Urinary Tract Large Cell Neuroendocrine Carcinoma: Diagnostic, Prognostic and Therapeutic Issues.

Large cell neuroendocrine carcinoma (LCNEC) of the urinary tract is a high-grade neuroendocrine tumor with distinct pathological features, usually portending an aggressive clinical behavior in comparison to conventional urothelial carcinoma. Due to its low prevalence, little is known about its clinical management and there is no current standard of care. The aim of this review was to summarize the current knowledge about LCNEC of the bladder, ureter and kidney, with relevance to diagnostic, prognostic and therapeutic issues, through a systematic analysis of clinical, pathological and outcome data retrieved from the literature.

Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3).

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

Large cell carcinoma of the lung: a tumor in search of an author. A clinically oriented critical reappraisal.

Large cell carcinoma (LCC) is a merely descriptive term indicating a subtype of lung cancer with no specific features of small-cell lung cancer (SCLC), adenocarcinoma (ADC) or squamous cell carcinoma (SQC). This diagnosis is allowed on surgical specimens only, whereas its counterpart in biopsy/cytology samples is non-small-cell lung carcinoma (NSCLC), not otherwise specified (NOS). Although these two terms do not fulfill the same concept, they can be interchangeable synonyms at the clinical level, reflecting, in different ways, the inability to define a specific subtype. Immunohistochemistry (IHC), next generation sequencing (NGS) analysis and, historically, electron microscopy have been unveiling diverse cell differentiation lineages in LCC, resulting in LCC-favor ADC, LCC-favor SQC and LCC-favor large-cell neuroendocrine carcinoma (LCNEC), the latter hopefully to be included into the neuroendocrine tumor (NET) group in the future. Paradoxically, however, the interpretation issues of LCC/NSCLC-NOS are not diminishing, but even increasing albeight an accurate diagnosis is oncologically required and crucial. Also, rare LCC/NSCLC-NOS cases exhibiting null/unclear phenotype, are difficult to classify, and this terminology could be maintained for the sake of classification (basically these tumors are serendipitous ADC, as also confirmed by the lack of p40). In this review article, seven relevant issues to LCC have been addressed by using a question-answer methodology, with final key points discussing major interpretation issues. In conclusion, most LCC/NSCLC-NOS may be eventually re-classified and addressed by exploiting IHC and/or molecular testing to satisfy the criteria of precision medicine (the right drug, to the right patient, at the right time).

Survival in women with NSCLC: the role of reproductive history and hormone use.

INTRODUCTION: Although lung cancer is the leading cause of cancer death in women, few studies have investigated the hormonal influence on survival after a lung cancer diagnosis and results have been inconsistent. We evaluated the role of reproductive and hormonal factors in predicting overall survival in women with non-small-cell lung cancer (NSCLC). METHODS: Population-based lung cancer cases diagnosed between November 1, 2001 and October 31, 2005 were identified through the Metropolitan Detroit Surveillance, Epidemiology, and End Results Registry. Interview and follow-up data were collected for 485 women. Cox proportional hazard regression models were used to determine hazard ratios (HRs) for death after an NSCLC diagnosis associated with reproductive and hormonal variables. RESULTS: Use of hormone therapy (HT) was associated with improved survival (HR, 0.69; 95% confidence interval, 0.54-0.89), adjusting for stage, surgery, radiation, education level, pack-years of smoking, age at diagnosis, race, and a multiplicative interaction between stage and radiation. No other reproductive or hormonal factor was associated with survival after an NSCLC diagnosis. Increased duration of HT use before the lung cancer diagnosis (132 months or longer) was associated with improved survival (HR, 0.54; 95% confidence interval, 0.37-0.78), and this finding remained significant in women taking either estrogen alone or progesterone plus estrogen, never smokers, and smokers. CONCLUSION: These findings suggest that HT use, in particular use of estrogen plus progesterone, and long-term HT use are associated with improved survival of NSCLC.

