Molecular Characterization of Testicular Mesothelioma and the Role of Asbestos as a Causative Factor.

CONTEXT.­: Mesothelioma of the tunica vaginalis testis (TVT) is an extremely rare form of mesothelioma. OBJECTIVE.­: To compare the clinical and molecular characteristics of mesothelioma of the TVT with those of mesothelioma at other more common sites, including the relationship with exposure to asbestos. DESIGN.­: We present clinical and pathological data for 9 cases of primary TVT mesothelioma. We performed whole-genome sequencing on 3 cases for the first time. RESULTS.­: The majority (7 of 9 cases) of TVT mesotheliomas were epithelioid, with the remaining 2 cases showing biphasic morphology. Morphology and immunohistochemical profiles were indistinguishable from mesothelioma elsewhere. Asbestos exposure was documented for 7 of the 9 cases, with no information for 2 cases. The 3 TVT mesothelioma cases that underwent whole-genome sequencing displayed a mutational profile similar to that of mesothelioma at other sites, including NF2 and TP53 mutations. CONCLUSIONS.­: The clinical and molecular profile of TVT mesothelioma is similar to that of mesothelioma elsewhere.

The Significance of Short Latency in Mesothelioma for Attribution of Causation: Report of a Case with Predisposing Germline Mutations and Review of the Literature.

Malignant mesothelioma is a tumour of the serosal membranes, related to asbestos exposure. Median latency is in the order of 40 years in various registries, but small numbers of cases with shorter latencies have long been reported and often dismissed as unrelated to asbestos exposure. However, emerging data regarding the significance of inherited mutations leading to a predisposition to mesothelioma suggest that the causative effect of asbestos may be associated with shorter latencies in a subset of patients. Here, we describe a male patient with germline mutations in RAD51 and p53 who developed peritoneal mesothelioma 8.5 years after well-documented asbestos exposure and discuss the current literature on the subject. Mesothelioma in situ is now a WHO-accepted diagnosis, but preliminary data reveal a potential lead time of 5 or more years to invasive disease, and this is also a factor which may affect the recording of latency (and potentially survival) in the future.

Self-selection in a population-based cohort study: impact on health service use and survival for bowel and lung cancer assessed using data linkage.

BACKGROUND: In contrast to aetiological associations, there is little empirical evidence for generalising health service use associations from cohort studies. We compared the health service use of cohort study participants diagnosed with bowel or lung cancer to the source population of people diagnosed with these cancers in New South Wales (NSW), Australia to assess the representativeness of health service use of the cohort study participants. METHODS: Population-based cancer registry data for NSW residents aged ≥45 years at diagnosis of bowel or lung cancer were linked to the 45 and Up Study, a NSW population-based cohort study (N~ 267,000). We measured hospitalisation, emergency department (ED) attendance and all-cause survival, and risk factor associations with these outcomes using administrative data for cohort study participants and the source population. We assessed bias in prevalence and risk factor associations using ratios of relative frequency (RRF) and relative odds ratios (ROR), respectively. RESULTS: People from major cities, non-English speaking countries and with comorbidites were under-represented among cohort study participants diagnosed with bowel (n = 1837) or lung (n = 969) cancer by 20-50%. Cohort study participants had similar hospitalisation and ED attendance compared with the source population. One-year survival after major surgical resection was similar, but cohort study participants had up to 25% higher post-diagnosis survival (lung cancer 3-year survival: RRF = 1.24, 95% confidence interval 1.12,1.37). Except for area-based socioeconomic position, risk factors associations with health service use measures and survival appeared relatively unbiased. CONCLUSIONS: Absolute measures of health service use and risk factor associations in a non-representative sample showed little evidence of bias. Non-comparability of risk factor measures of cohort study participants and non-participants, such as area-based socioeconomic position, may bias estimates of risk factor associations. Primary and outpatient care outcomes may be more vulnerable to bias.

Bibliometric analysis of gaps in research on asbestos-related diseases: declining emphasis on public health over 26 years.

