNA from 100 µl of plasma was amplified in the presence of peptide nucleic acid clamp to provide single-stranded template for the allele-specific arrayed primer extension reaction, incorporating cyanine-5-deoxycytidine triphosphate in the newly synthesized strands. The fluorescent product was visualized by laser at 670 nm. RESULTS: Eleven different types of EGFR TKI drug-sensitive mutants (SM) were identified in plasma-DNA from 46 of 51 patients. Five patients carried only wild-type sequence. Plasma-DNA finding was concordant in 36 of 37 cases with tumor-sequencing data. This method could detect as little as 62.5 copies of mutant L858R; 125 copies of E709K + G719A or 625 copies of del 746-750 in the presence of 100,000 copies of wild-type EGFR. In 21 patients on longitudinal follow-up for up to 18 months, SM was found in all initial plasma samples, except for three samples collected after recent chemotherapy. Nine of 16 patients (56%) who responded to TKI had undetectable plasma EGFR mutant. SM was present concurrently with drug-resistant mutant in 44% of patients with disease progression while on TKI, the remaining 56% might have other mechanisms of resistance. CONCLUSION: The EGFR array provides a sensitive, inexpensive, and robust method for monitoring non-small-cell lung cancer patients' response to TKI, and obviates the need of repeated lung biopsy.

Sputum cytology examination followed by autofluorescence bronchoscopy: a practical way of identifying early stage lung cancer in central airway.

BACKGROUND: The prognosis of early stage lung cancer was superior to that of late stages. We hypothesize that by using sputum cytology as the first screening method followed by autofluorescence bronchoscopy could detect early stage lung cancer in the central airway. METHODS: During 18-month recruitment period, subjects at high risk for lung cancer (ever smoker accumulated more than 20 pack-year and above 40 years) followed up at Chest Clinics were invited to submit sputum for cytological examination. Subjects with sputum atypia were invited to have bronchoscopy, and CT thorax. After a mean follow-up of 39+/-14 months, the characteristics of lung cancers detected in the group with sputum atypia and the group with normal sputum at baseline were assessed. RESULTS: 181 subjects submitted sputum and primary lung cancer were diagnosed in 13. 46.2% of the lung cancers were in early stages. Bronchoscopy were performed in 85, and seven were confirmed to have lung cancer (six were in early stages). 81 had CT done and 92.6% had radiological abnormalities, though three lung cancers (all stage 0) were missed by CT. Five more primary lung cancers were diagnosed during the follow-up period: one in sputum atypia group and the other four (three were advanced adenocarcinoma) in normal sputum group. The overall sensitivity of sputum cytology in detecting lung cancer was 71.4% for all histology and 100% for squamous cell lung cancer. CONCLUSIONS: Sputum cytology examination followed by bronchoscopy was a practical way of detecting early stage lung cancer in central airway.

The burden of lung disease in Hong Kong: a report from the Hong Kong Thoracic Society.

BACKGROUND AND OBJECTIVE: The burden of lung disease in Hong Kong is not known. This study determined the mortality and hospitalization rates of respiratory diseases in Hong Kong in 2005, their trend in the past decade and their incidence/prevalence. METHODS: Mortality data were obtained from the Department of Health and hospitalization data from the Hospital Authority, Hong Kong. Incidence/prevalence data were obtained from local registries or local studies. Trends of mortality and hospitalization rates of various respiratory diseases from 1997 and 2005 were calculated after age standardization and were tested for significance using negative binomial regression analysis. Age standardized mortality rates in Hong Kong were compared with those of the UK and globally. RESULTS: Respiratory disease was the most common cause of mortality and hospitalization in Hong Kong in 2005. Globally and in the UK, cardiovascular disease ranked first in mortality. Respiratory infections ranked first in respiratory mortality, followed by respiratory tract cancer and chronic obstructive lung disease. Respiratory infections also ranked first followed by chronic obstructive lung disease in the utilization of respiratory inpatient bed-days. While mortality rates from all respiratory diseases decreased in the past decade, hospitalization rates remained unchanged. Unlike other respiratory diseases, mortality from respiratory infections have increased since 2001. Smoking is the most important risk factor in non-communicable respiratory diseases. CONCLUSIONS: Respiratory disease is responsible for the highest health-care burden locally. Increased efforts in improving management and prevention of these diseases, including tobacco control, improving air quality and vaccination against influenza and pneumococci, are necessary.

