Epidemiological research as a driver of prevention: the Sibaté study. Commentary.

Although asbestos exposure and risks can be prevented, only five countries in Latin America have banned asbestos, including Colombia. Beginning in 2011, a collaboration between the Istituto Superiore di Sanità in Italy and Universidad de los Andes in Colombia was established, bringing together relevant expertise aiming to improve our understanding of the asbestos problem. An important result of this collaboration was a recently published study conducted in Sibaté, Colombia, a municipality where an asbestos-cement facility has operated since 1942. The evidence collected suggests the presence of a mesothelioma cluster in Sibaté. Landfilled zones with an underground layer of friable asbestos were also discovered in the urban area of the municipality. The importance of this type of collaboration can go beyond understanding the impact of asbestos at the local level, which is crucial, and may also contribute in solving unanswered questions of the problem in countries that banned asbestos decades ago.

[Possible health risks from asbestos in drinking water]. / Rischio clinico da ingestione di fibre di amianto in acqua potabile.

The recent finding of asbestos fibres in drinking water (up to 700.000 fibres/litres) in Tuscany (Central Italy) leads to concerns about health risks in exposed communities. Exposure to asbestos has been linked with cancer at several levels of the gastrointestinal tract, and it has been documented, in an animal model, a direct cytotoxic effect of asbestos fibres on the ileum. It has been recently described a possible link between asbestos and intrahepatic cholangiocarcinoma, and asbestos fibres have been detected in humans in histological samples from colon cancer and in gallbladder bile. Taken together, these findings suggest the possibility of an enterohepatic translocation of asbestos fibres, alternative to lymphatic translocation from lungs. In animal models, asbestos fibres ingested with drinking water act as a co-carcinogen in the presence of benzo(a) pyrene and, according to the International Agency for Research on Cancer (IARC ), there is evidence pointing to a causal effect of ingested asbestos on gastric and colorectal cancer. The risk seems to be proportional to the concentration of ingested fibres, to the extent of individual water consumption, to exposure timing, and to the possible exposure to other toxics (i.e., benzo(a)pyrene). Furthermore, the exposure to asbestos by ingestion could explain the epidemiological finding of mesothelioma in subjects certainly unexposed by inhalation. In conclusion, several findings suggest that health risks from asbestos could not exclusively derive from inhalation of fibres. Health hazards might also be present after ingestion, mainly after daily ingestion of drinking water for long periods. In Italy, a systemic assessment of the presence of asbestos fibres in drinking water is still lacking, although asbestos-coated pipelines are widely diffused and still operating. Despite the fact that the existence of a threshold level for health risks linked to the presence of asbestos in drinking water is still under debate, the precautionary principle should impose all possible efforts in order to revise health policies concerning this topic, and a systematic monitoring of drinking water to quantify the presence of asbestos is certainly needed in all regions. Further epidemiological studies aimed to the identification of exposed communities and to an adequate health risk assessment in their specific geographical areas are urgently needed.

[National epidemiological surveillance systems of mesothelioma cases]. / I sistemi nazionali di sorveglianza dei casi di mesotelioma.

INTRODUZIONE: sebbene la relazione causale tra esposizione ad amianto e malattie neoplastiche sia ben nota, in molti Paesi il consumo del materiale è ancora rilevante e crescente. A causa della lunga latenza, nei Paesi dove è stato bandito (come in Italia) è oggi in corso un'epidemia di malattie correlate ad amianto. OBIETTIVI: descrivere i sistemi di sorveglianza dei mesoteliomi attivi nel mondo mediante un'analisi comparativa. METODI: è stata condotta una revisione bibliografica della letteratura disponibile sui sistemi di sorveglianza epidemiologica dei mesoteliomi attivi nel mondo, comparando metodi e risultati disponibili. RISULTATI: sistemi di ricerca dei casi incidenti e di analisi anamnestica dei soggetti ammalati sono attivi solo in Italia, Francia e Corea del Sud. I Paesi presso i quali sono attivi sistemi di rilevazione e controllo dei casi incidenti di mesotelioma sono quelli in cui vige il bando dell'amianto e che hanno sperimentato consumi rilevanti in passato. Non sono stati istituiti sistemi epidemiologici di sorveglianza in molti Paesi dove il consumo di amianto è ancora importante (inclusi Russia, Cina, India e Brasile). CONCLUSIONI: si conferma l'importanza dei sistemi di sorveglianza epidemiologica dei mesoteliomi per la sanità pubblica, il sostegno alle politiche di welfare e la prevenzione dei rischi. Lo sviluppo di progetti per tendere a una maggiore uniformità nei metodi di ricerca dei casi, di classificazione delle diagnosi e dell'esposizione e nelle tecniche di analisi dei dati potrebbe consentire una maggiore fruibilità dei dati aggregati. La disponibilità di dati internazionali confrontabili può essere di stimolo all'adozione di provvedimenti di bando internazionale.

