Zhong J, Lardinois D, Szilard J, Tamm M, Roth M.

Pulmonary Cell Research, Department Biomedicine, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.

Abstract

Pleural malignant mesothelioma is a rare but deadly tumour mainly induced by asbestos inhalation. Despite the ban of asbestos in 1990 in 52 countries, mesothelioma cases still increase worldwide. In pleural mesothelioma, p38 mitogen activated protein kinases (MAPK) have been suggested to play a major role in carcinogenesis and aggressiveness of tumours. The aim of this study was to determine the role of the different four p38 MAPK isoforms and their effect on proliferation together with the underlying signalling pathways in a rat pleural mesothelioma cell line. Rat pleural mesothelioma cells were stimulated with platelet-derived growth factor (PDGF)-BB and/or transforming growth factor beta (TGF)-β. MAPK and transcription factor expression and activation was monitored in the cytosol and nucleus by immuno-blotting. Proliferation was determined by manual cell count and siRNAs were used to control MAPK and transcription factor expression and action. Only PDGF-BB, but not TGF-β1 induced proliferation via activated Erk1/2 and p38 MAPK. The p38α and δ isoforms were expressed in the cytosol, and upon activation p38δ translocated into the nucleus, while p38α remained in the cytosol. No other p38 isoform was expressed by rat mesothelioma cells. C/EBP-α was found in both the cytosol and the nucleus, while C/EBP-β was not expressed at all. PDGF-BB induced proliferation was suppressed by down-regulation of either Erk1/2, or p38δ MAPK, or C/EBP-α. Furthermore, TGF-β inhibited PDGF-BB induced proliferation by interruption of p38 MAPK signalling. From this rat model, we conclude that in pleural mesothelioma, p38δ in C/EBP-α mediate proliferation and thus may represent new targets in mesothelioma therapy.

Murali R, Park K, Leslie KO.

Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York.

Abstract

A wide variety of local, regional, and systemic diseases may have pleural manifestations. The scope of this pathology encompasses a wide spectrum ranging from minimal inflammatory changes to highly malignant neoplasms. An overview of the normal structure of the pleura is provided, along with the diseases that may be encountered. Pleural specimens from patients with pneumothorax are rarely encountered by pathologists. In contrast, pathologists frequently receive pleural specimens showing evidence of inflammation, repair, or neoplasm. In these circumstances, an awareness of less common (and often clinically highly important) conditions such as epithelioid hemangioendothelioma and primary pleural malignant mesothelioma is essential. Knowledge of the clinical setting (e.g., disease tempo) and radiological picture (e.g., laterality) is often of great value to the pathologist in arriving at a correct diagnosis. Similarly, knowledge of the normal anatomical considerations and familiarity with the expected pleural histopathology for the most clinically relevant pleural diseases are critical assets for pulmonary physicians in providing optimal care for their patients.

Keywords: Pleura – pathology – disease – infection – neoplasms – mesothelioma

Christensen BC, Houseman EA, Godleski JJ, Marsit CJ, Longacker JL, Roelofs CR, Karagas MR, Wrensch MR, Yeh RF, Nelson HH, Wiemels JL, Zheng S, Wiencke JK, Bueno R, Sugarbaker DJ, Kelsey KT.

Department of Community Health, Center for Environmental Health and Technology, Brown University, 70 Ship Street, Providence, RI 02903, USA.

Abstract

Mechanisms of action of nonmutagenic carcinogens such as asbestos remain poorly characterized. As pleural mesothelioma is known to have limited numbers of genetic mutations, we aimed to characterize the relationships among gene-locus-specific methylation alterations, disease status, asbestos burden, and survival in this rapidly fatal asbestos-associated tumor. Methylation of 1505 CpG loci associated with 803 cancer-related genes were studied in 158 pleural mesotheliomas and 18 normal pleura. After false-discovery rate correction, 969 CpG loci were independently associated with disease status (Q < 0.05). Classifying samples based on CpG methylation profile with a mixture model approach, methylation classes discriminated tumor from normal pleura (permutation P < 0.0001). In a random forests classification, the overall misclassification error rate was 3.4%, with <1% (n = 1) of tumors misclassified as normal (P < 0.0001). Among tumors, methylation class membership was significantly associated with lung tissue asbestos body burden (P < 0.03), and significantly predicted survival (likelihood ratio P < 0.01). Consistent with prior work, asbestos burden was associated with an increased risk of death (hazard ratio, 1.4; 95% confidence interval, 1.1-1.8). Our results have shown that methylation profiles powerfully differentiate diseased pleura from nontumor pleura and that asbestos burden and methylation profiles are independent predictors of mesothelioma patient survival. We have added to the growing body of evidence that cellular epigenetic dysregulation is a critical mode of action for asbestos in the induction of pleural mesothelioma. Importantly, these findings hold great promise for using epigenetic profiling in the diagnosis and prognosis of human cancers.