Sipa1 promoter polymorphism predicts risk and metastasis of lung cancer in Chinese.

Signal-induced proliferation associated gene 1 (Sipa1) is a signal transducer to activate the Ras-related proteins and modulate cell progression, differentiation, adhesion and cancer metastasis. In this study, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in Sipa1 are associated with lung cancer risk and metastasis. Three common SNPs (rs931127A > G, rs2448490G > A, and rs3741379G > T) were genotyped in a discovery set of southern Chinese population and then validated the promising SNPs in a validation set of an eastern Chinese population in a total of 1559 lung cancer patients and 1679 cancer-free controls. The results from the two sets were consistent, the rs931127GG variant genotype had an increased risk of lung cancer compared to the rs931127AA/GA genotypes (OR = 1.27; 95% CI = 1.09-1.49) after combination of the two populations, and the rs931127GG interacted with pack-year smoked on increasing lung cancer risk (P = 0.037); this SNP also had an effect on patients' clinical stages (P = 0.012) that those patients with the rs931127GG genotype had a significant higher metastasis rate and been advanced N, M stages at diagnosis. However, these associations were not observed for rs2448490G > A and rs3741379G > T in the discovery set. Our data suggest that the SNP rs931127A > G in the promoter of Sipa1 was significantly associated with lung cancer risk and metastasis, which may be a biomarker to predict the risk and metastasis of lung cancer.

Detection of Merkel cell polyomavirus with a tumour-specific signature in non-small cell lung cancer.

BACKGROUND: We searched for a viral aetiology for non-small cell lung cancer (NSCLC), focusing on Merkel cell polyomavirus (MCPyV). METHODS: We analysed 112 Japanese cases of NSCLC for the presence of the MCPyV genome and the expressions of RNA transcripts and MCPyV-encoded antigen. We also conducted the first analysis of the molecular features of MCPyV in lung cancers. RESULTS: PCR revealed that 9 out of 32 squamous cell carcinomas (SCCs), 9 out of 45 adenocarcinomas (ACs), 1 out of 32 large-cell carcinomas, and 1 out of 3 pleomorphic carcinomas were positive for MCPyV DNA. Some MCPyV DNA-positive cancers expressed large T antigen (LT) RNA transcripts. Immunohistochemistry showed that MCPyV LT antigen was expressed in the tumour cells. The viral integration sites were identified in one SCC and one AC. One had both episomal and integrated/truncated forms. The other carried an integrated MCPyV genome with frameshift mutations in the LT gene. CONCLUSION: We have demonstrated the expression of a viral oncoprotein, the presence of integrated MCPyV, and a truncated LT gene with a preserved retinoblastoma tumour-suppressor protein-binding domain in NSCLCs. Although the viral prevalence was low, the tumour-specific molecular signatures support the possibility that MCPyV is partly associated with the pathogenesis of NSCLC in a subset of patients.

A functional trinucleotide repeat polymorphism in the 5'-untranslated region of the glutathione biosynthetic gene GCLC is associated with increased risk for lung and aerodigestive tract cancers.

Glutathione (GSH), the major intracellular antioxidant, protects against cancer development by detoxifying carcinogens and free radicals and strengthening the immune system. Recently, a GAG-trinucleotide repeat polymorphism in the 5'-untranslated region of the gene for the rate-limiting enzyme for GSH biosynthesis, γ-glutamine cysteine ligase (GCL), was shown to be associated with lowered GCL activity and GSH levels in vitro and in vivo. We tested the hypothesis that this functional polymorphism in GCL is associated with the risk for lung and aerodigestive tract cancers. To this end, we conducted a case-control study that included 375 lung cancer cases, 200 aerodigestive tract cancer cases, and 537 controls. GAG repeat genotype (4, 7, 8, 9, and 10 repeat alleles) was determined by capillary electrophoresis of PCR products from the repeat region of the GCL catalytic subunit (GCLC). Odds ratios (OR) were calculated by logistic regression and adjusted for risk factors, including age, sex, body mass index, and smoking history. The GAG-7/7 genotype was associated with a 1.9-fold increased risk of lung cancer and 2.6-fold increased risk of aerodigestive tract cancer compared to the wild-type GAG-9/9 (P < 0.05). Similarly, the GAG-7 allele was associated with an increased risk of lung cancer (OR = 1.5, P = 0.01) and aerodigestive tract cancer (OR = 2.3, P < 0.001) compared to subjects without GAG-7 allele. These findings suggest that GSH synthesis affects the risk of lung and aerodigestive tract cancers, and further implicates a role for oxidative stress in the development of these cancers.

