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Bibliography on: Mesothelioma and Asbestos

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 24 Feb 2021 at 01:49 Created: 

Mesothelioma and Asbestos

Mesothelioma is a rare, but deadly form of cancer that is often (nearly always) associated with prior exposure to asbestos. The latency between exposure and disease onset is long, usually 20-50 years, making this a difficult cause-effect system to study.

Created with PubMed® Query: asbestos AND mesothelioma NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2021-02-22

Ierardi AM, Urban A, GM Marsh (2021)

A quantitative weight of evidence assessment of Hill's guidelines for causal inference for cosmetic talc as a cause of mesothelioma.

Toxicology and applied pharmacology pii:S0041-008X(21)00068-5 [Epub ahead of print].

Cosmetic talc has been suggested to cause mesothelioma. To assess a potential causal relationship between cosmetic talc and mesothelioma, a quantitative weight of evidence analysis was performed in accordance with Hill's nine original guidelines for causal inference using a published empirical model to weight each respective guideline. Various epidemiological, toxicological, and exposure studies related to cosmetic talc and risk of mesothelioma were included in an evaluation of each of Hill's guidelines. Probabilities that the guidelines were true were assigned based on expert judgment. We applied a sensitivity analysis to evaluate the variability of our probability estimates. The overall probability of causality for cosmetic talc and mesothelioma was approximately 1.29% (range: 0.73%-3.96%). This low probability of causality supports the conclusion that cosmetic talc is not related to the development of mesothelioma.

RevDate: 2021-02-22

Cheng YY, Yuen ML, H Jin (2021)

Editorial: Epigenetic Modifications in Mesothelioma.

Frontiers in oncology, 11:650136.

RevDate: 2021-02-22

Pestak CR, Boyce TW, Myers OB, et al (2021)

A Population-Based Feasibility Study of Occupation and Thoracic Malignancies in New Mexico.

Southwest journal of pulmonary & critical care, 22(1):23-25.

Background: Occupational exposures in mining and oil/gas extraction are known risk factors for thoracic malignancies (TMs). Given the relatively high proportion of these industries in New Mexico (NM), we conducted a feasibility study of adult lifetime occupational history among TM cases. We hypothesized a higher proportion of occupational TM in NM relative to the estimated national average of 10-14%.

Methods: We identified incident TM cases through the population-based New Mexico Tumor Registry (NMTR), from 2017-2018. Cases completed a telephone interview. An adjudication panel reviewed case histories and classified cancers as probable, possible, or non-occupational related, taking into account the presence, duration, and latency of exposures. We characterized recruitment and describe job titles and exposures among those with occupational TMs. We also compared the distributions of industry between those with and without occupational TM.

Results: The NMTR identified 400 eligible TM cases, 290 of which were available to be recruited (n=285 lung/bronchial cancer; n=5 mesotheliomas). Of the latter, 60% refused and 18% were deceased, 9% had invalid addresses, 11% were unable to be reached by telephone, and 3% were too ill to participate. The 43 cases who completed an interview held 236 jobs. A total of 33% of cases were classified as probable occupational TM and 5% as possible occupational TM.

Conclusions: High rates of early mortality and refusals were significant barriers to study participation. Nonetheless, the proportion of probable occupational TMs greatly exceeded the estimated national average, highlighting the need for further study of occupational TM in the state.

RevDate: 2021-02-12

Malpica A, Euscher ED, Marques-Piubelli ML, et al (2021)

Malignant Peritoneal Mesothelioma Associated With Endometriosis: A Clinicopathologic Study of 15 Cases.

International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists pii:00004347-900000000-98967 [Epub ahead of print].

Only a few cases of malignant peritoneal mesothelioma (MPeM) associated with endometriosis have been published; with chronic inflammation of the peritoneum associated with the latter being postulated as an inducing factor in the pathogenesis of this tumor. We assessed the clinicopathologic characteristics of MPeM associated with endometriosis to determine if there were other factors besides inflammation that may contribute to the pathogenesis in this patient population. Fifteen MPeM associated with endometriosis were retrieved from our files. Most presented with abdominal/pelvic pain, mass or distention; median age was 45 yr. Only 16% of patients had a history of asbestos exposure. In contrast, a third of the patients had a personal history of other neoplasms, and >80% had a family history of malignancies. Although most tumors had gross and microscopic features typical of MPeM, some had confounding features including "adhesion-like" appearance or gelatinous cysts/nodules, and signet ring cells. Tumors were epithelioid (9) and biphasic (6). MPeM was misdiagnosed as Müllerian carcinoma in 40% of cases. All patients (n=15) had cytoreductive surgery in addition to other therapies. Only 2/12 patients died of disease (17%). The 3- and 5-yr overall survival was 90%. MPeM associated with endometriosis tends to occur in patients with personal/familial history of malignancies, which may be a predisposing factor. In light of this finding, the role of endometriosis in the pathogenesis of MPeM is likely less relevant. The favorable outcome seen in these patients may be related to germline mutations or the hormonal milieu and needs further investigation.

RevDate: 2021-02-12

Sato T, Mukai S, Ikeda H, et al (2021)

Silencing of SmgGDS, a novel mTORC1 inducer that binds to RHEBs, inhibits malignant mesothelioma cell proliferation.

Molecular cancer research : MCR pii:1541-7786.MCR-20-0637 [Epub ahead of print].

Malignant mesothelioma (MM) is an aggressive tumor that typically develops after a long latency following asbestos exposure. Although mechanistic target of rapamycin complex 1 (mTORC1) activation enhances MM cell growth, the mTORC1 inhibitor everolimus has shown limited efficacy in clinical trials of MM patients. We explored the mechanism underlying mTORC1 activation in MM cells and its effects on cell proliferation and progression. Analysis of the expression profiles of 87 MMs from The Cancer Genome Atlas revealed that 40 samples (46%) displayed altered expression of RPTOR (mTORC1 component) and genes immediately upstream that activate mTORC1. Among them, we focused on RHEB and RHEBL1, which encode direct activators of mTORC1. Exogenous RHEBL1 expression enhanced MM cell growth, indicating that RHEB-mTORC1 signaling acts as a pro-oncogenic cascade. We investigated molecules that directly activate RHEBs, identifying SmgGDS as a novel RHEB-binding protein. SmgGDS knockdown reduced mTORC1 activation and inhibited the proliferation of MM cells with mTORC1 activation. Interestingly, SmgGDS displayed high binding affinity with inactive GDP-bound RHEBL1, and its knockdown reduced cytosolic RHEBL1 without affecting its activation. These findings suggest that SmgGDS retains GDP-bound RHEBs in the cytosol, whereas GTP-bound RHEBs are localized on intracellular membranes to promote mTORC1 activation. We revealed a novel role for SmgGDS in the RHEB-mTORC1 pathway and its potential as a therapeutic target in MM with aberrant mTORC1 activation. Implications: Our data showing that SmgGDS regulates RHEB localization to activate mTORC1 indicate that SmgGDS can be used as a new therapeutic target for MM exhibiting mTORC1 activation.

RevDate: 2021-02-11

Keller M, Reis K, Hjerpe A, et al (2021)

Cytoskeletal Organization Correlates to Motility and Invasiveness of Malignant Mesothelioma Cells.

Cancers, 13(4): pii:cancers13040685.

