Cholangiocarcinoma and Occupational Exposure to Asbestos: Insights From the Italian Pooled Cohort Study.

BACKGROUND: Recent studies supported the association between occupational exposure to asbestos and risk of cholangiocarcinoma (CC). Aim of the present study is to investigate this association using an update of mortality data from the Italian pooled asbestos cohort study and to test record linkage to Cancer Registries to distinguish between hepatocellular carcinoma (HCC) and intrahepatic/extrahepatic forms of CC. METHODS: The update of a large cohort study pooling 52 Italian industrial cohorts of workers formerly exposed to asbestos was carried out. Causes of death were coded according to ICD. Linkage was carried out for those subjects who died for liver or bile duct cancer with data on histological subtype provided by Cancer Registries. RESULTS: 47 cohorts took part in the study (57,227 subjects). We identified 639 causes of death for liver and bile duct cancer in the 44 cohorts covered by Cancer Registry. Of these 639, 240 cases were linked to Cancer Registry, namely 14 CC, 83 HCC, 117 cases with unspecified histology, 25 other carcinomas, and one case of cirrhosis (likely precancerous condition). Of the 14 CC, 12 occurred in 2010-2019, two in 2000-2009, and none before 2000. CONCLUSION: Further studies are needed to explore the association between occupational exposure to asbestos and CC. Record linkage was hampered due to incomplete coverage of the study areas and periods by Cancer Registries. The identification of CC among unspecific histology cases is fundamental to establish more effective and targeted liver cancer screening strategies.

Cause specific mortality in an Italian pool of asbestos workers cohorts.

BACKGROUND: Asbestos is a known human carcinogen and is causally associated with malignant mesothelioma, lung, larynx and ovarian cancers. METHODS: Cancer risk was studied among a pool of formerly asbestos-exposed workers in Italy. Fifty-two Italian asbestos cohorts (asbestos-cement, rolling-stock, shipbuilding, and other) were pooled and their mortality follow-up was updated to 2018. Standardized mortality ratios (SMRs) were computed for major causes of death considering duration of exposure and time since first exposure (TSFE), using reference rates by region, age and calendar period. RESULTS: The study included 63,502 subjects (57,156 men and 6346 women): 40% who were alive, 58% who died (cause known for 92%), and 2% lost to follow-up. Mortality was increased for all causes (SMR: men = 1.04, 95% confidence interval [CI] 1.03-1.05; women = 1.15, 95% CI 1.11-1.18), all malignancies (SMR: men = 1.21, 95% CI 1.18-1.23; women = 1.29, 95% CI 1.22-1.37), pleural and peritoneal malignancies (men: SMR = 10.46, 95% CI 9.86-11.09 and 4.29, 95% CI 3.66-5.00; women: SMR = 27.13, 95% CI 23.29-31.42 and 7.51, 95% CI 5.52-9.98), lung (SMR: men = 1.28, 95% CI 1.24-1.32; women = 1.26, 95% CI 1.02-1.53), and ovarian cancer (SMR = 1.42, 95% CI 1.08-1.84). Pleural cancer mortality increased during the first 40 years of TSFE (latency), reaching a plateau thereafter. CONCLUSIONS: Analyses by time-dependent variables showed that the risk for pleural neoplasms increased with latency and no longer increases at long TSFE, consistent with with asbestos clearance from the lungs. Peritoneal neoplasm risk increased over all observation time.

Estimating Overall and Cause-Specific Excess Mortality during the COVID-19 Pandemic: Methodological Approaches Compared.

During the COVID-19 pandemic, excess mortality has been reported worldwide, but its magnitude has varied depending on methodological differences that hinder between-study comparability. Our aim was to estimate variability attributable to different methods, focusing on specific causes of death with different pre-pandemic trends. Monthly mortality figures observed in 2020 in the Veneto Region (Italy) were compared with those forecasted using: (1) 2018-2019 monthly average number of deaths; (2) 2015-2019 monthly average age-standardized mortality rates; (3) Seasonal Autoregressive Integrated Moving Average (SARIMA) models; (4) Generalized Estimating Equations (GEE) models. We analyzed deaths due to all-causes, circulatory diseases, cancer, and neurologic/mental disorders. Excess all-cause mortality estimates in 2020 across the four approaches were: +17.2% (2018-2019 average number of deaths), +9.5% (five-year average age-standardized rates), +15.2% (SARIMA), and +15.7% (GEE). For circulatory diseases (strong pre-pandemic decreasing trend), estimates were +7.1%, -4.4%, +8.4%, and +7.2%, respectively. Cancer mortality showed no relevant variations (ranging from -1.6% to -0.1%), except for the simple comparison of age-standardized mortality rates (-5.5%). The neurologic/mental disorders (with a pre-pandemic growing trend) estimated excess corresponded to +4.0%/+5.1% based on the first two approaches, while no major change could be detected based on the SARIMA and GEE models (-1.3%/+0.3%). The magnitude of excess mortality varied largely based on the methods applied to forecast mortality figures. The comparison with average age-standardized mortality rates in the previous five years diverged from the other approaches due to the lack of control over pre-existing trends. Differences across other methods were more limited, with GEE models probably representing the most versatile option.