Expression of nicotinic acetylcholine receptor subunit genes in non-small-cell lung cancer reveals differences between smokers and nonsmokers.

Nicotine and its derivatives, by binding to nicotinic acetylcholine receptors (nAChR) on bronchial epithelial cells, can regulate cellular proliferation and apoptosis via activating the Akt pathway. Delineation of nAChR subtypes in non-small-cell lung cancers (NSCLC) may provide information for prevention or therapeutic targeting. Expression of nAChR subunit genes in 66 resected primary NSCLCs, 7 histologically non-involved lung tissues, 13 NSCLC cell lines, and 6 human bronchial epithelial cell lines (HBEC) was analyzed with quantitative PCR and microarray analysis. Five nonmalignant HBECs were exposed to nicotine in vitro to study the variation of nAChR subunit gene expression with nicotine exposure and removal. NSCLCs from nonsmokers showed higher expression of nAChR alpha6 (P < 0.001) and beta3 (P = 0.007) subunit genes than those from smokers, adjusted for gender. In addition, nAChR alpha4 (P < 0.001) and beta4 (P = 0.029) subunit gene expression showed significant difference between NSCLCs and normal lung. Using Affymetrix GeneChip U133 Sets, 65 differentially expressed genes associated with NSCLC nonsmoking nAChR alpha6beta3 phenotype were identified, which gave high sensitivity and specificity of prediction. nAChR alpha1, alpha5, and alpha7 showed significant reversible changes in expression levels in HBECs upon nicotine exposure. We conclude that between NSCLCs from smokers and nonsmokers, different nAChR subunit gene expression patterns were found, and a 65-gene expression signature was associated with nonsmoking nAChR alpha6beta3 expression. Finally, nicotine exposure in HBECs resulted in reversible differences in nAChR subunit gene expression. These results further implicate nicotine in bronchial carcinogenesis and suggest targeting nAChRs for prevention and therapy in lung cancer.

High resolution analysis of genomic aberrations by metaphase and array comparative genomic hybridization identifies candidate tumour genes in lung cancer cell lines.

Tumours develop from clonally expanded population of cells harbouring aberrations of oncogenes and tumour suppressor genes. In this study, metaphase and array comparative genomic hybridization showed good correlation of aberration profiles in lung adenocarcinoma cell lines from patients with different tobacco exposure. Recurrent DNA gains were found at chromosomes 1, 7, 8, 17, 20, and deletions at 1, 3, 8, 9, 10, 12, 17, 18, 19. Candidate tumour loci and encompassed genes at 7p21 (AGR2), 8q21(TPD52), 20q13 (ZNF217, WFDC2, EEF1A2) and 10p15 (KLF6) were analyzed by dual colour FISH for genomic changes and quantitative PCR for expression changes. Results indicated that EEF1A2 and KLF6 were strong candidates of oncogene and tumour suppressor genes, respectively. This study illustrates, a practical strategy for identifying candidate cancer genes from microarray data.

Prevalence of tuberculous infection and active tuberculosis in old age homes in Hong Kong.

OBJECTIVES: To assess the prevalence of tuberculous infection and active tuberculosis (TB) in old age homes in Hong Kong and to determine whether there is institutional transmission in these homes. DESIGN: Cross-sectional. SETTING: Old age homes. PARTICIPANTS: Total of 2,243 residents, representing 84.6% of all residents in 15 old age homes; 1,698 were women, and 545 were men, with an average age of 82. MEASUREMENTS: All residents had a questionnaire-based interview, medical record review, two-stage tuberculin testing using two units purified protein derivative-RT23, and a chest x-ray. Those with radiological abnormalities had sputum examined for acid-fast bacilli. RESULTS: The estimated prevalence rate of active TB in this population was 669 per 100,000, significantly higher in men than in women (1,101 per 100,000 vs 530 per 100,000). The proportion with positive tuberculin reactivity (> or =10 mm induration) after two-stage testing was 68.6%, significantly higher in men than in women. There was no evidence of active transmission of disease in these old age homes, with restriction fragment length polymorphism (RFLP) analysis performed on five cases of active pulmonary TB in the home with the highest rate of TB showing unique RFLP patterns. CONCLUSION: The rate of active TB and TB infection in old age homes in Hong Kong is still high. Because treatment for latent TB carries a high risk for liver dysfunction in this population, clinicians and other healthcare workers need a high index of suspicion and to diagnose and treat this disease as early as possible to prevent transmission.

Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features.