Moore AJ, Parker RJ, Wiggins J.

Department of Respiratory Medicine, Wexham Park Hospital, Wexham, Slough, Berkshire, UK. a.moore@ic.ac.uk

Abstract

Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10-20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational “environmental” exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis.

Tan BH, Kostapanagiotou K, Jilaihawi AN.

Department of Thoracic Surgery, Hairmyres Hospital, East Kilbride, Scotland, United Kingdom. benjamin.tan@ed.ac.uk

Abstract

Introduction: The Internet is a widely used information resource for patients with mesothelioma. The goal of this study is to assess the content and quality of mesothelioma information presented on the internet using Google as a search engine, as well as to test the hypothesis that more popular sites (i.e., higher Google rank) are of higher quality.

Methods: The top 100 websites appearing in Google using the terms “mesothelioma” were included in the study. Websites were evaluated using (a) JAMA benchmarks (authorship, references, currency, and disclosure), and (b) an Information score (IS) that awarded websites points (0-100) for specific information on various aspects of mesothelioma.

Results: Of the top 100 websites identified, 84 websites were suitable for scoring. Only 5 (6.0%) sites met all 4 criteria of the JAMA benchmarks. The mean IS was 23.8 (range, 0-86). There was a weak but significant positive correlation with Google ranking of websites and IS (r = 0.275, p = 0.006).

Conclusions: There is marked variation in the quality, integrity, and currency of the information in educational websites for mesothelioma patients. Google ranking has shown a weak but significant positive correlation to the quality of medical information relating to mesothelioma.

Park EK, Hannaford-Turner KM, Hyland RA, Johnson AR, Yates DH.

Research and Education Unit, Workers’ Compensation Dust Diseases Board of NSW, Sydney, Australia.

Abstract

Asbestos is a fibrous silicate which is recognized as causing a variety of lung disorders including malignant mesothelioma of the pleura, lung cancer and asbestosis. Asbestos use has been banned in most developed countries but exposure still occurs under strict regulation in occupational settings and also occasionally in domestic settings. Although the hazards of asbestos are well known in developed countries, awareness of its adverse health effects is less in other parts of the world, particularly when exposure occurs in non-occupational settings. Experience of asbestos use and its adverse heath effects in developed countries such as Australia have resulted in development of expertise in the diagnosis and treatment of asbestos-related diseases as well as in screening and this can be used to help developing countries facing the issue of asbestos exposure.

Keywords: Asbestos, Mesothelioma, Asbestos-related diseases, Occupational exposure, Public health

Ugolini D, Neri M, Canessa PA, Casilli C, Catrambone G, Ivaldi GP, Lando C, Marroni P, Paganuzzi M, Parodi B, Visconti P, Puntoni R, Bonassi S.

Department of Oncology, Biology and Genetics, University of Genoa, National Cancer Research Institute, Largo R. Benzi, 10-16132 Genoa, Italy. donatella.ugolini@istge.it

Abstract

Objectives: The Cancer of RESpiratory Tract (CREST) biorepository was established to investigate biological mechanisms and to develop tools and strategies for primary and secondary prevention of respiratory tract cancer. The CREST biorepository is focused on pleural malignant mesothelioma, a rare and severe cancer linked to asbestos exposure whose incidence is particularly high in the Ligurian region.

Methods: The CREST biorepository includes biological specimens from (a) patients with pleural malignant mesothelioma and lung cancer, (b) patients with nonneoplastic respiratory conditions, and (c) control subjects. Whole blood, plasma, serum, lymphocytes, pleural fluid, saliva, and biopsies are collected, and a questionnaire is administered. Collection, transportation, and storage are done according to international standards.