Rate advancement measurement for lung cancer and pleural mesothelioma in asbestos-exposed workers.

INTRODUCTION: Exposure to asbestos increases the risk of lung cancer and mesothelioma. Few studies quantified the premature occurrence of these diseases in asbestos-exposed workers. Focus on premature disease onset (rate advancement or acceleration) can be useful in risk communication and for the evaluation of exposure impact. We estimated rate advancement for total mortality, lung cancer and pleural mesothelioma deaths, by classes of cumulative asbestos exposure in a pooled cohort of asbestos cement (AC) workers in Italy. METHOD: The cohort study included 12 578 workers from 21 cohorts, with 6626 deaths in total, 858 deaths from lung cancer and 394 from pleural malignant neoplasm (MN). Rate advancement was estimated by fitting a competitive mortality Weibull model to the hazard of death over time since first exposure (TSFE). RESULT: Acceleration time (AT) was estimated at different TSFE values. The highest level of cumulative exposure compared with the lowest, for pleural MN AT was 16.9 (95% CI 14.9 to 19.2) and 33.8 (95% CI 29.8 to 38.4) years at TSFE of 20 and 40 years, respectively. For lung cancer, it was 13.3 (95% CI 12.0 to 14.7) and 26.6 (95% CI 23.9 to 29.4) years, respectively. As for total mortality, AT was 3.35 (95% CI 2.98 to 3.71) years at 20 years TSFE, and 6.70 (95% CI 5.95 to 7.41) at 40 years TSFE. CONCLUSION: The current study observed marked rate advancement after asbestos exposure for lung cancer and pleural mesothelioma, as well as for total mortality.

Mortality for Lung Cancer among PVC Baggers Employed in the Vinyl Chloride Industry.

Vinyl-chloride monomer (VCM) is classified as a known carcinogen of the liver; for lung cancer, some results suggest a potential association with polyvinyl chloride (PVC) dust. We evaluated the relationship between lung cancer mortality and exposure as PVC baggers in a cohort of workers involved in VCM production and polymerization in Porto Marghera (Venice, Italy) considering both employment status and smoking habits. The workers were studied between 1973 and 2017. A subset of them (848 over 1658) was interviewed in the 2000s to collect information about smoking habits and alcohol consumption. Missing values were imputed by the Multivariate Imputation by Chained Equations (MICE) algorithm. We calculated standardized mortality ratios (SMR) and 95% confidence intervals (95% CIs) using regional reference rates by task (never, ever, and exclusively baggers) and by smoking habits. Mortality rate ratios (MRR), adjusted for age, calendar time, time since first exposure, and smoking habits, were obtained via Poisson regression using Rubin's rule to combine results from imputed datasets calculating the fraction of information due to non-response. Lung cancer mortality was lower than the regional reference in the whole cohort (lung cancer SMR = 0.92; 95% CI 0.75-1.11). PVC baggers showed a 50% increase in lung cancer mortality compared to regional rates (SMR = 1.48; 95% CI 0.82-2.68). In the cohort analyses, a doubled risk of lung cancer mortality among PVC baggers was confirmed after adjustment for smoking and time-dependent covariates (MRR = 1.99, 95% CI 1.04-3.81). Exposure to PVC dust resulting from activity as bagger in a polymerization PVC plant was associated with an increase in lung cancer mortality risk after adjustment for smoking habits.

Dopamine DRD2 and DRD3 Polymorphisms Involvement in Nicotine Dependence in Patients with Treatment-Resistant Mental Disorders.