Malignant mesothelioma (MM) is a rare but highly aggressive cancer that primarily originates from the pleura, peritoneum or pericardium. There is a well-established link between asbestos exposure and progression of MM. Direct invasion of the surrounding tissues is the main feature of MM, which is dependent on dysregulated communication between the mesothelium and the microenvironment. This communication is dependent on the dynamic organization of the cytoskeleton. We have analyzed the organization and function of key cytoskeletal components in MM cell lines of increasing malignancies measured as migratory and invasive properties, and we show that highly malignant and invasive MM cells have an organization of the actin filament and vimentin systems that is distinct from the less malignant MM cell lines. In addition, the Hippo tumor suppressor pathway was inactivated in the invasive MM cells, which was seen as increased YAP nuclear localization.

RevDate: 2021-02-11

Lococo F (2021)

Malignant Pleural Mesothelioma: Time Is Running Out.

Journal of clinical medicine, 10(4): pii:jcm10040648.

Malignant pleural mesothelioma (MPM) is a rare but highly malignant disease of the pleura usually related to asbestos exposure [...].

RevDate: 2021-02-10

Emmett EA (2021)

Asbestos in High-Risk Communities: Public Health Implications.

International journal of environmental research and public health, 18(4): pii:ijerph18041579.

Asbestos-related diseases (ARDs)-mesothelioma, lung cancer, and asbestosis-are well known as occupational diseases. As industrial asbestos use is eliminated, ARDs within the general community from para-occupational, environmental, and natural exposures are more prominent. ARD clusters have been studied in communities including Broni, Italy; Libby, Montana; Wittenoom, Western Australia; Karain, Turkey; Ambler, Pennsylvania; and elsewhere. Community ARDs pose specific public health issues and challenges. Community exposure results in higher proportions of mesothelioma in women and a younger age distribution than occupational exposures. Exposure amount, age at exposure, fiber type, and genetic predisposition influence ARD expression; vulnerable groups include those with social and behavioral risk, exposure to extreme events, and genetic predispositions. To address community exposure, regulations should address all carcinogenic elongated mineral fibers. Banning asbestos mining, use, and importation will not reduce risks from asbestos already in place. Residents of high-risk communities are characteristically exposed through several pathways differing among communities. Administrative responsibility for controlling environmental exposures is more diffuse than for workplaces, complicated by diverse community attitudes to risk and prevention and legal complexity. The National Mesothelioma Registries help track the identification of communities at risk. High-risk communities need enhanced services for screening, diagnosis, treatment, and social and psychological support, including for retired asbestos workers. Legal settlements could help fund community programs. A focus on prevention, public health programs, particularization to specific community needs, and participation is recommended.

RevDate: 2021-02-10

Vogl M, Rosenmayr A, Bohanes T, et al (2021)

Biomarkers for Malignant Pleural Mesothelioma-A Novel View on Inflammation.

Cancers, 13(4): pii:cancers13040658.

Malignant pleural mesothelioma (MPM) is an aggressive disease with limited treatment response and devastating prognosis. Exposure to asbestos and chronic inflammation are acknowledged as main risk factors. Since immune therapy evolved as a promising novel treatment modality, we want to reevaluate and summarize the role of the inflammatory system in MPM. This review focuses on local tumor associated inflammation on the one hand and systemic inflammatory markers, and their impact on MPM outcome, on the other hand. Identification of new biomarkers helps to select optimal patient tailored therapy, avoid ineffective treatment with its related side effects and consequently improves patient's outcome in this rare disease. Additionally, a better understanding of the tumor promoting and tumor suppressing inflammatory processes, influencing MPM pathogenesis and progression, might also reveal possible new targets for MPM treatment. After reviewing the currently available literature and according to our own research, it is concluded that the suppression of the specific immune system and the activation of its innate counterpart are crucial drivers of MPM aggressiveness translating to poor patient outcome.

RevDate: 2021-02-08

Miyagawa C, Takaya H, Sakai K, et al (2021)

A novel malignant peritoneal mesothelioma with STRN exon 2 and ALK exon 20 : a case report and literature review.

The oncologist [Epub ahead of print].

Recently, several malignant peritoneal mesothelioma (MPMs) that occur in young women without asbestos exposure and with fusion genes such as anaplastic lymphoma kinase (ALK) and Ewing sarcoma breakpoint region 1 (EWSR1) have been reported. In the present case, we encountered MPM with STRN-ALK fusion in a 17-year-old female. The case did not respond to chemotherapy and is currently in a clinical trial of alectinib. This is the fourth reported case of MPM with STRN-ALK fusion. Of the 45 cancer cases with STRN-ALK fusion in which the fusion partners were examined, all cases except for the current case showed fusion of exon 3 of STRN and exon 20 of ALK. This is first case with fusion of exon 2 of STRN and exon 20 of ALK. Further advances in cancer genomic medicine may help clarify the clinical significance of this new fusion. KEY POINTS: Malignant peritoneal mesothelioma (MPMs) can occur in young women without asbestos exposure and show fusion genes that activate anaplastic lymphoma kinase (ALK) by gene rearrangement. ALK rearrangement and the fusion partner can be detected by companion diagnostics and by next generation sequencing. MPM patients with ALK rearrangement may benefit from target therapy.

RevDate: 2021-02-05

Franko A, Goricar K, Dodic Fikfak M, et al (2021)

The role of polymorphisms in glutathione-related genes in asbestos-related diseases.

Radiology and oncology pii:raon-2021-0002 [Epub ahead of print].

BACKGROUND: The study investigated the influence of GCLC, GCLM, GSTM1, GSTT1 and GSTP1 polymorphisms, as well as the influence of interactions between polymorphism and interactions between polymorphisms and asbestos exposure, on the risk of developing pleural plaques, asbestosis and malignant mesothelioma (MM).

SUBJECTS AND METHODS: The cross sectional study included 940 asbestos-exposed subjects, among them 390 subjects with pleural plaques, 147 subjects with asbestosis, 225 subjects with MM and 178 subjects with no asbestos-related disease. GCLC rs17883901, GCLM rs41303970, GSTM1 null, GSTT1 null, GSTP1 rs1695 and GSTP1 rs1138272 genotypes were determined using PCR based methods. In statistical analysis, logistic regression was used.

RESULTS: GSTT1 null genotype was associated with the decreased risk for pleural plaques (OR = 0.63; 95% CI = 0.40-0.98; p = 0.026) and asbestosis (OR = 0.51; 95% CI = 0.28-0.93; p = 0.028), but not for MM. A positive association was found between GSTP1 rs1695 AG + GG vs. AA genotypes for MM when compared to pleural plaques (OR = 1.39; 95% CI = 1.00-1.94; p = 0.049). The interactions between different polymorphisms showed no significant influence on the risk of investigated asbestos-related diseases. The interaction between GSTT1 null polymorphism and asbestos exposure decreased the MM risk (OR = 0.17; 95% CI = 0.03-0.85; p = 0.031).

CONCLUSIONS: Our findings suggest that GSTT1 null genotype may be associated with a decreased risk for pleural plaques and asbestosis, may modify the association between asbestos exposure and MM and may consequently act protectively on MM risk. This study also revealed a protective effect of the interaction between GSTP1 rs1695 polymorphism and asbestos exposure on MM risk.

RevDate: 2021-02-05

De Rienzo A, Coleman MH, Yeap BY, et al (2021)

Association of RERG Expression with Female Survival Advantage in Malignant Pleural Mesothelioma.

Cancers, 13(3): pii:cancers13030565.