OBJECTIVES: The global burden of asbestos-related diseases (ARDs) is significant, and most of the world's population live in countries where asbestos use continues. We examined the gaps between ARD research and suggestions of WHO and the International Labour Organization on prevention. METHODS: From the Web of Science, we collected data on all articles published during 1991-2016 and identified a subset of ARD-related articles. We classified articles into three research areas-laboratory, clinical and public health-and examined their time trends. For all and the top 11 countries publishing ARD-related articles, we calculated the proportions of all ARD-related articles that were in each of the three areas, the average rates of ARD-related articles over all articles, and the average annual per cent changes of rates. RESULTS: ARD-related articles (n=14 284) accounted for 1.3‰ of all articles in 1991, but this had declined to 0.8‰ by 2016. Among the three research areas, the clinical area accounted for the largest proportion (65.0%), followed by laboratory (26.5%) and public health (24.9%). The public health area declined faster than the other areas, at -5.7% per year. Discrepancies were also observed among the top 11 countries regarding emphasis on public health research, with Finland and Italy having higher, and China and the Netherlands lower, emphases. CONCLUSIONS: There is declining emphasis on the public health area in the ARD-related literature. Under the ongoing global situation of ARD, primary prevention will remain key for some time, warranting efforts to rectify the current trend in ARD-related research.

Australia's Ongoing Legacy of Asbestos: Significant Challenges Remain Even after the Complete Banning of Asbestos Almost Fifteen Years Ago.

The most effective way of reducing the global burden of asbestos-related diseases is through the implementation of asbestos bans and minimising occupational and non-occupational exposure to respirable asbestos fibres. Australia's asbestos consumption peaked in the 1970s with Australia widely thought to have had among the highest per-capita asbestos consumption level of any country. Australia's discontinuation of all forms of asbestos and asbestos-containing products and materials did not occur at a single point of time. Crocidolite consumption ceased in the late 1960s, followed by amosite consumption stopping in the mid 1980s. Despite significant government reports being published in 1990 and 1999, it was not until the end of 2003 that a complete ban on all forms of asbestos (crocidolite, amosite, and chrysotile) was introduced in Australia. The sustained efforts of trade unions and non-governmental organisations were essential in forcing the Australian government to finally implement the 2003 asbestos ban. Trade unions and non-government organisations continue to play a key role today in monitoring the government's response to Australian asbestos-related disease epidemic. There are significant challenges that remain in Australia, despite a complete asbestos ban being implemented almost fifteen years ago. The Australian epidemic of asbestos-related disease has only now reached its peak. A total of 16,679 people were newly diagnosed with malignant mesothelioma between 1982 and 2016, with 84% of cases occurring in men. There has been a stabilisation of the age-standardised malignant mesothelioma incidence rate in the last 10 years. In 2016, the incidence rate per 100,000 was 2.5 using the Australian standard population and 1.3 using the Segi world standard population. Despite Australia's complete asbestos ban being in place since 2003, public health efforts must continue to focus on preventing the devastating effects of avoidable asbestos-related diseases, including occupational and non-occupational groups who are potentially at risk from exposure to respirable asbestos fibres.

Geographic and socioeconomic factors in patients with malignant pleural mesothelioma in New South Wales and their impact upon clinical outcomes.

BACKGROUND AND OBJECTIVE: Whilst the impact of clinicopathological factors on the prognosis of malignant pleural mesothelioma (MPM) is well understood, socioeconomic and geographic factors have received less attention. We analysed the relationship between geographic and socioeconomic factors upon survival and treatment provision in a large series of patients with MPM. METHODS: We assessed MPM patients awarded compensation between 2002 and 2009 with additional MPM incidence data from the New South Wales (NSW) Cancer Registry. The impact of geographic remoteness, distance from oncological multidisciplinary team (MDT) and Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) upon survival, clinical features and treatment received was analysed. RESULTS: We identified 910 patients (67% residing in major cities; 92% <50 km from MDT). Median overall survival was 10.0 months. On multivariate analysis, age >70 (hazard ratio (HR) = 1.39), male gender (HR =1.36), non-epithelioid histological subtype (HR = 2.18) and IRSAD status by decreasing quintile (HR = 1.06) were independent prognostic factors. There was no significant advantage for patients residing in major cities (10.6 months vs 8.8 months; P = 0.162) or within 50 km of MDT (10.3 months vs 7.8 months; P = 0.539). Patient's geographic location and distance to MDT did not impact chemotherapy, adjuvant radiotherapy or extrapleural pneumonectomy provision. Socioeconomically disadvantaged patients were significantly less likely to receive chemotherapy (37.4% vs 54.8%; P = 0.001). CONCLUSION: This study provides evidence for differences in the treatment and survival according to socioeconomic status for compensated MPM patients in NSW. Further research is warranted to seek additional explanations for the differences noted by comparing the treatments and outcomes of compensated and non-compensated MPM patients in NSW.

