CDKN2A copy number and p16 expression in malignant pleural mesothelioma in relation to asbestos exposure.

BACKGROUND: Deletion of the CDKN2A locus is centrally involved in the development of several malignancies. In malignant pleural mesothelioma (MPM), it is one of the most frequently reported genomic alteration. MPM is strongly associated with a patients' asbestos exposure. However, the status of CDKN2A and the expression of the corresponding protein, p16, in relation to MPM patient's asbestos exposure is poorly known. Copy number alterations in 2p16, 9q33.1 and 19p13 have earlier been shown to accumulate in lung cancer in relation to asbestos exposure but their status in MPM is unclear. METHODS: We studied DNA copy numbers for CDKN2A using fluorescence in situ hybridization (FISH) and p16 expression by immunohistochemistry (IHC) in 92 MPM patients, 75 of which with known asbestos exposure status. We also studied, in MPM, copy number alterations in 2p16, 9q33.1 and 19p13 by FISH. RESULTS: We were unable to detect an association between p16 expression and pulmonary asbestos fiber count in MPM tumor cells. However, significantly more MPM patients with high pulmonary asbestos fiber count (> 1 million fibers per gram [f/g]) had stromal p16 immunoreactivity than MPM of patients with low exposure (≤ 0.5 million f/g) (51.4% vs 16.7%; p = 0.035, Chi-Square). We found that an abnormal copy number of CDKN2A in MPM tumor cells associated with a high pulmonary asbestos fiber count (p = 0.044, Fisher's Exact test, two-tailed). In contrast to our earlier findings in asbestos associated lung cancer, DNA copy number changes in 2p16, 9q33 and 19p13 were not frequent in MPM although single cases with variable copy numbers on those regions were seen. CONCLUSIONS: We found two instances where the gene locus CDKN2A or its corresponding protein expression, is associated with high asbestos exposure levels. This suggests that there may be biological differences between the mesotheliomas with high pulmonary asbestos fiber count and those with low fiber count.

Malignant pleural mesothelioma in Finland: regional and gender variation.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare occupational cancer with a poor prognosis. Even with a multimodality treatment approach, the treatment outcomes remain unsatisfactory. The use of asbestos has been banned in most developed countries, but MPM continues to be a significant occupational disease also in these countries. Aim of this study is to identify modern epidemiology and assess equality in care. METHODS: Our study cohort consists of 1010 patients diagnosed with MPM in Finland during 2000-2012. The data were collected from the Finnish Cancer Registry, the National Workers' Compensation Center Registry and the National Registry of Causes of Death, Statistics Finland. RESULTS: Women were diagnosed a mean of 4.5 years later than males (p = .001), but survival did not differ (overall median survival 9.7 months). A workers' compensation claim was more common in males (OR 11.0 [95% CI 7.5-16.2]) and in regions with a major asbestos industry (OR 1.7 [95% CI 1.3-2.2]). One-year and three-year survivals did not differ regionally. Patients without chemotherapy treatment had an inferior survival (RR 1.8 [95% CI 1.5-2.0]). The initial survival benefit gained with pemetrexed was diluted at 51 months. CONCLUSIONS: MPM is a disease with a poor prognosis, although chemotherapy appears to improve survival time. Significant gender and regional variation exists among patients, with notable differences in diagnostic and treatment practices. Long-term outcomes with pemetrexed remain indeterminate. IMPACT: Emphasize centralized consult services for the diagnosis, treatment and support that patients receive for MPM, facilitating equal outcomes and compensation.

Computed tomography in the evaluation of malignant pleural mesothelioma-Association of tumor size to a sarcomatoid histology, a more advanced TNM stage and poor survival.