Sex differences in incidence, prognosis, and treatment response have been described for many cancers. In malignant pleural mesothelioma (MPM), a lethal disease associated with asbestos exposure, men outnumber women 4 to 1, but women consistently live longer than men following surgery-based therapy. This study investigated whether tumor expression of genes associated with estrogen signaling could potentially explain observed survival differences. Two microarray datasets of MPM tumors were analyzed to discover estrogen-related genes associated with survival. A validation cohort of MPM tumors was selected to balance the numbers of men and women and control for competing prognostic influences. The RAS like estrogen regulated growth inhibitor (RERG) gene was identified as the most differentially-expressed estrogen-related gene in these tumors and predicted prognosis in discovery datasets. In the sex-matched validation cohort, low RERG expression was significantly associated with increased risk of death among women. No association between RERG expression and survival was found among men, and no relationship between estrogen receptor protein or gene expression and survival was found for either sex. Additional investigations are needed to elucidate the molecular mechanisms underlying this association and its sex specificity.

RevDate: 2021-02-04

Nadal E, Bosch-Barrera J, Cedrés S, et al (2021)

SEOM clinical guidelines for the treatment of malignant pleural mesothelioma (2020).

Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico pii:10.1007/s12094-020-02532-2 [Epub ahead of print].

Mesothelioma is a rare and aggressive tumour with dismal prognosis arising in the pleura and associated with asbestos exposure. Its incidence is on the rise worldwide. In selected patients with early-stage MPM, a maximal surgical cytoreduction in combination with additional antitumour treatment may be considered in selected patients assessed by a multidisciplinary tumor board. In patients with unresectable or advanced MPM, chemotherapy with platinum plus pemetrexed is the standard of care. Currently, no standard salvage therapy has been approved yet, but second-line chemotherapy with vinorelbine or gemcitabine is commonly used. Novel therapeutic approaches based on dual immunotherapy or chemotherapy plus immunotherapy demonstrated promising survival benefit and will probably be incorporated in the future.

RevDate: 2021-02-04

Rossini M, Martini F, Torreggiani E, et al (2020)

Metformin Induces Apoptosis and Inhibits Notch1 in Malignant Pleural Mesothelioma Cells.

Frontiers in cell and developmental biology, 8:534499.

Malignant pleural mesothelioma (MPM) is an aggressive asbestos-related cancer arising from the mesothelial cells lining the pleural cavity. MPM is characterized by a silent clinical progression and a highly resistance to conventional chemo/radio-therapies. MPM patients die in a few months/years from diagnosis. Notch signaling is a well-conserved cell communication system, which regulates many biological processes. In humans, the dysregulation of Notch pathway potentially contributes to cancer onset/progression, including MPM. Metformin is the first-line drug used to treat type 2 diabetes mellitus. Metformin is proven to be an effective antitumor drug in preclinical models of different types of cancer. To date, clinical efficacy is being studied in many clinical trials. In this study, the anti-proliferative effect of metformin on MPM cells and the putative involvement of Notch1 as a mediator of metformin activities, were investigated. MPM cells showed high levels of Notch1 activation compared to normal pleural mesothelial cells. Furthermore, metformin treatment hampered MPM cell proliferation and enhanced the apoptotic process, accompanied by decreased Notch1 activation.

RevDate: 2021-02-03

Fukui T, Okubo T, Tanimoto N, et al (2021)

Malignant pleural mesothelioma in a patient with pneumothorax: A cumbersome subtype both clinically and pathologically.

Here, we report a case of malignant pleural mesothelioma (MPM) that was very difficult to diagnose. A 62-year-old woman with a surgical history of recurrent bilateral pneumothorax was admitted to our hospital with severe dysphagia. Computed tomography (CT) detected stenosis in the lower esophagus. Immunohistochemical examination of a biopsy sample from the stenotic region was suggestive of MPM. Chemotherapy was initiated, but the patient soon weakened and died. Autopsy revealed atypical cells, identical to those seen in the biopsy sample which had spread into the stenotic esophagus and entire thoracic cavity. Although neither pleural thickening/nodules nor asbestos bodies were observed, we finally diagnosed the tumor as a biphasic-type MPM. We re-examined previous surgical specimens of pneumothorax and acknowledged foci of bland mesothelial cell proliferation which had the same pathological findings as tumor cells at autopsy. The lack of asbestos exposure and pleural thickening, an initial manifestation of pneumothorax, and faint cytological atypia prevented an early diagnosis. In cases of recurrent pneumothorax in elderly patients, MPM should be included in the differential diagnosis.

RevDate: 2021-02-03

Piro R, Fontana M, Livrieri F, et al (2021)

Pleural mesothelioma: When echo-endoscopy (EUS-B-FNA) leads to diagnosis in a minimally invasive way.

Malignant pleural mesothelioma (MPM) is an asbestos-related and locally invasive tumor with poor prognosis. The acquisition of histological material is mandatory in order to establish a diagnosis. In this situation, the sampling of tissue is generally performed via a thoracoscopic pleural biopsy, either medically or surgically. The use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) or transesophageal fine needle aspiration with an EBUS scope (EUS-B-FNA) of pleural lesions have only rarely been reported due to the theoretical limitations of tissue acquisition in such cases. We herein report a rare case of MPM successfully diagnosed via EUS-B-FNA in a 49-year-old woman with an unusual presentation characterized by solid thickening in the right mediastinal pleura.

RevDate: 2021-02-03

Dell LD, Gallagher AE, Yost LJ, et al (2021)

Integration of Evidence on Community Cancer Risks from Elongate Mineral Particles in Silver Bay, Minnesota.

Risk analysis : an official publication of the Society for Risk Analysis [Epub ahead of print].

The potential for cancer-related risks to community members from ambient exposure to elongate mineral particles (EMPs) in taconite processing has not been formally evaluated. We evaluated 926 ambient air samples including 12,928 EMPs (particle structures with length-to-width ratio ≥3:1) collected over 26 years near a taconite processing facility in Silver Bay, Minnesota. Eighty-two percent of EMPs were ≤3 μm in length and 97% of EMPs had an average aspect ratio <20:1. A total of 935 (7.3%) EMPs had length >5 μm and AR ≥3:1. Average ambient concentration of NIOSH countable amphibole EMPs over all years was 0.000387 EMPs per cubic centimeter (EMP/cm3). Of 12,765 nonchrysotile EMPs, the number of amphiboles with length and width dimensions that correlate best with asbestos-related carcinogenicity ranged from four (0.03%) to 13 (0.1%) and the associated ambient amphibole air concentrations ranged from 0.000003 to 0.000007 EMP/cm3 . After 65 years of taconite processing in Silver Bay, evidence of an increased risk of mesothelioma and lung cancer in community members who did not work in the taconite industry is lacking. The absence of an increased risk of asbestos-related cancer in the Silver Bay community is coherent with supporting evidence from epidemiological and toxicological studies, as well as ambient exposure data and lake sediment data collected in Minnesota Iron Range communities. Collectively, the data provide consistent evidence that nonasbestiform amphibole minerals lack the carcinogenic potential exhibited by amphibole asbestos.

RevDate: 2021-01-30

Nowak AK (2021)

New and old treatments for malignant mesothelioma: not just immunotherapy.

The Lancet. Respiratory medicine pii:S2213-2600(20)30516-6 [Epub ahead of print].

RevDate: 2021-01-29

Cook AM, McDonnell A, Millward MJ, et al (2021)

A phase 1b clinical trial optimising regulatory T cell depletion in combination with platinum-based chemotherapy in thoracic cancers.

Expert review of anticancer therapy [Epub ahead of print].

