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.

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.

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.

[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).

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.

Excess lung cancer risk in a synthetic chemicals plant.

A standardized mortality ratio of 1.49 for respiratory system cancer (42 observed deaths versus 28.2 expected, p less than 0.01) was observed among a cohort of 4806 males employed at a synthetic chemicals plant since its startup in 1942. Upon review of pathologic material, the excess was found to be limited to adenocarcinoma and large cell undifferentiated lung cancer. Many of the workers had been exposed to vinyl chloride, as well as to chlorinated solvents, poly(vinyl chloride) (PVC) dust, acrylates and acrylonitrile. To evaluate the association between lung cancer and occupational chemical exposures, detailed work histories for each cohort member were combined with exposure ratings for each of 19 chemicals for each job for each calendar year since 1942. A serially additive expected dose model was then constructed which compared the doses of the chemicals observed for the lung cancer cases to the doses expected based on subcohorts without lung cancer individually matched to the cases. PVC dust appeared to be the most likely etiologic agent (p = 0.037). Time trends of PVC dust exposure indicated a potential latent period of 5-16 years before death.

Immunohistochemical detection of pulmonary cytochrome P450IA and metabolic activities associated with P450IA1 and P450IA2 isozymes in lung cancer patients.

The main polycyclic aromatic hydrocarbon-inducible cytochrome P450 was studied in lung tissue from 57 lung cancer patients by immunohistochemistry, using a monoclonal antibody (1-7-1) that recognizes P450IA1 and P450IA2 isozymes. The intensity of immunostaining was compared with the pulmonary activity of a P450IA1-dependent enzyme, aryl hydrocarbon hydroxylase (AHH), and with P450IA2-related metabolic activity estimated from the ratio of caffeine metabolites in urine. Immunostaining was not observed in peripheral lung tissue of nonsmokers or ex-smokers but was seen in the bronchiolar and alveolar epithelium of all patients who were smokers and had a peripheral carcinoma (16/16) and of 60% (10/17) of those who had a bronchial carcinoma. AHH activity was positively related to the intensity of immunostaining, and an almost 2-fold increase due to smoking was detected in the ratios of caffeine metabolites. These results demonstrate that tobacco smoke induces P450IA1 in the lung and probably P450IA2 in the liver, and suggest a role for certain metabolic phenotypes of P450IA1 in peripheral pulmonary carcinoma.

Small cell lung carcinoma and Bowen's disease 40 years after arsenic ingestion.

A non-smoking woman presented with ectopic ACTH syndrome associated with disseminated small cell carcinoma of lung. The patient had Bowen's disease and had taken oral arsenic for psoriasis 40 years ago. It is postulated that the previous therapeutic arsenic ingestion caused both her arsenical dermatosis and her small cell carcinoma of lung.

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.

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.

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.

Histopathology of sinonasal and lung cancers in nickel refinery workers.

Histopathological diagnoses were compiled for 100 sinonasal cancers and 259 lung cancers in nickel refinery workers, including cases from Wales, Canada, and Norway. The sinonasal cancers comprised squamous cell carcinomas (48 percent), anaplastic and undifferentiated carcinomas (39 percent), adenocarcinomas (6 percent), transitional cell carcinomas (3 percent), and other malignant tumors (4 percent). The lung tumors comprised squamous cell carcinomas (67 percent), anaplastic, small cell, and oat cell carcinomas (15 percent), adenocarcinomas (8 percent), large cell carcinomas (3 percent), other malignant tumors (1 percent), and cancers not otherwise specified (6 percent). Possible selection bias in these data cannot be excluded, since the histological diagnoses represent 63 percent, 68 percent, and 100 percent of cases of sinonasal cancer and 24 percent, 47 percent, and 86 percent of cases of lung cancer in the Welsh, Canadian, and Norwegian workers. This study suggests that (a) the sinonasal cancers in nickel refinery workers conformed to the usual distribution of histological types observed in the general population (in contrast to the predilection for adenocarcinomas in wood workers), and (b) the lung cancers in nickel-refinery workers showed preponderance of squamous cell carcinomas and deficit of adenocarcinomas, compared to prevalent proportions of these neoplasms, possibly reflecting the paucity of women in the cohorts and temporal trends during the six decades in which the tumors were diagnosed.

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.

[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.

[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.

[Investigations of the pathogenesis of lung cancer observed among chromate factory workers].

In order to clarify the relationship between the chromate compound and occurrence of lung cancer, the author studied the characteristics of patients with lung cancer among workers of chromate factory and measured the chromium contents of each tissues obtained from 14 patients at surgery and autopsy. The incidence of the chromate lung cancer was 413 per 100,000 population, which was 16 times that of the general population. All were male. The age ranged from 26 to 74 year old (average 53). The histological type was mostly squamous and small cell carcinoma. Location of carcinoma occurrence was mainly limited to the large bronchi. The average total labor period of patients with lung cancer was 258 months and the latent period was 305 months. The working history of the patients in hexavalent-chromium producing process was longer than that of the control group. Patients with small cell carcinoma was mainly engaged in the monochromate producing process. The labor and latent period of patients with squamous cell carcinoma was longer than those of small cell carcinoma. Measurement of chromium contents in the respiratory system of chromate workers revealed much higher chromium content than in control group. The chromium content of tissues in the non-respiratory system was a little higher than that of the control group. High chromium content itself did not have any relation with the occurrence of lung cancer because the primary location of chromate lung cancer was limited to the large bronchi, not to the peripheral lungs which contained the highest chromium content. The longer was the exposure period, the higher was chromium content in the lung. Chromium content in the upper lobe was higher than that in the lower lobe. From these studies, the author concluded that hexavalent-chromate compound might be the compound responsible for lung cancer occurrence.

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.