Mechanisms and shapes of causal exposure-response functions for asbestos in mesotheliomas and lung cancers.

This paper summarizes recent insights into causal biological mechanisms underlying the carcinogenicity of asbestos. It addresses their implications for the shapes of exposure-response curves and considers recent epidemiologic trends in malignant mesotheliomas (MMs) and lung fiber burden studies. Since the commercial amphiboles crocidolite and amosite pose the highest risk of MMs and contain high levels of iron, endogenous and exogenous pathways of iron injury and repair are discussed. Some practical implications of recent developments are that: (1) Asbestos-cancer exposure-response relationships should be expected to have non-zero background rates; (2) Evidence from inflammation biology and other sources suggests that there are exposure concentration thresholds below which exposures do not increase inflammasome-mediated inflammation or resulting inflammation-mediated cancer risks above background risk rates; and (3) The size of the suggested exposure concentration threshold depends on both the detailed time patterns of exposure on a time scale of hours to days and also on the composition of asbestos fibers in terms of their physiochemical properties. These conclusions are supported by complementary strands of evidence including biomathematical modeling, cell biology and biochemistry of asbestos-cell interactions in vitro and in vivo, lung fiber burden analyses and epidemiology showing trends in human exposures and MM rates.

Assessment of Risk of Hereditary Predisposition in Patients With Melanoma and/or Mesothelioma and Renal Neoplasia.

Importance: In BAP1 tumor predisposition syndrome, clear cell renal cell carcinoma (RCC) is frequently associated with melanoma and/or mesothelioma, while germline MITF p.E318K alterations are being increasingly reported in melanoma/RCC. Limited data exist on the co-occurrence of melanoma and/or mesothelioma with renal neoplasia and the prevalence of associated germline alterations. Objective: To assess the frequency of melanoma and/or mesothelioma co-occurring with renal neoplasia using our institutional nephrectomy registry and to determine the prevalence of BAP1 and MITF alterations within this cohort. Design, Setting, and Participants: In this genetic association study, medical records from 8295 patients from 1970 to 2018, renal neoplasia co-occurring with melanoma and/or mesothelioma within a single institutional nephrectomy registry was reevaluated based on contemporary histopathologic criteria and the medical records were reviewed. Data were analyzed from September 2019 to May 2021. Main Outcomes and Measures: Identified cases were screened for BAP1 loss using immunohistochemistry; while patients with melanoma and clear cell RCC were screened for MITF p.E318K alterations. Tumors from patients with potential germline alterations were analyzed with comprehensive molecular profiling using a 514-gene next generation sequencing panel. Results: Of a total of 8295 patients, 93 (1.1%; 95% CI, 0.9%-1.4%) had melanoma and/or mesothelioma co-occurring with renal neoplasia (cutaneous melanoma, n = 76; uveal melanoma, n = 11; mesothelioma, n = 6). A total of 69 (74.2%) were male; 24 (25.8%) were female; median age at diagnosis of renal neoplasia was 63 years (IQR, 58-70 years) and the median duration of follow-up was 8.5 years (IQR, 5.0-14.6 years). Two patients with clear cell RCC had germline BAP1 alterations in the setting of cutaneous melanoma and mesothelioma. Two patients with hybrid oncocytic tumors had biallelic inactivation of FLCN in a setting of Birt-Hogg-Dubé (BHD) syndrome associated with uveal melanoma and mesothelioma. Tumor-only screening of clear cell RCC associated with cutaneous (n = 53) and uveal melanoma (n = 6) led to the identification of 1 patient with a likely germline MITF p.E318K alteration. After excluding benign renal neoplasia (such as oncocytoma and angiomyolipoma), alterations of BAP1, FLCN, and MITF were identified in 5 of 81 patients (6.2%) with melanoma and/or mesothelioma and renal neoplasia. In contrast to hybrid oncocytic tumors in BHD, no unique genotype-phenotype correlations were seen for clear cell RCC with pathogenic BAP1/ MITF alterations and VHL loss of function variants. Four of 5 cases (80%) met current National Comprehensive Cancer Network criteria for germline testing based on a combination of age, multifocality, histologic findings, and family history. Conclusions and Relevance: In this genetic association study, findings support the continued use of these National Comprehensive Cancer Network criteria and suggest more stringent screening may be warranted in this patient population.