The polymorphisms and haplotypes of WWOX gene are associated with the risk of lung cancer in southern and eastern Chinese populations.

The WW domain-containing oxidoreductase (WWOX) gene is an identified tumor suppressor gene, of which several single nucleotide polymorphisms have been reported to contribute to cancer susceptibility. We hypothesized that genetic variations in WWOX are associated with lung cancer risk. In two independent case-control studies conducted in southern and eastern Chinese, we genotyped five tagSNPs of WWOX gene (rs10220974C > T, rs3764340C > G, rs12918952G > A, rs383362G > T, and rs12828G > A) in 1,559 lung cancer cases and 1,679 controls. Logistic regression analysis showed that two tagSNPs (rs3764340C > G; rs383362G > T) were significantly associated with lung cancer risk in dominant model (rs3764340C > G, GC/GG vs. CC: adjust OR = 1.35, 95% CI = 1.11-1.65; rs383362G > T, TG + TT vs. GG: adjust OR = 1.33, 95% CI = 1.14-1.55). The haplotype analysis further shown that the haplotype "G-T" was associated with the highest increased risk of lung cancer (OR = 2.20; 95% CI = 1.43-3.37). After combined these two loci, the number of the risk genotypes was associated with increased cancer risk in a dose-response manner (Ptrend = 3.16 × 10(-6) ). In addition, a gene-based association analysis by using VEGAS software suggested the WWOX as a susceptible gene for lung cancer (P = 0.009). However, for rs10220974C > T, rs12918952G > A, and rs12828G > A, no significant association was observed for lung cancer risk. Taken together, our data suggested that genetic variants in WWOX may be genetic biomarkers for susceptibility to lung cancer.

Reproductive and hormonal factors and the risk of lung cancer: the EAGLE study.

Evidence about the role for reproductive and hormonal factors in the etiology of lung cancer in women is conflicting. To clarify this question, we examined 407 female cases and 499 female controls from the Environment And Genetics in Lung cancer Etiology population-based case-control study. Subjects were interviewed in person using a computer-assisted personal interview to assess demographics, education, smoking history, medical history, occupational history, reproductive and hormonal factors. Associations of interest were investigated using logistic regression models, adjusted for catchment area and age (matching variables), cigarette smoking (status, pack-years and time since quitting). Additional confounding variables were investigated but did not substantially affect the results. We observed a reduced risk of lung cancer among women with later age at first live birth [≥31 years: odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.31-1.06, p-trend = 0.05], later age at menopause (≥51 years: OR = 0.49, 95%CI = 0.31-0.79, p-trend = 0.003) and longer reproductive periods (≥41 years: OR = 0.44, 95%CI = 0.25-0.79, p-trend = 0.01). A reduced risk was also observed for hormone replacement therapy (OR = 0.63, 95%CI = 0.42-0.95, p = 0.03) and oral contraceptive use (OR = 0.67, 95%CI = 0.45-1.00, p = 0.05) but no trend with duration of use was detected. Menopausal status (both natural and induced) was associated with an augmented risk. No additional associations were identified for other reproductive variables. This study suggests that women who continue to produce estrogens have a lower lung cancer risk. Large studies with great number of never smoking women, biomarkers of estrogen and molecular classification of lung cancer are needed for a more comprehensive view of the association between reproductive factors and lung cancer risk.