Background: Single-agent cyclophosphamide can deplete regulatory T-cells (Treg). We aimed to determine optimal dosing and scheduling of oral cyclophosphamide, alongside pemetrexed-based chemotherapy, to deplete Treg in mesothelioma or non-small-cell lung cancer patients. Methods: 31 Patients received pemetrexed +/- cisplatin or carboplatin on day 1 of a 21-day cycle (maximum 6 cycles). From cycle two, patients received cyclophosphamide, 50 mg/day, with intrapatient escalation to maximum 100/150 mg/day alternately. Immunological changes were examined by flow cytometry. Primary endpoint was Treg proportion of CD4+ T-cells, with doses tailored to target Treg nadir <4%. Results: Reduction in Treg proportion was observed on day 8 of all cycles, and was not augmented by cyclophosphamide. Few patients achieved the <4% Treg target. Treg proliferation reached nadir one week after chemotherapy, and peaked on day 1 of the subsequent cycle. Efficacy parameters were similar to chemotherapy alone. 17% of patients ceased cyclophosphamide due to toxicity. Conclusions: Specific Treg depletion to the degree seen with single-agent cyclophosphamide was not observed during pemetrexed-based chemotherapy. This study highlights the poor evidence basis for use of cyclophosphamide as an immunotherapeutic in combination with chemotherapy, and the importance of detailed flow cytometry studies. Trial registration: Clinical trial registration: www.anzctr.org.au identifier is 12609000260224.

RevDate: 2021-01-28

Barone Adesi F, Bruno C, Calisti R, et al (2020)

[Effects of Asbestos on Human Health. Document of the Italian Epidemiological Association (AIE)].

Epidemiologia e prevenzione, 44(5-6):In press.

OBJECTIVES: the Italian Epidemiological Association (AIE) intends to formulate assessments and recommendations on the most relevant and critical aspects in the preparation, conduct, and interpretation of epidemiological investigations on the health effects of exposure to asbestos and asbestos-like fibres.

the document was prepared by a working group of AIE associates, with a broad curriculum of epidemiological investigations, starting from the evaluation of scientific evidence, and was subsequently evaluated by the AIE governing body.

RESULTS: the topics covered included: • consumption and presence of asbestos; • association between asbestos exposure and disease; • epidemiological surveillance of asbestos related diseases in Italy; • risk function for asbestos related diseases; • increased risk and anticipation of the disease; • interaction between asbestos and other carcinogens; • diagnosis in epidemiological studies; • assessment of exposure to asbestos; • epidemiological evidence on asbestos related diseases.

CONCLUSIONS: the document ends with a summary of the conclusions of scientific research shared by AIE, with reflection on the methodology to be followed for the application at individual level of the results of epidemiological studies, and the proposal of themes on which to direct research.

RevDate: 2021-01-27

Ringgaard Petersen T, Panou V, Meristoudis C, et al (2021)

Clinical prognostic factors in pleural mesothelioma: best supportive care and anti-tumor treatments in a real-life setting.

Acta oncologica (Stockholm, Sweden) [Epub ahead of print].

BACKGROUND: This study aims to investigate patient- and disease characteristics associated with survival in malignant pleural mesothelioma (MPM) patients with anti-tumor treatment or with best supportive care (BSC).

MATERIALS AND METHODS: Consecutive MPM cases diagnosed in North Denmark Region from 1972 to 2015 were reevaluated and verified by two pathologists using modern immunohistochemical techniques. Danish registries and hospital records were used to gather patient-, asbestos exposure-, and disease information.

RESULTS: Of the 279 patients, anti-tumor treatment was administered to 184 patients (66.0%). All of those received chemotherapy alone or as part of a multimodal treatment, where pemetrexed was given to 126 (68.5%) patients. Asbestos exposure was documented in 92.5% of all patients. In the treated group, mean age was lower (66 years versus 74 years, p < 0.01), rate of occupational asbestos exposure was higher (74.5 versus 54.7%, p < 0.01), more patients had better performance score (98.4 versus 60%, p < 0.01) and stage was lower (81 versus 63.2%, p < 0.01) compared to the BSC group. Multivariate analysis showed that epithelioid subtype was the only common prognostic factor for OS in both groups. In BSC patients, good PS and female gender was associated with improved OS. Median overall survival (OS) was 17 versus 4 months (p < 0.01), and independently of the histopathological subtype, the median and 2-year survival was higher in the treated versus the BSC group (p < 0.02).

CONCLUSIONS: This retrospective study showed that epithelioid subtype is the only independent positive prognostic factor of survival in treated patients with MPM. For BSC patients, the epithelioid subtype, good PS, and female gender were positive prognostic factors, while age and comorbidities were not significant. This study with long-term follow-up of treated and BSC MPM patients can contribute to the clinical stratification of patients. Further validation is appropriate to verify these findings.

RevDate: 2021-01-27

Kwak K, Zoh KE, D Paek (2021)

Incidence of Cancer and Asbestos-Related Diseases among Residents Living near Abandoned Asbestos Mines in South Korea: A Retrospective Cohort Study Using National Health Insurance Database.

International journal of environmental research and public health, 18(3): pii:ijerph18030875.

The use of asbestos has been banned since 2009 in South Korea. However, there is still a risk of exposure to environmental asbestos originating from abandoned asbestos mines. We constructed a retrospective dynamic cohort using the National Health Insurance Database of South Korea. We determined the risk of developing asbestos-related diseases (ARDs) among residents living near asbestos mines compared with those living in the control area and the general population. The risks of asbestosis (adjusted hazards ratio [HR] 65.40, 95% CI = 35.02-122.12) and pleural plaques (adjusted HR 3.55, 95% CI = 1.96-6.41) were significantly increased among residents living near the asbestos mines compared with the control area. The risk of malignant mesothelioma was increased near asbestos mines compared with the control area; however, it was not significant (adjusted HR 1.83, 95% CI = 0.61-5.47). When a separate analysis according to sex was conducted, the risk of mesothelioma among male residents was statistically significant (adjusted HR 8.30, 95% CI = 1.04-66.63), and the standardized incidence ratio (SIR) was significantly increased (SIR 3.48, 95% CI = 1.50-6.85). The risk of ARDs was increased due to environmental asbestos exposure near abandoned asbestos mines in South Korea.

RevDate: 2021-01-21

Asciak R, George V, NM Rahman (2021)

Update on biology and management of mesothelioma.

European respiratory review : an official journal of the European Respiratory Society, 30(159): pii:30/159/200226.

Malignant pleural mesothelioma is an aggressive, incurable cancer that is usually caused by asbestos exposure several decades before symptoms arise. Despite widespread prohibition of asbestos production and supply, its incidence continues to increase. It is heterogeneous in its presentation and behaviour, and diagnosis can be notoriously difficult. Identification of actionable gene mutations has proven challenging and current treatment options are largely ineffective, with a median survival of 10-12 months.However, the past few years have witnessed major advances in our understanding of the biology and pathogenesis of mesothelioma. This has also revealed the limitations of existing diagnostic algorithms and identified new treatment targets.Recent clinical trials have re-examined the role of surgery, provided new options for the management of associated pleural effusions and heralded the addition of targeted therapies. The increasing complexity of mesothelioma management, along with a desperate need for further research, means that a multidisciplinary team framework is essential for the delivery of contemporary mesothelioma care.This review provides a synthesised overview of the current state of knowledge and an update on the latest research in the field.

RevDate: 2021-01-20

Marcq E, Van Audenaerde JRM, De Waele J, et al (2021)

The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3.

Cancers, 13(2): pii:cancers13020282.

Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous asbestos exposure in most afflicted patients. The prognosis of patients remains dismal, with a median overall survival of only 9-12 months, due to the limited effectiveness of any conventional anti-cancer treatment. New therapeutic strategies are needed to complement the limited armamentarium against MPM. We decided to focus on the combination of different immune checkpoint (IC) blocking antibodies (Abs). Programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), and lymphocyte activation gene-3 (LAG-3) blocking Abs were tested as monotherapies, and as part of a combination strategy with a second IC inhibitor. We investigated their effect in vitro by examining the changes in the immune-related cytokine secretion profile of supernatant collected from treated allogeneic MPM-peripheral blood mononuclear cell (PBMC) co-cultures. Based on our in vitro results of cytokine secretion, and flow cytometry data that showed a significant upregulation of PD-L1 on PBMC after co-culture, we chose to further investigate the combinations of anti PD-L1 + anti TIM-3 versus anti PD-L1 + anti LAG-3 therapies in vivo in the AB1-HA BALB/cJ mesothelioma mouse model. PD-L1 monotherapy, as well as its combination with LAG-3 blockade, resulted in in-vivo delayed tumor growth and significant survival benefit.

RevDate: 2021-01-20

Mensi C, Dallari B, Polonioli M, et al (2021)

Mesothelioma in Agriculture in Lombardy, Italy: An Unrecognized Risk.

International journal of environmental research and public health, 18(1): pii:ijerph18010358.

Cohort studies showed consistently low risks for malignant mesothelioma (MM) among agricultural workers, however the investigated exposures did not include asbestos. Our aim is to describe sources of asbestos exposure of MM in agriculture. Twenty-six MM cases in agricultural or seed trades workers were identified through the MM registry of the Lombardy region, Italy in 2000-2016. Asbestos exposures were investigated through a standardized questionnaire. The most frequent exposure circumstances were recycled jute bags previously containing asbestos (11 cases) and maintenance and repair of asbestos roofs (12 subjects). Three subjects performed maintenance and repair of tractor asbestos brakes and two used asbestos filters for wine production. Our data suggest asbestos exposure opportunities in the agricultural setting, underlining the need to look for this exposure in subjects affected with mesothelioma.

RevDate: 2021-01-19

Eccher A, Girolami I, Lucenteforte E, et al (2021)

Diagnostic mesothelioma biomarkers in effusion cytology.

Cancer cytopathology [Epub ahead of print].

Malignant mesothelioma is a rare malignancy with a poor prognosis whose development is related to asbestos fiber exposure. An increasing role of genetic predisposition has been recognized recently. Pleural biopsy is the gold standard for diagnosis, in which the identification of pleural invasion by atypical mesothelial cell is a major criterion. Pleural effusion is usually the first sign of disease; therefore, a cytological specimen is often the initial or the only specimen available for diagnosis. Given that reactive mesothelial cells may show marked atypia, the diagnosis of mesothelioma on cytomorphology alone is challenging. Accordingly, cell block preparation is encouraged, as it permits immunohistochemical staining. Traditional markers of mesothelioma such as glucose transporter 1 (GLUT1) and insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) are informative, but difficult to interpret when reactive proliferations aberrantly stain positive. BRCA1-associated protein 1 (BAP1) nuclear staining loss is highly specific for mesothelioma, but sensitivity is low in sarcomatoid tumors. Cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16 homozygous deletion, assessed by fluorescence in situ hybridization, is more specific for mesothelioma with better sensitivity, even in the sarcomatoid variant. The surrogate marker methylthioadenosine phosphorylase (MTAP) has been found to demonstrate excellent diagnostic correlation with p16. The purpose of this review is to provide an essential appraisal of the literature regarding the diagnostic value of many of these emerging biomarkers for malignant mesothelioma in effusion cytology.

RevDate: 2021-01-13

Borrelli EP, CG McGladrigan (2021)

A Review of Pharmacologic Management in the Treatment of Mesothelioma.

Current treatment options in oncology, 22(2):14.

OPINION STATEMENT: Mesothelioma is a rare and severe form of cancer that is associated with asbestos exposure. Approximately 2500 Americans die annually from this condition with a median survival of 1 year. The latency period of this disease ranges anywhere from 20 to 70 years, with shorter latency periods associated with a higher exposure intensity to asbestos. Therefore, cases of mesothelioma are expected in the coming decades. This highlights the need for clinicians to understand the pharmacologic regimens available for treating this rare, yet serious malignancy. With multiple treatment regimens available in the treatment of this condition, clinicians should take an evidence-based approach and consider the totality of evidence and safety information while considering the best patient-centered approach for treatment. This article provides a review of current pharmacologic treatment options available for mesothelioma and goes into detail about the recommended medication regimens and dosages and the available evidence of efficacy, effectiveness, and/or safety and estimates the annual cost of treatment for these medications on the U.S. healthcare system per patient. A brief introduction is provided for several promising agents currently under investigation for mesothelioma as well.

RevDate: 2021-01-13

Germine M, JH Puffer (2021)

Anthophyllite asbestos from Staten Island, New York: Longitudinal fiber splitting.

Archives of environmental & occupational health [Epub ahead of print].

Asbestos ore was sampled from a historical anthophyllite mine in Staten Island, New York. High-resolution transmission electron microscopy (HRTEM) was used to image the structure of nineteen fibers of the anthophyllite asbestos. The anthophyllite was characterized by a high level of chain width disorder, involving wide chain multiplicity faults (CMFs) that were frequent in fibers, randomly spaced, and ranged from one to eight chains in width. This chain width disorder was manifest by streaking of electron diffraction rows of chain width. The anthophyllite asbestos fibers were found to be produced by longitudinal splitting rather than crystal growth. Such splitting is a function of cleavage along CMFs rather than crystal boundaries. The morphology of the fibers is consistent with anthophyllite asbestos mined in Finland associated with lung cancer and mesothelioma. These findings may have regulatory implications.

RevDate: 2021-01-11
CmpDate: 2021-01-11

Manangama G, Gramond C, Audignon-Durand S, et al (2020)

Occupational exposure to unintentionally emitted nanoscale particles and risk of cancer: From lung to central nervous system - Results from three French case-control studies.

Environmental research, 191:110024.

OBJECTIVES: Nanoscale particles (1-100 nm) can be of natural origin, and either intentionally or unintentionally produced by human activities. Toxicological data have suggested a possible carcinogenic effect of such particles. The aim of this study was to estimate the association between occupational exposure to nanoscale particles and risk of lung cancer, pleural mesothelioma and brain tumors in adults.

METHODS: Three French population-based case-control studies were analyzed: 1) the ICARE study including 2029 lung cancer cases and 2591 controls; 2) the PNSM study including 371 pleural mesothelioma cases and 730 controls and 3) the CERENAT study including 257 brain tumor cases and 511 controls. Occupational exposure to unintentionally emitted nanoscale particles (UNPs) was retrospectively assessed by a job exposure matrix providing a probability and a frequency of exposure.

RESULTS: In adjusted analyses among men, significant associations between occupational exposure to UNPs and lung cancer (OR = 1.51; 95% CI: 1.22-1.86 and brain tumors (OR = 1.69; 95% CI: 1.17-2.44) were observed. No increased OR was observed for pleural mesothelioma (OR = 0.78; 95% CI: 0.46-1.33).

CONCLUSION: This is the first study showing positive associations between occupational exposure to UNPs and increased risk of lung cancer and brain tumors. These preliminary results should encourage further epidemiological research.