Patients affected by mental disorders smoke more than the general population. The reasons behind this habit are genetic, environmental, etc. This study aims to investigate the correlations between some polymorphisms and the smoking habits and nicotine dependence in patients with psychiatric disorders. We recruited 88 patients with treatment-resistant mental disorders, including 35 with major depressive disorder, 43 with bipolar spectrum disorder, and 10 with schizophrenia spectrum disorder. We carried out a clinical and psychometric assessment on current smoking habits, years of smoking, number of daily cigarettes, and level of nicotine addiction. The patients performed a peripheral blood sample for DNA analyses of different polymorphisms. We searched for correlations between the measures of nicotine addiction and analysed genotypes. The expression of the T allele of the DRD2 rs1800497 and DRD3 rs6280 polymorphisms significantly correlated with a lower level of nicotine dependence and lower use of cigarettes. We did not find significant correlations between nicotine dependence and OPRM1 rs1799971, COMT rs4680 and rs4633 polymorphisms, CYP2A6 rs1801272 and rs28399433, or 5-HTTLPR genotype. Concluding, DRD2 rs1800497 and DRD3 rs6280 polymorphisms are involved in nicotine dependence and cigarette smoking habits in patients with treatment-resistant mental disorders.

Increasing epilepsy-related mortality: A multiple causes of death study in Northern Italy.

PURPOSE: to assess the burden of epilepsy as the underlying or contributory cause of death, to investigate time trends in mortality with epilepsy, and to examine the main associated comorbidities. METHODS: All deaths from January 1, 2008 to December 31, 2019 with any mention of epilepsy were retrieved from the mortality register of the Veneto Region (Italy). The average annual percent change (AAPC) in age-standardized mortality rates was estimated by log-linear models. The association between mention of epilepsy and of selected disease categories in death certificates was assessed by conditional logistic regression. RESULTS: Any mention of epilepsy was reported in 5,907 death certificates; of these, epilepsy was selected as the underlying cause in 1,020 decedents. Deaths with epilepsy represented 0.8% of total mortality in 2008-2011, increasing to 1.3% in 2016-2019. The AAPC was 4.7% for males (95% CI 3.0-6.4, p<0.001) and 6.2% for females (95% CI 4.5-7.9, p<0.001). A strong association was found between mention of epilepsy and meningitis/encephalitis, congenital anomalies/cerebral palsy and other paralytic syndromes, central nervous system tumours, cerebrovascular diseases, and dementia/Alzheimer. CONCLUSIONS: The present analysis from Southern Europe confirms recent reports limited to the UK and the US on increasing epilepsy-related mortality rates. aging of the population and the growing prevalence of neurological disorders are among long-term causes of this unfavorable trend; further studies on mortality data and other health archives are warranted.

Is Mesothelioma Unrelated to the Lung Asbestos Burden? Comment on Visonà et al. Inorganic Fiber Lung Burden in Subjects with Occupational and/or Anthropogenic Environmental Asbestos Exposure in Broni (Pavia, Northern Italy): An SEM-EDS Study on Autoptic Samples. Int. J. Environ. Res. Public Health 2021, 18, 2053.

We read with interest the report by Visonà and coworkers on the lung asbestos fiber burden in an autopsy series of decedents from mesothelioma (MM: 59 cases) and individuals who "suffered from asbestosis and died of its complications" (13 cases) [...].

Causes of mortality in a large population-based cohort of psychiatric patients in Southern Europe.

The World Health Organization considers excess morbidity and mortality among people with mental disorders as a high public health priority. This study aims to estimate the mortality risk and causes of death among a large population-based cohort of psychiatric patients. All residents in Veneto (Northeastern Italy) aged between 18 and 84 years with a contact with Community Mental Health Centers in 2008 and a psychiatric diagnosis (n = 54,350) were followed-up for 10 years. Standardized Mortality Ratios (SMR) and excess mortality were computed, with the general regional population as a reference. Mortality was more than doubled (males SMR = 2.4; females SMR = 2.2) and the relative increase in mortality was much larger in young and middle-aged adults (18-44 and 45-64 years) across all diagnostic groups. The most frequent causes were circulatory diseases (27%) and neoplasms (26%). Although the risk was increased by about tenfold, deaths from suicide were limited to 6% and 4% of all decedents in males and females, respectively. Patients with schizophrenia showed a very high risk for mortality for diabetes and cardiovascular disorders. A large excess was found also for respiratory diseases and a two-fold increase for lung cancer in males and breast cancer in females. Although chronic physical disorders are known to be the main causes of mortality in such patients, they receive far less attention than suicide or accidents. Our results suggest that there is still a need to plan actions to prevent excess mortality and to improve the quality of life of patients with mental disorders.

Authors' response: Mezei et al's "Comments on a recent case-control study of malignant mesothelioma of the pericardium and the tunica vaginalis testis".