Glutathione-S-transferase (GSTM1, GSTT1) null phenotypes and risk of lung cancer in a Korean population.

PURPOSE: The aim of this study was to evaluate any association of GSTM1 and GSTT1 null genotypes with the risk of lung cancer in a South Korean population. METHODS: We conducted a large-scale, population-based case-control study including 3,933 lung cancer cases and 1,699 controls. Genotypes of GSTM1 and GSTT1 were determined using real-time polymerase chain reaction. RESULTS: In logistic regression analysis adjusted for age and smoking, we did not find any association between GSTM1 or GSTT1 and LC risk in women. However, in men, the GSTM1 and GSTTI null genotypes were borderline associated with risk (OR=1.18, 95% CI=0.99-1.41 for GSTM1, OR=1.18, 95% CI=0.99-1.41 for GSTT1), and combined GSTM1 and GSTT1 null genotypes conferred an increased risk for LC in men (OR=1.39, 95% CI=1.08-1.78). The OR for the GSTT1 null genotype was greater in subjects aged 55 years old or younger (OR=1.45, 95% CI=1.09-1.92 for men; OR=1.36, 95% CI=0.97-1.90 for women), than in those over age 55 (OR=1.03, 95% CI=0.83-1.27 for men; OR=0.86, 95% CI=0.66-1.12 for women) in both genders (p for interaction <0.05). CONCLUSIONS: In the Korean population, the GSTM1 and GSTT1 null genotypes are risk factors for LC in men; the GSTT1 null genotype has a more prominent effect on LC risk in younger people (age 55 years and under) than in older individuals.

Exposure to residential radon and lung cancer in never-smokers: the preliminary results of the LCRINS study.

INTRODUCTION AND OBJECTIVE: Residential radon is the second most important risk factor for lung cancer and the first among never-smokers. The objective of this study is to report the concentrations of residential radon in a series of never-smoker cases recruited in a multicenter study of cases and controls in northwestern Spain. In this study, all the hospitals in the Spanish province of Galicia and one from Asturias participated. PATIENTS AND METHODS: The present article includes a series of cases with residential radon measurements. All the subjects were personally interviewed, 3 ml of blood were taken from each, and they were each given instructions about how to place a residential radon detector in their homes. RESULTS: Sixty-nine case subjects were recruited, 84% of whom were women with a mean age of 71, and 81% of whom had adenocarcinoma. The average concentration of residential radon in the cases was 237 Bq/m(3), while the average concentration in the Galician population is 79 Bq/m(3). No relationship was observed between the concentration of residential radon and either sex or age at the time of diagnosis of the cases, but there was a tendency towards having a greater concentration in those diagnosed with small-cell and large-cell carcinoma. CONCLUSIONS: The concentrations of residential radon in the cases included are very high at about three times the average concentration of residential radon to which the general population of Galicia is exposed.

Nedaplatin and irinotecan in patients with large-cell neuroendocrine carcinoma of the lung.

BACKGROUND: No standard chemotherapy has been established for patients with large-cell neuroendocrine carcinoma (LCNEC). PATIENTS AND METHODS: Patients with LCNEC of the lung were treated with nedaplatin (NP) at 50 mg/m(2) and irinotecan at 50 mg/m(2) on days 1 and 8 every four weeks for four cycles. RESULTS: Data for 18 of the LCNEC patients were retrospectively analyzed. All patients were male, with a performance status 0 or 1, and the median age was 68 (range 58-80) years. Nine patients received adjuvant chemotherapy after undergoing complete surgical resection. Fourteen patients were able to receive four cycles of nedaplatin and irinotecan. Grade 4 leukopenia and neutropenia occurred in 5.6% and 16.7%, respectively. Four patients experienced grade 3 non-hematologic toxicities, such as diarrhea, enterocolitis, duodenal perforation and myocardial infarction. There were no treatment-related deaths. Two patients achieved complete response and four achieved partial response, and the median survival time was 12.3 months for the nine patients with advanced disease. CONCLUSION: Nedaplatin plus irinotecan is effective and safe for patients with LCNEC of the lung.