OBJECTIVES: Appropriate clinical staging of malignant pleural mesothelioma (MPM) is critical for correct treatment decisions. Newly revised TNM staging protocol has been released for MPM. We investigated baseline computed tomography (CT) characteristics of MPM patients, the new staging system and a simple tumor size (TS) assessment in terms of survival. MATERIALS AND METHODS: As part of our study that included all MPM patients diagnosed in Finland 2000-2012, we retrospectively reviewed 161 CT scans of MPM patients diagnosed between 2007 and 2012 in the Hospital District of Helsinki and Uusimaa. TS was estimated by using the maximal tumor thickness and grading tumor extension along the chest wall. Cox Regression models were used to identify relationships between survival, clinicopathological factors and CT-findings. RESULTS: The median length of follow-up was 9.7 months and the median survival 9.1 months. The right sided tumors tended to be more advanced at baseline and had worse prognosis in the univariate analyses. In the multivariate survival model, TS, pleural effusion along with non-epithelioid histology were predictors of poor survival. Tumor size correlated significantly with a sarcomatoid histopathological finding and several parameters linked to a more advanced TNM stage. Most patients were diagnosed with locally advanced stage, while 12 (7%) had no sign of the tumor in CT. CONCLUSION: In this study, we demonstrate a novel approach for MPM tumor size evaluation that has a strong relationship with mortality, sarcomatoid histology and TNM stage groups. TS could be used for prognostic purposes and it may be a useful method for assessing therapy responses.

Body mass index and risk of dementia: Analysis of individual-level data from 1.3 million individuals.

INTRODUCTION: Higher midlife body mass index (BMI) is suggested to increase the risk of dementia, but weight loss during the preclinical dementia phase may mask such effects. METHODS: We examined this hypothesis in 1,349,857 dementia-free participants from 39 cohort studies. BMI was assessed at baseline. Dementia was ascertained at follow-up using linkage to electronic health records (N = 6894). We assumed BMI is little affected by preclinical dementia when assessed decades before dementia onset and much affected when assessed nearer diagnosis. RESULTS: Hazard ratios per 5-kg/m2 increase in BMI for dementia were 0.71 (95% confidence interval = 0.66-0.77), 0.94 (0.89-0.99), and 1.16 (1.05-1.27) when BMI was assessed 10 years, 10-20 years, and >20 years before dementia diagnosis. CONCLUSIONS: The association between BMI and dementia is likely to be attributable to two different processes: a harmful effect of higher BMI, which is observable in long follow-up, and a reverse-causation effect that makes a higher BMI to appear protective when the follow-up is short.

Overweight, obesity, and risk of cardiometabolic multimorbidity: pooled analysis of individual-level data for 120 813 adults from 16 cohort studies from the USA and Europe.

BACKGROUND: Although overweight and obesity have been studied in relation to individual cardiometabolic diseases, their association with risk of cardiometabolic multimorbidity is poorly understood. Here we aimed to establish the risk of incident cardiometabolic multimorbidity (ie, at least two from: type 2 diabetes, coronary heart disease, and stroke) in adults who are overweight and obese compared with those who are a healthy weight. METHODS: We pooled individual-participant data for BMI and incident cardiometabolic multimorbidity from 16 prospective cohort studies from the USA and Europe. Participants included in the analyses were 35 years or older and had data available for BMI at baseline and for type 2 diabetes, coronary heart disease, and stroke at baseline and follow-up. We excluded participants with a diagnosis of diabetes, coronary heart disease, or stroke at or before study baseline. According to WHO recommendations, we classified BMI into categories of healthy (20·0-24·9 kg/m2), overweight (25·0-29·9 kg/m2), class I (mild) obesity (30·0-34·9 kg/m2), and class II and III (severe) obesity (≥35·0 kg/m2). We used an inclusive definition of underweight (<20 kg/m2) to achieve sufficient case numbers for analysis. The main outcome was cardiometabolic multimorbidity (ie, developing at least two from: type 2 diabetes, coronary heart disease, and stroke). Incident cardiometabolic multimorbidity was ascertained via resurvey or linkage to electronic medical records (including hospital admissions and death). We analysed data from each cohort separately using logistic regression and then pooled cohort-specific estimates using random-effects meta-analysis. FINDINGS: Participants were 120  813 adults (mean age 51·4 years, range 35-103; 71 445 women) who did not have diabetes, coronary heart disease, or stroke at study baseline (1973-2012). During a mean follow-up of 10·7 years (1995-2014), we identified 1627 cases of multimorbidity. After adjustment for sociodemographic and lifestyle factors, compared with individuals with a healthy weight, the risk of developing cardiometabolic multimorbidity in overweight individuals was twice as high (odds ratio [OR] 2·0, 95% CI 1·7-2·4; p<0·0001), almost five times higher for individuals with class I obesity (4·5, 3·5-5·8; p<0·0001), and almost 15 times higher for individuals with classes II and III obesity combined (14·5, 10·1-21·0; p<0·0001). This association was noted in men and women, young and old, and white and non-white participants, and was not dependent on the method of exposure assessment or outcome ascertainment. In analyses of different combinations of cardiometabolic conditions, odds ratios associated with classes II and III obesity were 2·2 (95% CI 1·9-2·6) for vascular disease only (coronary heart disease or stroke), 12·0 (8·1-17·9) for vascular disease followed by diabetes, 18·6 (16·6-20·9) for diabetes only, and 29·8 (21·7-40·8) for diabetes followed by vascular disease. INTERPRETATION: The risk of cardiometabolic multimorbidity increases as BMI increases; from double in overweight people to more than ten times in severely obese people compared with individuals with a healthy BMI. Our findings highlight the need for clinicians to actively screen for diabetes in overweight and obese patients with vascular disease, and pay increased attention to prevention of vascular disease in obese individuals with diabetes. FUNDING: NordForsk, Medical Research Council, Cancer Research UK, Finnish Work Environment Fund, and Academy of Finland.

