Identification of a new potential plasmatic biomarker panel for the diagnosis of malignant pleural mesothelioma

Background:Malignant pleural mesothelioma (MPM) is a rare, highly aggressive tumor strongly associated with asbestos exposure and characterized by poor prognosis. Currently, diagnosis is based on invasive techniques; thus, there is a need to identify non-invasive biomarkers to detect the disease. In the present study, we measured the plasmatic concentrations of Mesothelin, Fibulin-3, and HMGB1 protein biomarkers and of hsa-miR-30e-3p and hsa-miR-103a-3p Extracellular-Vesicles- embedded micro RNAs (EV-miRNAs). We tested the ability of these biomarkers to discriminate between MPM and PAE subjects alone and in combination.Methods:The study was conducted on a population of 26 patients with MPM and 54 healthy subjects with previous asbestos exposure (PAE). Mesothelin, Fibulin-3, and HMGB1 protein biomarkers were measured by the enzyme-linked immunosorbent assay (ELISA) technique; the levels of hsa-miR-30e-3p and hsa-miR-103a-3p EV-miRNAs was assessed by real-time quantitative PCR (qPCR).Results:The most discriminating single biomarker resulted to be Fibulin-3 (AUC 0.94 CI 95% 0.88-1.0; Sensitivity 88%; Specificity 87%). After investigating the possible combinations, the best performance was obtained by the three protein biomarkers Mesothelin, Fibulin-3, and HMGB1 (AUC 0.99 CI 95% 0.97-1.0; Sensitivity 96%; Specificity 93%).Conclusions:The results obtained contribute to identifying new potential non-invasive biomarkers for diagnosing MPM. Further studies are needed to validate the evidence obtained to assess the reliability of the proposed biomarker panel.     

Diffuse malignant pleural mesothelioma in an urban hospital: clinical spectrum and trend in incidence over time

This retrospective analysis reviews the clinical experience of a major urban referral hospital with diffuse malignant pleural mesothelioma during the 14-year period from 1973 through 1986. Seventy-five cases of definite or equivocal mesothelioma were identified. There were four cases of primary malignant peritoneal mesothelioma, seven cases of benign fibrous mesothelioma, and 64 cases of diffuse malignant pleural mesothelioma. In 43 cases (67%) of diffuse malignant pleural mesothelioma, there was historic evidence of asbestos exposure. In 21 cases (33%), there was no known history of asbestos exposure. An increase in annual incidence of diffuse malignant pleural mesothelioma was observed over the study period, from three cases in 1973 to ten cases in 1986. Despite greater awareness of this disease, the diagnosis remains a difficult one to establish given the nonspecific symptoms, signs and radiographic appearance, variable histologic appearance, and poor diagnostic sensitivity and specificity of thoracentesis and closed pleural biopsy. Thoracotomy, thoracoscopy, and CT-guided needle biopsies gave higher yields and are the diagnostic measures of choice when diffuse malignant pleural mesothelioma is suspected.     

青石棉污染区恶性胸膜间皮瘤发病危险因素的调查

目的　探讨间皮瘤发病的影响因素 ,以期为间皮瘤的预防及进一步研究发病机制提供流行病学依据。方法　采用 1∶1配比的病例 -对照设计调查了 2 3例间皮瘤病例和对照 ,比较两组间的石棉接触情况、生活方式及一级亲属恶性肿瘤发病情况。结果　病例组平均年龄 5 7.96岁 ,间皮瘤平均潜伏期为 5 2年 ,与对照组相比 ,其石棉接触年龄、接触时间以及吸烟、饮酒习惯的差异均无显著性 (P >0 .0 5 ) ;病例组平均累积石棉纤维接触剂量为 37.2× 10 5f,明显高于对照组 (32 .3× 10 5f) ,差异有显著性 (P =0 .0 0 5 ) ,且随剂量的增高 ,OR值有升高趋势。病例组一级亲属患恶性肿瘤的比例(2 6 .1%)高于对照组 (4 .4%) ,差异有显著性 (P <0 .0 5 ) ,OR =7.75 (95 %CI:0 .85～ 71.43)。结论　石棉接触与间皮瘤发病间可能存在剂量 -效应关系 ;癌家族史可能是间皮瘤的一个危险因素 ,或者在相同的石棉接触水平下可增加个体对间皮瘤的易感性。     

Pleural malignant mesothelioma in Tuscany, Italy (1970-1988): II. Identification of occupational exposure to asbestos.