Mezei et al's letter (1) is an opportunity to provide more details about our study on pericardial and tunica vaginalis testis (TVT) mesothelioma (2), which is based on the Italian national mesothelioma registry (ReNaM): a surveillance system on mesothelioma, with individual asbestos exposure assessment. Incidence of pericardial mesothelioma has been estimated around 0.5 and 0.2 cases per 10 million person-years in men and women, respectively, and around 1 case for TVT mesothelioma. ReNaM collected 138 cases thanks to its long period of observation (1993-2015) and national coverage. Conducting a population-based case-control study with incidence-density sampling of controls across Italy and over a 23 year time-span should have been planned in 1993 and would have been beyond feasibility and ReNaM scope. We rather exploited two existing series of controls (3). The resulting incomplete time- and spatial matching of cases and controls is a limitation of our study and has been acknowledged in our article. The analysis of case-control studies can nevertheless be accomplished in logistic models accounting for the variables of interest, in both individually and frequency matched studies (4). Furthermore, analyses restricted to (i) regions with enrolled controls, (ii) cases with definite diagnosis, (iii) incidence period 2000-2015, and (iv) subjects born before 1950 have been provided in the manuscript, confirming the strength of the association with asbestos exposure (supplemental material tables S4-7). Following Mezei et al's suggestion, we performed further sensitivity analyses by restriction to regions with controls and fitting conditional regression models using risk-sets made of combinations of age and year of birth categories (5-year classes for both). We confirmed positive associations with occupational exposure to asbestos of pericardial mesothelioma, with odds ratios (OR) (adjusted for region) of 9.16 among women [95% confidence interval (CI) 0.56-150] and 5.63 (95% CI 1.02-31.0) among men; for TVT mesothelioma the OR was 7.70 (95% CI 2.89-20.5). Using risk sets of age categories and introducing year of birth (5-year categories) as a covariate (dummy variables) the OR were similar: OR (adjusted for region) of 9.17 among women (95% CI 0.56-150) and 5.76 (95% CI 1.07-31.0) among men; for TVT the OR was 9.86 (95% CI 3.46-28.1). Possible bias from incomplete geographical overlap between cases and controls has been addressed in the paper (table S4) and above. In spatially restricted analyses, OR were larger than in those including cases from the whole country, indicating that bias was towards the null. Mezei et al further noted that "the regional distribution of controls is different from that of person-time observed". This objection is not relevant because the above analyses were adjusted by region. Our controls were provided by a population-based study on pleural mesothelioma (called MISEM) and a hospital-based study on cholangiocarcinoma (called CARA). In MISEM, the response rate was 48.4%, a low but not unexpected rate as participation among population controls is usually lower and has been declining over time (5). It is important to underline that ReNaM applied the same questionnaire that was used for interviews and carried out the same exposure assessment as both MISEM and CARA. As repeatedly stated in ReNaM papers (6-7), each regional operating center assesses asbestos exposure based on the individual questionnaire, other available information, and knowledge of local industries. Occupational exposure to asbestos is classified as definite, probable or possible. Occupational exposure is (i) definite when the subject`s work was reported or otherwise known to have involved the use of asbestos or asbestos-containing materials (MCA); (ii) probable when subjects worked in factories where asbestos or MCA were used, but their personal exposure could not be documented; and (iii) possible when they were employed in industrial activities known to entail the use of asbestos or MCA. Hence, the definite and probable categories are closer to one another and were combined in our analyses. In any case, restricting analyses to subjects with definite occupational exposure and using each set of controls separately, as suggested by Mezei et al, yielded elevated OR for TVT and pericardial mesothelioma among men using both the above described modelling strategies; the OR could not be calculated