The effect of demographic factors on occupational injuries.

OBJECTIVES: In Finland about 120,000 occupational injuries occur annually, the cost of which is over EUR 2 billion per year. This is why it is reasonable to analyze the effect of demographic factors like gender, age, tenure and mother tongue on occupational injuries. METHODS: The participants consisted of 1681 employees from four Finnish companies, who reported their injuries from the last 3 years. RESULTS: Gender or mother tongue did not associate with injury involvement. Employees younger than 25 years of age were more often involved in injuries than employees aged over 55 (odds ratio [OR] = 2.69, 95% confidence interval [CI] [1.70, 4.23]). Employees with 2-10 years of experience in the company had a higher injury frequency than both novice and very experienced employees (OR = 2.01, 95% CI [1.60, 2.52]). CONCLUSIONS: This study showed that age was a more important factor in injury involvement than gender, tenure or mother tongue. However, age was closely related to experience in the company. Prevention measures in the companies should thus focus on novice employees.

Shift rotation and age - interactions with sleep-wakefulness and inflammation.

The interaction of age with shift rotation in relation to sleep-wakefulness and inflammation were studied among male employees (n = 772). Cross-sectional analyses in day, two-shift and three-shift work with different shift rotations, as well as changes in leukocytes and hsCRP among three shift workers who changed their shift system during the 2.5- yr follow-up were completed. Shift work was associated with problems to fall asleep (p < 0.001) and feeling of the current working time being harmful to sleep and wakefulness (p < 0.001). Quickly forward-rotation shift workers considered their working time less harmful compared with slower backward-rotation shift workers. Age did not influence sleep in general, but older workers in the quickly forward-rotating three-shift system had less sleep complaints than their younger colleagues. The age differences in the inflammatory markers partly depended on the shift system. The results give some support that rapidly forward-rotating shift systems are more 'age-friendly' than backward-rotating shift systems.

Association between lowered endothelial function measured by peripheral arterial tonometry and cardio-metabolic risk factors - a cross-sectional study of Finnish municipal workers at risk of diabetes and cardiovascular disease.

