Repetitive nicotine exposure leads to a more malignant and metastasis-prone phenotype of SCLC: a molecular insight into the importance of quitting smoking during treatment.

Cigarette smoking is strongly correlated with the onset of lung cancer. Nicotine, a major component in cigarette smoke, has been found to promote tumor growth and angiogenesis, as well as protect cancer cells from apoptosis. Among all lung cancer cases, small cell lung cancer (SCLC) is found almost exclusively in smokers; metastasis and chemoresistance are the main reasons for the high mortality rates associated with SCLC. Retrospective studies have shown that patients with tobacco-related cancers who continue to smoke after their diagnosis display lower response rates and a shorter median survival compared with those who stop smoking. In the current work, we examined the effects of acute and repetitive exposure to nicotine, in the concentrations found in the lungs of active smokers, on the malignant properties of N417 SCLC cells in vitro. We observed that repetitive nicotine exposure induced a neuronal-like appearance in N417 cells along with increased adhesion to the extracellular matrix and chemoresistance. These changes were accompanied by enhanced migration through collagen matrices and adhesion to and transmigration across lymphatic endothelial cell monolayers. SCLC differentiation reverted after cessation of nicotine exposure. Here, we provide evidence for the leading role of the CXCR4/CXCL12 axis in these phenomena. Finally, we show how nicotine-differentiated N417 cells produced bigger and more vascularized tumors in mice, with lower apoptotic rates, than their nondifferentiated counterparts. In short, these findings identify the mechanisms through which nicotine increases SCLC malignancy and provide further evidence that CXCR4 is a potential anticancer target for nicotine-associated SCLC.

Aberrations of chromosome 19 in asbestos-associated lung cancer and in asbestos-induced micronuclei of bronchial epithelial cells in vitro.

Exposure to asbestos is known to induce lung cancer, and our previous studies have suggested that specific chromosomal regions, such as 19p13, are preferentially aberrant in lung tumours of asbestos-exposed patients. Here, we further examined the association between the 19p region and exposure to asbestos using array comparative genomic hybridization and fluorescence in situ hybridization (FISH) in lung tumours and FISH characterization of asbestos-induced micronuclei (MN) in human bronchial epithelial BEAS 2B cells in vitro. We detected an increased number of 19p losses in the tumours of asbestos-exposed patients in comparison with tumours from non-exposed subjects with similar distribution of tumour histology in both groups (13/33; 39% versus 3/25; 12%, P = 0.04). In BEAS 2B cells, a 48 h exposure to crocidolite asbestos (2.0 microg/cm(2)) was found to induce centromere-negative MN-harbouring chromosomal fragments. Furthermore, an increased frequency of rare MN containing a 19p fragment was observed after the crocidolite treatment in comparison with untreated controls (6/6000 versus 1/10 000, P = 0.01). The results suggest that 19p has significance in asbestos-associated carcinogenesis and that asbestos may be capable of inducing specific chromosome aberrations.

Aspirin and lung cancer risk in a cohort study of women: dosage, duration and latency.

Aspirin may reduce the risk of cancer at some sites but its effect at the lung is unclear. We prospectively examined associations between aspirin use and risk of lung cancer in 109,348 women in the Nurses' Health study from 1980 to 2004. During this time, 1,360 lung cancers were documented in participants 36-82 years of age. Aspirin use and smoking were assessed every 2 years. Risk of lung cancer was a non-significant 16% lower for regular aspirin users of one or two tablets per week and a significant 55% higher for users of 15 or more tablets per week compared with women who never regularly used aspirin. Results were similar when limited to never smokers. For both the low and high quantity aspirin users, risk of lung cancer did not decline or increase with longer durations of use, and associations attenuated as the latency period between aspirin assessment and lung cancer diagnosis was lengthened. Our findings, together with those from previous clinical trials and prospective studies, do not provide consistent evidence that aspirin influences the development of lung cancer and further investigation is required with adjustment for smoking.

Loss of GFI1 impairs pulmonary neuroendorine cell proliferation, but the neuroendocrine phenotype has limited impact on post-naphthalene airway repair.

