III Italian Consensus Conference on Malignant Mesothelioma of the Pleura. Epidemiology, Public Health and Occupational Medicine related issues.

The III Italian Consensus Conference on Pleural Mesothelioma (MM) convened on January 29th 2015. This report presents the conclusions of the 'Epidemiology, Public Health and Occupational Medicine' section. MM incidence in 2011 in Italy was 3.64 per 100,000 person/years in men and 1.32 in women. Incidence trends are starting to level off. Ten percent of cases are due to non-occupational exposure. Incidence among women is very high in Italy, because of both non-occupational and occupational exposure. The removal of asbestos in place is proceeding slowly, with remaining exposure. Recent literature confirms the causal role of chrysotile. Fibrous fluoro-edenite was classified as carcinogenic by IARC (Group 1) on the basis of MM data. A specific type (MWCNT-7) of Carbon Nanotubes was classified 2B. For pleural MM, after about 45 years since first exposure, the incidence trend slowed down; with more studies needed. Cumulative exposure is a proxy of the relevant exposure, but does not allow to distinguish if duration or intensity may possibly play a prominent role, neither to evaluate the temporal sequence of exposures. Studies showed that duration and intensity are independent determinants of MM. Blood related MM are less than 2.5%. The role of BAP1 germline mutations is limited to the BAP1 cancer syndrome, but negligible for sporadic cases. Correct MM diagnosis is baseline; guidelines agree on the importance of the tumor gross appearance and of the hematoxylin-eosin-based histology. Immunohistochemical markers contribute to diagnostic confirmation: the selection depends on morphology, location, and differential diagnosis. The WG suggested that 1) General Cancer Registries and ReNaM Regional Operational Centres (COR) interact and systematically compare MM cases; 2) ReNaM should report results presenting the diagnostic certainty codes and the diagnostic basis, separately; 3) General Cancer Registries and COR should interact with pathologists to assure the up-to-date methodology; 4) Necroscopy should be practiced for validation. Expert referral centres could contribute to the definition of uncertain cases. Health surveillance should aim to all asbestos effects. No diagnostic test is recommended for MM screening. Health surveillance should provide information on risks, medical perspective, and smoking cessation. The economic burden associated to MM was estimated in 250,000 Euro per case.

Cancer risk after cessation of asbestos exposure: a cohort study of Italian asbestos cement workers.

OBJECTIVES: We aimed to study mortality for asbestos related diseases and the incidence of mesothelioma in a cohort of Italian asbestos cement workers after cessation of asbestos exposure. METHODS: The Eternit factory operated from 1907 to 1986. The cohort included 3434 subjects active in 1950 or hired in 1950-86, ascertained from company records, without selections. Local reference rates were used for both mortality and mesothelioma incidence. RESULTS: Mortality was increased in both sexes for all causes (overall 1809 observed (obs) vs 1312.3 expected (exp); p<0.01), pleural (135 obs vs 3.6 exp; p<0.01) and peritoneal (52 vs 1.9; p<0.01) malignancies and lung cancer (249 vs 103.1; p<0.01). In women, ovarian (9 vs 4.0; p<0.05) and uterine (15 vs 5.8; p<0.01) malignancies were also in excess. No statistically significant increase was found for laryngeal cancer (16 obs vs 12.2 exp). In Poisson regression analyses, the RR of death from pleural neoplasm linearly increased with duration of exposure, while it showed a curvilinear increase with latency and time since cessation of exposure. RR for peritoneal neoplasm continued to increase by latency, duration and time since cessation of exposure. RR for lung cancer showed a reduction after 15 years since cessation of exposure and levelled off after 40 years of latency. CONCLUSION: This study of a cohort of asbestos exposed workers with very long follow-up confirmed the reduction in risk of death from lung cancer after the end of exposure. It also suggested a reduction in risk for pleural mesothelioma with over 40 years of latency, while risk for peritoneal mesothelioma showed a continuing increase.

[Mortality from pleural and peritoneal cancer in a cohort of asbestos workers, many years after start of the exposure: possible role of fibers clearance]. / Mortalità per tumore pleurico e peritoneale in una coorte di lavoratori del cemento amianto, dopo lunghi periodi di latenza: valutazione di un possibile ruolo della clearance delle fibre.