BACKGROUND: The aim of this cross-sectional study was to determine the association between lowered endothelial function measured by peripheral arterial tonometry (PAT) and cardio-metabolic risk factors. The study population consisted of Finnish municipal workers who were at risk of diabetes or cardiovascular disease and who had expressed a need to change their health behaviour. METHODS: A total of 312 middle-aged municipal workers underwent a physical medical examination and anthropometry measurements. Levels of total cholesterol, HDL cholesterol, triglycerides, fasting glucose, glycated haemoglobin, and high sensitivity C-reactive protein were taken from the blood samples. PAT measured the increase in digital pulse volume amplitude during reactive hyperemia, and the index of endothelial function, F-RHI, was defined as the ratio of post-deflation amplitude to baseline amplitude. RESULTS: In the linear regression model, male sex was associated with lower F-RHI. In sex-adjusted linear regression models, each of the variables; waist circumference, fasting glucose, glycated hemoglobin, triglycerides, body fat percentage, body mass index, current smoking, and impaired fasting glucose or diabetes were separately associated with lower F-RHI, and HDL cholesterol and resting heart rate were associated with higher F-RHI.HDL cholesterol, sex, body mass index, and current smoking entered a stepwise multivariable regression model, in which HDL cholesterol was associated with higher F-RHI, and smoking, male sex and body mass index were associated with lower F-RHI. This model explains 28.3% of the variability in F-RHI. CONCLUSIONS: F-RHI is associated with several cardio-metabolic risk factors; low level of HDL cholesterol, male sex, overweight and smoking being the most important predictors of a lowered endothelial function. A large part of variation in F-RHI remains accounted for by unknown factors.

Accumulation of genomic alterations in 2p16, 9q33.1 and 19p13 in lung tumours of asbestos-exposed patients.

We have previously demonstrated an association between genomic alterations in 19p13, 2p16, and 9q33.1 and asbestos exposure in patients' lung tumours. This study detected allelic imbalance (AI) in these regions in asbestos-exposed lung cancer (LC) patients' histologically normal pulmonary epithelium. We extended the analyses of tumour tissue to cover a large LC patient cohort and studied DNA copy number alteration (CNA) and AI in 19p13, 2p16, and 9q33.1 for the first time in combination. We found both CNA and AI in ≥2/3 of the regions to be significantly and dose-dependently (P < 0.001) associated with pulmonary asbestos fibre count. Twenty percent of the exposed patients' LC showed CNA in ≥2/3 of the regions, whereas none of the non-exposed patients' LC showed CNA in more than one region. AI was evident in 89% of the exposed and in only 26% of the non-exposed patients' LC. The genomic alterations in 19p13, 2p16, and 9q33.1 in compilation identified asbestos-exposed patients' lung tumours better than each of the regions alone. These alterations form the basis for the development of a combinatorial molecular assay that could be used to identify asbestos-related LC.

Occupational burnout, eating behavior, and weight among working women.

BACKGROUND: Eating behavior affects weight and thus the development of obesity. Studies on the effect of occupational burnout (exhaustive fatigue, cynicism, and lost occupational self-respect caused by chronic work stress) on eating behavior are lacking. OBJECTIVE: The objective was to investigate associations between occupational burnout, eating behavior, and weight among working women. DESIGN: A total of 230 working women participated in a randomized controlled intervention trial (Nuadu) that aimed at changing the health behaviors of those with health risks. We assessed eating behavior using the Three-Factor Eating Behavior Questionnaire 18 and burnout using the Bergen Burnout Indicator 15 at both baseline and 12 mo. Body weight and percentage body fat were also measured at baseline and at 12 mo. The intervention and control groups were combined and divided by burnout and weight-change variables. RESULTS: Women experiencing burnout at baseline had significantly higher scores in emotional eating (EE; P = 0.002) and uncontrolled eating (UE; P = 0.001) than did those without burnout. A significant difference was found between the change in UE from baseline to 12 mo in those with and without burnout (P = 0.05). UE decreased significantly among those without burnout at baseline (P < 0.001). CONCLUSIONS: Those experiencing burnout may be more vulnerable to EE and UE and have a hindered ability to make changes in their eating behavior. We recommend that burnout should be treated first and that burnout and eating behavior should be evaluated in obesity treatment.

Factors in the fatigue of heavy vehicle drivers.