Naphthalene exposure kills lung airway epithelial (Clara) cells, but is rapidly followed by Clara cell reconstitution coincident with proliferation of pulmonary neuroendocrine cells (PNEC). Although a role for mature PNEC in the reconstitution process has been excluded, the reconstituting progenitor cells have been suggested to enter a transient neuroendocrine (NE) differentiation phase before differentiating to Clara cells. Furthermore, these progenitors were suggested to be the target population for transformation to a NE tumor; small cell lung cancer (SCLC). Although the NE phenotype is central to SCLC oncogenesis, the relevance of NE differentiation to post naphthalene reconstitution remains to be determined. The Growth factor independent-1 (Gfi1) transcription factor is expressed in SCLC and is required for the NE differentiation of PNEC. Gfi1(-/-) mice display a 70% reduction in airway cells that express NE markers, and cells that stain for NE markers show weak expression of some markers. Therefore, to determine the relevance of the NE phenotype to post-naphthalene reconstitution, we examined post-naphthalene reconstitution in Gfi1(-/-) mice. Our analyses indicate that the post-naphthalene regeneration process includes both airway epithelial proliferation and apoptosis. Gfi1 deletion lowered both airway epithelial proliferation and apoptosis; however, the post-naphthalene rate of increase in growth and apoptosis was not significantly different between Gfi1(-/-) mice and wild-type littermates. Moreover, the timing and extent of CC10+ cell regeneration was unaffected by Gfi1 deletion. These data suggest that neither Gfi1 nor the NE phenotype play a dominant role in the regeneration process. However, the few Gfi1(-/-) cells capable of NE differentiation show a significant reduction in post-naphthalene proliferation. The modest proliferation seen in Gfi1(-/-) NE cells is consistent with the previously proposed role for Gfi1 in controlling neuroendocrine cancer growth.

Differences between small-cell lung cancer and non-small-cell lung cancer among tobacco smokers.

It is known that smoking increases the risk for all histological subtypes of lung cancer. To date, the factors that determine why some patients develop small-cell lung cancer (SCLC) while others develop non-small-cell lung cancer (NSCLC) remain unknown. We compared the characteristics of 774 smokers with SCLC and NSCLC diagnosed during the period January 1999 till December 2002. Multivariate logistic regression was used to estimate the odds ratio (OR) with 95% CI. Testing of linear trend across categories of pack-years was also conducted. Six hundred and sixty-five NSCLC were compared to 109 SCLC. Among SCLC, there were significantly more females (20.2% versus 12.8%), current-smokers (81.7% versus 71.9%) as well as smokers who had smoked more than 40 pack-years (75.6% versus 50.3%). Comparing SCLC with NSCLC among the men only, having smoked more than 40 pack-years was associated with a significantly elevated odds ratio (OR) of 3.71 of developing SCLC (95% CI, 1.05-13.1; p=0.041). There was a decreasing trend in OR with increasing smoking cessation period. When comparing SCLC with adenocarcinoma, the women had a higher OR of 2.37 of developing SCLC (95% CI, 1.05-5.31; p=0.037) compared to the men. Our findings suggest that cumulative smoking exposure in terms of pack-years smoked is an important determining factor for the preferred development of SCLC among smokers.

[Microcellular lung carcinoma in patient with hepatosplenic T-cell lymphoma: a case report]. / Mikrocelularni karcinom pluca u bolesnika s hepatosplenicnim t-stanicnim limfomom: prikaz bolesnika.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare form of extranodal non-Hodgkin lymphoma derived from cytotoxic T-cells, usually manifesting by sinusoidal infiltration of spleen, liver and bone marrow. In 1997 World Health Organization classified malignant lymphomas and placed HSTCL among peripheral T-cell neoplasms. The course of the diseases is usually very agressive with a median survival time of 8 to 16 moths despite multiagent chemotherapy. We present a case of a 48-year-old male patient whose initial symptoms were fatigue, weight loss and night sweats, which were followed by splenomegaly and pancytopenia. After clinical examination we suspected him to have HSTCL which was proved pathohistologically upon splenectomy and it is the first case of this lymphoma diagnosed in "Merkur" Clinical Hospital. As a first line of lymphoma therapy we decided to apply FED course (fludarabine, cyclophosphamide, prednisone), being aware of the published poor results the standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone) yields. As far as we know, the results of this chemotherapy course in the therapy of this tumor have never been published. The patient underwent 6 courses of FED therapy, which he tolerated well and was in good clinical condition. Upon the completion of the 6th course of therapy he was diagnosed with lung anaplastic microcellular carcinoma and was treated with 3 course of PE therapy (cisplatin, etoposide).