The multistage theory of carcinogenesis assumes rates of mesothelioma increasing monotonically as a function of time since first exposure (TSFE) to asbestos. However, some authors have suggested that the increase in mesothelioma rate with TSFE might be attenuated by clearance of asbestos from the lungs. We estimated mortality time trends from pleural and peritoneal cancer in a cohort of 3443 asbestos-cement workers. The role of asbestos clearance was explored using the traditional mesothelioma multistage model, generalized to include a term representing elimination over time. We observed 139 deaths from pleural and 56 from peritoneal cancer during the period 1950-2003. The rate of pleural cancer increased during the first 40 years of TSFE and reached a plateau thereafter. In contrast, the rate of peritoneal cancer increased monotonically with TSFE. The model allowing for asbestos elimination fitted the data better than the traditional model for pleural (p = 0.02) but not for peritoneal cancer (p = 0.22). The risk for pleural cancer, rather than showing an indefinite increase, might reach a plateau when a sufficiently long time has elapsed since exposure. The different trends for pleural and peritoneal cancer might be related to clearance of the asbestos from the workers' lungs.

Role of tobacco and alcoholic beverages in the etiology of cancer of the oral cavity/oropharynx in Torino, Italy.

A population-based case-control study of cancer of oral cavity-oropharynx was conducted in the city of Torino, Italy, between 1982 and 1984. One hundred twenty-two cases (86 males and 36 females) and 606 controls (385 males and 221 females) were compared with respect to lifelong alcohol and tobacco consumption. A 4- to 6-fold increase in risk among subjects with medium or high tobacco consumption was observed, as well as a trend in increasing risk with duration and with earlier age at the start of smoking. Other findings included a sharp reduction in risk with cessation of smoking, no clear protective effect of usage of filter, no differences in risk according to color of tobacco, and a higher risk for cigar versus pipe/cigarette smokers. An effect of alcoholic beverages was found in subjects with an average daily consumption of 120 or more grams of alcohol, with a higher risk in beer drinkers. Among heavy consumers of alcohol and tobacco, risks of both oral and oropharyngeal cancer were very high. A positive association between oral cancer and low educational level, after adjustment for alcohol and tobacco, was found. Attributable risks for alcohol and tobacco in the population were 23% and 72% in men and 34% and 54% in women.

Effects of timing and type of tobacco in cigarette-induced bladder cancer.

We analyzed a case-control study of bladder cancer in Torino (512 male and 55 female cases; 596 male and 202 female controls) with emphasis on the timing of cigarette smoking and the use of black or blond tobacco. The risk of bladder cancer was 2 to 3 times higher among smokers of black tobacco than among smokers of blond tobacco. Both groups of smokers showed a beneficial effect of smoking cessation, with an immediate decline in risk. This pattern is consistent with a late-stage effect of smoking. Among smokers of black tobacco, there was a gradient of risk with early exposure, and smokers who had quit never showed a drop to base-line levels of risk. These patterns, not apparent in users of blond tobacco, suggest an early stage effect of black tobacco, perhaps due to the higher concentration of aromatic amines in black than blond tobacco smoke and the higher blood levels of the hemoglobin adduct with 4-aminobiphenyl (a human bladder carcinogen) among smokers of black tobacco.

The scientific basis of a total asbestos ban.

Worldwide, in the new millennium, standards for the protection of workers and the general population from as-bestos risks are not equally stringent in all countries. The present review analyzes some arguments which in recent years have been proposed as a rationale for the reconsideration of the scientific background of a total asbestos ban, such as that adopted in the European Union. The conclusion is that in order to ensure adequate protection, there is no alternative to a total ban. The evidence for carcinogenicity of chrysotile is as good as for the amphiboles, the carcinogenic potency of chrysotile is lower than that of the amphiboles, but risk estimates must also be based on extent of exposure (nowadays chrysotile represents 95% of asbestos used worldwide). The fact that induction of mesothelioma by asbestos results from the interaction of environmental exposure and genetic factors reflects a general phenomenon in carcinogenesis and does not warrant any re-consideration of the role of asbestos. The role of SV40 as yet is unclear: even assuming that current risk estimates are correct (which is debatable), this agent would interact with asbestos in only a faction of mesothelioma cases. The effectiveness of protocols suggested for "controlled use" has not been tested with a scientfiic approach: they seem hardly practicable, particularly in the countries which are currently the major consumers of asbestos.

Population-based survival after childhood lymphoblastic leukaemia in time periods corresponding to specific clinical trials from 1979 to 1998--a report from the Childhood Cancer Registry of Piedmont (Italy).