This study assessed work-related and driver-related factors in fatigue among Finnish heavy vehicle drivers. 683 professional drivers responded to a questionnaire, 27.8% of whom reported often feeling fatigue during their work shifts. Of the respondents, 27.5% reported having momentarily fallen asleep at the wheel while driving during the past year. Almost half (46.8%) of the fatigued drivers estimated the reasons for momentarily falling asleep were work-related. Long working shifts and short sleeps significantly increased the risk of momentarily falling asleep at the wheel. The risk of fatigue was the highest for the drivers who were unable to choose the time of their breaks.

Molecular alterations at 9q33.1 and polyploidy in asbestos-related lung cancer.

PURPOSE: Asbestos causes DNA damage and the fibers, together with tobacco smoke, have a synergistic effect on lung cancer risk. We recently identified 18 chromosomal regions that showed differences in DNA copy number between the lung tumors of asbestos-exposed and nonexposed patients. One of the previously identified asbestos-associated chromosomal regions at 9q was further analyzed for allelic imbalance and DNA copy number alterations (CNA) in the lung tumors of asbestos-exposed and nonexposed patients. In addition, the ploidy level of the tumors was studied. EXPERIMENTAL DESIGN: Allelic imbalance was analyzed at 9q31.3-34.3 with 15 microsatellite markers in 52 lung tumor samples from asbestos-exposed and nonexposed patients. CNA at 9q32-34.3 were characterized by fluorescent in situ hybridization (FISH) with six bacterial artificial chromosome probes in 95 lung tumors. The ploidy level was analyzed in 100 lung tumors with FISH using three to five centromere probes. RESULTS: Allelic imbalance at 9q31.3-q34.3 was found in all asbestos-exposed patient tumors (100%, 17 of 17) compared with 64% (14 of 22) in the nonexposed cases (P = 0.005). The most significant difference was detected at 9q33.1 (P = 0.002). FISH results showed that also CNA were more frequent at 9q33.1 in the three major histologic types of non-small-cell lung tumors of exposed patients, and the association showed a dose-dependent trend (P = 0.03). Furthermore, we detected more frequent polyploidy among the exposed (48%, 28 of 58) than among the nonexposed (29%, 12 of 42) patient tumors (P < 0.05). CONCLUSIONS: These results provide a basis for the development of a method to identify asbestos-related lung cancer on a molecular level.

Effects of shift rotation and the flexibility of a shift system on daytime alertness and cardiovascular risk factors.

OBJECTIVES: A controlled intervention study was conducted to evaluate the effects of two changes in shift characteristics on alertness and cardiovascular risk factors: a change in shift rotation (direction and speed) and a change in the flexibility of the shift system. METHODS: Altogether 84 male workers currently working in a backward-rotating shift system volunteered for the study. A total of 40 men changed to a rapidly forward-rotating shift system, 22 changed to a more flexible shift system, and 22 remained with the old shift system. Health effects were studied with the use of clinical measurements, blood tests, and questionnaires before and after the shift changes. Analyses of variance were used with repeated measures to study associations of cardiovascular risk factors and daytime sleepiness according to the change in shift systems. RESULTS: The mean number of days on which the workers reported sleepiness decreased in the group with the forward-rotating shift system when compared with that of the group on the old shift system (from 2.9 to 2.1 days/week, P=0.02). Systolic blood pressure decreased (from 142 to 136 mm Hg, P=0.049), and heart rate showed a declining trend (from 66 to 60 beats/minute, P=0.06) in the flexible shift system when the three groups were compared. CONCLUSIONS: The study indicates that a faster speed, together with a change to the forward direction, in shift rotation alleviates daytime sleepiness. Combining individual flexibility with company-based flexibility in a shift system may have favorable effects on shift workers' blood pressure.

Evaluation of an organizational stress management program in a municipal public works organization.

