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The Position Paper (PP) on asbestos of the Italian Society of Occupational Medicine (SIML) aims at providing a tool to the occupational physician to address current diagnostic criteria and results of epidemiological studies, and their consequences in terms of preventive and evaluation actions for insurance, compensation and litigation. The PP was based on an extensive review of the scientific literature and was compiled by a Working Group comprising researchers who have contributed to the international literature on asbestos-related diseases, as well as occupational physicians with extensive experience in the evaluation of risks and the medical surveillance of workers currently and formerly exposed to asbestos. The PP was drafted and reviewed between 2017 and 2018; its final version was prepared according to the guidelines of AGREE Reporting Checklist. All the members of the Working Group subscribed to the document, which was eventually approved by SIML’s Executive Committee. The first section addresses industrial hygiene issues, such as methods for environmental monitoring, advantages and limitations of different microscopy techniques, the potential role of microfibers and approaches for retrospective assessment of exposure, in particular in epidemiological studies. The second section reviews the biological effects of asbestos with particular attention to the diagnostic aspects of asbestosis, pleural changes, mesothelioma and lung cancer. In the following section the criteria of causal attribution are discussed, together with different hypotheses on the form of the risk functions, with a comparison of the opinions prevalent in the literature. In particular, the models of the risk function for mesothelioma were examined, in the light of the hypothesis of an acceleration or anticipation of the events in relation to the dose. The last section discusses topics of immediate relevance for the occupational physician, such as health surveillance of former exposed and of workers currently exposed in remediation activities.

Asbestos-related diseases are characterized by a long latency time since exposure. This accounts for a health surveillance programme addressed to asbestos workers to be performed for decades after the cessation of occupational exposure. We describe the health surveillance programme for former asbestos-exposed workers in Tuscany Region (Central Italy), with particular attention to organization and related critical issues. The Deliberation of the Regional Administration of Tuscany (No. 396/2016) supports the programme, defined by a regional group of experts, and defines the public health services where the programme has to be implemented. The programme activities are classified in two levels: a first level for a basic health evaluation and a second level for in-depth analyses. The former asbestos workers, aged less than 80 years and with cessation of occupational asbestos exposure in the last 30 years, that might be included free of charge in the programme are about 5.600. The funds assigned to develop the programme from 2016 to 2024 were 2,044,808 euros. The Regional Administration of Tuscany decided to offer and guarantee a homogeneous programme in the whole region. The identification of a specific public health programme and the cooperation of social stakeholders, defined with specific regional agreements, might facilitate to overcome the problems which are still open, such as a broaden invitation to adhere to the programme, an extended knowledge on the service, and the application of a similar health programme for still-working former asbestos workers.

The incidence of mesothelioma in Italy shows wide geographical variation, with the highest incidence rates in Genoa and Friuli Venezia Giulia (FVG). For mesothelioma, national standard incidence rates are not available prior to the calendar year 2006.

SENTIERI-ReNaM Project analysed the incidence of malignant mesothelioma (MM) for the period 2000-2011 in 39 National Priority Contaminated Sites (NPCSs), and assessed the overall impact of mesothelioma in different types of NPCSs. In the study period, 2,683 incident cases of malignant mesothelioma were recorded: 1,998 males (74.5%), 685 females (25.5%). Excluding cases with non attributable exposure and those non interviewed, exposure was identified in 1,926 cases (70% of all cases): 1,541 males (occupational exposure: 1,414; environmental exposure: 82), 385 females (occupational exposure: 103; environmental exposure: 141). Women experienced mainly environmental and domestic exposures to asbestos. Standard Incidence Ratio (SIR) excesses were observed in men in 27 out of 39 NPCSs and defects in the remaining 12; in women, 20 NPCSs showed SIR excesses, defects in 15; in 4 NPCSs no MM cases occurred among female population. The highest rates were found in NPCSs with asbestos-cement plants (Broni and Casale Monferrato), respectively, 98 per 100,000 per year and 68.6 in men, 72.1 and 45.8 in women. Excluding these two sites, the highest incidence rates were found in the group with harbours and shipyards, where the rates were, respectively, 13.2 among men and 2.5 among women. The results of this report will be communicated to national and local institutions, as well as to NPCSs resident populations.

