The threshold length for fibre-induced acute pleural inflammation: shedding light on the early events in asbestos-induced mesothelioma

• Received February 10, 2012.

Abstract

Suspicion has been raised that high aspect ratio nanoparticles or nanofibres might possess asbestos-like pathogenicity. The pleural space is a specific target for disease in individuals exposed to asbestos and, by implication nanofibres. Pleural effects of fibres depends on fibre length, but the key threshold length beyond which adverse effects occur has never been identified up to now since all asbestos and vitreous fibre samples are heterogeneously distributed in their length. Nanotechnology advantageously allows for highly defined length distribution of synthetically engineered fibres which enable for in depth investigation of this threshold length. We utilised the ability to prepare silver-nanofibres of five defined length classes to demonstrate a threshold fibre length for acute pleural inflammation. Nickel-nanofibres and carbon nanotubes were then used to strengthen the relationship between fibre length and pleural inflammation. A method of intrapleural injection of nanofibres in female C57Bl/6 strain mice was used to deliver the fibre dose and we then assessed the acute pleural inflammatory response. Chestwall sections were examined by light and by scanning electron microscopy to identify areas of lesion; furthermore cell-nanowires interaction on the mesothelial surface of the parietal pleura in vivo, were investigated. Our results showed a clear threshold effect demonstrating that fibres beyond 4 µm in length are pathogenic to the pleura. The identification of the threshold length for nanofibre induced pathogenicity in the pleura has important implications for understanding the structure-toxicity relationship for asbestos-induced mesothelioma and consequent risk assessment with the aim to contribute to the engineering of synthetic nanofibres by the adoption of a benign-by-design approach.

Post Mortem Findings of Malignant Pleural Mesothelioma: A Two-Centre Study of 318 patients

Abstract

Background: Malignant pleural mesothelioma (MPM) is an incurable cancer with a rising incidence. MPM is often perceived as a locally invasive cancer and the exact cause of death is poorly understood.

Aim: This two-centre study describes the anatomical features of patients with MPM at post-mortem.

Methods: The Mesothelioma Registry of Western Australia (WA) and the Avon region (UK) Coroner’s reports were interrogated for the post-mortem records of confirmed mesothelioma cases.

Results: Post-mortem records of 318 pleural mesothelioma patients (169 from WA and 149 from Avon) were identified. Most (91.5%) patients were male (mean age 68.4±11.5) and MPM was right sided in 55.3%. Extrapleural dissemination of tumor was found in 87.7% of cases and lymph node involvement in 53.3%. Tumor dissemination in extra-thoracic sites was common (55.4% of patients) and almost all organs were involved, including liver (31.9%), spleen (10.8%), thyroid (6.9%), and the brain (3.0%). Pulmonary emboli (PE) were found in 6% of cases and considered as directly contributing to death in 13 (4.1%) patients. The precise cause of death could only be determined in 63 (19.8%) cases even after post-mortem. The body mass index was significantly lower in cases which had no identifiable anatomical cause of death at post-mortem (18.8±4.3 vs. 21.0±4.7, p=0.034).

Conclusion: In this largest post-mortem series on MPM, extra-thoracic dissemination of mesothelioma was common and often under-recognized. No anatomical cause of death was identified in the majority of patients even at autopsy, raising the possibility of physiological and metabolic causes of death.

HighWire Medline Abstract

Malignant mesothelioma incidence among talc miners and millers in New York State. MM Finkelstein Am J Ind Med, April 27, 2012; .   Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada; Program in Occupational Health and Environmental Medicine, McMaster University, Hamilton, Ontario, Canada. murray.finkelstein@utoronto.ca.
BACKGROUND: There is controversy about the potential for dust from the talc mines and mills of New York State to cause mesothelioma. Honda et al. published a study of mortality among New York talc workers and concluded that it was unlikely that the two deaths from mesothelioma were caused by talc ore dust. However, fibers of tremolite and anthophyllite have been found in the lungs of talc workers and Hull concluded that “New York talc exposure is associated with mesothelioma, and deserves further public health attention.” METHODS: Data concerning additional cases of mesothelioma in the cohort have been posted by NIOSH. I used information from the NIOSH website and the Honda report to analyze the incidence of mesothelioma during the years 1990-2007. RESULTS: There were at least five new cases of mesothelioma in the cohort and mesothelioma incidence rates were at least five (1.6-11.7) times the rate in the general population (P?<?0.01). CONCLUSIONS: I conclude that: (1) mesothelioma has been diagnosed among members of the cohort at a rate in excess of that in the general population; (2) fibers of tremolite and anthophyllite have been detected in dust and the lungs of talc workers; and (3) these fibers are known causes of mesothelioma. It is prudent, on the balance of probabilities, to conclude that dusts from New York State talc ores are capable of causing mesothelioma in exposed individuals.