Chronic lymphocytic leukaemia, synchronous small cell carcinoma and squamous neoplasia of the urinary bladder in a paraplegic man following long-term phenoxybenzamine therapy.

STUDY DESIGN: A case report. OBJECTIVE: To raise awareness among spinal cord clinicians of the possible carcinogenic effect of phenoxybenzamine and of the rare occurrence of small cell carcinoma in the neuropathic bladder. SETTING: Regional Spinal Injuries Centre and District General Hospital, Southport, Merseyside, United Kingdom. CASE REPORT: A 28-year-old man sustained a fracture dislocation of L-1 with consequent paraplegia (ASIA impairment scale A). Phenoxybenzamine treatment enabled his indwelling catheter to be discarded in favour of a penile sheath, but it caused unacceptable dizziness and was stopped after 7 years. After 20 years, he developed chronic lymphocytic leukaemia, which was treated with chlorambucil and fludarabine. After 2 years, investigation of bilateral hydronephrosis revealed a primary small cell carcinoma of the bladder with coexistent squamous dysplasia. Uraemia supervened and, declining active treatment, the patient died 3 weeks after diagnosis. CONCLUSION: Phenoxybenzamine, a known carcinogen in rodents, is likely also to be carcinogenic in humans, and patients with spinal cord injury who have received the drug for any significant period of time, need close follow-up to allow early detection of cancer. Phenoxybenzamine should not be prescribed on a long-term basis, and should instead be replaced with a selective alpha-blocker.

A case of Bowen's disease and small-cell lung carcinoma: long-term consequences of chronic arsenic exposure in Chinese traditional medicine.

Chronic arsenic toxicity occurs primarily through inadvertent ingestion of contaminated water and food or occupational exposure, but it can also occur through medicinal ingestion. This case features a 53-year-old lifetime nonsmoker with chronic asthma treated for 10 years in childhood with Chinese traditional medicine containing arsenic. The patient was diagnosed with Bowen's disease and developed extensive-stage small-cell carcinoma of the lung 10 years and 47 years, respectively, after the onset of arsenic exposure. Although it has a long history as a medicinal agent, arsenic is a carcinogen associated with many malignancies including those of skin and lung. It is more commonly associated with non-small-cell lung cancer, but the temporal association with Bowen's disease in the absence of other chemical or occupational exposure strongly points to a causal role for arsenic in this case of small-cell lung cancer. Individuals with documented arsenic-induced Bowen's disease should be considered for more aggressive screening for long-term complications, especially the development of subsequent malignancies.

Effect of pesticide exposure on HER-2/neu overexpression seen in patients with extensive stage small cell lung carcinoma.

PURPOSE: The aim of this study was to evaluate the relationship, if any, between pesticide exposure and overexpression of the HER-2/neu oncoprotein in extensive stage small cell lung cancer (ESSCLC). EXPERIMENTAL DESIGN: The records of all patients with a diagnosis of ESSCLC from January 1991 through April 2001 were reviewed in our retrospective study. Pesticide risk (herbicide and insecticide) was assessed by telephone interviews using a predetermined questionnaire with emphasis on type of exposure, use of protective measures, and duration of exposure. An exposure index was calculated (h/day x days/year x years), and patients with an index > 2400 h were considered as exposed. HER-2/neu overexpression was assessed by immunohistochemistry using the Hercep test developed by Dako. Statistical analysis was performed using SPSS-10. RESULTS: A total of 193 patients (84 females and 109 males), with a mean age of 68.5 years (range, 42-90 years) were included in the study. Of these, 57 (29.5%) revealed HER-2/neu overexpression by immunohistochemistry. After adjusting for age, smoking, Eastern Cooperative Oncology Group score, and treatment, HER-2/neu overexpression was associated with a statistically significant diminished survival (P < 0.001; Mann-Whitney U test). We contacted 53 of 57 patients with overexpression and 121 of 136 patients without HER-2/neu overexpression to ascertain a history of pesticide exposure. Forty-one of 53 (77.4%) patients with HER-2/neu overexpression and 47 of the 121 patients without overexpression (38.8%) were exposed to pesticides. We found that patients with history of pesticide exposure had a higher risk of having HER-2/neu overexpression (odds ratio, 5.38; P < 0.01, 95% confidence interval, 2.5-11.2) CONCLUSIONS: HER-2/neu is overexpressed in approximately 30% patients with ESSCLC and is associated with decreased survival. Also, pesticide exposure seems to be related to HER-2/neu overexpression seen in our patient population. Future studies are needed to validate our findings and also to determine which pesticide(s)/pesticide components are actually responsible for HER-2/neu overexpression seen in ESSCLC.