Malignant mesothelioma in Australia 2015: Current incidence and asbestos exposure trends.

Australia is known to have had the highest per-capita asbestos consumption level of any nation, reaching a peak in the 1970s. Although crocidolite was effectively banned in the late 1960s, and amosite use ceased in the mid 1980s, a complete asbestos ban was not implemented until 2003. This resulted in an epidemic of asbestos-related disease, which has only now reached its peak. Between 1982 and 2011, 13,036 individuals were newly diagnosed with malignant mesothelioma, with 690 diagnosed in 2011. A further 778 cases were identified between 1945 and 1981 from retrospective searches and the first 2 years of the Australian Mesothelioma Program. The age-standardized malignant mesothelioma incidence rate has leveled off in the last 10 years (2.8 per 100,000 in 2011). There has been a marked increase over time in the age-specific incidence rates for individuals aged 75 years or older. Data from the current Australian Mesothelioma Registry on asbestos exposure history in Australia is available for 449 subjects diagnosed between July 1, 2010, and April 1, 2015. This asbestos exposure history data show that 60% (n = 268) of cases had probable or possible occupational asbestos exposure, with trade-based jobs being the most frequent sources of occupational asbestos exposure. In addition, out of the 449 cases, 377 were recorded as having probable or possible nonoccupational asbestos exposure. Continuous vigilance toward changes over time in the settings in which people are exposed to asbestos and in the descriptive epidemiology of malignant mesothelioma is recommended to enable a comprehensive understanding of the current and future impact of asbestos-related diseases in Australia.

Estimating the incidence of malignant mesothelioma in Vietnam: a pilot descriptive cancer registration study.

INTRODUCTION: Global asbestos consumption has shifted toward lower income countries, particularly in the Asian region including Vietnam where asbestos and asbestos-containing products have been imported since the late 1960s. METHODS: This pilot descriptive epidemiological study aimed to provide contemporary estimates of malignant mesothelioma incidence (histological subtype M9050/3; ICD-O-3) by gender and age group as recorded across nine cancer registries in Vietnam. RESULTS: We identified 148 incident cases of malignant mesothelioma during 1987-2013. The majority of cases were recorded in the Hanoi region (n = 93) and were aged 55 years or older (n = 96). DISCUSSION: By carefully reviewing existing cancer registry records in Vietnam, we identified a larger number of malignant mesothelioma cases than previously estimated. We recommend the use of cancer registry data in tracking future asbestos-related disease in Vietnam.

Incidence and survival trends for malignant pleural and peritoneal mesothelioma, Australia, 1982-2009.

BACKGROUND: Australia is known to have had one of the highest per-capita asbestos consumption rates, yet there are few contemporary reports on malignant mesothelioma trends. METHODS: Data on 10 930 people with malignant pleural mesothelioma (MPM) and 640 people with malignant peritoneal mesothelioma diagnosed in Australia during 1982-2009 were analysed. Observed incidence rate trends were quantified. Incidence rates were projected up to 2030 using observed incident cases during 1982-2012. The relative per-decade change in excess mortality during 1999-2009 was estimated. RESULTS: During 1982-2009, acceleration in MPM age-standardised incidence rates were highest for women and those aged 75 years and above, with average annual percentage changes of +4.9 (95% CI 3.6 to 6.2) and +7.2 (95% CI 5.4 to 9.0), respectively. Age-standardised incidence rates for men with MPM aged 0-64 years decelerated rapidly during 2003-2009, an average annual percentage change of -5.1% (95% CI -7.6% to -2.5%). Overall, male age-specific MPM incidence rates in the age group of 65-74 year during 2010-2030 are projected to decline with rates projected to increase for older men and women with MPM. There was a statistically significant 16% relative reduction in the excess mortality rate (EMR) up to 5 years postdiagnosis for people diagnosed with malignant pleural and peritoneal mesothelioma combined in 2009 compared with those diagnosed in 1999, an EMR ratio of 0.84 (95% CI 0.77 to 0.92). CONCLUSIONS: Australia's malignant mesothelioma incidence rates appear to have reached maximum levels but with differences over time by age, gender and tumour location. Improvements over time in survival provide a glimpse of hope for this almost invariably fatal disease.

Patterns in the incidence, mortality and survival of malignant pleural and peritoneal mesothelioma, New South Wales, 1972-2009.