for women. There were 70 (25 pericardial and 45 TVT) occupationally exposed mesothelioma cases. In population-based studies, analyses by occupation are limited by the low prevalence of most specific jobs. As briefly reported in our paper, for purely descriptive purposes, the industrial activity of exposure (cases may have multiple exposures), were construction (22 exposures, 7 and 15 for pericardial and TVT mesotheliomas, respectively), steel mills and other metal working industries (4 and 11), textile industries (2 and 3), and agriculture (2 and 5); other sectors had lower exposure frequencies. The absence of industries like asbestos-cement production, shipbuilding and railway carriages production/repair should not be surprising and had already been observed (7). In the Italian multicenter cohort study of asbestos workers (8), given the person-years of observation accrued by workers employed in these industries and gender- and site-specific crude incidence rates, approximately 0.1 case of pericardial and 0.2 of TVT mesothelioma would have been expected from 1970 to 2010. Even increasing ten-fold such figures to account for higher occupational risks among these workers would not change much. Asbestos exposure in agriculture has been repeatedly discussed in ReNaM reports (9: pages 70, 73, 128, 164 and 205). Exposure opportunities included the presence of asbestos in wine production, reuse of hessian bags previously containing asbestos, or construction and maintenance of rural buildings. Similarly, mesothelioma cases and agricultural workers exposed to asbestos have been noted in France (10). In conclusion, the additional analyses we performed according to Mezei et al's suggestions confirm the association between asbestos exposure and pericardial and TVT mesothelioma, supporting the causal role of asbestos for all mesotheliomas. ReNaM`s continuing surveillance system with national coverage is a precious platform for launching analytical studies on pleural and extra pleural mesothelioma. References 1. Mezei G, Chang ET, Mowat FS, Moolgavkar SH. Comments on a recent case-control study of malignant mesothelioma of the pericardium and the tunica vaginalis testis Scand J Work Environ Health. 2021;47(1):85-86. https://doi.org/10.5271/3909 2. Marinaccio A, Consonni D, Mensi C, Mirabelli D, Migliore E, Magnani C et al.; ReNaM Working Group. Association between asbestos exposure and pericardial and tunica vaginalis testis malignant mesothelioma: a case-control study and epidemiological remarks. Scand J Work Environ Health. 2020;46(6):609-617. https://doi.org/10.5271/sjweh.3895. 3. Greenland S. Control-initiated case-control studies. Int J Epidemiol 1985 Mar;14(1):130-4. https://doi.org/10.1093/ije/14.1.130. 4. Pearce N. Analysis of matched case-control studies. BMJ 2016 Feb;352:i969. https://doi.org/10.1136/bmj.i969. 5. Bigert C, Gustavsson P, Straif K, Pesch B, Brüning T, Kendzia B et al. Lung cancer risk among cooks when accounting for tobacco smoking: a pooled analysis of case-control studies from Europe, Canada, New Zealand, and China. J Occup Environ Med 2015 Feb;57(2):202-9. https://doi.org/10.1097/JOM.0000000000000337. 6. Marinaccio A, Binazzi A, Marzio DD, Scarselli A, Verardo M, Mirabelli D et al.; ReNaM Working Group. Pleural malignant mesothelioma epidemic: incidence, modalities of asbestos exposure and occupations involved from the Italian National Register. Int J Cancer 2012 May;130(9):2146-54. https://doi.org/10.1002/ijc.26229. 7. Marinaccio A, Binazzi A, Di Marzio D, Scarselli A, Verardo M, Mirabelli D et al. Incidence of extrapleural malignant mesothelioma and asbestos exposure, from the Italian national register. Occup Environ Med 2010 Nov;67(11):760-5. https://doi.org/10.1136/oem.2009.051466. 8. Ferrante D, Chellini E, Merler E, Pavone V, Silvestri S, Miligi L et al.; the working group. Italian pool of asbestos workers cohorts: mortality trends of asbestos-related neoplasms after long time since first exposure. Occup Environ Med 2017 Dec;74(12):887-98. https://doi.org/10.1136/oemed-2016-104100. 9. ReNaM VI Report. Available from: https://www.inail.it/cs/internet/docs/alg-pubbl-registro-nazionale-mesoteliomi-6-rapporto.pdf. Italian 10. Marant Micallef C, Shield KD, Vignat J, Baldi I, Charbotel B, Fervers B et al. Cancers in France in 2015 attributable to occupational exposures. Int J Hyg Environ Health 2019 Jan;222(1):22-9. https://doi.org/10.1016/j.ijheh.2018.07.015.