Ovarian carcinoma in an adolescent with transgenerational exposure to diethylstilbestrol.

Small cell carcinoma of the ovary is rare in adolescence. The etiology of such tumors is unknown. Several reports suggest that transgenerational exposure to diethylstilbestrol (DES) may have deleterious effects on the genitourinary tract. The authors describe a 15-year-old girl with small cell carcinoma of the ovary whose maternal grandmother had been taking DES while she was pregnant with the patient's mother. This case, while anecdotal, suggests that a transgenerational history of DES exposure should be noted, and that granddaughters with persistent abdominal pain even during childhood may need evaluation for genital tract abnormalities.

Receptor-mediated effects of nicotine and its nitrosated derivative NNK on pulmonary neuroendocrine cells.

Pulmonary neuroendocrine cells (PNECs) have been implicated in the development of small cell lung carcinoma (SCLC) and pediatric asthma, and smoking is a risk factor for both diseases. We as well as others have shown that the alpha(7) nicotinic acetylcholine receptor (alpha(7) nAChR) regulates the release of 5-hydroxytryptamine (5-HT, serotonin) in PNECs and SCLC. Serotonin is an autocrine growth factor for PNECs and SCLC and acts as broncho-constrictor. We found that nicotine and its nitrosated carcinogenic derivative 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) bind to the alpha(7) nAChR in SCLC and PNECs, resulting in the influx of Ca(2+), release of 5-HT, and activation of a mitogenic pathway mediated by protein kinase C (PKC), Raf-1, mitogen activated protein kinase (MAPK) and c-myc. Exposure to 10% CO(2) acted synergistically. Unstimulated SCLC cells from smokers demonstrated high base levels of 5-HT release and of individual downstream signaling components in comparison to PNECs. Subchronic exposure of PNECs to NNK up-regulated the alpha(7) nAChR and its associated serotonergic mitogenic pathway in PNECs, an effect that may contribute to the development of SCLC in smokers and pediatric asthma in children of mothers who smoke.

[Small-cell mesothelioma of the pleura: description of a case]. / Mesotelioma a piccole cellule della pleura: descrizione di un caso.

A case of mesothelioma with a small cell component in a 53-year-old, non-smoker woman. The patient had a history of asbestos exposure, and presented with thoracic pain. A total body computed tomogram showed a left pleural effusion and a 7.5-cm pleural mass. Thoracoscopy revealed a diffuse nodular thickening of the left parietal pleura, and a biopsy was performed. The patient died of the disease 4 months after diagnosis. Microscopically, the pleural neoplasm was composed of three different components: 40% of the tumor showed the classic histology of a malignant epithelial mesothelioma, 40% was composed of small- to medium-sized cells with open nuclear chromatin, evident nucleoli and high mitotic activity, and 20% of the neoplasm was indistinguishable from a small cell carcinoma. Immunohistochemically, the first component was diffusely and strongly positive for cytokeratin AE1/AE3, cytokeratin CAM 5.2 and EMA, focally positive for BER-EP4, and negative for CD15, B 72.3, CEA, LCA, chromogranin, synaptophysin, TTF-1 and CD99. The cells of the second component were positive only for cytokeratin AE1/AE3 and cytokeratin CAM 5.2, and the elements of the third component were negative for all the antibodies tested. Pleural mesothelioma with a small cell component is rare. The most useful parameters to distinguish it from other small cell malignancies that may involve the pleura, particularly small cell carcinoma of pulmonary origin, are discussed.

Elevated mortality from lung cancer associated with arsenic exposure for a limited duration.

In 1959, arsenic poisoning was detected in the town of Nakajo in Japan. The cause was exposure to inorganic arsenic in well water during 1954 to 1959. To examine the long-term effects of limited-duration arsenic exposure, we conducted mortality and survival studies for patients with chronic arsenic exposure and for control subjects from 1959 to 1992. The ratio of observed deaths to expected deaths from lung cancer was significantly high (7:0.64) for male patients. The lung cancer mortality rate was elevated markedly in subgroups with higher clinical severities of symptoms. Small cell carcinoma was specific to the exposed patients. The cumulative change of survival declined significantly in the exposed patients compared with the controls. The decline disappeared when lung cancer deaths were treated as lost to follow-up. The results showed that a 5-year period of arsenic exposure was associated with risk of lung cancer.