Following the finding of an unexpected cluster of mesotheliomas in textile workers, a surveillance system of malignant mesotheliomas was implemented in the region of Tuscany, Italy. This article reports on the investigation of 124 cases of mesothelioma diagnosed and reviewed by the Institutes of Morbid Anatomy and Histopathology at the Universities of Florence, Pisa, and Siena between 1970 and 1988. A complete occupational and asbestos exposure history was assessed through a semi-structured questionnaire directly administered to resident cases of Tuscany or, if deceased, to their closest living relatives, for a total of 100 interviews. The hypothesis of past occupational asbestos exposure was verified and documented. Seventy-two cases have been classified as occupationally exposed to asbestos; four were classified in the category of "possible domestic" exposure to asbestos. For two others, the role of other risk factors was stressed, and for 22 cases, either no asbestos exposure was found or the available data were not adequate to define it. The present study allowed identification of some unknown or scarcely known occupational asbestos exposures in the study area.     

Environmental household exposures to asbestos and occurrence of pleural mesothelioma.

We reviewed the certificates of 39,650 deaths which occurred in the period 1975-1988 in Leghorn and of 45,900 in La Spezia (Italy) in the period 1958-1988. In total 262 cases have been recorded as pleural mesothelioma. The main occupational exposures occurred in the shipbuilding industry. Regarding non-occupational exposures to asbestos, 13 cases of mesothelioma were found in women who had washed the work clothes of their relatives at home; we also found other domestic uses of asbestos which were rarely or never discussed previously in the literature: six cases might be explained by the installation of fireproof or non-conductive materials in the domestic environment. These exposures probably are more frequent than realized until now.     

Gallium scanning in differentiating malignant from benign asbestos-related pleural disease

In order to assess the utility of 67gallium citrate in delineating malignant pleural mesothelioma from benign asbestos-related pleural disease, 49 patients with malignant mesothelioma and 16 with benign asbestos-related pleural disease were studied. Seven patients with malignant mesothelioma had no history of asbestos exposure, while the remaining 58 patients were exposed. Forty-three of the 49 patients (88%) with malignant mesothelioma had a positive 67gallium scan including 36 of the 42 (86%) patients with asbestos exposure and all 7 patients without a history of asbestos exposure. Three of 16 patients (19%) with benign asbestos-related pleural disease had a positive scan. 67Gallium radionuclide imaging is nonspecific but may be valuable in noninvasive monitoring of asbestos-exposed populations, which have a high risk for the late development of benign and/or malignant pleural disease.     

Chrysotile asbestos is the main cause of pleural mesothelioma

In contrast to amphibole forms of asbestos, chrysotile asbestos is often claimed to be only a minor cause of malignant pleural mesothelioma, a highly fatal cancer of the lining of the thoracic cavity. In this article we examine the evidence from animal and human studies that relates to this issue. Reported data do not support widely quoted views regarding the relative inertness of chrysotile fibers in mesothelioma causation. In fact, examination of all pertinent studies makes it clear that chrysotile asbestos is similar in potency to amphibole asbestos. Since asbestos is the major cause of mesothelioma, and chrysotile constitutes 95% of all asbestos use world wide, it can be concluded that chrysotile asbestos is the main cause of pleural mesothelioma in humans. © 1996 Wiley-Liss, Inc.     

Pleural mesothelioma after a short interval from first exposure in the wine filter industry

Pleural mesotheliomas are usually reported after a long interval has passed since first exposure to asbestos. We, however, describe a case observed after a latent period of only 7.5 years in a worker exposed in a factory manufacturing auxiliary products for wine treatment, including chrysotile asbestos filters. The exposure to asbestos lasted 3-4 months per year, during which airborne fiber concentrations ranged from 1 to 4 ff/cc in the patient's workplace. Due to the characteristics of the manufacturing process, the asbestos fibers were very thin in diameter. The patient also suffered from nasal breathing impairment. An examination of the literature showed that asbestos-related mesotheliomas have been reported, albeit rarely, after less than 10 years from onset of exposure. Therefore, it is believed that this case should be related to past exposure to asbestos.     