RevDate: 2021-01-10

Ejegi-Memeh S, Darlison L, Moylan A, et al (2020)

Living with mesothelioma: A qualitative study of the experiences of male military veterans in the UK.

European journal of oncology nursing : the official journal of European Oncology Nursing Society, 50:101889 pii:S1462-3889(20)30169-1 [Epub ahead of print].

PURPOSE: The UK has the highest incidence of mesothelioma in the world. Evidence in the United States suggests that mesothelioma may disproportionately affect military veterans. However, there has been no investigation of the experience of UK veterans living with mesothelioma. The Military Mesothelioma Experience Study (MiMES) aimed to understand the experience and health/support needs of British Armed Forces personnel/veterans with mesothelioma.

METHODS: Semi-structured interviews were conducted with 13 veterans living with mesothelioma, and nine family members of veterans living with mesothelioma. Participants were recruited via charities and asbestos support groups. Data were analysed using thematic analysis.

RESULTS: Participants' experiences are presented using three themes, i) exposure to asbestos and awareness of asbestos related diseases, ii) using military strategies to cope with mesothelioma and iii) preferences for information and support. MiMES indicates that the nature and range of UK military veterans' asbestos exposure is varied and not limited to high risk occupations. Participants' knowledge of asbestos and experience of mesothelioma influenced their experiences of diagnosis. Participants had coping strategies influenced by their military experiences. Assistance in navigating health and military systems was considered beneficial, especially if support was provided by professionals with knowledge or experience of the military. Attributes which may inhibit veterans from seeking professional support are discussed.

CONCLUSION: MiMES provides insight into how UK military veterans experience and cope with mesothelioma. Key implications focus on the role that Mesothelioma Nurse Specialists, Asbestos Support Groups and veterans groups play in providing acceptable support for UK veterans.

RevDate: 2021-01-09

Affatato R, Mendogni P, Del Gobbo A, et al (2020)

Establishment and Characterization of Patient-Derived Xenografts (PDXs) of Different Histology from Malignant Pleural Mesothelioma Patients.

Cancers, 12(12): pii:cancers12123846.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a very aggressive tumor originating from mesothelial cells. Although several etiological factors were reported to contribute to MPM onset, environmental exposure to asbestos is certainly a major risk factor. The latency between asbestos (or asbestos-like fibers) exposure and MPM onset is very long. MPM continues to be a tumor with poor prognosis despite the introduction of new therapies including immunotherapy. One of the major problems is the low number of preclinical models able to recapitulate the features of human tumors. This impacts the possible discovery of new treatments and combinations.

METHODS: In this work, we aimed to generate patient-derived xenografts (PDXs) from MPM patients covering the three major histotypes (epithelioid, sarcomatoid, and mixed) occurring in the clinic. To do this, we obtained fresh tumors from biopsies or pleurectomies, and samples were subcutaneously implanted in immunodeficient mice within 24 h.

RESULTS: We successfully isolated different PDXs and particularly concentrated our efforts on three covering the three histotypes. The tumors that grew in mice compared well histologically with the tumors of origin, and showed stable growth in mice and a low response to cisplatin, as was observed in the clinic.

CONCLUSIONS: These models are helpful in testing new drugs and combinations that, if successful, could rapidly translate to the clinical setting.

RevDate: 2021-01-08

Granieri A, Bonafede M, Marinaccio A, et al (2020)

SARS-CoV-2 and Asbestos Exposure: Can Our Experience With Mesothelioma Patients Help Us Understand the Psychological Consequences of COVID-19 and Develop Interventions?.

Frontiers in psychology, 11:584320.

Since its emergence, the novel coronavirus disease of 2019 (COVID-19) has had enormous physical, social, and psychological impacts worldwide. The aim of this article was to identify elements of our knowledge on asbestos exposure and malignant mesothelioma (MM) that can provide insight into the psychological impact of the COVID-19 pandemic and be used to develop adequate interventions. Although the etiology of Covid-19 and MM differs, their psychological impacts have common characteristics: in both diseases, there is a feeling of being exposed through aerial contagion to an "invisible killer" without boundaries that can strike even the strongest individuals. In both cases, affected persons can experience personality dysfunction, anxiety, depression, and posttraumatic symptoms; helplessness, hopelessness, and projection of destructive thoughts onto external forces often emerge, while defense mechanisms such as denial, splitting, repression, and reduced emotional expression are used by individuals to contain their overwhelming anxieties. We believe that in both diseases, an integrated multidimensional intervention offered by hospitals and other public health services is the most effective approach to alleviating patients' and caregivers' psychological distress. In particular, we emphasize that in the context of both MM and COVID-19, Brief Psychoanalytic Group therapy can help patients and caregivers attribute meaning to the significant changes in their lives related to the experience of the disease and identify adaptive strategies and more realistic relational modalities to deal with what has happened to them. We also highlight the importance of developing a surveillance system that includes individual anamnestic evaluation of occupational risk factors for COVID-19 disease.

RevDate: 2021-01-08

Gunatilake S, Lodge D, Neville D, et al (2021)

Predicting survival in malignant pleural mesothelioma using routine clinical and laboratory characteristics.

BMJ open respiratory research, 8(1):.

INTRODUCTION: The prognosis of malignant pleural mesothelioma (MPM) is poor, with a median survival of 8-12 months. The ability to predict prognosis in MPM would help clinicians to make informed decisions regarding treatment and identify appropriate research opportunities for patients. The aims of this study were to examine associations between clinical and pathological information gathered during routine care, and prognosis of patients with MPM, and to develop a 6-month mortality risk prediction model.

METHODS: A retrospective cohort study of patients diagnosed with MPM at Queen Alexandra Hospital, Portsmouth, UK between December 2009 and September 2013. Multivariate analysis was performed on routinely available histological, clinical and laboratory data to assess the association between different factors and 6-month survival, with significant associations used to create a model to predict the risk of death within 6 months of diagnosis with MPM.

RESULTS: 100 patients were included in the analysis. Variables significantly associated with patient survival in multivariate analysis were age (HR 1.31, 95% CI 1.09 to 1.56), smoking status (current smoker HR 3.42, 95% CI 1.11 to 4.20), chest pain (HR 2.14, 95% CI 1.23 to 3.72), weight loss (HR 2.13, 95% CI 1.18 to 3.72), platelet count (HR 1.05, 95% CI 1.00 to 1.10), urea (HR 2.73, 95% CI 1.31 to 5.69) and adjusted calcium (HR 1.47, 95% CI 1.10 to 1.94). The resulting risk model had a c-statistic value of 0.76. A Hosmer-Lemeshow test confirmed good calibration of the model against the original dataset.

CONCLUSION: Risk of death at 6 months in patients with a confirmed diagnosis of MPM can be predicted using variables readily available in clinical practice. The risk prediction model we have developed may be used to influence treatment decisions in patients with MPM. Further validation of the model requires evaluation of its performance on a separate dataset.

RevDate: 2021-01-05

Reis K, Arbiser JL, Hjerpe A, et al (2020)

Inhibitors of cytoskeletal dynamics in malignant mesothelioma.

Oncotarget, 11(50):4637-4647 pii:27843.

Malignant mesotheliomas (MMs) are highly aggressive mesenchymal tumors that originate from mesothelial cells lining serosal cavities; i.e., the pleura, peritoneum, and pericardium. Classically, there is a well-established link between asbestos exposure, oxidative stress, release of reactive oxygen species, and chronic inflammatory mediators that leads to progression of MMs. MMs have an intermediate phenotype, with co-expression of mesenchymal and epithelial markers and dysregulated communication between the mesothelium and the microenvironment. We have previously shown that the organization and function of key cytoskeletal components can distinguish highly invasive cell lines from those more indolent. Here, we used these tools to study three different types of small-molecule inhibitors, where their common feature is their influence on production of reactive oxygen species. One of these, imipramine blue, was particularly effective in counteracting some key malignant properties of highly invasive MM cells. This opens a new possibility for targeted inhibition of MMs based on well-established molecular mechanisms.