Association between carcinogen-DNA adducts in white blood cells and lung cancer risk in the physicians health study.

In this matched case-control study nested within the prospective Physicians' Health Study, we evaluated whether DNA damage in blood samples collected at enrollment significantly predicted risk, consistent with our hypothesis that cases have greater biological susceptibility to polycyclic aromatic hydrocarbons and other aromatic tobacco carcinogens. The subjects were 89 cases of primary lung cancer and 173 controls, all males, matched on smoking, age, and duration of follow-up. Aromatic-DNA adducts were measured in WBCs by the nuclease P1-enhanced (32)P-postlabeling method that primarily detects smoking-related adducts. Among current smokers, but not former or nonsmokers, there was a significant increase in mean adduct levels of cases compared with controls (11.04 versus 5.63; P = 0.03). "Healthy" current smokers who had elevated levels of aromatic DNA adducts in WBCs were approximately three times more likely to be diagnosed with lung cancer 1-13 years later than current smokers with lower adduct concentrations (odds ratio, 2.98; 95% confidence interval, 1.05-8.42; P = 0.04). We were not able to discern case-control differences in former smokers and nonsmokers. The findings are of interest because they suggest that individuals who become cases have greater biological susceptibility to tobacco carcinogens, a biological difference, which manifests most clearly while exposure is ongoing.

Nicotinic receptor-mediated activation by the tobacco-specific nitrosamine NNK of a Raf-1/MAP kinase pathway, resulting in phosphorylation of c-myc in human small cell lung carcinoma cells and pulmonary neuroendocrine cells.

OBJECTIVE: Small cell lung carcinoma (SCLC) expresses phenotypic features of pulmonary neuroendocrine cells and demonstrates a strong etiologic association with smoking. SCLC cell lines express a Raf-1-dependent mitogenic signal transduction pathway, which is thought to transduce the mitogenic signals initiated by neuropeptide autocrine growth factors. Recent studies have identified the tobacco-specific carcinogenic nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as a site-selective high-affinity agonist for the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR), which regulates the growth of a significant subset of SCLC in vitro by stimulating the release of the autocrine growth factor serotonin. The purpose of this study was to identify signaling events initiated by binding of NNK to the alpha7 nAChR. DESIGN: We have used a human SCLC cell line and fetal hamster pulmonary neuroendocrine cells with in vitro kinase activation assays and western blots to assess the levels of expression and activation of Raf-1, MAPK and c-myc to address this issue. RESULTS: Our data show that NNK activates the Raf-1, MAP kinase pathway, resulting in phosphorylation of c-myc. The activation of this signal transduction pathway by NNK was inhibited by the site-selective antagonist for the alpha7 nAChR alpha-bungarotoxin (alpha-BTX) or by the serotonin reuptake inhibitor imipramine, suggesting that the responses to NNK were mediated by nicotinic receptor-initiated release of serotonin. Accordingly, NNK-induced 5-HT release was blocked by alpha-BTX while NNK-induced DNA synthesis was inhibited by alpha-BTX, imipramine, the PKC inhibitor sphingosine or the MEK inhibitor PD98059. SCLC cells demonstrated high basal levels of 5-HT release, DNA synthesis, and over-expressed Raf-1 and MAPK protein suggesting the constitutive activation of an upstream regulator such as the alpha7 nAChR. CONCLUSION: Our findings link, for the first time, the stimulation of a nicotinic acetylcholine receptor by a cancer-causing agent with the activation of a Raf-1/MAPK/c-myc signaling pathway. Furthermore, our data suggest that serotonin uptake inhibitors may protect against the development or be useful in the clinical management of SCLC.

The spectrum of cutaneous and internal malignancies in chronic arsenic toxicity.

We report 3 patients of chronic arsenic poisoning with characteristic skin changes. All 3 patients had a past history of asthma and were treated with Traditional Chinese Medication. We believe that the Chinese medications were the source of arsenic poisoning. Two of the 3 patients also had internal malignancy. The association of arsenic with internal malignancy is reviewed.