Inhibition of PAI-1 Limits Tumor Angiogenesis Regardless of Angiogenic Stimuli in Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor that secretes various angiogenic factors. The main inhibitor of plasminogen activators, PAI-1 (SERPINE1), has been implicated in tumor progression and angiogenesis, and high PAI-1 expression has been associated with poor prognosis in MPM patients. In this study, we examined the antiangiogenic effects of PAI-1 inhibition in MPM. We administered the PAI-1 inhibitor, SK-216, to orthotopic mouse models in which MPM cells expressing high levels of VEGF (VEGFA) or bFGF (FGF2) were intrapleurally transplanted. SK-216 administration reduced tumor weights and the degree of angiogenesis in intrapleural tumors, irrespective of their angiogenic expression profiles. In addition, a combination of SK-216 and the chemotherapeutic agent cisplatin significantly reduced tumor weights compared with monotherapy, prolonging the survival of animals compared with cisplatin treatment alone. Furthermore, SK-216 inhibited migration and tube formation of cultured human umbilical vein endothelial cells induced by various angiogenic factors known to be secreted by MPM. These findings suggest that PAI-1 inactivation by SK-216 may represent a general strategy for inhibiting angiogenesis, including for the treatment of MPM. Cancer Res; 76(11); 3285-94. ©2016 AACR.

Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention.

INTRODUCTION: Histological diagnosis of malignant mesothelioma requires an invasive procedure such as CT-guided needle biopsy, thoracoscopy, video-assisted thorascopic surgery (VATs) or thoracotomy. These invasive procedures encourage tumour cell seeding at the intervention site and patients can develop tumour nodules within the chest wall. In an effort to prevent nodules developing, it has been widespread practice across Europe to irradiate intervention sites postprocedure--a practice known as prophylactic irradiation of tracts (PIT). To date there has not been a suitably powered randomised trial to determine whether PIT is effective at reducing the risk of chest wall nodule development. METHODS AND ANALYSIS: In this multicentre phase III randomised controlled superiority trial, 374 patients who can receive radiotherapy within 42 days of a chest wall intervention will be randomised to receive PIT or no PIT. Patients will be randomised on a 1:1 basis. Radiotherapy in the PIT arm will be 21 Gy in three fractions. Subsequent chemotherapy is given at the clinicians' discretion. A reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy 6 months after randomisation would be clinically significant. All patients will be followed up for up to 2 years with monthly telephone contact and at least four outpatient visits in the first year. ETHICS AND DISSEMINATION: PIT was approved by NRES Committee North West-Greater Manchester West (REC reference 12/NW/0249) and recruitment is currently on-going, the last patient is expected to be randomised by the end of 2015. The analysis of the primary end point, incidence of chest wall nodules 6 months after randomisation, is expected to be published in 2016 in a peer reviewed journal and results will also be presented at scientific meetings and summary results published online. A follow-up analysis is expected to be published in 2018. TRIAL REGISTRATION NUMBER: ISRCTN04240319; NCT01604005; Pre-results.

Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis.

Few people expected that asbestos, a fibrous mineral, would be carcinogenic to humans. In fact, asbestos is a definite carcinogen in humans, causing a rare but aggressive cancer called malignant mesothelioma (MM). Mesothelial cells line the three somatic cavities and thus do not face the outer surface, but reduce the friction among numerous moving organs. MM has several characteristics: extremely long incubation period of 30-40 years after asbestos exposure, difficulty in clinical diagnosis at an early stage, and poor prognosis even under the current multimodal therapies. In Japan, 'Kubota shock' attracted considerable social attention in 2005 for asbestos-induced mesothelioma and, thereafter, the government enacted a law to provide the people suffering from MM a financial allowance. Several lines of recent evidence suggest that the major pathology associated with asbestos-induced MM is local iron overload, associated with asbestos exposure. Preclinical studies to prevent MM after asbestos exposure with iron reduction are in progress. In addition, novel target genes in mesothelial carcinogenesis have been discovered with recently recognized mesothelioma-prone families. Development of an effective preventive strategy is eagerly anticipated because of the long incubation period for MM.