PURPOSE: This study evaluated the mutational profile of epidermal growth factor receptor (EGFR) and KRAS in non-small cell lung cancers in Hong Kong and determined their relation with smoking history and other clinicopathologic features. EXPERIMENTAL DESIGN: Mutational profile of exons 18 to 21 of EGFR and codons 12, 13, and 61 of KRAS were determined in 215 adenocarcinomas, 15 squamous cell (SCC), and 11 EBV-associated lymphoepithelioma-like carcinomas (LELC). RESULTS: EGFR mutations were prevalent in adenocarcinomas (115 of 215), uncommon in LELC (1 of 11), and not found in SCC (P < 0.001). Among adenocarcinomas, mutations were associated with nonsmokers (83 of 111; P < 0.001), female gender (87 of 131; P < 0.001), and well-differentiated (55 of 86) compared with poorly differentiated (11 of 41) tumors (P < 0.001). Decreasing mutation rates with increasing direct tobacco exposure was observed, with 74.8% (83 of 111) in nonsmokers, 61.1% (11 of 18) in passive, 35.7% (10 of 28) in previous, and 19.0% (11 of 58) in current smokers. There were 53% amino acid substitutions, 43% in-frame deletions, and 4% insertions. Complex patterns with 13% double mutations, including five novel substitutions, were observed. For KRAS, mutations occurred in adenocarcinoma only (21 of 215) and were associated with smokers (11 of 58; P = 0.003), men (14 of 84; P = 0.009) and poorly differentiated (7 of 41) compared with well-differentiated (4 of 86) tumors (P = 0.037). EGFR and KRAS mutations occurred in mutually exclusive tumors. Regression analysis showed smoking history was the significant determinant for both mutations, whereas gender was a confounding factor. CONCLUSION: This study shows EGFR mutations are prevalent in lung adenocarcinoma and suggests that it plays an increasing oncogenic role with decreasing direct tobacco damage.

Establishment and expression profiling of new lung cancer cell lines from Chinese smokers and lifetime never-smokers.

BACKGROUND: Bronchogenic adenocarcinoma is the predominant histologic subtype of lung cancer, which ranks top in the cancer mortality in both men and women. Female nonsmokers and adenocarcinoma have emerged as a distinct combination in patients with lung cancer in recent decades. Lung cancer cell lines established from patients with known clinical characteristics such as gender and smoking habit would be useful for future research on lung cancer. METHODS: Four new lung adenocarcinoma cell lines (HKULC 1-4) were established from Chinese patients with primary lung adenocarcinomas and with different clinical characteristics with respect to age, gender, smoking habits, tumor staging, and previous therapy. They were characterized by immunohistochemical and growth kinetic studies, tests for tumorigenicity in nude mice, epidermal growth factor receptor (EGFR) gene mutation analysis, and in situ hybridization, and gene expression profiling with Affymetrix GeneChip HG-U133A. RESULTS: The newly established HKULC lung adenocarcinoma cell lines were maintained for over 70 passages and demonstrated morphologic and immunohistochemical features and growth kinetics of tumor cell lines. One of the four HKULC cell lines, HKULC 3 (derived from a female nonsmoking patient with lung adenocarcinoma), was found to have a deletion at exon 19 of the EGFR gene. EGFR in situ hybridization showed no EGFR gene amplification in these cell lines. HKULC 1 and 4 formed tumor xenografts after inoculation in nude mice. A list of 71 genes that were differentially expressed or showing class predictive significance was identified. These genes included putative tumor suppressor genes (DKK3, SERPINF1, CDH11, DSC3, and KLF6), genes involved in or related to the EGFR pathways (ERBB3, MUC1, VAV1), genes involved in regulation of cell cycle and proliferation (CDKN1A and CDKN2A), a putative oncogene (EEF1A2), and a gene related to metastasis (MTSS1). DISCUSSION: Four new lung adenocarcinoma cell lines were established from patients with different clinical characteristics. These characterized cell lines and their gene expression profiles will provide resources for studies of lung cancer biology and in vitro chemotherapeutic drug study.

Lung cancer in Asian women-the environment and genes.

