Pleural mesothelioma: epidemiological and public health issues. Report from the Second Italian Consensus Conference on Pleural Mesothelioma.

Malignant mesothelioma is closely connected to asbestos exposure, with epidemiological patterns closely reshaping the geography and history of asbestos exposure. Mechanisms of causation and of interaction of asbestos fibres with pleura are complex and currently not yet completely understood. Curative efforts so far provided little results. Italy shows one of the highest incidence of MM and developed a network of specialized cancer registries in order to monitor disease occurrence and describe its epidemiology in details. The second Italian Consensus Conference on Pleural Mesothelioma convened in Torino on November 24th-25th, 2011. Besides the main consensus report summarizing the contribution of the different expertises, that was published elsewhere, the participants in 'Public Health and Epidemiology' section decided to report in major details the evidence and the conclusions regarding epidemiology, causative mechanisms and the public health impact of the disease.

Cell-growth and migration inhibition of human mesothelioma cells induced by 3-O-methylfunicone from Penicillium pinophilum and cisplatin.

Malignant pleural mesothelioma is a fatal malignancy linked to asbestos exposure. The main challenge for mesothelioma treatment is to go beyond the drug resistance, in particular against cisplatin (CDDP), one of the most used chemotherapeutic drug. 3-O-methylfunicone (OMF) is a metabolite produced by the fungus Penicillium pinophilum; its antiproliferative properties have been previously studied in vitro. Particularly, OMF is able to inhibit mesothelioma cell motility. To improve the effects of CDDP by-passing the resistance of mesothelioma cells to this drug, in the present study we investigated the combined treatment of OMF with CDDP respectively in an established mesothelioma cell line (NCI) and primary mesothelioma cells (Mest). As compared to the effect of single treatments, the combination of OMF and CDDP resulted in a stronger inhibition of NCI and Mest cell proliferation. OMF combination with CDDP was also able to affect the migratory ability of NCI and Mest cells by down-regulating αv and ß5 expression and reducing metalloproteinase 2 (MMP-2) production. In addition, this association was effective in modulating VEGF gene expression. This finding highlights the possibility to use OMF and CDDP together to regulate angiogenesis and tumour progression in mesothelioma.

Analysis of latency time and its determinants in asbestos related malignant mesothelioma cases of the Italian register.

Italy was an important producer of raw asbestos until 1992 (when it was banned) and it is now experiencing severe public health consequences due to large-scale industrial use of asbestos in shipbuilding and repair, asbestos-cement production, railways, buildings, chemicals and many other industrial sectors. Latency of malignant mesothelioma generally shows a large variability and the relationship with the modality of asbestos exposure is still not fully clarified. We present an analysis of latency period among the case list collected by the Italian mesothelioma register (ReNaM) in the period of diagnosis 1993-2001 (2544 malignant mesothelioma (MM) cases with asbestos exposure history). Exposure is assessed retrospectively by interview. Statistical univariate analyses were performed to estimate median and variability measures of latency time by anatomical site, gender and diagnosis period. The role of diagnostic confidence level, the morphology of the tumour and the modalities of asbestos exposure were verified in a regression multivariate model. We found a median latency period of 44.6 years increasing in recent years with a linear trend. Anatomical site, gender and morphology were not relevant for MM latency time whereas a shorter latency period was documented among occupationally exposed subjects (43 years) with respect to environmentally and household exposed ones (48 years).

[Epidemiological surveillance of malignant mesothelioma cases in Italy: incidence and asbestos exposure figures by the Italian mesothelioma registry (ReNaM)]. / La sorveglianza epidemiologica del mesotelioma maligno in Italia: dati d'incidenza ed esposizione ad amianto del Registro nazionale dei mesoteliomi (ReNaM).

The Study describes the epidemiological surveillance of mesothelioma cases carried out by the Italian mesothelioma register (ReNaM). A Regional Operating Centre (COR) is present in nearly all Italian regions (17 out of 20) and it collects malignant mesothelioma cases and investigate the modalities of asbestos exposure by using a structured questionnaire. The register produces malignant mesothelioma incidence measures and analyses of the modalities of the asbestos exposure. The standardized incidence rate of malignant mesothelioma in 2001 was 2.98 (in 100,000 inhabitants) among men and 0.98 among women; a professional (certain, probable, possible) exposure has been detected in 67.4% of defined cases. In addition to the conventional sectors (shipbuilding, railways repair and demolition, asbestos-cement production), also textile, building, transport, chemical and glass industries, petroleum and sugar refineries, electricity production and distribution plants are getting involved. Despite the absence of some regions completing the national coverage and the non homogeneity in collecting and coding data, the epidemiological surveillance of malignant mesothelioma carried out by ReNaM is an important tool for the scientific knowledge and the prevention of asbestos-related diseases.

Cancer mortality in an area of Campania (Italy) characterized by multiple toxic dumping sites.

