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Concept: Mesothelioma

307

Malignant mesothelioma is a neoplasm associated with occupational and environmental inhalation exposure to asbestos* fibers and other elongate mineral particles (EMPs) (1-3). Patients have a median survival of approximately 1 year from the time of diagnosis (1). The latency period from first causative exposure to malignant mesothelioma development typically ranges from 20 to 40 years but can be as long as 71 years (2,3). Hazardous occupational exposures to asbestos fibers and other EMPs have occurred in a variety of industrial operations, including mining and milling, manufacturing, shipbuilding and repair, and construction (3). Current exposures to commercial asbestos in the United States occur predominantly during maintenance operations and remediation of older buildings containing asbestos (3,4). To update information on malignant mesothelioma mortality (5), CDC analyzed annual multiple cause-of-death records(†) for 1999-2015, the most recent years for which complete data are available. During 1999-2015, a total of 45,221 deaths with malignant mesothelioma mentioned on the death certificate as the underlying or contributing cause of death were reported in the United States, increasing from 2,479 deaths in 1999 to 2,597 in 2015 (in the same time period the age-adjusted death rates(§) decreased from 13.96 per million in 1999 to 10.93 in 2015). Malignant mesothelioma deaths increased for persons aged ≥85 years, both sexes, persons of white, black, and Asian or Pacific Islander race, and all ethnic groups. Despite regulatory actions and the decline in use of asbestos the annual number of malignant mesothelioma deaths remains substantial. The continuing occurrence of malignant mesothelioma deaths underscores the need for maintaining measures to prevent exposure to asbestos fibers and other causative EMPs and for ongoing surveillance to monitor temporal trends.

Concepts: Cancer, Death, Demography, United States, Race, Mesothelioma, Asbestos, Pacific Islander American

173

Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.

Concepts: Gene, Cancer, Oncology, Copy number variation, Chromosome, Chemical reaction, Rat, Mesothelioma

146

Asbestos is a harmful and exceptionally persistent natural material. Malignant mesothelioma (MM), an asbestos-related disease, is an insidious, lethal cancer that is poorly responsive to current treatments. Minimally invasive, specific, and sensitive biomarkers providing early and effective diagnosis in high-risk patients are urgently needed. MicroRNAs (miRNAs, miRs) are endogenous, non-coding, small RNAs with established diagnostic value in cancer and pollution exposure. A systematic review and a qualitative meta-analysis were conducted to identify high-confidence miRNAs that can serve as biomarkers of asbestos exposure and MM.

Concepts: Cancer, Oncology, Medical terms, MicroRNA, Mesothelioma, Asbestos, Asbestos and the law, Wittenoom, Western Australia

144

Multiwalled carbon nanotubes (MWCNT) have a fibrous structure and physical properties similar to asbestos and have been shown to induce malignant mesothelioma of the peritoneum after injection into the scrotum or peritoneal cavity in rats and mice. For human cancer risk assessment, however, data after administration of MWCNT via the airway, the exposure route that is most relevant to humans, is required. The present study was undertaken to investigate the carcinogenicity of MWCNT-N (NIKKISO Co., Ltd) after administration to the rat lung. MWCNT-N was fractionated by passing it through a sieve with a pore size of 35 μm. The average lengths of the MWCNT were 4.2 μm before filtration and 2.6 μm in the flow-through fraction; the length of the retained MWCNT could not be determined. 10-week-old F344/Crj male rats were divided into 5 groups: no treatment, vehicle control, MWCNT-N before filtration, MWCNT-N flow-through, and MWCNT-N retained groups. Administration was by the trans-tracheal intrapulmonary spraying (TIPS) method. Rats were administered a total of 1 mg/rat during the initial 2-weeks of the experiment and then observed up to 109 weeks. The incidences of malignant mesothelioma and lung tumors (bronchiolo-alveolar adenomas and carcinomas) were 6/38 and 14/38, respectively, in the three groups administered MWCNT and 0/28 and 0/28, respectively, in the control groups. All malignant mesotheliomas were localized in the pericardial pleural cavity. The sieve fractions did not have a significant effect on tumor incidence. In conclusion, administration of MWCNT to the lung in the rat induces malignant mesothelioma and lung tumors. This article is protected by copyright. All rights reserved.

Concepts: Cancer, Oncology, Lung cancer, Rat, Carbon nanotube, Mesothelioma, Asbestos, Copyright

142

Malignant Mesothelioma (MM) is a tumor of the serous membranes linked to exposure to asbestos. A chronic inflammatory response orchestrated by mesothelial cells contributes to the development and progression of MM. The evidence that: (a) multiple signaling pathways are aberrantly activated in MM cells; (b) asbestos mediated-chronic inflammation has a key role in MM carcinogenesis; © the deregulation of the immune system might favor the development of MM; and (d) a drug might have a better efficacy when injected into a serous cavity thus bypassing biotransformation and reaching an effective dose has prompted investigations to evaluate the effects of polyphenols for the therapy and prevention of MM. Dietary polyphenols are able to inhibit cancer cell growth by targeting multiple signaling pathways, reducing inflammation, and modulating immune response. The ability of polyphenols to modulate the production of pro-inflammatory molecules by targeting signaling pathways or ROS might represent a key mechanism to prevent and/or to contrast the development of MM. In this review, we will report the current knowledge on the ability of polyphenols to modulate the immune system and production of mediators of inflammation, thus revealing an important tool in preventing and/or counteracting the growth of MM.