This study aims at investigating, in asbestos exposed workers, the time trend of their risk of mesothelioma and of other neoplasm after very long latency and after the cessation of asbestos exposure. We pooled a large number of Italian cohorts of asbestos workers and updated mortality follow-up. The pool of data for statistical analyses includes 51,988 workers, of which 6,058 women: 54.2% was alive at follow-up, 42.6% was dead, and 2.8%was lost. Cause of death is known for 94.3%: 2,548 deaths from lung cancer, 748 frompleural cancer, 173 fromperitoneal cancer, and 434 from asbestosis. An exposure index is being developed to compare the different cohorts. Data analysis is in progress. This study will have the size for analysing not only time trends in mesothelioma, but also the occurrence of rarer diseases and cancer specific mortality in women.

Mesothelioma incidence has been analyzed in National Priority Contaminated Sites (NPCSs) to estimate the health impact of asbestos exposure on resident people. The burden of professional and environmental exposures has been identified through data of the Regional Operational Centres (CORs), made available by the Italian National Mesothelioma Registry (ReNaM). An excess of mesothelioma incidence is confirmed in sites with a known past history of direct use of asbestos, such as Balangero, Casale Monferrato, Broni, Bari-Fibronit, and in coastal areas, where shipyards, harbours and other industries that involved a wide use of asbestos are represented (e.g., Trieste, La Spezia, Venice, and Leghorn). An excess of mesothelioma has been observed in settings where the asbestos is not mentioned as contaminant in the decree that included these sites among NPCSs, such as Cengio and Saliceto in Northern Italy; Falconara Marittima and the Bacino Idrografico Fiume Sacco in the Central Italy; the Litorale Domizio Flegreo and Agro Aversano, Milazzo, and Gela in the Southern Italy. Observed excess in the various NPCSs confirms the large-scale occurrence in contaminated Italian sites of a significant amount of total mesothelioma cases observed at national level. The analysis of occupational risk in epidemiological studies with an ecological design helps in defining the contribution of different factors to the overall risk.

Adenosine is a purine nucleoside that is commonly expressed in the body and involved in a wide range of physiological processes. The effects of adenosine are mediated through specific G-protein coupled cell surface receptors, named A1, A2A, A2B and A3 adenosine receptors (ARs). It is now well recognized that extracellular levels of adenosine markedly increase under metabolically stressful conditions and in the last two decades it has become clear that adenosine is a mediator involved in the pathogenesis of lung inflammatory disorders and in cancer. Indeed adenosine induces bronchoconstriction in animal models and in patients with airway diseases such as asthma and chronic obstructive pulmonary diseases (COPD). COPD is defined as an inflammatory respiratory disease, largely caused by exposure to tobacco smoke. The disease is characterized by a progressive and incompletely reversible airflow obstruction. The key elements of COPD are exposure to cigarette smoke, airway inflammation, and airflow obstruction that is not fully reversible. In addition, an high concentration of adenosine have been reported in cancer tissues, where it appears to be implicated in the growth of tumors, and in the regulation of cell death and proliferation. The development of pleural-based abnormalities such as malignant pleural mesothelioma (MPM), is caused by inhalation of asbestos fibers. To study the interaction between adenosine and pulmonary diseases, the presence and functionality of ARs were explored in human healthy subjects in comparison with COPD patients by using lung tissues and bronchoalveolar lavage (BAL). The aim of this study was to investigate the expression, affinity and density of ARs in peripheral lung parenchyma and in BAL from age-matched smokers with COPD and smokers with normal lung function. The data, obtained in lung samples from COPD patients, suggest a downregulation of A2BARs and an upregulation of A2A and A3ARs. A correlation among ARs expression and clinical parameters such as FEV1/FVC ratio, an established index of airflow obstruction, was observed. Moreover the subcellular location of A2BARs in BAL macrophages of patients with COPD and healthy smokers was investigated, revealing a significant decrease in A2BARs expression in BAL from COPD patients compared to an age-matched group of control smokers with normal lung function. This reduction was associated with a decrease in A2BARs mRNA expression, suggesting a regulation at the transcriptional level. ARs were also studied in MPM patients by using membranes or primary cultures from pleura of MPM patients in comparison with healthy tissues or cells. Furthermore, to better understand the interaction between adenosine and MPM, the presence and the functionality of ARs were explored in healthy mesothelial cells (HMC) and malignant mesothelioma cells (MMC). ARs were analyzed by using RT-PCR, western blotting and saturation binding assays. HMC were treated with crocidolite asbestos, which is the principal risk factor of MPM. The dual effect of ARs stimulation on healthy and cancer cell growth was studied by means of proliferation, apoptosis and cytotoxicity assays. The main result was that A3ARs were up-regulated in MPM when compared with healthy mesothelial pleura. Stimulation of A3ARs decreases proliferation and exerts cytotoxic and pro-apoptotic effect on MMC and on HMC exposed to asbestos and TNF-�, but not in control HMC. These data support the potential for modulating ARs function in pulmonary diseases such as inflammation and cancer. In particular, the modulation of A2BARs by using selective antagonists in alveolar macrophages as a new potential pharmacological tool could be used in the COPD disease. Moreover, the stimulation of A3ARs by selective agonists could be involved as novel pharmacological treatment for malignant pleural mesothelioma.