Functional genetic variants of c-Jun and their interaction with smoking and drinking increase the susceptibility to lung cancer in southern and eastern Chinese.

Human proto-oncogene c-Jun and c-Fos assemble the activator protein-1 complex which is a crucial transcription factor responding to environmental factors and promotes tumorgenesis. We hypothesized that genetic variants in these two genes may alter the carriers' susceptibility to lung cancer. In two independent case-control studies, we genotyped three putative functional polymorphisms (-1318T>G and -673T>C of c-Jun; -60C>T of c-Fos) in southern Chinese and then validated the association in eastern Chinese. We found that compared to -1318TT genotype, the -1318GT/GG variant genotypes had an increased lung cancer risk (OR=1.46, 95% CI=1.26-1.69), and the -673CC genotype had an increased lung cancer risk compared to -673TT/CT genotypes (OR=1.35, 95% CI=1.17-1.56) in the total 1,559 cases versus 1,679 controls. After combining these two loci, the number of the risk genotypes was associated with increased cancer risk in a dose-response manner (ptrend=2.21×10(-11)); moreover, the risk genotypes interacted with smoking or drinking status on increasing cancer risk (p values of interaction were 0.009 and 0.007, respectively). Further, we found that those with -1318GT/GG genotypes, -673CC genotypes or both genotypes in c-Jun had higher mRNA and protein expression levels in vivo, and those variants had higher transcription activities in reporter genes in vitro, especially under the stimuli with tobacco extract or alcohol mixture as luciferase assay shown. However, for -60C>T of c-Fos, no significant association was observed for lung cancer risk. Our data suggested that the genetic variants in c-Jun (-1318T>G and -673T>C) increase the carriers' susceptibility to lung cancer via interaction with smoking or drinking on increasing the c-Jun's expression.

Smoking, occupational risk factors, and bronchial tumor location: a possible impact for lung cancer computed tomography scan screening.

INTRODUCTION: The aim of this study was to describe associations between lung tumor location and smoking as well as selected occupational exposures. In the context of lung cancer screening by computed tomography scan, tumor location may have an interest. Computed tomography scan is known to better detect more peripheral tumors. METHODS: Lung cancer cases diagnosed in two French University hospitals between 1997 and 2009 were included. Tumors visible on white-light bronchoscopy were defined as central. Occupational exposures were assessed by the same expert. Data were analyzed by case-case comparisons using unconditional logistic regressions. RESULTS: A total of 1701 cases were included, comprising mainly men (86.3%), current smokers (52.8%), or former smokers (42.8%). Main histological subtypes of cancer were adenocarcinomas (33.8%) and squamous cell carcinomas (32.6%). The tumor location was found to be central in 61% of cases, and never smokers and women had more often peripheral tumors. Exposure to asbestos was significantly associated with central location with dose-response relationship (odds ratio [OR] for peripheral tumors = 0.45, 95% confidence interval [CI] 0.29-0.70) for the highest level of exposure. Exposure to silica dust was significantly associated with peripheral tumor (OR for peripheral tumors = 3.28, 95%CI 1.50-7.17) for the highest level of exposure. Exposure to welding fumes was associated with central location (OR for peripheral tumors = 0.51, 95% CI 0.26-0.96) for the first level of exposure). CONCLUSIONS: Smoking characteristics and occupational exposures have to be considered to define more accurately high-risk populations suitable for lung cancer screening or early detection programs.

Circulating markers of interstitial lung disease and subsequent risk of lung cancer.