Treatment of Malignant Peritoneal Mesothelioma.

Malignant mesothelioma is a highly malignant disease that most often occurs in the pleura of the thoracic cavity, followed by the peritoneum, pericardium, or tinea vaginalis testis. Malignant peritoneal mesothelioma (MPM) accounts for 10-15% of all mesotheliomas. The most significant risk factor for MPM is exposure to asbestos. There is no specific symptomatology, and imaging (computed tomography) and histopathology are crucial for diagnosis. There are no generally accepted guidelines for radical treatment of MPM. Previously, the prognosis of MPM patients was poor, with survival of up to 1 year. However, median survival of patients who are suitable candidates for radical therapy is currently 3-5 years. A combination of cytoreductive surgery (CRS) and hyperthermic perioperative chemotherapy (HIPEC) is recommended in selected patients, while chemotherapy alone has insufficient efficacy. Systemic chemotherapy remains the only treatment option for patients who are unsuitable for CRS and HIPEC. In selected patients scheduled for or currently undergoing CRS and HIPEC, surgery may be performed in combination with systemic chemotherapy in the neoadjuvant or adjuvant setting; however, the benefit is unclear. There are no recommendations for follow-up of MPM patients after radical surgery. Existing guidelines for the pleural form (e.g., those issued by the European Society for Medical Oncology) do not specify the frequency or method of investigation. In the absence of specific serum markers, only CA 125 and mesothelin are generally available. Imaging methods include ultrasonography, computed tomography, and magnetic resonance imaging.

Malignant Peritoneal Mesothelioma: Patterns of Care and Survival in the Netherlands: A Population-Based Study.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare and aggressive disease. Recently, focus has shifted toward a more aggressive and multimodal treatment approach. This study aimed to assess the patterns of care and survival for MPM patients in the Netherlands on a nationwide basis. METHODS: The records of patients with a diagnosis of MPM from 1993 to 2016 were retrieved from the Dutch Cancer Registry. Data regarding diagnosis, staging, treatment, and survival were extracted. Cox regression analyses and Kaplan-Meier survival curves were used to study overall survival. RESULTS: Between 1993 and 2016, MPM was diagnosed for 566 patients. Overall, the prognosis was very poor (24% 1-year survival). The most common morphologic subtype was the epithelioid subtype (88%), followed by the biphasic (8%) and sarcomatoid (4%) subtypes. Surgical treatment has become more common in recent years, which most likely has resulted in improved survival rates. In this study, improved survival was independently associated with hyperthermic intraperitoneal chemotherapy (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.21-0.55) and surgery with adjuvant systemic chemotherapy (HR, 0.33; 95% CI, 0.23-0.48). Nonetheless, most patients (67%) do not receive any form of anti-cancer treatment. CONCLUSION: This study indicated that MPM still is a rare and fatal disease. The survival rates in the Netherlands have improved slightly in the past decade, most likely due to more aggressive treatment approaches and increased use of surgery. However, most patients still do not receive cancer-directed treatment. To improve MPM management, and ultimately survival, care should be centralized in expert medical centers.

Mortality Update of a Cohort of Canadian Petroleum Workers.

OBJECTIVE: This study updates the mortality experience of over 25,000 workers in a large Canadian petroleum company through December 31, 2006. METHODS: Standardized mortality ratios were generated for all-cause and specific cause mortality. RESULTS: All cause and all cancer mortality were favorable compared with the general Canadian population. Cancers of previous interest were largely consistent with expectation. There is a continuing excess of mesothelioma, which is of similar magnitude as the previous update, although based on larger numbers. This excess is mostly attributable to men who died in their 50s and 60s and who worked in the refining sector. CONCLUSION: Most causes of death show mortality rates lower than the Canadian general population. Given the excess of mesothelioma observed, this study supports ongoing vigilance in asbestos exposure control programs, as refineries continue to remove asbestos from their facilities.

The Victorian Comprehensive Cancer Centre lung cancer clinical audit: collecting the UK National Lung Cancer Audit data from hospitals in Australia.