Malignant pleural mesothelioma is a rare malignancy with a dismal prognosis. The clinical management of most of the patients with this disease is quite challenging, and, overall, the therapeutic strategy has not yet benefited from the recent advances in molecular biology. Randomized evidence supports the use of cisplatin in combination with pemetrexed or raltitrexed as first-line treatments. In elderly patients with comorbidities cisplatin may be replaced by carboplatin because of a lesser burden of toxicities. The role of second-line chemotherapy is unproven, although pemetrexed can be regarded as the standard option in pemetrexed-naive patients and therapeutic rechallenge with pemetrexed may be considered in selected patients with prolonged disease control after first-line therapy. Targeted therapies failed to demonstrate any substantial activity; however, immunotherapies may complement other treatment strategies. In summary, there is an unmet clinical need and innovative approaches to select new potentially active drugs are highly warranted.

The Lombardy Mesothelioma Register (LMR) collects all incident cases of Malignant Mesothelioma (MM) occurring since January 1, 2000 in residents of the Lombardy Region. For each "possible case" reported to the Registry by Lombardy hospitals, diagnosis is ascertained through examination of clinical records (including histology reports) according to ISPESL Guidelines. For confirmed cases, a standardized questionnaire is administered to the subject or next-of-kin in order to verify the possible sources of asbestos exposure in his/her lifetime. A panel composed of industrial hygienists, occupational health physicians and occupational epidemiologists evaluate asbestos exposure in the workplace and environmental settings. Case ascertainment completeness is routinely verified using other sources such as hospital discharge records and death certificates coded as 163 (ICD IX). In the period 2000-2004, 1563 cases were collected, of whom 887 have been evaluated: the diagnosis was confirmed for 626 (70.6%) 9 out of 887 evaluated cases. The age and gender standardized incidence rate for pleural mesothelioma in the Lombardy Region, in the year 2000 (the only one with completed data), was 2.4 (males 3.7; females 1.4) per 100,000 residents/year The 70.5% of certain and probable MM has an asbestos exposure, in particular the 64.5% of cases has an occupational exposure. The experience gathered over the years by the LMR has allowed to implement an efficient information network among different institutions and health services. In addition practical skills have been gained in processing epidemiological data, a useful tool to address new scientific hypothesis and to plan ad-hoc researches. In our experience the LMR represents a potential resource transferable to the epidemiological surveillance of different occupational tumours (i.e. sino-nasal cancers).

At present biological monitoring of the asbestos formerly exposed workers does not have early biomarkers to assure effective sanitary surveillance for pleural malignant mesothelioma. The research project coordinated by Campania Mesothelioma Registry plans to identify and validate two early biomarkers at gene level (gene expression profiling) and at serum level (SMRP = serum mesothelin-related protein).