BACKGROUND: Inflammation and pulmonary diseases, including interstitial lung diseases, are associated with increased lung cancer risk. Circulating levels of surfactant protein-D (SP-D) and Krebs von Lungren-6 (KL-6) are elevated in interstitial lung disease patients and may be useful markers of processes contributing to lung cancer. METHODS: We conducted a nested case-control study, including 532 lung cancer cases, 582 matched controls, and 150 additional controls with chest X-ray (CXR) evidence of pulmonary scarring, in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Serum SP-D and KL-6 levels were measured using enzyme immunoassay. Logistic regression was used to estimate the associations of SP-D and KL-6 with lung cancer and CXR scarring. RESULTS: Cases had higher levels than controls for SP-D (median 118.7 vs. 105.4 ng/mL, P = 0.008) and KL-6 (372.0 vs. 325.8 µg/mL, P = 0.001). Lung cancer risk increased with SP-D (P(trend) = 0.0003) and KL-6 levels (P(trend) = 0.005). Compared with the lowest quartile, lung cancer risk was elevated among those with the highest quartiles of SP-D (OR = 1.87, 95% CI: 1.32-2.64) or KL-6 (OR = 1.58, 95% CI: 1.11-2.25). Among controls, participants with CXR scarring were more likely than those without scarring to have elevated levels of SP-D (quartile 4 vs. quartile 1: OR = 1.67, 95% CI: 1.04-2.70, P(trend) = 0.05) but not of KL-6 (OR = 1.04, 95% CI: 0.64-1.68, P(trend) = 0.99). CONCLUSION: Circulating levels of SP-D and KL-6 are associated with subsequent lung cancer risk. IMPACT: Our findings support a potential role for interstitial lung disease in lung cancer etiology or early detection, but additional research is needed.

Primary lung cancer arising from the wall of a giant bulla in which positron emission tomography was useful for preoperative diagnosis.

We report a case of lung cancer arising from the wall of a giant bulla. A 58-year-old man consulted a physician because of bloody sputum. Chest computed tomography (CT) revealed a left upper giant bulla with partial thickness of the wall. Cytology of both sputum and transbronchial brushing was negative at that time. After 6 months follow-up CT scans showed more thickness of the wall, and positron emission tomography (PET) revealed high accumulation of fluorodeoxyglucose in the thickened wall. Because lung cancer was highly suspected, we performed an operation without a definitive diagnosis. The postoperative pathological diagnosis was large cell carcinoma arising from the wall of a giant bulla. Because a preoperative diagnosis is difficult in the case of lung carcinoma associated with bullous disease due to the lack of a characteristic radiological appearance and the difficulty of pathological examination, we emphasize that PET is a useful diagnostic tool.

Spontaneous smoking cessation before lung cancer diagnosis.

INTRODUCTION: We have observed that many patients with lung cancer stop smoking before diagnosis, usually before clinical symptoms, and often without difficulty. This led us to speculate that spontaneous smoking cessation may be a presenting symptom of lung cancer. METHODS: Patients from the Philadelphia Veterans Affairs Medical Center with lung cancer and for comparison, prostate cancer and myocardial infarction underwent a structured interview about their smoking habits preceding diagnosis. Severity of nicotine addiction was graded using the Fagerström Test for Nicotine Dependence. Among former smokers, dates of cessation, onset of symptoms, and diagnosis were recorded. Difficulty quitting was rated on a scale of 0 to 10. Distributions of intervals from cessation to diagnosis were compared between groups. RESULTS: All 115 patients with lung cancer had been smokers. Fifty-five (48%) quit before diagnosis, and only six of these (11%) were symptomatic at quitting. Patients with lung cancer who quit were as dependent on nicotine, when smoking the most, as those who continued to smoke, unlike the other groups. Despite this, 31% quit with no difficulty. The median interval from cessation to diagnosis was 2.7 years for lung cancer, 24.3 years for prostate cancer, and 10.0 years for patients with myocardial infarction. CONCLUSIONS: These results challenge the notion that patients with lung cancer usually quit smoking because of disease symptoms. The hypothesis that spontaneous smoking cessation may be a presenting symptom of lung cancer warrants further investigation.

Methylation induced gene silencing of HtrA3 in smoking-related lung cancer.