Mesothelioma Associated With Commercial Use of Vermiculite Containing Libby Amphibole. KK Dunning, S Adjei, L Levin, AM Rohs, T Hilbert, E Borton, V Kapil, C Rice, GK Lemasters, and JE Lockey J Occup Environ Med, April 25, 2012; .
OBJECTIVES:: To describe asbestos-related mortality among manufacturing workers who expanded and processed Libby vermiculite that contained amphibole fiber. METHODS:: Standardized mortality ratio was calculated for 465 white male workers 31 years after last Libby vermiculite exposure. RESULTS:: Two workers died from mesothelioma, resulting in a significantly increased standardized mortality ratio of 10.5 (95% confidence interval, 1.3 to 38.0). These workers were in the upper 10th percentile of cumulative fiber exposure, that is, 43.80 and 47.23 fiber-years/cm, respectively. One additional worker with cumulative fiber exposure of 5.73 fiber-years/cm developed mesothelioma but is not deceased. There were no other significantly increased standardized mortality ratios. CONCLUSIONS:: Workers expanding and processing Libby vermiculite in a manufacturing setting demonstrated an increased risk for the development of mesothelioma following exposure to the amphibole fiber contained within this vermiculite ore source.

UH researcher leads breakthrough on a deadly cancer

By Star-Advertiser staff

POSTED: 07:46 p.m. HST, May 06, 2012

An international team led by University of Hawaii Cancer Center researcher Haining Yang has identified a protein known as HMGB1 as a critical link in the development of malignant mesothelioma, one of the deadliest forms of cancer.

The findings were published in the current issue of the online journal “Cancer Research.”

Mesothelioma has been linked to occupational and environmental exposure to asbestos and the naturally occurring mineral fiber erionite. The average survival for those diagnosed with the disease is less than one year, in part because the cancer is highly aggressive and resistant to current treatments, and partly because it is usually diagnoses it its late states.

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Pulmonary Carcinoid Tumors and Asbestos Exposure

• Received November 10, 2011.
• Accepted February 14, 2012.

Abstract

Objectives: The hypothesis that asbestos exposure may have more specific associations with particular histological types of lung cancer remains controversial. The aim of this study was to analyze the relationships between asbestos exposure and pulmonary carcinoid tumors.

Methods: A retrospective case–control study was conducted in 28 cases undergoing surgery for pulmonary carcinoid tumors and aged >40 years and in 56 controls with lung cancer of a different histological type, matched for gender and age, from 1994 to 1999, recruited in two hospitals in the region of Paris. Asbestos exposure was assessed via expertise of a standardized occupational questionnaire and mineralogical analysis of lung tissue, with quantification of asbestos bodies (AB).

Results: Definite asbestos exposure was identified in 25% of cases and 14% of controls (ns). Cumulative asbestos exposure was significantly higher in cases than in controls (P < 0.05), and results of the quantification of AB tended to be higher in cases than in controls (24 and 9% had >1000 AB per gram dry lung tissue, respectively, P = 0.09). Mean cumulative smoking was lower in cases than in controls (P < 0.05).

Conclusions: This study argues in favor of a relationship between asbestos exposure and certain pulmonary carcinoid tumors.

Asbestos victims claim some justice in James Hardie ruling

 

Australian Broadcasting Corporation

Broadcast: 03/05/2012

Reporter: Matt Peacock

Australia’s highest court has found seven directors of former asbestos manufacturer James Hardie guilty of breaches over the company’s asbestos compensation fund.

Transcript

CHRIS UHLMANN, PRESENTER: It’s been a long and bitter journey, but today the High Court ruled that seven former James Hardie directors broke the law by making a misleading statement about the company’s asbestos compensation fund.