Malignant mesothelioma can be considered a rare neoplasm, very aggressive, chemo- and radio-resistant, characterized by high percentage of mortality and precarious quality of life. Surgery, radio- and chemo-therapy must be administered with articulate strategy and with realistic objective of palliation. Our experience can represent a model in this direction: we treated a patient with palliative surgery and following loco-regional and "maintenance" systemic chemotherapy with taxol at minimal efficacious dosage (135 mg/m2 every 3 weeks). After 27 months the patient is alive and with a good quality of life. Malignant mesothelioma can be considered a rare neoplasm, very aggressive, chemo- and radio-resistant, characterized by high percentage of mortality and precarious quality of life. Surgery, radio- and chemo-therapy must be administered with articulate strategy and with realistic objective of palliation. Our experience can represent a model in this direction: we treated a patient with palliative surgery and following loco-regional and 'maintenance' systemic chemotherapy with Taxol at minimal efficacious dosage (135 mg/m2 every 3 weeks). After 27 months the patient is alive and with a good quality of life.

This paper describes methods and results of the Piedmont Malignant Mesothelioma Registry. The Registry is active since 1990 and collects all histologically confirmed incident cases of malignant mesothelioma (m.m.) occurring in the residents of Piedmont. In the period 1990-95, 346 cases of pleural m.m. (211 males and 135 females) and 41 (28 males and 13 females) of peritoneal m.m. have been observed. Amongst the inhabitants of the Local Health Authority of Casale Monferrato, where manufacturing of cement asbestos has determined serious asbestos exposures both in the work place and general environment, there have been 105 pleural m.m. and 17 peritoneal m.m. (incidence rate were 15.6 for men and 13.0 for women and 3.6 for men and 0.6 for women respectively). Leaving out the Local Health Authority (LHA) of Casale Monferrato, the annual incidence rate in Piedmont (for 10(5) person-years, age standardised on the 1981 Italian population), has been 1.0 in men and 0.6 in women for the pleural m.m. (respectively 154 and 87 cases) and 0.09 and 0.06 for peritoneal m.m. (14 and 10 cases). Possible cases of m.m. (cytological and/or x-ray diagnosis) have been searched in the file of hospital admission and discharges (SDO) in 1994-95: 46 additional cases were found, with a 25% increase in incidence rates. The analysis of incidence according to geographical aggregations (defined according to the LHA borders) has identified, besides some already known important sources of exposures, as Casale Monferrato and the LHA of Lanzo (Balangero mine), other areas with excess of incidence as the LHA's of Galliate and Caluso which show an increased incidence of pleural m.m. in men or Vercelli and Chieri with increased incidence of pleural m.m. in women. These observation deserves further analysis.

Solitary fibrous tumors of the pleura represent a rare clinicopathological entity: 456 cases only have been reported since 1991. A interesting case of solitary fibrous tumor of the pleura is described here, because it turned up in a female patient followed up for a bilateral breast cancer and so with the exact determination of the period of beginning. The complex morphological picture is illustrated in relation to other cases reported in the literature. Immunohistochemical results are stressed, particularly as regards the coexpression of vimentin and desmin without necrosis and the low number of mitosis. As there are no criteria to determine the possible aggressive or malignant behaviour of the tumor, surgical resection of the lesion is indispensable both to resolve the diagnosis and to carry out the only proposable therapy.

We describe the cytohistological, immunohistochemical and ultrastructural findings in a 55-yr-old-man with history of asbestos exposure and diffuse malignant mesothelioma (DMM) of the pleura, peritoneum, and tunica vaginalis presenting with chest pain and scrotal swelling. Pleural fine-needle aspiration (FNA) revealed mesenchymal elements and spindle-shaped epithelial-like cells, while biopsy showed pure sarcomatous tumor invading lung parenchymal. In both samples tumor cells coexpressed cytokeratin and vimentin. Peritoneal and hydrocele effusions contained aggregates of malignant mesothelial cells. Electron microscopy showed intermediate filaments, rare desmosomes and sparse microvilli. Morphological findings were consistent with a DMM, with a biphasic pattern in the pleura and an epithelial one in the peritoneum and tunica vaginalis. Although the possibility of a multicentric origin cannot be ruled out, clinical chronologic sequence suggests that the pleura was the primary involved site, followed by spread to peritoneum and tunica vaginalis.