Italian pool of asbestos workers cohorts: asbestos related mortality by industrial sector and cumulative exposure.

OBJECTIVE: Italy has been a large user of asbestos and asbestos containing materials until the 1992 ban. We present a pooled cohort study on long-term mortality in exposed workers. METHODS: Pool of 43 Italian asbestos cohorts (asbestos cement, rolling stock, shipbuilding, glasswork, harbors, insulation and other industries). SMRs were computed by industrial sector for the 1970-2010 period, for the major causes, using reference rates by age, sex, region and calendar period. RESULTS: The study included 51 801 subjects (5741 women): 55.9% alive, 42.6% died (cause known for 95%) and 1.5% lost to follow-up. Asbestos exposure was estimated at the plant and period levels. Asbestos related mortality was significantly increased. All industrial sectors showed increased mortality from pleural malignancies, and most also from peritoneal and lung cancer and asbestosis, with exposure related trend. Increased mortality was also observed for ovarian cancer and for bladder cancer. DISCUSSION: The study confirmed the increased risk for cancer of the lung, ovary, pleura and peritoneum but not of the larynx and the digestive tract. A large increase in mortality from asbestosis was observed.

Factors Affecting Asbestosis Mortality Among Asbestos-Cement Workers in Italy.

OBJECTIVES: This study was performed with the aim of investigating the temporal patterns and determinants associated with mortality from asbestosis among 21 cohorts of Asbestos-Cement (AC) workers who were heavily exposed to asbestos fibres. METHODS: Mortality for asbestosis was analysed for a cohort of 13 076 Italian AC workers (18.1% women). Individual cumulative asbestos exposure index was calculated by factory and period of work weighting by the different composition of asbestos used (crocidolite, amosite, and chrysotile). Two different approaches to analysis, based on Standardized Mortality Ratios (SMRs) and Age-Period-Cohort (APC) models were applied. RESULTS: Among the considered AC facilities, asbestos exposure was extremely high until the end of the 1970s and, due to the long latency, a peak of asbestosis mortality was observed after the 1990s. Mortality for asbestosis reached extremely high SMR values [SMR: males 508, 95% confidence interval (CI): 446-563; females 1027, 95% CI: 771-1336]. SMR increased steeply with the increasing values of cumulative asbestos exposure and with Time Since the First Exposure. APC analysis reported a clear age effect with a mortality peak at 75-80 years; the mortality for asbestosis increased in the last three quintiles of the cumulative exposure; calendar period did not have a significant temporal component while the cohort effect disappeared if we included in the model the cumulative exposure to asbestos. CONCLUSIONS: Among heaviest exposed workers, mortality risk for asbestosis began to increase before 50 years of age. Mortality for asbestosis was mainly determined by cumulative exposure to asbestos.

Association between asbestos exposure and pericardial and tunica vaginalis testis malignant mesothelioma: a case-control study and epidemiological remarks.

Objectives The purposes of this study are to describe the epidemiology of pericardial and tunica vaginalis testis mesothelioma and assess the role of asbestos exposure for these rare diseases. Methods Based on incident pericardial and tunica vaginalis testis mesothelioma cases collected from the Italian national mesothelioma registry (ReNaM) in the period 1993-2015, incidence rates, survival median period and prognostic factors have been evaluated. A case-control study has been performed to analyze the association with asbestos exposure (occupational and non-occupational) for these diseases. Results Between 1993 and 2015, 58 pericardial (20 women and 38 men) and 80 tunica vaginalis testis mesothelioma cases have been registered with a mean annual standardized (world standard population as reference) incidence rates of 0.049 (per million) in men and 0.023 in women for the pericardial site, and 0.095 for tunica vaginalis testis mesothelioma. Occupational exposure to asbestos was significantly associated with the risk of the diseases [odds ratio (OR) 3.68, 95% confidence interval (CI) 1.85-7.31 and OR 3.42, 95% CI 1.93-6.04 in pericardial and tunica vaginalis testis mesothelioma, respectively]. The median survival was 2.5 months for pericardial and 33.0 months for tunica vaginalis testis mesotheliomas. Age was the main predictive factor for survival for both anatomical sites. Conclusions For the first time in an analytical study, asbestos exposure was associated with pericardial and tunica vaginalis testis mesothelioma risk, supporting the causal role of asbestos for all anatomical sites. The extreme rarity of the diseases, the poor survival and the prognostic role of age have been confirmed based on population and nationwide mesothelioma registry data.

Overall mortality and causes of death in newly admitted nursing home residents.

BACKGROUND: In spite of a rapidly ageing population, there is a lack of population-based data on mortality among nursing home residents in Southern Europe. AIMS: To assess mortality rates, their determinants, and causes of death in newly admitted nursing home residents in the Veneto region (northeastern Italy). METHODS: 19,392 subjects aged ≥ 65 years admitted to regional nursing homes during 2015-2017 were recruited in a cohort mortality study based on linked health records. Risk factors for mortality were investigated by Cox regression. The distribution of causes of death was retrieved from death certificates. RESULTS: Mortality peaked in the first 4 months after admission; thereafter the monthly mortality rate fluctuated around 3% in males and 2% in females. Overall mortality was 23% at 6 months and 34% at 1 year. In addition to age, gender, and dependency, main risk factors for mortality were recent hospitalization (first 4 months after entry into the facility), and the burden of comorbidities (subsequent follow-up period). The most represented causes of mortality were similar in the first and in the subsequent period after admission: cardio-cerebrovascular diseases, neurodegenerative diseases, respiratory diseases, and infections. DISCUSSION: The first months after admission represent a period at high risk of mortality, especially for patients with a recent hospitalization. Causes reported in death certificates suggest mainly an acute deterioration of pre-existing chronic conditions. CONCLUSION: Health care plans should be personalized for newly admitted vulnerable patients. Palliative care needs should be recognized and addressed for high-risk non-cancer patients.