The decision is a major victory for the corporate regulator. But asbestos victims say justice has still not been done and that there’s still nothing in law to stop companies from hiding behind the corporate veil.

Matt Peacock has been covering the James Hardie saga since the 1970′s and he filed this report.

MATT PEACOCK, REPORTER: 11 years on, Australia’s highest court finds the directors of the former asbestos manufacturer guilty.

SERAFINA SALUCCI, MESOTHELIOMA SUFFERER: Obviously I’m pleased. I think it just sends a message that companies and corporations can’t get away with doing whatever they think they can get away with.

GREG MEDCRAFT, ASIC CHAIRMAN: No person is beyond the law. And Australians would expect nothing less from us.

TANYA SEGELOV, BERNIE BANTON’S LAWYER: Finally there is some justice for asbestos victims. A small amount of justice, but justice nevertheless.

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Anger over asbestos mine’s deadly legacy

By Matt Peacock

Updated May 01, 2012 09:45:17

More than 2,000 people from Wittenoom have died from asbestos diseases.

Campaigners say they are becoming increasingly angered by the rising toll of mesothelioma deaths from the site of Australia’s biggest industrial disaster.

More than two dozen people are setting out today to walk across the desert from Kalgoorlie to Perth to highlight the urgent need for more research into the deadly asbestos cancer.

Perth is one of the world’s mesothelioma hotspots, mainly because of the now-abandoned blue asbestos mine at Wittenoom in the Pilbara.

More than 2,000 former workers and residents from Wittenoom have died from asbestos diseases and the toll is climbing.

Alarmingly, it is now increasingly the children of Wittenoom who are falling ill.

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Pro-asbestos advocacy group shuts its doors

By Robert Hiltz, Postmedia News April 30, 2012

A decades-old pro-asbestos lobby group, currently funded by the Quebec government, will be shutting its doors after notifying the federal government of its plan to dissolve.

The Montreal-based Chrysotile Institute issued the notice in the Canada Gazette — the government’s official publication for announcing new laws and other public information. The institute, first formed in 1984, promotes the safe use of chrysotile asbestos on behalf of Canada’s asbestos mining industry.

NDP MP Pat Martin — a longtime critic of the asbestos industry and former miner himself — said the closing of the institute signals the “death knell” of asbestos mining in Canada.

“I see it as a real tipping point in the movement to get Canada out of the asbestos industry,” Martin said. “It’s just another demonstration of the death rattle of the asbestos industry in this country.”

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Serum Mesothelin for Diagnosing Malignant Pleural Mesothelioma: An Individual Patient Data Meta-Analysis

1. Presented in part at the 10th International Congress of the International Mesothelioma Interest Group, August 31 to September 3, 2010, Kyoto, Japan.

Abstract

Purpose Mesothelin is currently considered the best available serum biomarker of malignant pleural mesothelioma. To examine the diagnostic accuracy and use of serum mesothelin in early diagnosis, we performed an individual patient data (IPD) meta-analysis.

Methods The literature search identified 16 diagnostic studies of serum mesothelin, measured with the Mesomark enzyme-linked immunosorbent assay. IPD of 4,491 individuals were collected, including several control groups and 1,026 patients with malignant pleural mesothelioma. Mesothelin levels were standardized for between-study differences and age, after which the diagnostic accuracy and the factors affecting it were examined with receiver operating characteristic (ROC) regression analysis.

Results At a common diagnostic threshold of 2.00 nmol/L, the sensitivities and specificities of mesothelin in the different studies ranged widely from 19% to 68% and 88% to 100%, respectively. This heterogeneity can be explained by differences in study population, because type of control group, mesothelioma stage, and histologic subtype significantly affected the diagnostic accuracy. The use of mesothelin in early diagnosis was evaluated by differentiating 217 patients with stage I or II epithelioid and biphasic mesothelioma from 1,612 symptomatic or high-risk controls. The resulting area under the ROC curve was 0.77 (95% CI, 0.73 to 0.81). At 95% specificity, mesothelin displayed a sensitivity of 32% (95% CI, 26% to 40%).

Conclusion In patients suspected of having mesothelioma, a positive blood test for mesothelin at a high-specificity threshold is a strong incentive to urge further diagnostic steps. However, the poor sensitivity of mesothelin clearly limits its added value to early diagnosis and emphasizes the need for further biomarker research.