Post-occupational health surveillance of asbestos workers.

BACKGROUND: Italian law requires an extensive health surveillance of workers after cessation of their employment status in the case of occupational exposure to carcinogens, including asbestos. Nonetheless, Italian law does not specify the timeframe of these clinical checks, nor who has financial and organizational responsibility for this surveillance. A literature search confirmed a lack of consensus around the objectives and methods to follow up workers with past occupational exposure to asbestos. OBJECTIVES: To develop an updated evidence-based methodology for an appropriate health surveillance programme. METHODS: We present an overview of the field experience developed by the Veneto Region from 2000 to 2011, and new studies that could contribute to establishing a national policy for the medical surveillance of workers with past asbestos exposure. RESULTS: There were three specific topics: (1) definition of a reliable method to identify asbestos workers (through multiple sources and procedures that meet current confidentiality regulations); (2) detection of asbestos fibres in biological media (to support the etiological diagnosis of asbestos-related diseases); (3) creation of a national protocol of health surveillance (through the assessment of policies developed by other Regions in this field, and recruiting from these regions a cohort of past-exposed workers: the epidemiological study should offer relevant suggestions for specific surveillance approaches, based on either estimated cumulative asbestos exposure or detection of x-ray patterns of pleural plaques and/or asbestosis). CONCLUSIONS: These studies will support the Regions in setting up health care policies directed at workers with past asbestos exposure.

[Epidemiological and occupational medicine aspects of pleural mesothelioma]. / Epidemiologie und arbeitsmedizinische Aspekte des Pleuramesothelioms.

Malignant mesothelioma of the pleura represents a signal tumour for (occupational) exposure to asbestos. Almost 20 years after the ban of asbestos in Germany, incident cases are still occurring due to the long latency period between the initial exposure to asbestos and the onset of the tumour. Of particular interest is the development of mesothelioma epidemiology. In Germany, it is extensively discussed whether the incidence of malignant pleura mesothelioma continues to rise, has already reached a plateau or is expected to decline in the next few years. The development is predominantly caused by the total asbestos use, its application and the gradual substitution of asbestos. The prevention of asbestos-related diseases due to former exposures, but also due to existing asbestos contaminations and their restoration is still a hot topic in occupational medicine. It is thus of major importance to ensure an adequate occupational safety and to care for asbestos-exposed workers - even after cessation of their exposure - with effective and efficient measures of early detection. New technologies, such as nanotechnology with carbon nanotubes, represent new potential health hazards.

[Epidemiologic surveillance of mesothelioma for the prevention of asbestos exposure also in non-traditional settings]. / Sorveglianza epidemiologica dei mesoteliomi per la prevenzione dell'esposizione ad amianto anche in attività non tradizionalmente coinvolte.

OBJECTIVE: To show how malignant mesothelioma (MM) surveillance not only identifies settings of exposure representing past industrial history, but it may also detect conditions of current exposure relevant for the prevention, if the wide spectrum of asbestos uses is considered. DESIGN: Active search of MM cases and exposure assessment at individual level through a questionnaire; identification of exposure circumstances relevant for prevention. SETTING AND PARTICIPANTS: Italy, all the Regions where a Regional Operating Centre (COR) is established to identify all MM cases diagnosed in the population and analyze their occupational, residential, household and environmental histories. Period of diagnosis: 1993-2008. MAIN OUTCOME MEASURES: Descriptive analysis of MM cases and of asbestos exposures. RESULTS: ReNaM includes 15,845 cases of MM diagnosed between 1993 and 2008.The male/female ratio is 2.5. Mean age at diagnosis is 69 years. Pleural MMs represent 93% of all cases. Exposures have been investigated in 12,065 cases (76%). The median latency time is 46 years. In addition to clusters of MM cases in activities well known to entail asbestos use, different current exposure circumstances requiring intervention have been evidenced. CONCLUSIONS: On the basis of this experience, epidemiological surveillance of all occupational cancers should be implemented to foster synergies with the compensation system and the Local Health Authorities' occupational safety and health services, as required by the Italian Legislative Decree N. 81/2008.