PURPOSE: Some 85% of lung cancers are smoking related. Here, we investigate the role of serine protease HtrA3 in smoking-related lung cancer. EXPERIMENTAL DESIGN: We assess HtrA3 methylation and its corresponding expression in the human bronchial cell line BEAS-2B following cigarette smoke carcinogen treatment, in lung cancer cell lines and in primary lung tumors from light, moderate, and heavy smokers. We also show the effects of HtrA3 downregulation on MTT reduction and clonogenic survival with etoposide and cisplatin treatment and the corresponding effects of HtrA3 re-expression during treatment. RESULTS: We show for the first time that HtrA3 expression is reduced or completely lost in over 50% of lung cancer cell lines and primary lung tumors from heavy smokers. Treatment of HtrA3-deficient cell lines with 5-aza-2'-deoxycytidine resulted in a dose-dependent increase in HtrA3 transcription. Further, sequence analysis of bisulfite-modified DNA from lung cancer cell lines and from primary lung tumors showed an increased frequency of methylation within the first exon of HtrA3 with a corresponding loss of HtrA3 expression, particularly in tumors from smokers. In BEAS-2B, treatment with the cigarette smoke carcinogen 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone resulted in HtrA3 downregulation with a corresponding increase in methylation. Additional studies indicate resistance to etoposide and cisplatin cytotoxicity as a functional consequence of HtrA3 loss. Finally, immunohistochemical analysis of primary lung tumors revealed a strong correlation between low HtrA3 expression and heavy smoking history. CONCLUSIONS: Collectively, these results suggest that cigarette smoke-induced methylation of HtrA3 could contribute to the etiology of chemoresistant disease in smoking-related lung cancer.

Surgery for bronchogenic cysts: always easy?

A few cases of major complications after surgery for bronchogenic cyst have been reported. The purpose of this study was to analyze the complicated and unusual cases among 30 consecutive patients with bronchogenic cysts treated surgically at our institution between 1975 and 2007. There were 3 cases of mediastinal bronchogenic cyst characterized by significant surgical complications or very unusual pathological findings. The operations were performed through a thoracotomy in 25 patients, and by video-assisted thoracoscopic surgery in 5. Two patients suffered iatrogenic injury of the contralateral main bronchus during excision of a mediastinal cyst; in one of them, late development of foreign body granuloma was related to migration towards the bronchial wall of cyanoacrylate used to reinforce suturing of the bronchial tear. Histological examination of one resected specimen showed a large-cell anaplastic carcinoma arising from the wall of a mediastinal bronchogenic cyst. Bronchogenic cysts should be excised before they become symptomatic or infected, which leads to more difficult surgery and complications. The small risk of developing malignancy within a bronchogenic cyst also justifies early intervention.

Characteristics of menstruation and pregnancy and the risk of lung cancer in women.

Lung tissue, both normal and cancerous, has been found to express estrogen receptors and patterns of expression have differed between men and women, suggesting a possible role for hormone-related factors in lung carcinogenesis in women. Few epidemiological studies have examined hormone-related variables and lung cancer risk and the findings have not been consistent. We investigated the association between characteristics of menstruation and pregnancy in relation to lung cancer risk in a population-based case-control study carried out in Montreal, Canada, including 422 women with lung cancer and 577 controls. For each variable, odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression modeling. Associations were also examined according to level of smoking and by lung cancer histology. All statistical tests were two-sided. Most characteristics of menstruation and pregnancy were not associated with lung cancer risk. However, an increased risk was observed for women who had had a non-natural menopause, which predominantly included women who had had a bilateral oophorectomy, compared with women who had had a natural menopause (OR = 1.92, 95% CI: 1.22-3.01). An inverse association with age at menopause was suggested. These results did not vary by level of smoking and they were similar for adenocarcinomas compared with other histological types. Our results suggest that hormonal factors, related to early menopause and/or ovary removal, may play a role in the risk of lung cancer. Further studies are needed to confirm these findings, and to assess the possible contribution of hormone replacement therapy.