Incidence of malignant mesothelioma in Germany 2009-2013.

PURPOSE: The malignant mesothelioma is a rare malignancy and mainly caused by occupational exposure to asbestos. German cancer registries are providing a national database to investigate temporal and regional patterns of mesothelioma incidence. These may be of interest for healthcare planning and for surveillance programs aiming at the formerly exposed workforce. METHODS: We analyzed population-based incidence data of malignant mesothelioma by site, type, sex, age, as well as district and state of patient's residence. Age-standardized incidence rates (AIRs40+) were calculated according to the European standard population truncated to the age of 40 years and older. We present rates at national, state, and district level and trends of incidence of northern states of Germany. RESULTS: In total, 7,547 malignant mesotheliomas were reported to German cancer registries diagnosed between 2009 and 2013-90% located to the pleura. On average, 1,198 men and 312 women were affected each year. We estimated AIR40+ of 4.77 in 100,000 German men and 0.98 in 100,000 German women. Regional clusters were predominantly located to the seaports of West Germany. The highest regional AIR40+ was 20 per 100,000 men. Corresponding rates in northeast Germany were between 2 and 4 per 100,000 men. CONCLUSION: Regional clusters of high incidence indicate districts with former shipyards and steel industry, but predominantly in the western part of Germany. The West-to-East difference corresponds to patterns of mortality. Twenty years after banning asbestos in Germany, Bremen and Hamburg are presenting the highest mesothelioma incidence but show steadily decreasing trends.

Considerations for the design and technical setup of a human whole-body exposure chamber.

Exposures to air contaminants, such as chemical vapors and particulate matter, pose important health hazards at workplaces. Short-term experimental exposures to chemical vapors and particles in humans are a promising attempt to investigate acute effects of such hazards. However, a significant challenge in this field is the determination of effects of co-exposures to more than one chemical or mixtures of chemical vapors and/or particles. To overcome such a challenge, studies have to be conducted under standardized exposure characterization and real time measurements, if possible. A new exposure laboratory (ExpoLab) was installed at IPA, combining sophisticated engineering designs with new analytical techniques, to fulfill these requirements. Low-dose as well as high-dose exposure scenarios are achieved by means of a calibration-gas-generator. Exposure monitoring can be carried out with a high performance real time mass spectrometer and other suitable analyzers (e.g. gas chromatograph). Numerous automated security facilities guarantee the physical integrity of the volunteers, and the waste atmosphere is removed using either charcoal filtration or catalytic post-combustion. Measurements of sulfur hexafluoride, carbon dioxide, aniline and carbon black are presented to demonstrate the performance of the exposure unit with respect to the temporal and spatial stability of generated atmospheres. The variations of generated contents in the atmospheres at steady state are slightly higher than the measurement precision of the analyzers (the typical standard deviation of generated atmospheres is < 2%). The technical components of ExpoLab and its monitoring systems ensure high quality standards in validity and reliability of generating and measuring exposure atmospheres.

Major histopathological patterns of lung cancer related to arsenic exposure in German uranium miners.

OBJECTIVE: The mechanisms of action of arsenic in the development of lung cancer are still not yet elucidated. Considering the relationship between arsenic and squamous cell carcinomas of the skin, we hypothesized that arsenic exposure may be more closely associated with squamous cell carcinoma of the lung. METHODS: A comprehensive histopathological database and a detailed job-exposure matrix developed for former German uranium miners with exposure to arsenic, radon, and quartz were analyzed to quantitatively assess the effect of arsenic regarding cell type of lung cancer. The distributions of major lung cancer cell types in 1,786 German uranium miners were associated with levels of arsenic exposure under control for the other lung carcinogens. To evaluate the arsenic effects in association with a frequent occupational lung disease in miners stratification by silicosis was performed. RESULTS: There was an arsenic-related increase of the proportion of squamous cell carcinoma of the lung but restricted to miners without silicosis. The increase was found at all levels of co-exposure to radon and quartz dust. In miners with silicosis, the proportion of adenocarcinoma increased with rising arsenic exposure. Arsenic exposure was associated with non-small cell lung cancer. Silicosis turned out as major determinant of the cell type related with arsenic. CONCLUSION: These results indicate a cell type characteristic effect of arsenic in the development of lung cancer.