The mortality rate of lung cancer in Asian women has increased significantly in the past few decades. Environmental factors include tobacco smoke (active and environmental), other indoor pollutions (cooking oil vapours, coal burning, fungus spores), diet, and infections. Active tobacco smoking is not the major factor. The relative risk of lung cancer among non-smoking women ever exposed to environmental smoke from their husbands was 1.20 from a meta-analysis. Cooking oil vapours associated with high temperature wok cooking and indoor coal burning for heating and cooking in unvented homes, particularly in rural areas, are risk factors for Chinese women. Chronic benign respiratory diseases due to the fungus Microsporum canis probably accounts for the high incidence of lung cancer in northern Thai women at Sarapee. Diets rich in fruits, leafy green vegetables, and vitamin A are protective, while cured meat (Chinese sausage, pressed duck and cured pork), deep-fried cooking, and chili increased the risk. Tuberculosis is associated with lung cancer. Also, a Taiwanese study showed that the odds ratio of papillomavirus (HPV) 16/18 infection in non-smoking female lung cancer patients was 10.1, strongly suggesting a causative role. Genetic factors have also been studied in Chinese women, including human leucocyte antigens, K-ras oncogene activation, p53 mutation, polymorphisms of phase I activating enzymes (cytochrome P450, N-acetyltransferase slow acetylator status), and phase II detoxifying enzymes (glutathione-S-transferases, N-acetyltransferase rapid acetylator status). New molecular screening technology would facilitate identification of molecular targets for future studies. The interaction between environmental and genetic factors should also be further elucidated.

Lung cancer susceptibility and polymorphisms of glutathione-S-transferase genes in Hong Kong.

OBJECTIVE: To study the potential role of genetic polymorphisms of glutathione-S-transferases GSTM1, GSTT1 and GSTP1 in susceptibility to lung cancer in Hong Kong Chinese. METHODS: 229 consecutive incident patients with a histological diagnosis of lung cancer from a regional hospital and 197 healthy population-based controls were recruited for this study between July 1999 and June 2001. Genetic polymorphisms of GSTT1 and GSTM1 were determined using PCR-based technique. RESULTS: The frequencies of GSTT1 and GSTM1 null genotypes were 51.8 and 59.4% in healthy controls and 63 and 54.7%, respectively, in lung cancer patients. GSTP1 Val105/Val105 genotype was found in only 1% of healthy controls. The risk for lung cancer with GSTT1 null genotype was significantly higher, adjusted odds ratio (OR) 1.69, 95% confidence interval (CI) 1.12-2.56, compared with those with the GSTT1 genotype; the increase in risk was found only in non-smokers. GSTM1 null genotype, combined GSTT1 and GSTM1 null genotype and GSTP1 Val105/Val105 genotype did not confer any increase risk for lung cancer. CONCLUSION: GSTT1 null genotype is associated with an increased risk for lung cancer in non-smoking Chinese in Hong Kong.

Computed tomographic evaluation of the role of craniofacial and upper airway morphology in obstructive sleep apnea in Chinese.

OBJECTIVES: To evaluate the relationship between cephalometric parameters, upper airway morphological factors and obstructive sleep apnea (OSA) in Chinese subjects. DESIGN: Polysomnogram (PSG) were performed and scored using standard criteria. Supine lateral cephalometric parameters and pharyngeal cross-sectional areas at the level of velopharynx (VA) and hypopharynx (HA) were measured from computed tomographic scans. The roles of these parameters and other anthropometric/demographic characteristics in OSA (apnea hypopnea index, AHI > or = 5) and their relationship with severity of OSA were explored by multiple logistic and multinominal regression analysis. RESULTS: Ninety-two subjects, ranging from normal (n = 36), mild/moderate OSA (n = 34) to severe OSA (n = 22), were evaluated. Compared with normal subjects, OSA subjects were heavier (body mass index 27 vs. 24 kg/m2) and older (47 vs. 42 years of age); had smaller VA size and VA to HA ratio, lower positioned hyoid bone, longer and thicker soft palate, and more retropositioned mandible relative to maxilla. After controlling for body mass index and age, subjects with severe OSA (AHI > 30) had more retropositioned mandible relative to maxilla (odds ratio, OR 1.31, P = 0.044) and longer soft palate (OR 1.16, P = 0.01), while those with mild/moderate OSA had larger VA to HA ratio (OR 0.17, P = 0.018). CONCLUSIONS: Craniofacial factors and upper airway morphology contributed to severity of OSA in Chinese subjects. Having controlled for obesity, more retropositioned mandible was associated with more severe OSA.

A community study of sleep-disordered breathing in middle-aged Chinese women in Hong Kong: prevalence and gender differences.