Several recent studies have documented that a widespread practice of dumping toxic wastes has taken place for many years in the Provinces of Naples and Caserta. Extensive programs of environmental monitoring are currently ongoing in the area. In this frame, the Department of Civil Defence of the Italian Government has appointed an ad hoc study group in order to assess the health status of the population resident in the area of interest. The first investigation performed by the study group has been a geographic study on cancer mortality and occurrence of malformations in 196 municipalities constituting the two Provinces. The study detected an area located in the southeastern part of the Province of Caserta and in the northwestern part of the Province of Naples, where cancer mortality and congenital malformations show significantly increased rates with respect to expected figures derived from the regional population. The area highlighted by the study is, in general terms, overlapping with the area where most illegal dumping of toxic wastes took place. It is now recommended that mortality studies be extended to take into account other health outcomes, to search for correlations with environmental exposures, and consider possible confounding factors.

[Geographical distribution of mortality from malignant pleural neoplasms and of former asbestos-exposed workers in the Campania Region]. / Distribuzione geografica della mortalità per tumore maligno della pleura e dei soggetti ex esposti professionalmente ad amianto in Campania.

AIM: The purpose of the present paper is to describe the geographical distribution at municipality level of mortality from malignant pleural neoplasms in the Campania Region, along with the distribution of former asbestos-exposed workers. A GIS (Geographical Information System) application has been developed to integrate exposure and mortality data. STUDY DESIGN: The number of asbestos workers by municipality has been estimated by merging data provided by the National Institute for Insurance against Occupational Accidents (INAIL), the Ministry of Labour and an association of formerly exposed workers (AUSER Flegrea). The number of deaths from malignant pleural neoplasms by municipality has been derived from published studies regarding two consecutive periods: 1988-1994 and 1995-1997. RESULTS: In the first period most deaths occurred in areas with a high number of formerly exposed asbestos workers, whilst in the second period mesothelioma mortality increased extending to other areas without registered exposed workers. CONCLUSION: This finding may be attributable to the presence of atypical occupational exposures, not reported by the current information systems, or to environmental, non occupational exposure patterns.

[Mortality study of a cohort of insulation workers]. / Studio di mortalità di una coorte di coibentatori.

Cause specific mortality was investigated in a cohort of insulators employed by a company which operated in various parts of Italy. Follow-up covered the years 1960-1996. The cohort, which included 893 subjects, was derived from company files of relatively poor quality, which resulted in a high rate of lost to follow-up (10.1%) and of deaths with unknown cause (12.4%). The mortality experience of the cohort was contrasted with that of the Italian population. Overall mortality (SMR 141, 90% CI 118-167, 97 observed), and cancer mortality (SMR 165, 90% CI 123-216, 38 observed) were significantly increased. Among neoplasms, significant increases were observed for lung cancer (SMR 202, 90% CI 124-311, 15 observed), pleural neoplasms (SMR 2667, CI 90% 911-6103, 4 observed), and peritoneal neoplasms (SMR 1853, 90% CI 329-5832, 2 observed). The excess mortality for lung cancer was especially pronounced in subjects with latency time longer than ten years (SMR 237.1, 90% CI 140-377, 13 observed).

[Cause-specific mortality in an area of Campania with numerous waste disposal sites]. / Mortalità per causa in un'area della Campania con numerose discariche di rifiuti.

OBJECTIVE: To investigate cause-specific mortality in an area of Campania region, in the surroundings of Naples, characterized by many toxic waste dumping grounds sites and by widespread burning of urban wastes. DESIGN: The study area was characterized by examining the spatial distribution of waste disposal sites and toxic waste dumping grounds, using a geographic information system (GIS). Mortality (1986-2000) was studied in the three municipalities of Giugliano in Campania, Qualiano and Villaricca, encompassing a population of about 150,000 inhabitants. Mortality rates of the population resident in the Campania region were used in order to generate expected figures. OUTCOMES: Causes of death of a priori interest where those previously associated to residence in the neighbourhood of (toxic) waste sites, including lung cancer, bladder cancer, leukemia and liver cancer. RESULTS: Overall 39 waste sites, 27 of which characterized by the likely presence of toxic wastes, were identified in the area of interest. A good agreement was found between two independent surveys of the Regional Environmental Protection Agency and of the environmentalist association Legambiente. Cancer mortality was significantly increased, with special reference to malignant neoplasm of lung, pleura, larynx, bladder, liver and brain. Circulatory diseases were also significantly in excess and diabetes showed some increases. CONCLUSIONS: Mortality statistics provide preliminary evidence of the disease load in the area. Mapping waste dumping grounds provides information for defining high risk areas. Improvements in exposure assessment together with the use of a range of health data (hospital discharge cards, malformation notifications, observations of general practitioners) will contribute to second generation studies aimed at inferring causal relationships.

Mesothelioma incidence in the neighbourhood of an asbestos-cement plant located in a national priority contaminated site.