Results: As of January 31, 2008, the overall number of subjects recruited was 1,590 (446 lung cancer, 209 pleural malignant mesothelioma, and 935 controls). The biorepository includes a total of 10,055 aliquots (4,741 serum; 3,082 plasma; 1,599 whole blood; 633 pleural fluid; and 561 lymphocytes) and 107 biopsies. Demographic, clinical, and epidemiologic information is collected for each subject and processed in a dedicated database.

Conclusions: The CREST biorepository is a valuable tool for molecular epidemiology and translational studies. This structure relies on a network of contacts with local health districts that allows for an active search for patients. This is a particularly efficient approach, especially when the object of the study is a rare cancer type. The CREST experience suggests that the presence of limited resources can be overcome by the biorepository specialization, the high quality of the epidemiologic information, and the variety of samples.

Teta MJ, Mink PJ, Lau E, Sceurman BK, Foster ED.

Exponent Inc., Health Sciences Practice, New York, New York, USA. jteta@exponent.com

Abstract

Mesothelioma rates are declining toward background levels, although estimates of the background rate have varied. We expanded upon earlier analyses and provided a data-based estimate of the background rate. We analyzed US male and female patterns for five age groups using the National Cancer Institute’s Surveillance Epidemiology and End Results registry data from 1973 to 2002. Age-specific and age-adjusted incidence rates per 1 000 000 persons per year, standardized to the 2000 US population, were calculated for total, pleural, and peritoneal mesothelioma. We also calculated rates for persons who attained working age after the US Occupational Safety and Health Administration asbestos exposure limits took effect. Mesothelioma rates observed among young males and females varied little over time. We observed a decline and convergence of recent male and female rates in older age groups, except those who are between the age of 60 and above, for whom the 2002 male rate was approximately five times greater than that of females. As expected, rates were higher in major shipyard areas on the West coast. Rates for persons with little or no opportunity for occupational asbestos exposure were 1.15 (95% confidence interval: 0.90-1.45) for men and 0.94 (95% confidence interval: 0.87-1.24) for women. Mesothelioma is rare in younger age groups, and rates have been relatively stable and similar for both sexes. Rates continue to decline in older age groups, but remain high for males at 60 years or older. Rates among females at older ages suggest an impact of occupational exposure. The background rate for persons below age 50 is approximately one per million, independent of sex. Future data are needed to estimate this rate for older age groups.

LaMontagne AD, Hunter CE, Vallance D, Holloway AJ.

McCaughey Centre: VicHealth Centre for the Promotion of Mental Health and Community Wellbeing, School of Population Health, University of Melbourne, 207 Bouverie Street, Melbourne, Victoria 3010, Australia. alamonta@unimelb.edu.au

Abstract

This article provides an overview and analysis of recent developments in policy and practice in relation to asbestos disease in Australia. It complements three other concurrent publications in this issue representing important contributions of people and organizations toward addressing the health and social impacts of Australia’s asbestos disease epidemic. The campaign to “Make James Hardie Pay” as well as the efforts of workers and advocates are profiled in this article as well as in this issue’s Documents and Voices sections. Discussion of recent developments in asbestos-related disease research and mesothelioma surveillance is followed by articulation of the comprehensive public and social health response that is needed to fully engage and address the asbestos disease legacy and to apply lessons learned to help revive the currently waning societal commitment to occupational health and safety in Australia and elsewhere.

Moore S, Teehan C, Cornwall A, Ball K, Thomas J.

Royal Marsden NHS Foundation Trust, Downs Road Sutton, Surrey, UK. sally.moore@rmh.nhs.uk

Abstract

Expertise and management of mesothelioma are known to vary throughout the UK. The support needs of people with mesothelioma and their family members are poorly understood and poorly met. Support group participation can contribute to the supportive care of people with cancer and their family members by improving adaptation and reinforcing effective coping strategies. This paper describes the initial experience of establishing a support group for people affected by mesothelioma. The structure and process of developing and running the group are described and the challenges involved are discussed. The findings of a small evaluation of the group are presented.

Keywords: support group, mesothelioma