STUDY OBJECTIVES: To investigate the prevalence of sleep-disordered breathing (SDB) and obstructive sleep apnea syndrome (OSAS) in community-based, middle-aged Chinese women, and to compare the differences between gender with a similar study in men. DESIGN: A cross-sectional study conducted in Hong Kong from 1998 to 2000. SETTING: Sleep questionnaires were distributed to women (30 to 60 years old) in three offices and two community centers. All were invited to undergo full polysomnography in a sleep laboratory. PARTICIPANTS: Questionnaires were distributed to 1,532 women, and 854 questionnaires were returned. Polysomnography was conducted in 106 respondents. MEASUREMENTS AND RESULTS: Conservative estimated prevalence of SDB (apnea-hypopnea index [AHI] > = 5) and OSAS (AHI > or = 5 plus excessive daytime sleepiness [EDS]) were 3.7% and 2.1%, respectively. Age-specific prevalence of OSAS was 0.5%, 2.2%, and 6.1% in the 30- to 39-year-old, 40- to 49-year-old, and 50- to 60-year-old age groups, respectively. Stepwise multiple logistic regression analysis identified body mass index (BMI) and age as predictors of SDB. Compared to Chinese men, the prevalence of SDB and OSAS in women was lower, but the gender difference decreased with age. The AHI of affected women was also significantly lower despite comparable BMI. Compared to men, women with SDB had same degree of self-reported snoring and a similar degree of EDS despite the lower AHI. CONCLUSIONS: This study demonstrated an estimated prevalence of OSAS at 2.1% among middle-aged Chinese women in Hong Kong, with a 12-fold rise from the fourth to the sixth decade of life. BMI and age were significant independent predictors of SDB. Compared to men, women with SDB had lower AHIs, despite similar BMIs.

Endothelial function in obstructive sleep apnea and response to treatment.

Impaired endothelium-dependent vascular relaxation is a prognostic marker of atherosclerosis and cardiovascular disease. We evaluated endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent nitroglycerin (NTG)-induced dilation of the brachial artery with Doppler ultrasound in 28 men with obstructive sleep apnea (OSA) and 12 men without OSA. Subjects with OSA (apnea-hypopnea index; mean +/- SD, 46.0 +/- 14.5) had lower FMD compared with subjects without OSA (5.3 +/- 1.7% vs. 8.3 +/- 1.0%, p < 0.001), and major determinants of FMD were the apnea-hypopnea index and age. There was no significant difference in NTG-induced dilation. Subjects with OSA were randomized to nasal continuous positive airway pressure (nCPAP) or observation for 4 weeks. Subjects on nCPAP had significant increase in FMD, whereas those on observation had no change (4.4% vs. -0.8%, difference of 5.2%, p < 0.001). Neither group showed significant change in NTG-induced vasodilation. Eight subjects who used nCPAP for over 3 months were reassessed on withdrawing treatment for 1 week. On nCPAP withdrawal, FMD became lower than during treatment (p = 0.02) and were similar to baseline values. Our findings demonstrated that men with moderate/severe OSA have endothelial dysfunction and treatment with nCPAP could reverse the dysfunction; the effect, however, was dependent on ongoing use.

Chromosomal aberrations of primary lung adenocarcinomas in nonsmokers.

BACKGROUND: Lung carcinoma is a common malignancy, and tobacco carcinogenesis is the major cause. Studies on individual genes or loci have suggested, that in tumors from nonsmokers, different genetic alterations are present compared with tumors from smokers. It is possible that distinct genetic pathways may be involved. However, the targets remain largely unknown; and, to the authors' knowledge, molecular cytogenetics studies on lung carcinomas from nonsmokers have not been reported. METHODS: Comparative genomic hybridization (CGH) analysis was performed on primary lung adenocarcinoma samples from 32 patients who never smoked to identify loci of frequent aberrations. RESULTS: Different extents of aberration were found in 31 of the 32 samples studied. The most frequently altered locus was gain of 16p (59% of samples) followed by gain of 20q (44% of samples), with the minimal overlapping regions at 16p13.1-p13.2 and 20q13.2, respectively. Other over-represented loci with > 30% frequency were observed at 5p (34% of samples), 7p (41% of samples), 8q (31% of samples), 17q (34% of samples), and 19q (34% of samples); and high-level DNA amplifications were detected at 1q, 7p, 12q, 19q, and 20q. DNA under-representation was observed less commonly and included 8p (28% of samples), 9p (22% of samples), 13q (28% of samples), and 18q (38% of samples). CONCLUSIONS: The current study identified targets of frequent genetic aberration in primary adenocarcinomas from nonsmokers. Compared with reported CGH findings in the literature, the current findings suggest that DNA gain at 16p is the distinct aberration involved in these tumors. Other frequently altered loci involve commonly reported oncogenic and tumor suppressor loci, suggesting an overlap with the genetic pathways of tobacco-induced lung carcinogenesis.