BACKGROUND: Clinical audit may improve practice in cancer service provision. The UK National Lung Cancer Audit (NLCA) collects data for all new cases of thoracic cancers. AIM: To collect similar data for our Victorian patients from six hospitals within the Victorian Comprehensive Cancer Centre and associated Western and Central Melbourne Integrated Cancer Service. METHODS: We conducted a retrospective audit of all newly diagnosed patients with lung cancer and mesothelioma in 2013 across the six Victorian Comprehensive Cancer Centre/Western and Central Melbourne Integrated Cancer Service hospitals. The objectives were to adapt the NLCA data set for use in the Australian context, to analyse the findings using descriptive statistics and to determine feasibility of implementing a routine, ongoing audit similar to that in the UK. Individual data items were adapted from the NLCA by an expert steering committee. Data were collated from the Victorian Cancer Registry, Victorian Admitted Episodes Dataset and individual hospital databases. Individual medical records were audited for missing data. RESULTS: Eight hundred and forty-five patients were diagnosed across the sites in 2013. Most were aged 65-80 (55%) and were male (62%). Most had non-small-cell lung cancer (81%) with 9% diagnosed with small cell lung cancer and 2% with mesothelioma. Data completeness varied significantly between fields. For those with higher levels of completeness, headline indicators of clinical care were comparable with NLCA data. The Victorian population seem to lack access to specialist lung cancer nurse services. CONCLUSION: Lung cancer care at participating hospitals appeared to be comparable with the UK in 2013. In future, prospective data collection should be harmonised across sites and correlated with survival outcomes. One area of concern was a lack of documented access to specialist nursing services.

Mesothelioma in Australia: a review.

The incidence of malignant mesothelioma in Australia is among the highest in the world as a result of widespread use of asbestos by industry and in construction throughout the 20th century. The risk of developing malignant mesothelioma after asbestos exposure is dose-related; a transient, low dose exposure confers a correspondingly very low risk of disease. Malignant mesothelioma is a heterogeneous disease, partly explaining the limited role of biomarkers in screening and diagnosis. The prognosis remains poor, and early advice on medico-legal compensation and a collaborative team approach to managing malignant mesothelioma are both essential. Chemotherapy can have a modest treatment effect in some people. New therapies, such as immunotherapy, do not yet have a defined role in the treatment of malignant mesothelioma. As treatment options for malignant mesothelioma are limited and no cure is available, there is no established role for early detection or screening of at risk populations. A multidisciplinary approach to caring for patients with malignant mesothelioma and their carers is vital.

Protocol of the Australasian Malignant Pleural Effusion-2 (AMPLE-2) trial: a multicentre randomised study of aggressive versus symptom-guided drainage via indwelling pleural catheters.

INTRODUCTION: Malignant pleural effusions (MPEs) can complicate most cancers, causing dyspnoea and impairing quality of life (QoL). Indwelling pleural catheters (IPCs) are a novel management approach allowing ambulatory fluid drainage and are increasingly used as an alternative to pleurodesis. IPC drainage approaches vary greatly between centres. Some advocate aggressive (usually daily) removal of fluid to provide best symptom control and chance of spontaneous pleurodesis. Daily drainages however demand considerably more resources and may increase risks of complications. Others believe that MPE care is palliative and drainage should be performed only when patients become symptomatic (often weekly to monthly). Identifying the best drainage approach will optimise patient care and healthcare resource utilisation. METHODS AND ANALYSIS: A multicentre, open-label randomised trial. Patients with MPE will be randomised 1:1 to daily or symptom-guided drainage regimes after IPC insertion. Patient allocation to groups will be stratified for the cancer type (mesothelioma vs others), performance status (Eastern Cooperative Oncology Group status 0-1 vs ≥2), presence of trapped lung (vs not) and prior pleurodesis (vs not). The primary outcome is the mean daily dyspnoea score, measured by a 100 mm visual analogue scale (VAS) over the first 60 days. Secondary outcomes include benefits on physical activity levels, rate of spontaneous pleurodesis, complications, hospital admission days, healthcare costs and QoL measures. Enrolment of 86 participants will detect a mean difference of VAS score of 14 mm between the treatment arms (5% significance, 90% power) assuming a common between-group SD of 18.9 mm and a 10% lost to follow-up rate. ETHICS AND DISSEMINATION: The Sir Charles Gairdner Group Human Research Ethics Committee has approved the study (number 2015-043). Results will be published in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: ACTRN12615000963527; Pre-results.