A Two-Level Biobank Data Protection Concept for Project-Driven Human Sample Collections.

Legal and ethical demands for more transparent and strict data protection measures to enhance research participant privacy have grown with an increasing number of human biobanks providing biomaterial collections long term for unspecified future research questions. The design of a data protection scheme that minimizes the risk of donor reidentification and promotes biomaterial and data use in research is a big challenge to all kinds of human biobanks. Yet, there is a lack of publications which address this basic building block of a biobank. In this study, we present the data protection concept of our project driven, stand-alone biobank, focusing on meeting two biomaterial and data management areas simultaneously: operation of primary research projects involved in sample collection and long-term provision of biomaterial for future research purposes. The concept is based on national and international laws and ethical demands. Since the presented measures are transparent and basic, they should encourage biobanks in defining their own data protection concept and be easily transferable to different legal requirements.

A study on lung cancer mortality related to radon, quartz, and arsenic exposures in German uranium miners.

Between 1946 and 1990 uranium mining was undertaken on a large scale in East Germany. This study evaluates the proportional lung cancer risk of German uranium miners from radon, quartz, and arsenic exposure during mining operations at the WISMUT Corporation. The database of the WISMUT tissue repository and a comprehensive job-exposure matrix were used to compare exposure levels of lung cancer cases with deaths from diseases of the circulatory system for risk analysis. In addition, the ratio of lung cancer cases was compared to cases from diseases of the circulatory system to the corresponding ratio in the general population. The proportional lung cancer mortality of German uranium miners was 2.9-fold higher than in the general population of East Germany. Cumulative radon, quartz, and arsenic exposure were determined as risk factors for lung cancer among German uranium miners, where silicosis modified the risk of cumulative radon and quartz exposure. Silicotics were exposed to higher levels of quartz, radon, and arsenic than nonsilicotics. Because selection of the study population was based on a tissue repository, the results need to be interpreted with caution.

Mutational analysis of the nf2 tumour suppressor gene in three subtypes of primary human malignant mesotheliomas.

Fourteen primary human malignant mesothelioma (HMM) samples obtained from 14 patients were screened for point mutations and microdeletions/microinsertions in exons 1-16 of the chromosome 22q-located tumour suppressor gene neurofibromin 2 (nf2) by single strand conformation polymorphism (SSCP) analysis. In one tumour (7%) a 10 basepair microdeletion of exon 10 was detected by SSCP and subsequently characterised in detail by sequencing. Deletion of the second nf2 allele in laser-microdissected regions of the 10 bp mutation-harbouring tumour was demonstrated by denaturing gradient gel electrophoresis (DGGE) analysis. Simultaneous comparative genomic hybridisation (CGH) analysis also showed losses at chromosome 22q. Our data indicate that functional loss of the NF2 protein may be involved in the formation of a subset of HMMs.

NOTCH1, HIF1A and other cancer-related proteins in lung tissue from uranium miners--variation by occupational exposure and subtype of lung cancer.

BACKGROUND: Radon and arsenic are established pulmonary carcinogens. We investigated the association of cumulative exposure to these carcinogens with NOTCH1, HIF1A and other cancer-specific proteins in lung tissue from uranium miners. METHODOLOGY/PRINCIPAL FINDINGS: Paraffin-embedded tissue of 147 miners was randomly selected from an autopsy repository by type of lung tissue, comprising adenocarcinoma (AdCa), squamous cell carcinoma (SqCC), small cell lung cancer (SCLC), and cancer-free tissue. Within each stratum, we additionally stratified by low or high level of exposure to radon or arsenic. Lifetime exposure to radon and arsenic was estimated using a quantitative job-exposure matrix developed for uranium mining. For 22 cancer-related proteins, immunohistochemical scores were calculated from the intensity and percentage of stained cells. We explored the associations of these scores with cumulative exposure to radon and arsenic with Spearman rank correlation coefficients (r(s)). Occupational exposure was associated with an up-regulation of NOTCH1 (radon r(s) = 0.18, 95% CI 0.02-0.33; arsenic: r(s) = 0.23, 95% CI 0.07-0.38). Moreover, we investigated whether these cancer-related proteins can classify lung cancer using supervised and unsupervised classification. MUC1 classified lung cancer from cancer-free tissue with a failure rate of 2.1%. A two-protein signature discriminated SCLC (HIF1A low), AdCa (NKX2-1 high), and SqCC (NKX2-1 low) with a failure rate of 8.4%. CONCLUSIONS/SIGNIFICANCE: These results suggest that the radiation-sensitive protein NOTCH1 can be up-regulated in lung tissue from uranium miners by level of exposure to pulmonary carcinogens. We evaluated a three-protein signature consisting of a physiological protein (MUC1), a cancer-specific protein (HIF1A), and a lineage-specific protein (NKX2-1) that could discriminate lung cancer and its major subtypes with a low failure rate.