This study evaluated the outcome after childhood acute lymphoblastic leukaemia (ALL) in a population aged 0-14 years served by the Childhood Cancer Registry of Piedmont (CCRP) during the accrual periods to nationwide clinical studies run by the Italian Association for Paediatric Haematology and Oncology (AIEOP). In the time period considered (March 1979-December 1998) the CCRP recorded 498 incident cases of ALL. The living status on 31 December 2000 was known for 497 cases. Overall survival at 5 years was 74.1% standard error (S.E.) 2.0%). It increased from 58.6% (S.E. 4.9%) for cases diagnosed in March 1979-July 1982 to 87.3 (S.E. 3.6) in May 1995-December 1998. Results observed from data in our population-based study in Piedmont were similar to those presented in the nationwide clinical trials. Survival was better (statistically significant) for children aged 1-4 years, with a white blood cell (WBC) count lower than 10 000 x 10(3) cells/litre and for B-precursor ALL. Differences by immunophenotype were statistically significant only in the univariate analyses. Girls showed a non-statistically significant survival advantage over boys. Results of the present study show the impact on the population of recent clinical trials and emphasise the role of population-based cancer registries in evaluating childhood cancer care delivery in a given population.

Childhood cancer survival in Europe: an overview.

Other articles in this issue of the European Journal of Cancer have described population-based survival analyses of specific types of childhood cancer included in the EUROCARE database, diagnosed since 1979. The present paper summarises the relevant estimates and comments on intercountry differences, focusing on possible distortions in the intercountry comparisons based on data produced by the cancer registries. Potential biases include a lack of exhaustiveness of both case ascertainment and follow-up for living status and also a lack of consistency in the use of classification of the childhood cancer types. Nevertheless, despite such biases, consistent differences are observed between European countries in the probability of survival following the diagnosis of a paediatric cancer. In most cases, poor population-based survival rates are probably explained by inadequacies in the adoption and implementation of therapeutic protocols that have been proved to be effective. In some instances, the cause of unsatisfactory estimates was the inclusion of a sizeable proportion of children with cancer in clinical trials which were found to be ineffective. A regression analysis of incidence, mortality and survival rates during 1978-1989 over the whole EUROCARE database strongly indicates that the prognostic improvements over time are real and cannot be attributed to changes in diagnostic procedures.

Population density and childhood leukaemia: results of the EUROCLUS Study.

The EUROCLUS study assembled incidence data for 13,551 cases of childhood leukaemia (CL) diagnosed between 1980 and 1989 in 17 countries (or regions of countries). These were referenced by location at diagnosis to small census areas of which there were 25,723 in the study area. Population counts, surface area and, hence, population density were available for all these small areas. Previous analyses have shown limited extra-Poisson variation (EPV) of case counts within small areas; this is most pronounced in areas of intermediate population density (150-499 persons/km2). In this study, the data set was examined in more detail for evidence that variations in incidence and EPV of CL are associated with population density. Incidence showed a curvilinear association with population density and was highest in areas which were somewhat more densely populated (500-750 persons/km2), where the incidence rate ratio relative to areas having > or = 1000 persons/km2 was 1.16 (95% confidence interval 1.07-1.26) and the P value for quadratic trend across eight strata of population density was 0.02. Incidence in these areas is uniformly elevated and showed no evidence of heterogeneity (i.e. EPV). Statistically significant evidence of EPV was evident amongst some of the areas previously classified as intermediate density areas (specifically, those with a density of 250-499 persons/km2, P < 0.001 for CL). These results were interpreted in terms of the current aetiological hypotheses for CL which propose that exposure to localised epidemics of one or more common infectious agent may contribute to the development of leukaemia. They suggest that such epidemics arise regularly in moderately densely populated areas and also sporadically in areas which are somewhat less densely populated. Although other interpretations are possible, these results may assist in the identification of characteristics which infectious agents must possess if direct or indirect causes of CL.

Evidence of a multiplicative effect between cigarette smoking and occupational exposures in the aetiology of bladder cancer.

A case-control study on urinary tract cancer in men is ongoing in the Province of Torino. The analysis of tobacco smoke and occupational histories of the first 225 case-control pairs is described. The overall relative risks (RR) for tobacco smoke and for occupations known to entail a risk for bladder cancer were respectively 4.8 (95% confidence limits (C.L.) 2.4--9.3) and 1.7 (1.0--2.7). There was a clearcut dose-response relationship between different categories of cigarette consumption and risk for urinary tract cancer. For each level of cigarette consumption, relative risks were compared between men reporting and non-reporting occupation at risk. This analysis suggested a multiplicative effect between the 2 factors.