RevDate: 2021-01-05

Argani P, Lian DWQ, Agaimy A, et al (2021)

Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases.

The American journal of surgical pathology, Publish Ahead of Print: pii:00000478-900000000-97284 [Epub ahead of print].

Pediatric mesotheliomas are rare and their pathogenesis remains undefined. In this study, we report 5 cases of malignant mesothelioma in children, characterized by fusions involving the anaplastic lymphoma kinase (ALK) gene. Four cases occurred in females involving the abdominal cavity and were characterized by a pure epithelioid morphology. The fifth arose in the tunica vaginalis of a 15-year-old male and displayed a biphasic epithelioid-sarcomatoid phenotype. All cases demonstrated the classic morphologic and immunohistochemical features of malignant mesothelioma, including tubulopapillary architecture and cuboidal epithelioid cells with eosinophilic cytoplasm and uniform nuclei with vesicular chromatin. Immunohistochemically, all cases showed labeling for ALK, cytokeratins, WT1, and calretinin, while lacking expression of adenocarcinoma immunomarkers. Four cases demonstrated weak-moderate labeling for PAX8 protein, which resulted in diagnostic challenges with primary peritoneal serous carcinoma. The ALK genetic abnormalities were investigated by a combination of molecular methods. Archer FusionPlex was performed in 2 cases, showing fusions between ALK with either STRN or TPM1 genes, resulting in a transcript that retained the ALK kinase domain. One case was further studied by DNA targeted sequencing, but no additional genetic alterations were observed. In 1 case, cytogenetic analysis showed the presence of a t(2;15)(p23;q22) and fluorescence in situ hybridization confirmed the ALK gene break-apart. In the remaining 2 cases, ALK gene rearrangements were demonstrated by fluorescence in situ hybridization. Unlike adult mesotheliomas, which are tightly linked to asbestos exposure, often show loss of BAP1 expression and have complex karyotypes, ALK-rearranged mesothelioma appears to be similar to other fusion-positive mesotheliomas, such as those harboring EWSR1/FUS-ATF1 fusions, sharing significant morphologic overlap, occurring in young patients and displaying a simple, translocation-driven genetic profile.

RevDate: 2021-01-03

Marinaccio A, Consonni D, Mensi C, et al (2021)

Authors' response: Mezei et al's "Comments on a recent case-control study of malignant mesothelioma of the pericardium and the tunica vaginalis testis".

Scandinavian journal of work, environment & health, 47(1):87-89.

Mezei et al's letter (1) is an opportunity to provide more details about our study on pericardial and tunica vaginalis testis (TVT) mesothelioma (2), which is based on the Italian national mesothelioma registry (ReNaM): a surveillance system on mesothelioma, with individual asbestos exposure assessment. Incidence of pericardial mesothelioma has been estimated around 0.5 and 0.2 cases per 10 million person-years in men and women, respectively, and around 1 case for TVT mesothelioma. ReNaM collected 138 cases thanks to its long period of observation (1993-2015) and national coverage. Conducting a population-based case-control study with incidence-density sampling of controls across Italy and over a 23 year time-span should have been planned in 1993 and would have been beyond feasibility and ReNaM scope. We rather exploited two existing series of controls (3). The resulting incomplete time- and spatial matching of cases and controls is a limitation of our study and has been acknowledged in our article. The analysis of case-control studies can nevertheless be accomplished in logistic models accounting for the variables of interest, in both individually and frequency matched studies (4). Furthermore, analyses restricted to (i) regions with enrolled controls, (ii) cases with definite diagnosis, (iii) incidence period 2000-2015, and (iv) subjects born before 1950 have been provided in the manuscript, confirming the strength of the association with asbestos exposure (supplemental material tables S4-7). Following Mezei et al's suggestion, we performed further sensitivity analyses by restriction to regions with controls and fitting conditional regression models using risk-sets made of combinations of age and year of birth categories (5-year classes for both). We confirmed positive associations with occupational exposure to asbestos of pericardial mesothelioma, with odds ratios (OR) (adjusted for region) of 9.16 among women [95% confidence interval (CI) 0.56-150] and 5.63 (95% CI 1.02-31.0) among men; for TVT mesothelioma the OR was 7.70 (95% CI 2.89-20.5). Using risk sets of age categories and introducing year of birth (5-year categories) as a covariate (dummy variables) the OR were similar: OR (adjusted for region) of 9.17 among women (95% CI 0.56-150) and 5.76 (95% CI 1.07-31.0) among men; for TVT the OR was 9.86 (95% CI 3.46-28.1). Possible bias from incomplete geographical overlap between cases and controls has been addressed in the paper (table S4) and above. In spatially restricted analyses, OR were larger than in those including cases from the whole country, indicating that bias was towards the null. Mezei et al further noted that "the regional distribution of controls is different from that of person-time observed". This objection is not relevant because the above analyses were adjusted by region. Our controls were provided by a population-based study on pleural mesothelioma (called MISEM) and a hospital-based study on cholangiocarcinoma (called CARA). In MISEM, the response rate was 48.4%, a low but not unexpected rate as participation among population controls is usually lower and has been declining over time (5). It is important to underline that ReNaM applied the same questionnaire that was used for interviews and carried out the same exposure assessment as both MISEM and CARA. As repeatedly stated in ReNaM papers (6-7), each regional operating center assesses asbestos exposure based on the individual questionnaire, other available information, and knowledge of local industries. Occupational exposure to asbestos is classified as definite, probable or possible. Occupational exposure is (i) definite when the subject`s work was reported or otherwise known to have involved the use of asbestos or asbestos-containing materials (MCA); (ii) probable when subjects worked in factories where asbestos or MCA were used, but their personal exposure could not be documented; and (iii) possible when they were employed in industrial activities known to entail the use of asbestos or MCA. Hence, the definite and probable categories are closer to one another and were combined in our analyses. In any case, restricting analyses to subjects with definite occupational exposure and using each set of controls separately, as suggested by Mezei et al, yielded elevated OR for TVT and pericardial mesothelioma among men using both the above described modelling strategies; the OR could not be calculated for women. There were 70 (25 pericardial and 45 TVT) occupationally exposed mesothelioma cases. In population-based studies, analyses by occupation are limited by the low prevalence of most specific jobs. As briefly reported in our paper, for purely descriptive purposes, the industrial activity of exposure (cases may have multiple exposures), were construction (22 exposures, 7 and 15 for pericardial and TVT mesotheliomas, respectively), steel mills and other metal working industries (4 and 11), textile industries (2 and 3), and agriculture (2 and 5); other sectors had lower exposure frequencies. The absence of industries like asbestos-cement production, shipbuilding and railway carriages production/repair should not be surprising and had already been observed (7). In the Italian multicenter cohort study of asbestos workers (8), given the person-years of observation accrued by workers employed in these industries and gender- and site-specific crude incidence rates, approximately 0.1 case of pericardial and 0.2 of TVT mesothelioma would have been expected from 1970 to 2010. Even increasing ten-fold such figures to account for higher occupational risks among these workers would not change much. Asbestos exposure in agriculture has been repeatedly discussed in ReNaM reports (9: pages 70, 73, 128, 164 and 205). Exposure opportunities included the presence of asbestos in wine production, reuse of hessian bags previously containing asbestos, or construction and maintenance of rural buildings. Similarly, mesothelioma cases and agricultural workers exposed to asbestos have been noted in France (10). In conclusion, the additional analyses we performed according to Mezei et al's suggestions confirm the association between asbestos exposure and pericardial and TVT mesothelioma, supporting the causal role of asbestos for all mesotheliomas. ReNaM`s continuing surveillance system with national coverage is a precious platform for launching analytical studies on pleural and extra pleural mesothelioma. References 1. Mezei G, Chang ET, Mowat FS, Moolgavkar SH. Comments on a recent case-control study of malignant mesothelioma of the pericardium and the tunica vaginalis testis Scand J Work Environ Health. 2021;47(1):85-86. https://doi.org/10.5271/3909 2. Marinaccio A, Consonni D, Mensi C, Mirabelli D, Migliore E, Magnani C et al.; ReNaM Working Group. Association between asbestos exposure and pericardial and tunica vaginalis testis malignant mesothelioma: a case-control study and epidemiological remarks. Scand J Work Environ Health. 2020;46(6):609-617. https://doi.org/10.5271/sjweh.3895. 3. Greenland S. Control-initiated case-control studies. Int J Epidemiol 1985 Mar;14(1):130-4. https://doi.org/10.1093/ije/14.1.130. 4. Pearce N. Analysis of matched case-control studies. BMJ 2016 Feb;352:i969. https://doi.org/10.1136/bmj.i969. 5. Bigert C, Gustavsson P, Straif K, Pesch B, Brüning T, Kendzia B et al. Lung cancer risk among cooks when accounting for tobacco smoking: a pooled analysis of case-control studies from Europe, Canada, New Zealand, and China. J Occup Environ Med 2015 Feb;57(2):202-9. https://doi.org/10.1097/JOM.0000000000000337. 6. Marinaccio A, Binazzi A, Marzio DD, Scarselli A, Verardo M, Mirabelli D et al.; ReNaM Working Group. Pleural malignant mesothelioma epidemic: incidence, modalities of asbestos exposure and occupations involved from the Italian National Register. Int J Cancer 2012 May;130(9):2146-54. https://doi.org/10.1002/ijc.26229. 7. Marinaccio A, Binazzi A, Di Marzio D, Scarselli A, Verardo M, Mirabelli D et al. Incidence of extrapleural malignant mesothelioma and asbestos exposure, from the Italian national register. Occup Environ Med 2010 Nov;67(11):760-5. https://doi.org/10.1136/oem.2009.051466. 8. Ferrante D, Chellini E, Merler E, Pavone V, Silvestri S, Miligi L et al.; the working group. Italian pool of asbestos workers cohorts: mortality trends of asbestos-related neoplasms after long time since first exposure. Occup Environ Med 2017 Dec;74(12):887-98. https://doi.org/10.1136/oemed-2016-104100. 9. ReNaM VI Report. Available from: https://www.inail.it/cs/internet/docs/alg-pubbl-registro-nazionale-mesoteliomi-6-rapporto.pdf. Italian 10. Marant Micallef C, Shield KD, Vignat J, Baldi I, Charbotel B, Fervers B et al. Cancers in France in 2015 attributable to occupational exposures. Int J Hyg Environ Health 2019 Jan;222(1):22-9. https://doi.org/10.1016/j.ijheh.2018.07.015.