A mortality study on male subjects exposed to polyfluoroalkyl acids with high internal dose of perfluorooctanoic acid.

OBJECTIVES: The aim of the present study was to examine the association between exposure to polyfluoroalkyl substances (PFASs) and mortality (1970-2018) in a cohort of 462 male employees who had worked at least six months before 2009 for a factory (14,658 person-years; 107 deaths, average follow-up time 31.7 years), which had been producing perfluorooctanoic acid (PFOA), perfluorooctanesulfonyl fluoride (PFOS) and other chemicals since 1968. METHODS: Employees were classified as follows: 1) by probability of exposure to PFASs; 2) by tertiles of PFOA serum concentrations. In a fraction (n = 120) of workers measurements of internal PFOA serum concentration were used to predict a cumulative serum PFOA concentration of each cohort member. Mortality rates were compared to that of the regional population using the standardized mortality ratio (SMR), and to that of the workers of a nearby metalworking factory in terms of risk ratio (RR), across categories of probability of PFASs exposure and tertiles of cumulative serum PFOA concentrations. RESULTS: Internal PFOA serum concentration among 120 workers in the 2000-2013 period was very high (Geometric Mean: 4048 ng/mL; range 19-91,900 ng/mL). The mortality of the chemical cohort was increased for liver cancer (SMR: 2.32; CI: 1.11-4.87), malignant neoplasm of lymphatic and haematopoietic tissue (SMR: 2.26; CI: 1.08-4.73). In the comparison with the cohort of workers from the metalworking factory, the RRs for mortality of the cohort were increased for overall mortality (RR: 1.42; CI: 1.12-1.79), diabetes (RR: 5.95; CI: 1.08-32.8), liver cancer (RR: 6.69; CI: 1.71-26.2) and liver cirrhosis (RR: 3.87; CI: 1.18-12.7). Mortality for these causes increased in association with probability of PFASs exposure and with tertiles of cumulative PFOA serum concentrations. CONCLUSION: The present is a small observational study with limited control over confounding factors. The cohort showed increased mortality for all causes and subjects in the highest cumulative internal dose of PFOA had a statistically significant increase for mortality of liver cancer, liver cirrhosis, diabetes, malignant neoplasms of lymphatic and haematopoietic tissue in both comparisons. Toxicological studies on PFOA and PFOS provide support for causality for the observed association with the risk for liver cirrhosis and liver cancer.

Occupational exposure to vinyl chloride and liver diseases.

Portal hypertension, liver fibrosis, and angiosarcoma of the liver (ASL) have been reported among workers exposed to vinyl chloride monomer (VCM) since the 1970s. In 2007, the International Agency for Research on Cancer established the association of VCM with hepatocellular carcinoma (HCC), though only on the basis of the few cases available. Thereafter, recent reports from the United States cohort and a European sub-cohort of vinyl chloride workers provided compelling evidence of a strong association between cumulative VCM exposure and HCC risk. Further areas of research include the risk of liver cancer at lower levels of exposure and different patterns of risk of ASL and HCC with the time since exposure. The evidence of interaction between VCM exposure and other known liver carcinogens such as alcohol and chronic viral infection provides clues for the health surveillance of exposed workers. Notably, also the risk of VCM-associated chronic liver disease is modulated by alcohol consumption, viral infection, and genetic polymorphism. A counter-intuitive finding from cohort studies of exposed workers is the lower mortality from liver cirrhosis with respect to the general population; this can be attributed to the healthy worker effect and to the selection of liver cancer as the cause of death in the presence of concomitant chronic liver disease. Studies designed to overcome these intricacies confirmed an association between cumulative VCM exposure and the risk of liver cirrhosis.

Role of asbestos clearance in explaining long-term risk of pleural and peritoneal cancer: a pooled analysis of cohort studies.