Cigarette smoking and bladder cancer in females.

In a hospital-based case-control study, 55 women with bladder cancer and 202 female surgical controls were compared for life-long smoking habits. The relative risk associated with cigarette smoking was 2.1; the proportion of bladder cancers attributable to such habit was estimated to be 22%. In comparison with a parallel study in men, it seems that age at diagnosis and age at start of smoking play a different role in the two sexes.

Cancer mortality among relatives of children with soft-tissue sarcoma: a national survey in Italy.

Information was obtained on the living status or cause of death of 2223 close relatives of 195 children with soft-tissue sarcomas (STS) diagnosed under age 15. Three-hundred nine relatives had died, from all causes, before STS diagnosis in the index child. The expected figure estimated from age- and sex-specific mortality rates in Italy was 293.3. Cancer was reported as cause of death in 76 relatives (75.1 expected). Seven grandmothers, 2 aunts, 1 uncle and 0 mothers died from breast cancer vs. 4.6, 0.9, 0.0 and 0.2 expected. Three siblings died from cancer (0.2 expected, P less than 0.01), i.e. STS, ependymoma and non-Hodgkin lymphoma. These results confirm and expand previous observations that STS in children are associated with other cancers, particularly childhood and breast cancer, in members of the same family.

Increased risk of malignant mesothelioma of the pleura after residential or domestic exposure to asbestos: a case-control study in Casale Monferrato, Italy.

The association of malignant mesothelioma (MM) and nonoccupational asbestos exposure is currently debated. Our study investigates environmental and domestic asbestos exposure in the city where the largest Italian asbestos cement (AC) factory was located. This population-based case-control study included pleural MM (histologically diagnosed) incidents in the area in 1987-1993, matched by age and sex to two controls (four if younger than 60). Diagnoses were confirmed by a panel of five pathologists. We interviewed 102 cases and 273 controls in 1993-1995, out of 116 and 330 eligible subjects. Information was checked and completed on the basis of factory and Town Office files. We adjusted analyses for occupational exposure in the AC industry. In the town there were no other relevant industrial sources of asbestos exposure. Twenty-three cases and 20 controls lived with an AC worker [odds ratio (OR) = 4.5; 95% confidence interval (CI), 1.8-11.1)]. The risk was higher for the offspring of AC workers (OR = 7.4; 95% CI, 1.9-28.1). Subjects attending grammar school in Casale also showed an increased risk (OR = 3.3; 95% CI, 1.4-7.7). Living in Casale was associated with a very high risk (after selecting out AC workers: OR = 20.6; 95% CI, 6.2-68.6), with spatial trend with increasing distance from the AC factory. The present work confirms the association of environmental asbestos exposure and pleural MM, controlling for other sources of asbestos exposure, and suggests that environmental exposure caused a greater risk than domestic exposure.

Health status measurement in Toxic Oil Syndrome.

Toxic Oil Syndrome (TOS) is a previously unreported condition which affected more than 20,000 people in Spain in 1981 and whose natural history is unknown. In 1993-94, a stratified random sample of 1400 survivors was drawn to measure their health status through clinical examination and their self-perception of well-being through the Nottingham Health Profile Questionnaire (NHPQ). Two-thirds of the sample population responded; indirect estimates suggest that selection bias was limited. Clear and intermediate signs of neuropathy were found in one-fifth and one-half of the patients, respectively. One-fourth and one-sixth showed some degree of scleroderma and contractures. All conditions were more frequent in women than in men and in age >50 than in younger ages. Although no concurrent control group was included in the study, prevalences of these conditions are well above expectations and are largely attributable to TOS. NHPQ scores increased with age in both sexes up to age 50, after which they reached a plateau (with values around 48 in men and 62 in women). Scores were associated to the occurrence of peripheral neurological changes, contractures, and scleroderma-like conditions. A multivariate analysis indicated age, sex, and severity of neurological conditions as major determinants of the NHPQ scores. This overall pattern of findings is peculiar to TOS and differs from the typical post-disaster nonspecific syndrome.

Cancer incidence and risk factors among Montreal residents of Italian origin.