Asbestos-related pleural diseases: dimensional criteria are not appropriate to differentiate diffuse pleural thickening from pleural plaques

BACKGROUND: In the literature, the criteria used to define pleural plaques (PP) and diffuse pleural thickening (DPT) are very heterogeneous and often imprecise. A multicenter restropective study was conducted to assess the relevance of two radiographic definitions of DPT. METHODS: The study population consisted of 287 subjects with asbestos-related pleural thickening. Two definitions were used to characterize DPT on postero-anterior chest radiographs: definition 1: pleural thickening associated with obliteration of the costophrenic angle; definition 2: pleural thickening at least 5 mm wide, extending for more than one quarter of the chest wall. Prevalence of respiratory symptoms and pulmonary function tests were compared in the DPT and PP groups resulting from the two definitions of DPT. RESULTS: According to definition 1, 34 patients (11.8%) were classified in the DPT group. Prevalence of chronic sputum, dyspnea, and chest pain was significantly higher in this group than in the PP group. FEV(1), FVC, and TLC were significantly lower. The differences persisted after adjustment for confounding factors. According to definition 2,102 patients (36.6%) were classified in the DPT group. DPT and PP groups did not differ in terms of prevalence of respiratory symptoms, or pulmonary function tests. Agreement between readers was significantly better when using definition 1. CONCLUSIONS: Obliteration of costophrenic angle is a much more reliable sign than dimensional criteria to characterize DPT.     

Pleural mesothelioma: forecasts of the death toll in the area of Casale Monferrato,Italy

In the city of Casale Monferrato, the largest Italian factory that produced asbestos‐cement goods was active from 1907 to 1985. Consequently, asbestos fibers scattered in the surrounding area and caused an enormous number of cases of pleural mesothelioma. Owing to the very long latency of this disease, many subjects have not exhibited its symptoms yet. The aim of this paper is to model and predict the future evolution of the number of deaths due to this disease among residents in the area around that city. The model used here is based on a cellular automata that is assumed to pass through three steps: exposure, contamination, and diagnosis. In this way, forecasts of the future evolution take into account the environmental conditions that changed over the last century because of different levels of plant activity. The model is fitted to annual diagnosis data from 1954 to 2008. Results show that deaths will not end until 2031 and that in the next two decades, at least 505 more subjects will be diagnosed with this disease. Copyright © 2012 John Wiley & Sons, Ltd.     

Pleural mesothelioma in New Caledonia: associations with environmental risk factors

Background

High incidences of malignant mesothelioma (MM) have been observed in New Caledonia. Previous work has shown an association between MM and soil containing serpentinite.

Objectives

We studied the spatial and temporal variation of MM and its association with environmental factors.

Methods

We investigated the 109 MM cases recorded in the Cancer Registry of New Caledonia between 1984 and 2008 and performed spatial, temporal, and space–time cluster analyses. We conducted an ecological analysis involving 100 tribes over a large area including those with the highest incidence rates. Associations with environmental factors were assessed using logistic and Poisson regression analyses.

Results

The highest incidence was observed in the Houaïlou area with a world age-standardized rate of 128.7 per 100,000 person-years [95% confidence interval (CI), 70.41–137.84]. A significant spatial cluster grouped 18 tribes (31 observed cases vs. 8 expected cases; p = 0.001), but no significant temporal clusters were identified. The ecological analyses identified serpentinite on roads as the greatest environmental risk factor (odds ratio = 495.0; 95% CI, 46.2–4679.7; multivariate incidence rate ratio = 13.0; 95% CI, 10.2–16.6). The risk increased with serpentinite surface, proximity to serpentinite quarries and distance to the peridotite massif. The association with serpentines was stronger than with amphiboles. Living on a slope and close to dense vegetation appeared protective. The use of whitewash, previously suggested to be a risk factor, was not associated with MM incidence.

Conclusions

Presence of serpentinite on roads is a major environmental risk factor for mesothelioma in New Caledonia.     

Localized pleural plaques and lung cancer.

In a mass chest radiography survey conducted in 1971 for 7,986 residents of three Finnish communities, 604 subjects (7.6%) with pleural plaques but not other asbestos-related radiographic signs were identified. The same number of referents, each individually matched to each plaque carrier on sex, birth year, and community, was selected from among persons in the same source population with no pleural plaques. The two groups were followed for investigation of incidence of lung cancer during 1972-1989. Twenty-eight of those with plaques and 25 referents contracted lung cancer (crude conditional RR = 1.1; CL95 = 0.7, 1.9). The application of the proportional hazards model, with adjustment for sex, age, and residence, resulted in a hazard ratio of 1.1 (CL = 0.6, 1.8). The risk ratio estimate may be biased; hence, the result is inconclusive in regard to the predictive assessment of lung cancer risk among carriers of pleural plaques.