The global health dimensions of asbestos and asbestos-related diseases.

The Collegium Ramazzini is an international scientific society that examines critical issues in occupational and environmental medicine with a view towards action to prevent disease and promote health. The Collegium derives its name from Bernardino Ramazzini, the father of occupational medicine, a professor of medicine of the Universities of Modena and Padua in the late 1600s and the early 1700s. The Collegium is comprised of 180 physicians and scientists from 35 countries, each of whom is elected to membership. The Collegium is independent of commercial interests.

Dietary vitamin D supplementation does not reduce the incidence or severity of asbestos-induced mesothelioma in a mouse model.

Epidemiological studies suggest that vitamin and mineral intake is associated with cancer incidence. A prevention strategy based on diet or dietary supplementation could have enormous benefit, both directly, by preventing disease, and indirectly by alleviating fear in millions of people worldwide who have been exposed to asbestos. We have previously shown that dietary supplementation with the antioxidants vitamins A, E, and selenium does not affect overall survival nor the time to progression of asbestos-induced mesothelioma in MexTAg mice. Here we have extended our analysis to vitamin D. We compared survival of asbestos-exposed MexTAg mice provided with diets that were deficient or supplemented with 4500 IU/kg vitamin D (cholecalciferol). Survival of supplemented mice was significantly shorter than mice given a standard AIN93 diet containing 1000 IU/kg cholecalciferol (median survival was 29 and 32.5 weeks respectively). However, mice deficient in vitamin D had the same rate of mesothelioma development as control mice. Neither the latency time from asbestos exposure to diagnosis nor disease progression after diagnosis were significantly different between mice on these diets. We conclude that vitamin D is unlikely to moderate the incidence of disease in asbestos-exposed populations or to ameliorate the pathology in patients with established mesothelioma.

[Active research, registration, and prevention of tumors of professional origin]. / Ricerca attiva, registrazione e prevenzione dei tumori di origine professionale.

Occupational cancer is an important public health concern in Italy and in many industrialized countries. The difficulties in monitoring and the complexity in retrieving occupational cancer cases have required the enrolment of a national epidemiologic sureveillance system at national scale with active search methods. A structured system for the registration of occupational cancer cases is normed by the Decree No. 81/2008, that accounts for the previous legislative procedures and experiences. Research activities and prevention of occupational cancer should be integrated with insurance policies to the purpose of an efficient protection of workers health.

Influence of co-morbidity on renal function assessment by Cockcroft-Gault calculation in lung cancer and mesothelioma patients receiving platinum-based chemotherapy.

BACKGROUND: Creatinine clearance (CrCl) estimation by Cockcroft-Gault calculation (CG) often replaces measurement of glomerular filtration rate (GFR) by [(51)Cr]-ethylenediaminetetraacetic acid clearance (EDTA). Co-morbidity, age, and renal impairment influence the accuracy of CG, whilst the relationship between CG and EDTA has been poorly assessed in lung cancer patients, a population significantly affected by these covariates. METHODS: Retrospective analysis of co-morbidity, nephrotoxic drug use, chemotherapy toxicity, and correlation between paired CG and EDTA, in 388 lung cancer and mesothelioma patients receiving platinum-based chemotherapy. RESULTS: Potentially nephrotoxic co-morbidity or medication use occurred in 47% of patients, and was twice as likely in those aged >70 years (OR=2.07; 95%CI: 1.25-3.44, p=0.003). Patients with co-morbidity or nephrotoxic medication use had a lower EDTA compared to those without these baseline factors (p=0.02), but were not significantly more likely to experience chemotherapy toxicity. CG and EDTA correlation was high (r(2)=0.68), but reduced in patients with ETDA<50 ml/min (r(2)=0.26, p=0.02) or >120 ml/min (r(2)=0.32, p=0.09), and in those with CG>120 ml/min (r(2)=0.20, p=0.01). The correlation between CG and EDTA was not significantly altered in patients with co-morbidity or nephrotoxic medication use. CG bias (mean percentage error) and precision (mean absolute percentage error, MAPE) were 7% and 26%, respectively, and precision was impaired in patients with abnormally raised serum creatinine (MAPE 65%, p<0.0001). CONCLUSION: CG estimation of CrCl is accurate and safe in lung cancer patients with potentially nephrotoxic co-morbidity or concomitant medication, but should not be used when values are outside the range 50-120 ml/min, or with abnormally elevated serum creatinine.