Concepts: Immune system, Inflammation, Cancer, Bacteria, Signal transduction, Asthma, Mesothelioma, Eicosanoid

133

The use of novel radiotherapy techniques is widely increasing, allowing clinicians to treat diseases that were previously difficult to treat with radiation therapy. Malignant pleural mesothelioma is a clear example of this clinical challenge. We describe our first experience with intensity-modulated radiotherapy technique which was used to treat a 73-year-old patient with multiple relapsing malignant pleural mesothelioma. Intensity-modulated radiation therapy has allowed to respect the QUANTEC (quantitative analyses of normal tissue effects in the clinic) dose constraints, patient has experienced a 14 months progression-free time, without relevant subacute or late lung toxicity.

Concepts: Medicine, Cancer, Ionizing radiation, Medical terms, Radiation therapy, Radiobiology, Mesothelioma

132

The differential diagnosis between pleural malignant mesothelioma (MM) and lung cancer is often challenging. Immunohistochemical (IHC) stains used to distinguish these malignancies include markers that are most often positive in MM and less frequently positive in carcinomas, and vice versa. However, in about 10-20% of the cases, the IHC results can be confusing and inconclusive, and novel markers are sought to increase the diagnostic accuracy. We stained 45 non-small cell lung cancer samples (32 adenocarcinomas and 13 squamous cell carcinomas) with a monoclonal antibody for BRCA1-associated protein 1 (BAP1) and also with an IHC panel we routinely use to help differentiate MM from carcinomas, which include, calretinin, Wilms Tumor 1, cytokeratin 5, podoplanin D2-40, pankeratin CAM5.2, thyroid transcription factor 1, Napsin-A, and p63. Nuclear BAP1 expression was also analyzed in 35 MM biopsies. All 45 non-small cell lung cancer biopsies stained positive for nuclear BAP1, whereas 22/35 (63%) MM biopsies lacked nuclear BAP1 staining, consistent with previous data. Lack of BAP1 nuclear staining was associated with MM (two-tailed Fisher’s Exact Test, P = 5.4 x 10-11). Focal BAP1 staining was observed in a subset of samples, suggesting polyclonality. Diagnostic accuracy of other classical IHC markers was in agreement with previous studies. Our study indicated that absence of nuclear BAP1 stain helps differentiate MM from lung carcinomas. We suggest that BAP1 staining should be added to the IHC panel that is currently used to distinguish these malignancies.

Concepts: Cancer, Metastasis, Lung cancer, Types of cancer, Carcinoma, Squamous cell carcinoma, Mesothelioma, Asbestos

131

Vasculogenic mimicry, the process in which cancer cells form angiomatoid structures independent of or in addition to host angiogenesis has been recorded in several otherwise non-endothelial malignant neoplasms. This study describes evidence of routine vascular mimicry by human mesothelioma cell lines in vitro, when the cell lines are cultured alone or co-cultured with human umbilical vascular endothelial cells, with the formation of angiomatoid tubular networks. Vasculogenic mimicry is also supported by immunohistochemical demonstration of human-specific anti-mitochondria antibody labelling of tumour-associated vasculature of human mesothelioma cells xenotransplanted into nude mice, and by evidence of vascular mimicry in some biopsy samples of human malignant mesotheliomas. These studies show mosaic interlacing of cells that co-label or label individually for immunohistochemical markers of endothelial and mesothelial differentiation. If vascular mimicry in mesothelioma can be characterised more fully, this may facilitate identification of more specific and targeted therapeutic approaches such as anti-angiogenesis in combination with chemotherapy and immunotherapy or other therapeutic approaches.

Concepts: Immune system, Gene expression, Cancer, Metastasis, Oncology, Angiogenesis, Endothelium, Mesothelioma

130

Malignant mesothelioma caused by asbestos exposure has a long latency period. A ban on asbestos use may not be apparent in decreased incidence in the population until after several decades. The aim was to evaluate changes in the incidence of malignant mesothelioma, and the possible impact of the asbestos ban implemented in Iceland in 1983.

Concepts: Cancer, Mesothelioma, Asbestos, Asbestos and the law, Wittenoom, Western Australia

125

Inhalation of asbestos fibres is the predominant cause of malignant mesothelioma. Domestic exposure to asbestos is a major community concern in the Australian Capital Territory (ACT) because of loose-fill asbestos home insulation. Little is known about how trends in mesothelioma rates in the ACT compare with those elsewhere. The objective of this study was to describe trends in mesothelioma rates in the ACT and compare them with those for the rest of Australia.

Concepts: Cancer, Australia, Mesothelioma, Asbestos, New South Wales, Australian Capital Territory, Asbestos and the law, Jervis Bay Territory