BACKGROUND: An epidemic of asbestos-related disease is ongoing in most industrialized countries, mainly attributable to past occupational exposure but partly due to environmental exposure. In this perspective, the incidence of pleural mesothelioma close to a former asbestos-cement plant in a national contaminated site was estimated. METHODS: The census-tracts interested by atmospheric dispersion of facilities in the contaminated site were identified. Two subareas with different estimated environmental asbestos impact were distinguished. An ecological study at micro-geographic level was performed. The standardized incidence ratios (SIR) for study area and the two subareas, in comparison with region and municipality were computed. The standardized incidence rate ratio (IRR) between the two subareas was computed. RESULTS: Mesothelioma incidence in the study area was increased: 46 cases were observed with respect to 22.23 expected (SIR: 2.02). The increase was confirmed in analysis considering only the subjects without an occupationally exposure to asbestos: 19 cases among men (SIR = 2.48; 95% CI: 1.49-3.88); 11 case among women (SIR = 1.34; 95% CI: 0.67-2.40). The IRR between the two subareas is less than one in overall population considering all age-classes and of 3 fold (IRR = 3.14, 95% CI: 0.65-9.17) in the age-classes below 55 years. CONCLUSIONS: The findings indicate an increased incidence of pleural mesothelioma in the neighbourhood of asbestos-cement plant, and a possible etiological contribution of asbestos environmental exposure in detected risks.

Mortality study in an asbestos cement factory in Naples, Italy.

The objective of this paper is to investigate mortality among 1247 male asbestos-cement workers employed in an asbestos-cement plant located in Naples. The cohort included 1247 men hired between 1950 and 1986. The follow-up began on January 1st 1965. The vital status and causes of death were ascertained up to December 31 2005. Cause-specific mortality rates of the Campania Region population were used as reference. Relative risks were estimated using Standardized Mortality Ratios (SMRs), and the confidence intervals were calculated at a 95% level (95% CI). A significant increase in mortality was observed for respiratory disease (81 deaths; SMR = 187; 95% CI = 149- 233), particularly for pneumoconiosis (42 deaths; SMR = 13 313; 95% CI = 9595-17 996) of which 41 deaths for asbestosis (SMR = 43 385; 95% CI = 31 134-58 857), for pleural cancer (24 deaths; SMR = 2617; 95% CI = 1677-3893), for lung cancer (84 deaths; SMR=153; 95% CI = 122-189) and for peritoneal cancer (9 deaths; SMR = 1985; 95% CI = 908-3769). Non-significant increases were also observed for rectum cancer (6 deaths; SMR = 157; 95% CI = 58-342). In conclusion, consistently with other mortality studies on asbestos-cement workers performed in different countries, an increased mortality from asbestosis, lung cancer, pleural and peritoneal mesothelioma was detected in the present cohort.

Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma.

BACKGROUND: Malignant mesothelioma (MM) is a rare, highly aggressive tumor, associated to asbestos exposure. To date no chemotherapy regimen for MM has proven to be definitively curative, and new therapies for MM treatment need to be developed. We have previously shown in vivo that piroxicam/cisplatin combined treatment in MM, specifically acts on cell cycle regulation triggering apoptosis, with survival increase. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed, at molecular level, the apoptotic increase caused by piroxicam/cisplatin treatment in MM cell lines. By means of genome wide analyses, we analyzed transcriptional gene deregulation both after the single piroxicam or cisplatin and the combined treatment. Here we show that apoptotic increase following combined treatment is mediated by p21, since apoptotic increase in piroxicam/cisplatin combined treatment is abolished upon p21 silencing. CONCLUSIONS/SIGNIFICANCE: Piroxicam/cisplatin combined treatment determines an apoptosis increase in MM cells, which is dependent on the p21 expression. The results provided suggest that piroxicam/cisplatin combination might be tested in clinical settings in tumor specimens that express p21.

Global gene expression profiling of human pleural mesotheliomas: identification of matrix metalloproteinase 14 (MMP-14) as potential tumour target.

BACKGROUND: The goal of our study was to molecularly dissect mesothelioma tumour pathways by mean of microarray technologies in order to identify new tumour biomarkers that could be used as early diagnostic markers and possibly as specific molecular therapeutic targets. METHODOLOGY: We performed Affymetrix HGU133A plus 2.0 microarray analysis, containing probes for about 39,000 human transcripts, comparing 9 human pleural mesotheliomas with 4 normal pleural specimens. Stringent statistical feature selection detected a set of differentially expressed genes that have been further evaluated to identify potential biomarkers to be used in early diagnostics. Selected genes were confirmed by RT-PCR. As reported by other mesothelioma profiling studies, most of genes are involved in G2/M transition. Our list contains several genes previously described as prognostic classifier. Furthermore, we found novel genes, never associated before to mesotheliom that could be involved in tumour progression. Notable is the identification of MMP-14, a member of matrix metalloproteinase family. In a cohort of 70 mesothelioma patients, we found by a multivariate Cox regression analysis, that the only parameter influencing overall survival was expression of MMP14. The calculated relative risk of death in MM patients with low MMP14 expression was significantly lower than patients with high MMp14 expression (P = 0.002). CONCLUSIONS: Based on the results provided, this molecule could be viewed as a new and effective therapeutic target to test for the cure of mesothelioma.