Retinol supplementation and mesothelioma incidence in workers earlier exposed to blue asbestos (Crocidolite) at Wittenoom, Western Australia.

Owing to the high rates of malignant mesothelioma in workers exposed to crocidolite earlier at Wittenoom and evidence of protection against cancer by vitamin A, a population-based cancer prevention programme providing retinol supplements (25 000 IU/day) was commenced in 1990. The former workers at Wittenoom known to be alive and living in Western Australia in June 1990 constitute the study population. The participants were classified into two groups: those who received supplemental retinol (intervention group) and those who received none (comparison group). The relative rate of mesothelioma for those receiving retinol was estimated using Cox regression, adjusting for cumulative asbestos exposure and age at first exposure to asbestos. Nine hundred and twenty-eight former Wittenoom workers received retinol at some stage of the programme, whereas 1471 workers never received retinol (comparison group). Those who received retinol were younger, had a greater exposure to asbestos and smoked less than the comparison group. There were 65 cases of mesothelioma in the retinol group and 88 in the comparison group. After adjustment, the hazard ratio was 0.99 (95% confidence interval=0.70-1.41). This result did not alter when the participants who received only retinol once or those who received beta-carotene earlier were excluded from the analysis. In conclusion, this study provides little support for possible preventive effects of retinol against mesothelioma in workers exposed to blue asbestos.

All cause mortality and incidence of cancer in workers in bauxite mines and alumina refineries.

Bauxite is a reddish clay that is refined to produce alumina, which is then reduced to aluminium. There have been studies examining the health of workers in aluminium smelters, but not workers in bauxite mining and alumina refining. A cohort of employees of 1 large aluminium company since 1983 was assembled (n = 6,485, 5,828 men). Deaths and incident cancers to 2002 were ascertained by linkage to national and state cancer and death registries. SIRs and SMRs were calculated compared to national rates standardizing for calendar year, sex and 5-year age group. The mortality from all causes (SMR 0.68, 95% CI: 0.60-0.77), and from circulatory and respiratory diseases, all cancers combined and injury in the male cohort were lower than in the Australian male population and were similar across work groups and with duration of employment. The only significant increased mortality risk was from pleural mesothelioma. The incidence of all cancers combined was similar to the Australian rate. The cohort had a lower risk of incident lymphohaematopoietic cancer (SIR 0.50, 95% CI: 0.31-0.88) and a higher risk of melanoma (SIR 1.30, 95% CI: 1.00-1.69) although no dose-responses were seen. There was also an increased risk of mesothelioma (SIR 3.49, 95% CI: 1.82-6.71), which was associated with exposures outside the aluminium industry. This study is the first to examine cancer and mortality amongst workers in bauxite mines and alumina refineries and found little evidence for increased cancer incidence or mortality in these workers.

Current treatment options and biology of peritoneal mesothelioma: meeting summary of the first NIH peritoneal mesothelioma conference.

Peritoneal mesothelioma is a rare cancer of the peritoneum with about 250 new cases diagnosed each year in the United States. It is the second most common site for mesothelioma development and accounts for 10-20% of all mesotheliomas diagnosed in the United States. A meeting sponsored by the NIH Office of Rare Diseases was held in Bethesda, Maryland on September 13 and 14, 2004. The objective of this meeting was to review the epidemiology, biology and current surgical and medical management of peritoneal mesothelioma. In addition, the meeting also discussed clinical and pre-clinical evaluation of novel treatments for mesothelioma as well as ongoing laboratory research to better understand this disease. This report summarizes the proceedings of the meeting as well as directions for future clinical and basic research.

Asbestos-related cancers in refinery workers in the Australian petroleum industry.