OBJECTIVES: Models based on the multistage theory of cancer predict that rates of malignant mesothelioma continuously increase with time since first exposure (TSFE) to asbestos, even after the end of external exposure. However, recent epidemiological studies suggest that mesothelioma rates level off many years after first exposure to asbestos. A gradual clearance of asbestos from the lungs has been suggested as a possible explanation for this phenomenon. We analysed long-term trends of pleural and peritoneal cancer mortality in subjects exposed to asbestos to evaluate whether such trends were consistent with the clearance hypothesis. METHODS: We used data from a pool of 43 Italian asbestos cohorts (51 801 subjects). The role of asbestos clearance was explored using the traditional mesothelioma multistage model, generalised to include a term representing elimination of fibres over time. RESULTS: Rates of pleural cancer increased until 40 years of TSFE, but remained stable thereafter. On the other hand, we observed a monotonic increase of peritoneal cancer with TSFE. The model taking into account asbestos clearance fitted the data better than the traditional one for pleural (p=0.004) but not for peritoneal (p=0.09) cancer. CONCLUSIONS: Rates of pleural cancer do not increase indefinitely after the exposure to asbestos, but eventually reach a plateau. This trend is well described by a model accounting for a gradual elimination of the asbestos fibres. These results are relevant for the prediction of future rates of mesothelioma and in asbestos litigations.

Cumulative asbestos exposure and mortality from asbestos related diseases in a pooled analysis of 21 asbestos cement cohorts in Italy.

BACKGROUND: Despite the available information on cancer risk, asbestos is used in large areas in the world, mostly in the production of asbestos cement. Moreover, questions are raised regarding the shape of the dose response relation, the relation with time since exposure and the association with neoplasms in various organs. We conducted a study on the relationship between cumulative asbestos exposure and mortality from asbestos related diseases in a large Italian pool of 21 cohorts of asbestos-cement workers with protracted exposure to both chrysotile and amphibole asbestos. METHODS: The cohort included 13,076 workers, 81.9% men and 18.1% women, working in 21 Italian asbestos-cement factories, with over 40 years of observation. Exposure was estimated by plant and period, and weighted for the type of asbestos used. Data were analysed with consideration of cause of death, cumulative exposure and time since first exposure (TSFE), and by gender. SMRs were computed using reference rates by region, gender and calendar time. Poisson regression models including cubic splines were used to analyse the effect of cumulative exposure to asbestos and TSFE on mortality for asbestos-related diseases. 95% Confidence Intervals (CI) were computed according to the Poisson distribution. RESULTS: Mortality was significantly increased for 'All Causes' and 'All Malignant Neoplasm (MN)', in both genders. Considering asbestos related diseases (ARDs), statistically significant excesses were observed for MN of peritoneum (SMR: men 14.19; women 15.14), pleura (SMR: 22.35 and 48.10), lung (SMR: 1.67 and 1.67), ovary (in the highest exposure class SMR 2.45), and asbestosis (SMR: 507 and 1023). Mortality for ARDs, in particular pleural and peritoneal malignancies, lung cancer, ovarian cancer and asbestosis increased monotonically with cumulative exposure. Pleural MN mortality increased progressively in the first 40 years of TSFE, then reached a plateau, while peritoneal MN showed a continuous increase. The trend of lung cancer SMRs also showed a flattening after 40 years of TSFE. Attributable proportions for pleural, peritoneal, and lung MN were respectively 96, 93 and 40%. CONCLUSIONS: Mortality for ARDs was associated with cumulative exposure to asbestos. Risk of death from pleural MN did not increase indefinitely with TSFE but eventually reached a plateau, consistently with reports from other recent studies.

Mortality from liver angiosarcoma, hepatocellular carcinoma, and cirrhosis among vinyl chloride workers.

BACKGROUND: Occupational exposure to vinyl chloride monomer (VCM) has been established as a cause of hepatocellular carcinoma (HCC) and liver angiosarcoma (ASL). However, some controversy remains due to conflicting results on liver cirrhosis, and to evidence on HCC based on few confirmed cases. The aim of the study is to clarify the association between VCM exposure and mortality from liver diseases. METHODS: In a cohort of 1658 workers involved in VCM production and polymerization, Poisson regression was adopted to estimate rate ratios (RR) across categories of VCM exposure for mortality due to ASL (n = 9), HCC (n = 31) confirmed by histological/clinical records, and the combination of deaths from liver cirrhosis and from liver cancer with clinical/histological evidence of cirrhosis (n = 63). RESULTS: Cumulative VCM exposure was associated with study outcomes; RRs in the highest compared to the lowest exposure category were: ASL 91.1 (95%Confidence Interval 16.8-497), HCC 5.52 (2.03-15.0), liver cirrhosis 2.60 (1.19-5.67). CONCLUSIONS: The risk of death from liver cirrhosis, as well as from HCC in the largest available series of confirmed cases, increased with VCM exposure.