Primary adenocarcinomas of the lung in nonsmokers show a distinct pattern of allelic imbalance.

Lung cancer development in nonsmokers, particularly in females, has long been observed,but the genetic pathways of oncogenesis are still unclear. The purpose of this study was to identify important targets of chromosomal alteration involved in non-tobacco-related adenocarcinomas of lung. In this study, loci of recurrent allelic imbalance (AI) were identified by microsatellite analysis, focusing on tumors with low frequencies of AI (FAL) relative to the mean level. We reasoned that studying such tumors would facilitate the identification of essential genetic changes needed for the malignant phenotype, which could be masked by genomic instability and widespread nonspecific alterations, especially in tumors showing high FAL. Forty-two adenocarcinomas from nonsmokers (NT-ADs) were analyzed by a broad spectrum of 84 markers covering all nonacrocentric chromosomal arms. Using the mean AI frequency (40%) as the threshold, loci in 7q31, 8p23.2, 10p14-p15, 13q12.3, 16q24, 17p13.1-p13.3, 17q22, 19q13.3, and Xq11.2-q12 showed recurrent AI in the low-FAL tumors, which suggested that essential targets of carcinogenesis may be present. To analyze whether loci, frequently altered in NT-ADs, were uniquely involved in these tumors, 43 loci were also studied in 29 adenocarcinomas from smokers. 2q, 6p, 10p, 13q, 16q, 17q, 19p, 19q, 20p, and 20q showed frequent aberrations in NT-ADs, whereas 1q, 2p, 3p, 3q, 7q, 8p, 9p, 9q, 10q, 11q, 13q, 14q, TP53, 17p, 18q, and 21q were commonly altered in both of the tumor groups. Further comparison of their low-FAL tumors showed that AI involving 16q24, 17q22, and 19q13.3 were significantly associated with NT-ADs; whereas those involving 7q31, 8p23.2, 10p14-p15, 13q12.3, and 17p13.1-p13.3 were observed in both. The findings suggest that oncogenesis in the lung of smokers and nonsmokers involve overlapping yet distinct genetic pathways, whereas the recurrent loci of alteration in NT-ADs may provide a basis for the further mapping of critical molecular targets in these pathways.

Obstructive sleep apnea is independently associated with insulin resistance.

Epidemiological studies have implicated obstructive sleep apnea (OSA) as an independent comorbid factor in cardiovascular and cerebrovascular diseases. It is postulated that recurrent episodes of occlusion of upper airways during sleep result in pathophysiological changes that may predispose to vascular diseases. Insulin resistance is a known risk factor for atherosclerosis, and we postulate that OSA represents a stress that promotes insulin resistance, hence atherogenesis. This study investigated the relationship between sleep-disordered breathing and insulin resistance, indicated by fasting serum insulin level and insulin resistance index based on the homeostasis model assessment method (HOMA-IR). A total of 270 consecutive subjects (197 male) who were referred for polysomnography and who did not have known diabetes mellitus were included, and 185 were documented to have OSA defined as an apnea-hypopnea index (AHI) > or =5. OSA subjects were more insulin resistant, as indicated by higher levels of fasting serum insulin (p = 0.001) and HOMA-IR (p < 0.001); they were also older and more obese. Stepwise multiple linear regression analysis showed that obesity was the major determinant of insulin resistance but sleep-disordered breathing parameters (AHI and minimum oxygen saturation) were also independent determinants of insulin resistance (fasting insulin: AHI, p = 0.02, minimum O(2), p = 0.041; HOMA-IR: AHI, p = 0.044, minimum O(2), p = 0.022); this association between OSA and insulin resistance was seen in both obese and nonobese subjects. Each additional apnea or hypopnea per sleep hour increased the fasting insulin level and HOMA-IR by about 0.5%. Further analysis of the relationship of insulin resistance and hypertension confirmed that insulin resistance was a significant factor for hypertension in this cohort. Our findings suggest that OSA is independently associated with insulin resistance, and its role in the atherogenic potential of sleep disordered breathing is worthy of further exploration.