A 60-year-old man with a large pericardial effusion was found to have a large intrapericardial mass located anteriorly to the right ventricle and firmly attached to the ascending aorta and pulmonary trunk. Histologically the mass, which was completely excised together with its large base of implant, was found to be a Solitary Fibrous Tumor. After a 46-months follow-up the patient is free from symptoms and signs of recurrence. Solitary Fibrous Tumor is considered a benign tumor and its excision curative, however aggressive variants and metastasis have been reported. Patternless architecture, fibrous collagenous stroma, exclusive vimentin positivity and the lack of ultrastructural mesothelial markers are important tools for the diagnosis. Because of the extreme rarity of intrapericardial location and lack of information on long-term behaviour of this tumor, close non-invasive follow-up is necessary.

The authors report 4 cases of patients with benign fibrous mesothelioma of the pleura, an extremely rare pathology (not more than 500 cases reported to date in the literature), and discuss biological behaviour, diagnosis and surgical treatment. Benign fibrous mesothelioma is generally diagnosed by chance during chest x-ray given that it is paucisymptomatic; diagnostic procedures include thoracic CT (which may be supplemented by transthoracic needle biopsy) and bronchoscopy. Treatment is surgical and consists of exeresis of the neoplasia; prognosis is excellent and cases are reported in the literature of 24-year follow-up without recurrence. Lastly, the authors underline the importance of modern immunohistochemical techniques which help the surgeon to formulate a precise diagnosis and to differentiate benign fibrous mesothelioma.

Population survival studies are usually carried out within population-based cancer registries and are useful mainly for geographical and temporal survival comparisons. Survival studies based on clinical series of patients are traditionally executed to evaluate the efficacy of a given treatment or to analyze the prognostic role of clinical factors. Subjects from a case-control study on incidence of larynx and hypopharynx cancers in Turin, for the period 1979-82, were followed-up in order to study their survival. The analysis was based on 347 cases of larynx cancer (319 males and 28 females) and 48 cases of hypopharynx cancer (47 males and 1 female). For larynx cancer, observed five-years survival was 59% in males and 64% in females. Hypopharynx cancer had a worse prognosis (21%). In males suffering from larynx cancer, older age, extent of spread, birth in Northern Italy, and being unmarried proved to be statistically significant negative prognostic factors. The same variables were also predictive of survival for hypopharynx cancer. The one- and three-year relative survival for larynx cancer in Turin was higher than that reported by other cancer registries. For males, relative five-year survival figures range from 47% to 65%. Survival for hypopharynx cancer is considerably lower, five-year figures ranging from 13% to 35%. The survival study on lung cancer was based on all the incident cases recorded by the Lombardy Cancer Registry (L.C.R.) from 1976 to 1981; during this period there were 2042 cases of primary lung cancers occurred in males and 217 in females. Observed survival at one, three and five years from diagnosis was 29%, 8% and 5%, respectively. Survival decreased with increasing age; no important differences between sexes are evident. Information on tumor stage was available in 1904 cases and histotype was known in 1605. Three-year survival was 17% for localized tumors, 8% for tumors with regional metastasis, and 1% for tumours with distant metastasis. Epidermoid carcinomas had a better prognosis than non-epidermoid carcinomas in the first year of follow-up, survival being 38% and 29%, respectively; among non-epidermoid carcinomas the worst prognosis was for small-cell carcinomas. Comparisons between the LCR relative survival and that reported by other cancer registries did not show important differences, five-year figures ranging from 5% to 10% in males.(ABSTRACT TRUNCATED AT 400 WORDS)

The difficulty involved in the diagnosis of primary pleural neoplasms (mesotheliomas) in described. Personal experience with assays of certain chemicals is the pleural fluid is reported with evidence of the value of pH, glucose and CEA as indications of malignity.