The aim of this study was to investigate the effects of employee participation in an organizational stress management program consisting of several interventions aiming to improve psychosocial work environment and well-being. Pre- and postintervention questionnaires were used to measure the outcomes with a 2-year interval. This article describes the background of the program, results of previously published effect studies, and a qualitative evaluation of the program. The authors also tested the effects of level of participation in all interventions among the employees of the service production units by 2 (time) x 3 (group) repeated measures ANOVAs (n = 625). "Active participation" (more than 5.5 days) had a positive effect on feedback from supervisor and flow of information. Work climate remained on a permanent level while it decreased in the categories of moderate and nonparticipation. The level of participation did not improve individual well-being or other aspects of psychosocial work environment as postulated by the work stress models. The qualitative evaluation and practical conclusions drawn by the management of the Organization provided a positive impression of the impact of the program.

Copy number gains on 5p15, 6p11-q11, 7p12, and 8q24 are rare in sputum cells of individuals at high risk of lung cancer.

UNLABELLED: Lung cancer specimens display recurrent copy number aberrations in distinguished chromosomal regions as compared with normal lung cells. Such alterations have been utilized in design of fluorescence in situ hybridization (FISH) probe sets in attempts to improve the cytological diagnosis of lung cancer. One of such probe sets, LAVysion, detects copy number changes in the centromeric region of chromosome 6 (CEP6), and regions 5p15, 8q24, and 7p12, often gained in lung cancer. METHODS: We evaluated the feasibility of the LAVysion multi-color probe set in detection of individuals at high risk of lung cancer by applying the FISH probe set on smears prepared of induced sputa obtained from 20 lung cancer patients, 43 asbestos-exposed workers, 21 heavy tobacco smokers, and 15 healthy never-smokers. The hybridized sputum smears were examined using fluorescence microscopy and the number of signals in epithelial cells was examined throughout the hybridized area. Additionally, we review here the previous studies using LAVysion probe set. RESULTS: The FISH probe set was slightly more sensitive than cytology alone in detecting lung cancer. No significant differences in copy number gain were found between high-risk individuals and healthy never-smokers. The proportions of individuals with copy number gains in sputa among the lung cancer patients, asbestos-exposed workers, tobacco smokers, and never-smokers were 50, 20, 12, and 27%, respectively, when three or more cells with a copy number gain detected by at least two different probes was used as the cut-off point. In comparison, the sensitivity of cytology in detecting lung cancer was 44%. In the lung cancer patients the number of abnormal cells by FISH correlated well with the cytologic atypia class (Spearman rank correlation coefficient 0.77, p<0.01). Using multivariant variance analysis, gains in CEP6, 5p15, 8q24 and 7p12 were not associated with smoking or asbestos exposure. CONCLUSIONS: FISH did not significantly exceed the sensitivity of sputum cytology in finding lung cancers. Significant differences were not found between sputa of asbestos-exposed individuals, heavy-smokers and never-smokers. More sensitive methods are needed for the follow-up of populations at high risk of contracting lung cancer.

Caveolins as tumour markers in lung cancer detected by combined use of cDNA and tissue microarrays.

To identify new potential diagnostic markers for lung cancer, the expression profiles of 37 lung tumours were analysed using cDNA arrays. Seven samples were from small-cell lung cancer (SCLC), two from large-cell neuroendocrine tumours (LCNEC), and 28 from other non-small-cell lung cancers (mainly squamous cell cancer and adenocarcinoma). Principal component analysis and the permutation test were used to detect differences in the gene expression profiles and a set of genes was found that distinguished high-grade neuroendocrine carcinomas (SCLC and LCNEC) from other lung cancers. In addition, several genes, such as caveolin-1 (CAV1) and caveolin-2 (CAV2), were constantly deregulated in all types of tumour sample, compared with normal tissue. The expression of these two genes was investigated further at the protein level on a tissue microarray containing tumours from 161 patients and normal tissues. Immunostaining for CAV1 was negative in 48% of tumours, whereas 28% of the tumours did not express CAV2. Lack of CAV1 protein expression was not caused by methylation or mutation. In stage I adenocarcinomas, CAV2 protein expression correlated with shorter survival. In conclusion, the present study was able to identify genes that have not previously been implicated in lung cancer by the combined use of two different array techniques. Some of these genes may provide novel diagnostic markers for lung cancer.