Cancer risks associated with Italian ethnicity were investigated using data from a large case-control study on the aetiology of several cancer sites in the male population of Montreal. Two approaches were taken. First, incidence rates were computed for Italians and for others in the Montreal area using our ascertained cases as numerators and census-derived denominators. Secondly, for respondents to the case-control study, an analysis was carried out with Italian ethnicity as the risk factor and a number of covariates as potential confounders. Out of 4553 incident cases in men aged 35-69, 301 were of Italian origin. As compared with other Montreal males, those of Italian origin had higher incidence rates for cancers of the stomach (p = 0.016, based on 31 cases) and of the colon and rectum (p = 0.102, based on 75 cases) and lower rates for cancer of the lung (p = 0.006) and prostate (p = 0.102, based on 24 cases). For other sites the differences between Montrealers of Italian and non-Italian origins were small. Montreal Italians manifested risks similar to those of the country of origin for cancer of the prostate and similar to the host country for cancers of the colon, rectum and liver. For other sites it was difficult to characterize the pattern because of wide variations among Italian registries. Over 80% of the study subjects in Montreal were interviewed and odds ratios (OR) for Italian ethnicity were estimated for each cancer site using all other sites as controls, adjusting for five potential confounders.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxic oil syndrome mortality: the first 13 years.

BACKGROUND: The toxic oil syndrome (TOS) epidemic that occurred in Spain in the spring of 1981 caused approximately 20000 cases of a new illness. Overall mortality and mortality by cause in this cohort through 1994 are described for the first time in this report. METHODS: We contacted, via mail or telephone, almost every living member of the cohort and family members of those who were known to have died in order to identify all deaths from 1 May 1981 through 31 December 1994. Cause of death data were collected from death certificates and underlying causes of death were coded using the International Classification of Diseases, 9th Revision. RESULTS: We identified 1663 deaths between 1 May 1981 and 31 December 1994 among 19 754 TOS cohort members, for a crude mortality rate of 8.4%. Mortality was highest during 1981, with a standardized mortality ratio (SMR) of 4.92 (95% confidence interval [CI]: 4.39-5.50) compared with the Spanish population as a whole. The highest SMR, (20.41, 95% CI: 15.97-25.71) was seen among women aged 20-39 years during the period from 1 May 1981 through 31 December 1982. Women <40 years old, who were affected by TOS , were at greater risk for death in most time periods than their unaffected peers, while older women and men were not. Over the follow-up period, mortality of the cohort was less than expected when compared with mortality of the general Spanish population, or with mortality of the population of the 14 provinces where the epidemic occurred. We also found that, except for deaths attributed to external causes including TOS and deaths due to pulmonary hypertension, all causes of death were decreased in TOS patients compared to the Spanish population. The most frequent underlying causes of death were TOS, 350 (21.1%); circulatory disorders, 536 (32.3%); and malignancies, 310 (18.7%). CONCLUSIONS: We conclude that while on average people affected by toxic oil syndrome are not at greater risk for death over the 13-year study period than any of the comparison groups, women <40 years old were at greater risk of death.

Malignant mesothelioma of the pleura: interobserver variability.

AIMS: To assess the consistency of histopathological diagnosis of pleural malignant mesothelioma by estimating interobserver agreement between five pathologists. METHODS: Eighty eight histological sets pertaining to original diagnoses of pleural malignant mesothelioma were reviewed separately by each pathologist. Diagnostic likelihood was graded as definite (A), probable (B), possible (C), improbable (D), and definitely not (E) malignant mesothelioma. The following indexes were estimated: observed proportion of agreement (Po), kappa statistics and proportion of agreement for "positive" (Ppos) and "negative" (Pneg) diagnoses. RESULTS: Sixty cases (68.2%) were rated by at least three reviewers as A or B and by none of the others as D or E. Five (5.7%) were rated by at least two reviewers as D or E and by none of the others as A or B. Nine (10.2%) showed a serious disagreement, rated A or B and D or E. Agreement for sets obtained at necropsy/surgery (median kappa w = 0.57) was similar to that for endoscopic material (median kappa w = 0.54). Agreement was poor on material obtained by needle biopsy (median kappa w = 0.21). The median value of Ppos varied between 0.94 (necropsy/surgery) and 0.67 (needle biopsy) and that of Pneg between 0.78 (necropsy/surgery) and 0.34 (unspecified biopsy). Interobserver agreement on histological typing was good overall (median kappa = 0.59). CONCLUSIONS: Of the original histological diagnoses, 70% were consistently reproduced through panel review. Most indexes of agreement between pathologists ranged from poor (needle biopsy) to moderate (necropsy/surgery). Agreement in confirming malignant mesothelioma was greater than that regarding exclusion of this diagnosis. Of the cases finally considered to have malignant mesothelioma, the reproducibility of histological typing was relatively satisfactory.