In this study of the incidence of asbestos-related cancer in the Australian petroleum industry, the authors traced a cohort of 16,543 petroleum industry workers for a total of 226,989 person-years. There were 18 cases of pleural mesothelioma; 12 occurred in refinery nonoffice workers, for whom the Standardized Incidence Ratio was 3.77 (95% confidence interval = 1.95-6.59). The incidence of lung cancer was significantly lower than that in the general male population. Lung cancer incidence was higher in maintenance workers than in nonmaintenance workers, but the excess was not statistically significant, as it was based on small numbers with wide confidence intervals. Lung cancer rates in refinery workers did not increase with duration of employment; however, they did tend to be higher in workers hired in earlier decades. Excess mesothelioma incidence in refinery workers is confirmed, but it is likely that there are few if any asbestos-related lung cancers.

[Cluster cases of malignant pleural mesothelioma in an oil factory]. / Cluster di casi di mesotelioma maligno della pleura in un oleificio.

BACKGROUND: The traditional occupational hazards of the productive cycle of oils are attributable to chemicals (use of solvents, pesticides and other agents), dusts, labour accidents (trauma, ignition, explosion), noise, manual lifting, work organization and hot-wet microclimate. The latest risk is due to the use of high temperatures (from 50 up to 250 degrees C) during the processes of extraction with solvent and refining. No cases are reported in literature of asbestos related disease in subjects who worked in oil factories. Nevertheless the structure and organization of the workplace, which is similar to that of sugar refineries, where cases of malignant mesothelioma have been described (moreover in workers employed in running and maintenance of the plants), led to the assumption that even in oil factories asbestos for the insulation of pipes and boilers could be present. OBJECTIVES: To describe 3 cases of Malignant Mesothelioma that occurred in workers of the same oil factory. METHODS: Since this occupational sector is not conventionally known for asbestos exposure the Local Health Unit and the Lombardy Mesothelioma Registry decided to investigate this industrial plant. RESULTS: Following examination of the archives of the Local Health Unit and inspection of the plant, an environmental asbestos contamination (pipes and boilers) was found. The 3 cases were defined as occupational disease and the required legal procedures were initiated. This underlines the importance of close cooperation with Local Health Units of occupational medicine and the Regional Mesothelioma Registry in the study and acknowledgment of cases which would otherwise not have been recognized, with consequent loss of precious information.

Update of a prospective study of mortality and cancer incidence in the Australian petroleum industry.

AIMS: To update the analysis of the cohort mortality and cancer incidence study of employees in the Australian petroleum industry. METHODS: Employees from 1981 to 1996 were traced through the Australian National Death Index and the National Cancer Statistics Clearing House. Cause specific mortality and cancer incidence were compared with those of the Australian population by means of standardised mortality ratios (SMRs) and standardised incidence ratios (SIRs). Associations between increased incidence of specific cancers and employment in the petroleum industry were tested by trends according to period of first employment, duration of employment, latency, and hydrocarbon exposure, adjusting for personal smoking history where appropriate. Total follow up time was 176 598 person-years for males and 10 253 person-years for females. RESULTS: A total of 692 of the 15 957 male subjects, and 16 of the 1206 female subjects had died by the cut off date, 31 December 1996. In males, the all-cause SMR and the SMRs for all major disease categories were significantly below unity. There was a non-significant increase of the all-cancer SIR (1.04, 95% CI 0.97 to 1.11). There was a significant increase of the incidence of melanoma (SIR 1.54, 95% CI 1.30 to 1.81), bladder cancer (SIR 1.37, 95% CI 1.00 to 1.83), and prostate cancer (SIR 1.19, 95% CI 1.00 to 1.40), and a marginally significant excess of pleural mesothelioma (SIR 1.80, 95% CI 0.90 to 3.22), leukaemia (SIR 1.39, 95%CI 0.91 to 2.02), and multiple myeloma (SIR 1.72, 95% CI 0.96 to 2.84). CONCLUSIONS: Most cases of mesothelioma are probably related to past exposure to asbestos in refineries. The melanoma excess may be the result of early diagnosis. The excess bladder cancer has not been observed previously in this industry and is not readily explained. The divergence between cancer incidence and cancer mortality suggests that the "healthy worker effect" may be related to early reporting of curable cancers, leading to increased likelihood of cure and prolonged mean survival time.