INTRODUCTION: Malignant pleural mesothelioma (MPM) and malignant peritoneal mesothelioma (MPeM) are often grouped together in descriptive epidemiological analyses, resulting in limited understanding of epidemiological patterns for these tumour types. METHODS: We studied patterns in the incidence, mortality and survival of people diagnosed with MPM (n=4,076) and MPeM (n=293) in New South Wales (NSW), Australia, 1972-2009. We also calculated 5-year relative survival for people diagnosed 1972-2006 followed up to 2007. We assessed patterns for each tumour type and histological subtype and, where possible, by combination of these categories. RESULTS: Annual MPM cases steadily increased over time (n=208 in 2009). There was an increasing trend in the MPM age-standardised incidence rate from 1972 up to 1994. This rate increase has levelled off in the past 10 years. Since 1999, 11 cases of MPeM were diagnosed each year, on average. Five-year relative survival remained stable for MPM and MPeM. However, 5-year relative survival in 2002-2006 was substantially higher for people with MPM epithelioid histological subtype (11.7% [95%CI 6.8-18.2%]) compared to all other non-epithelioid histological subtypes (6.9% [95%CI 5.0-9.1%]), a 70% difference. Survival was also greater for women with MPM (13.4% [95%CI 8.5-19.4%]) compared to men (7.0% [95%CI 5.1-9.2%]). INTERPRETATION: MPM incidence rates have stabilised since the mid-1990s, suggesting that maximum incidence levels have been reached. When more up-to-date data are available, survival estimates should be reanalysed to include people likely to benefit from the wide introduction of combination chemotherapy in 2007, including pemetrexed.

Trends in incidence and survival for anal cancer in New South Wales, Australia, 1972-2009.

INTRODUCTION: Little is known about the incidence and survival of anal cancer in New South Wales (NSW), Australia, as anal cancer cases are often grouped together with other colorectal cancers in descriptive epidemiological analyses. METHODS: We studied patterns and trends in the incidence and survival of people diagnosed with anal cancer in NSW, Australia, 1972-2009 (n=2724). We also predicted anal cancer incidence in NSW during 2010-2032. Given the human papilloma virus-associated aetiology for most anal cancers, we quantified these changes over time in incidence and survival by histological subtype: anal squamous cell carcinoma (ASCC); and anal adenocarcinoma (AAC). RESULTS: There was a linear increase in incident anal cancer cases in NSW with an average annual percentage change (AAPC) of 1.6 (95% CI 1.1-2.0) such that, in combination with age-period-cohort modelling, we predict there will be 198 cases of anal cancer in the 2032 calendar year (95% CI 169-236). Almost all of these anal cancer cases are projected to be ASCC (94%). Survival improved over time regardless of histological subtype. However, five-year relative survival was substantially higher for people with ASCC (70% (95% CI 66-74%)) compared to AAC (51% (95% CI 43-59%)), a 37% difference. Survival was also greater for women (69% (95% CI 64-73%)) with ASCC compared to men (55% (95% CI 50-60%)). It was not possible to estimate survival by stage at diagnosis particularly given that 8% of all cases were recorded as having distant stage and 22% had missing stage data. INTERPRETATION: Aetiological explanations, namely exposure to oncogenic types of human papillomavirus, along with demographic changes most likely explain the actual and projected increase in ASCC case numbers. Survival differences by gender and histological subtype point to areas where further research is warranted to improve treatment and outcomes for all anal cancer patients.

Trends in ethnic and socioeconomic inequalities in cancer survival, New Zealand, 1991-2004.

Improvements in cancer survival may be distributed inequitably throughout populations and across time. We assessed trends in cancer survival inequalities in New Zealand by ethnic and income group. 126,477 people diagnosed with cancer between 1991 and 2004, followed-up to 2006, were included. First, inequalities pooled over time were measured with excess mortality rate ratios (EMRRs). Second, interpretation of changes in inequalities over time can differ depending on whether one uses EMRRs, excess mortality rate differences (EMRD) or absolute differences in relative survival risks (RSRD); we estimated all three by cancer-site and (for EMRRs only) pooled across all sites. We found that pooled over time and all sites, Maori had an EMRR of 1.29 (95% CI, 1.24-1.34) compared to non-Maori. The low compared to high-income EMRR was 1.12 (95% CI, 1.09-1.15). Pooled over cancers, there was no change in the ethnic EMRR over time but the income EMRR increased by 9% per decade (1-17%). Changes over time in site-specific inequalities were imprecisely measured, but the direction of change was usually consistent across EMRRs, EMRDs and RSRDs. There were persistent ethnic inequalities in cancer survival over time, and slower improvements for low-income people.