Association between lymph node silicosis and lung silicosis in 4,384 German uranium miners with lung cancer.

This study investigates the association between lymph node-only and lung silicosis in uranium miners with lung cancer and exposure to quartz dust. Tissue slides of 4,384 German uranium miners with lung cancer were retrieved from an autopsy archive and reviewed by 3 pathologists regarding silicosis in the lungs and lymph nodes. Cumulative exposure to quartz dust was assessed with a quantitative job-exposure matrix. The occurrence of silicosis by site was investigated with regression models for exposure to quartz dust. Miners with lung silicosis had highest cumulative quartz exposure, followed by lymph node-only silicosis and no silicosis. At a cumulative quartz exposure of 40 mg/m(3) × years, the probability of lung silicosis was above 90% and the likelihood of lymph node-only silicosis and no silicosis do not differ anymore. The results support that lymph node silicosis can precede lung silicosis, at least in a proportion of subjects developing silicosis, and that lung silicosis strongly depends on the cumulative quartz dose.

Cancer mortality in a surveillance cohort of German males formerly exposed to asbestos.

The objective of this analysis was the estimation of the cancer risks of asbestos and asbestosis in a surveillance cohort of high-exposed German workers. A group of 576 asbestos workers was selected for high-resolution computer tomography of the chest in 1993-1997. A mortality follow-up was conducted through 2007. Standardised mortality ratios (SMRs) were calculated and Poisson regression was performed to assess mesothelioma risks. A high risk was observed for pleural mesothelioma (SMR 28.10, 95% CI 15.73-46.36) that decreased after cessation of exposure (RR 0.1; 95% CI 0.0-0.6 for > or =30 vs. <30 years after last exposure). Asbestosis was a significant risk factor for mesothelioma (RR 6.0, 95% CI 2.4-14.7). Mesothelioma mortality was still in excess in former asbestos workers although decreasing after cessation of exposure. Fibrosis was associated with subsequent malignancy.

Role of exposure to radon and silicosis on the cell type of lung carcinoma in German uranium miners.

BACKGROUND: In East Germany, uranium mining was undertaken on a large scale from 1946 to 1990. Poor working conditions led to a high level of exposure to ionizing radiation and quartz dust. This analysis evaluates the histopathology of lung carcinoma in uranium miners in relation to radon exposure and silicosis. METHODS: A database developed for autopsy cases ascertained in a pathological tissue repository of German uranium miners was used to estimate odds ratios for developing lung carcinoma by major cell type with regard to radon exposure and silicosis. Silicosis information was extracted from autopsy protocols. Working level months (WLM) were calculated with a job-exposure matrix to assess lifetime radon exposure. Risk estimates were based on 3414 male miners who died from small cell lung carcinoma (SCLC, n = 1446), squamous cell carcinoma (SqCC, n = 1006), or adenocarcinoma (AC, n = 962) between 1957 and 1990. RESULTS: SCLC and SqCC seem more likely to be associated with high radon exposure than AC. Mean cumulative radon exposure was 868 (SD 631) WLM in SCLC, 871 (SD 652) WLM in SqCC, and 743 (SD 598) WLM in AC. Silicosis prevalence was 26% in SCLC, 38% in SqCC, and 30% in AC. In silicotics, AC and SqCC had a relatively higher frequency at the expense of SCLC. SCLC occurred earlier than AC and SqCC. CONCLUSION: High radon exposure was associated with a higher relative frequency of SCLC and SqCC than AC. Silicosis tended to increase the appearance of SqCC and AC.