Tissue factor pathway inhibitor attenuates the progression of malignant pleural mesothelioma in nude mice.

Malignant pleural mesothelioma (MPM) is a rare cancer that is refractory to current treatments. It is characterized by a robust deposition of transitional fibrin that is in part promoted by tumor cells. MPM cells express tissue factor (TF) and the tissue factor pathway inhibitor (TFPI), but their contribution to the pathogenesis of MPM has been unclear. We found that REN MPM cells fail to express TFPI. Based on the tumor growth-promoting properties of TF, we hypothesized that the stable transfection of TFPI into REN MPM cells would decrease their aggressiveness. We tested our hypothesis using in vitro, in vivo, and ex vivo analyses. TFPI knock-in decreased the proliferation, invasion, and TF activity of REN cells in vitro. REN TFPI knock-in cells, empty vector, and naive control cells were next injected intrapleurally into nude mice. The expression of TFPI significantly decreased tissue invasion, inflammation, and the deposition of fibrin and collagen associated with tumor tissue, pleural effusions, and tumor burden. In ex vivo analyses, REN cells were cultured from harvested tumors. The overexpression of TFPI was maintained in cells propagated from TFPI knock-in tumors, and attenuated the activation of Factor X and the invasiveness of tumor cells. These analyses demonstrate that TFPI reduces the aggressiveness of MPM in vitro and in vivo, and that its effect involves the inhibition of TF procoagulant activity. These observations suggest that the interactions of TF and TFPI represent a novel therapeutic target in the treatment of MPM.

Increasing incidence of malignant mesothelioma after exposure to asbestos during home maintenance and renovation.

OBJECTIVE: To determine trends in incidence of malignant mesothelioma (MM) caused by exposure to asbestos during home maintenance and renovation. DESIGN, SETTING AND PARTICIPANTS: Using the Western Australian Mesothelioma Register, we reviewed all cases of MM diagnosed in WA from 1960 to the end of 2008, and determined the primary source of exposure to asbestos. Categories of exposure were collapsed into seven groups: asbestos miners and millers from Wittenoom; all other asbestos workers; residents from Wittenoom; home maintenance/renovators; other people exposed but not through their occupation; and people with unknown asbestos exposure; or no known asbestos exposure. Latency periods and age at diagnosis for each group were calculated and compared. RESULTS: In WA, 1631 people (1408 men, 223 women) were diagnosed with MM between 1960 and 2008. Since 1981, there have been 87 cases (55 in men) of MM attributed to asbestos exposure during home maintenance and renovation, and an increasing trend in such cases, in both men and women. In the last 4 years of the study (2005-2008), home renovators accounted for 8.4% of all men and 35.7% of all women diagnosed with MM. After controlling for sex and both year and age at diagnosis, the latency period for people exposed to asbestos during home renovation was significantly shorter than that for all other exposure groups, but the shorter follow-up and difficulty recalling when exposure first occurred in this group may partly explain this. CONCLUSIONS: MM after exposure to asbestos during home renovation is an increasing problem in WA, and these cases seem to have a shorter latency period than other types of exposure. MM cases related to renovation will probably continue to increase because of the many homes that have contained, and still contain, asbestos building products.

Carbon nanotubes and pleural damage: perspectives of nanosafety in the light of asbestos experience.

Carbon nanotubes are molecular-scale one-dimensional manufactured materials which display several potential applications in engineering and materials science. Burgeoning evidence demonstrates that carbon nanotubes and asbestos share comparable physical properties. Therefore carbon nanotubes might display toxic effects and the extent of the toxicity is more specifically directed to lung and pleura. These effects are related to properties of carbon nanotubes, such as their structure, length, aspects ratio, surface area, degree of aggregation, extent of oxidation, bound functional group, method of manufacturing, concentration and dose. At the present there is no global agreement about the risk of carbon nanotubes on human health and in particular on their transformation capacity. Safety concerns regarding carbon nanotubes can be ameliorated. In this context, it is important to put the known hazards of carbon nanotubes into perspective. Here is presented an overview about toxicity issues in the application of carbon nanotubes to biological systems, taking into consideration the already known asbestos-induced mechanisms of biological damages.