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2).

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems. FUNDING: Canadian Partnership Against Cancer (Toronto, Canada), Cancer Focus Northern Ireland (Belfast, UK), Cancer Institute New South Wales (Sydney, Australia), Cancer Research UK (London, UK), Centers for Disease Control and Prevention (Atlanta, GA, USA), Swiss Re (London, UK), Swiss Cancer Research foundation (Bern, Switzerland), Swiss Cancer League (Bern, Switzerland), and University of Kentucky (Lexington, KY, USA).

Bias in relative survival methods when using incorrect life-tables: lung and bladder cancer by smoking status and ethnicity in New Zealand.

Relative survival and excess mortality approaches are commonly used to estimate and compare net survival from cancer. These approaches are based on the assumption that the underlying (non-cancer) mortality rate of cancer patients is the same as that of the general population. This assumption is likely to be violated particularly in the context of smoking-related cancers. The magnitude of this bias has not been estimated. The objective of this article is to estimate the bias in relative survival ratios (RSRs) and excess mortality rate ratios (EMRRs) from using total population compared to correct subpopulation specific life-tables. Analyses were conducted on 1996-2001 linked census-cancer data (including smoking status) for people with lung and bladder cancer, using sex-specific (standard practice), sex- and ethnic-specific, sex- and smoking-specific and sex-, ethnic- and smoking-specific life-tables. Five-year RSRs using sex-specific life-tables, compared to fully stratified life-tables, were underestimated by 10-25% for current smoking and Maori populations. For example, the current smoker male bladder cancer RSR was 0.700 for sex-specific life-tables, compared to 0.838 for fully stratified life-tables. Similarly, EMRRs comparing current to never smokers and Maori to non-Maori were overestimated using sex-specific life-tables only: modestly only for lung cancer, but markedly for bladder cancer. For example, the EMRR comparing current to never smokers with bladder cancer in a fully adjusted regression model was 1.475 when using sex-specific life-tables only, but reduced to 1.098 when using fully stratified life-tables. Substantial bias can occur when estimating relative cancer survival across subpopulations if non-matching life-tables are used.

Trends in survival and life expectancy by ethnicity, income and smoking in New Zealand: 1980s to 2000s.

BACKGROUND: Survival and life expectancy are commonly used metrics to describe population health. There are two objectives to this paper: (1) to provide an explanation of methods and data used to develop New Zealand life-tables by ethnic, income and smoking groups; and (2) to compare cumulative survival and life expectancy trends in these subpopulations. METHOD: We generated sex-specific life-tables for seven subpopulations: ethnicity (Maori and non-Maori); income tertiles; smoking (never and current); and two-way combinations (ethnicity by income; ethnicity by smoking; and smoking by income). This was repeated for five census-mortality cohorts (1981-84, 1986-89, 1991-94, 1996-99, and 2001-04). The method used to create the life-tables brings together three pieces of information: (1) the official Statistics New Zealand (SNZ) life-tables by year and sex; (2) the proportionate distribution of the total population by subpopulation (e.g. smoking prevalence); and (3) estimates of the differences in subpopulation mortality rates (from the New Zealand Census-Mortality Study [NZCMS]). RESULTS: Survival and life expectancy improved in all subpopulations across the five census cohorts. However, improvements were greater in non-Maori compared to Maori and high income compared to low income subpopulations. This led to widening of the gap in life expectancy between 1981 and 2001 between Maori and non-Maori (males), which increased from 5.4 years in 1981 to 9.0 in 2001 and between low income and high income which increased from 4.4 in 1981 to 6.5 in 2001 for males. The gap in life expectancy between current and never smokers in 1996 was 7.6 in males and 6.7 in females. However, the size of this gap varied by ethnicity: 7.3 and 6.2 for non-Maori males and females, and 4.3 and 3.9 for Maori male and females. Correspondingly, the gap in life expectancy between Maori and non-Maori is greater among never smokers (9.7 and 8.4 for males and females) than among current smokers (4.3 and 6.6 for males and females). CONCLUSION: Life-tables have been successfully developed for subpopulations in New Zealand, and provide an alternative understanding of health and life in New Zealand over the past 20 years. Ethnic and income gaps in life expectancy have widened, and perhaps surprising results were found for smoking by ethnicity. These life-tables provide an important basis for subpopulation modelling and projections, and are freely available to researchers.