[Coexistence of obstructive lung diseases and lung cancer]. / Wspólistnienie przewleklej choroby obturacyjnej pluc z rakiem pluca.

Connection between histological type of lung cancer and existence of clinical and spirometric symptoms of COPD was analysed in 110 lung cancer patients (64 small cell, 23 adenocarcinoma, and 23 squamous). It was shown that adenocarcinoma was significantly more frequent among subjects with values of FEV1%VC over 70 than among subjects with small cell and squamous lung cancer. Also subjects with values of FEV1% VC over 70 had significantly higher oxygen blood pressure, and clinical and radiological symptoms of COPD were less intensive than in subjects with values of this index below 70. There was no correlation between histological type of lung cancer and bronchoscopic symptoms of bronchitis and radiological symptoms of emphysema.

Mutations of the p53 gene in human lung cancer from chromate-exposed workers.

We examined p53 mutations in 20 cancer samples from 19 chromate workers with lung cancer by Polymerase chain reaction-Single strand conformation polymorphism analysis and direct sequencing. Six missense mutations were identified in 4 (20%) of the 20 chromate lung cancer samples. Fewer mutations were found in the patients with lung cancers who had been exposed to chromate than in those who had not. However, the pattern of p53 mutations in lung cancer patients exposed to chromate differed from that of common lung cancers in 3 respects. There were no apparent G to T transversions, which are common base changes in lung cancers. Half of the mutational sites (3/ 6) had changes of AT base-pairs, and 2 of 4 mutational tumor samples had double missense mutations. Our results suggested that chromate exposure may induce point mutation of the p53 gene.

Air pollution and lung cancer in Trieste, Italy.

To investigate the relation between air pollution and histologic type of lung cancer, the authors conducted a case-control study among men who had died in Trieste, Italy, from 1979 to 1981 and from 1985 to 1986. Through the local autopsy registry, 755 cases of lung cancer and 755 controls were identified. Information on smoking habits, occupation, and place of residence was obtained from each subject's next of kin. Air pollution at the residence of each subject was estimated from the average value of total particulate at the nearest monitoring station. Logistic regression was used to evaluate the effect of residence and air pollution on lung cancer after adjustment for age, smoking habits, likelihood of exposure to occupational carcinogens, and social group. The risk of lung cancer increased with increasing level of air pollution for all types of lung cancer combined (p = 0.022), for small cell carcinoma (p = 0.016), and for large cell carcinoma (p = 0.049). Compared with inhabitants of the residential area, residents of the rural area had a relative risk (RR) of 0.6 (95% confidence interval (CI) 0.4-1.0). The RR was 1.5 (95% CI 1.0-2.2) for residents of the center of the city and 1.4 (95% CI 1.0-2.1) for residents of the industrial area. In the center of the city, the excess risk was almost completely restricted to small cell carcinoma (RR = 2.0) and to large cell carcinoma (RR = 2.6). In the industrial area, the risk was increased especially for adenocarcinoma (RR = 2.1). These results provide evidence that air pollution is a moderate risk factor for certain histologic types of lung cancer.

[Role of outdoor and indoor air pollution in the etiology of lung cancer]. / Rol' zagriazneniia atmosfernogo vozdukha i vozdukha pomeshchenii v étiologii raka legkogo.

The results of a case-control study of lung cancer risk in female non-smokers in Moscow are presented in the paper. The increase in a risk of lung cancer was found to be associated with outdoor pollution, the closure of the residence to chemical industry and ferrous and non-ferrous smelters, environmental tobacco smoke from husbands and exposure to radon (Rn) at home. The relative risk of lung cancer (RR) for those living in high air polluted versus relatively pure areas was 2.6 (95% CI = 1.2-5.6). RR of lung cancer related to the closure of the residence to chemical industry and ferrous and non-ferrous smelters were 2.0 (95% CI = 1.0-3.9) and 1.75 (95% CI = 1.0-3.1). The analysis has shown that there is an increase in lung cancer risk in women whose husbands smoke, which is as high as 1.9 (95% CI = 1.3-2.9). Lung cancer risk is associated with levels of exposure to Rn in the dwellings: RR was 2.48 (95% CI = 1.4-4.3) for the Rn concentration of > 24.3 Bq/m3 versus < 13 Bq/m3.