RevDate: 2021-01-01

Yoshikawa Y, Kuribayashi K, Minami T, et al (2020)

Epigenetic Alterations and Biomarkers for Immune Checkpoint Inhibitors-Current Standards and Future Perspectives in Malignant Pleural Mesothelioma Treatment.

Frontiers in oncology, 10:554570.

Malignant pleural mesothelioma (MPM) is strongly associated with occupational or environmental asbestos exposure and arises from neoplastic transformation of mesothelial cells in the pleural cavity. The only standard initial treatment for unresectable MPM is combination chemotherapy with cisplatin (CDDP) and pemetrexed (PEM). Further, CDDP/PEM is the only approved regimen with evidence of prolonged overall survival (OS), although the median OS for patients treated with this regimen is only 12 months after diagnosis. Thus, the development of new therapeutic strategies has been investigated for approximately 20 years. In contrast to recent advances in personalized lung cancer therapies, diagnostic and prognostic biomarker research has just started in mesothelioma. Epigenetic alterations include DNA methylation, histone modifications, and other chromatin-remodeling events. These processes are involved in numerous cellular processes including differentiation, development, and tumorigenesis. Epigenetic modifications play an important role in gene expression and regulation related to malignant MPM phenotypes and histological subtypes. An immune checkpoint PD-1 inhibitor, nivolumab, was approved as second-line therapy for patients who had failed initial chemotherapy, based on the results of the MERIT study. Various clinical immunotherapy trials are ongoing in patients with advanced MPM. In this review, we describe recent knowledge on epigenetic alterations, which might identify candidate therapeutic targets and immunotherapeutic regimens under development for MPM.

RevDate: 2020-12-31

Seastedt KP, Pruett N, CD Hoang (2020)

Mouse models for mesothelioma drug discovery and development.

Expert opinion on drug discovery [Epub ahead of print].

INTRODUCTION: Mesothelioma is an aggressive mesothelial lining tumor. Available drug therapies include chemotherapeutic agents, targeted molecular therapies, and immune system modulators. Mouse models were instrumental in the discovery and evaluation of such therapies, but there is need for improved understanding of the role of inflammation, tumor heterogeneity, mechanisms of carcinogenesis, and the tumor microenvironment. Novel mouse models may provide new insights and drive drug therapy discovery that improves efficacy.

AREAS COVERED: This review concerns available mouse models for mesothelioma drug discovery and development including the advantages and disadvantages of each. Gaps in current knowledge of mesothelioma are highlighted, and future directions for mouse model research are considered.

EXPERT OPINION: Soon, CRISPR-Cas gene-editing will improve understanding of mesothelioma mechanisms foundational to the discovery and testing of efficacious therapeutic targets. There are at least two likely areas of upcoming methodology development. One is concerned with precise modeling of inflammation - is it a causal process whereby inflammatory signals contribute to tumor initiation, or is it a secondary passenger process driven by asbestos exposure effects? The other area of methods improvement regards the availability of humanized immunocompromised mice harboring patient-derived xenografts. Combining human tumors in an environment with human immune cells will enable rapid innovation in immuno-oncology therapeutics.

RevDate: 2020-12-31

Oddone E, Bollon J, Nava CR, et al (2020)

Forecast of Malignant Peritoneal Mesothelioma Mortality in Italy up to 2040.

International journal of environmental research and public health, 18(1): pii:ijerph18010160.

Despite their differences, pleural and peritoneal mesothelioma are frequently lumped together to describe epidemic curves and to forecast future mesothelioma trends. This study aims to describe the malignant peritoneal mesothelioma (MPeM) epidemic in Italy (1996-2016) and to forecast future trends up to 2040 in order to contribute to the assessment of MPeM future burden. All MPeM deaths in Italy from 1996-2016 were collected (as provided by the Italian National Statistical Institute (ISTAT)) in order to estimate MPeM mortality rates for each 3-year period from 1996 to 2016. Poisson age-period-cohort (APC) models were then used to forecast MPeM future trends. Between 2017 and 2040, 1333 MPeM deaths are expected. The number of MPeM deaths, as well as mortality rates, are expected to constantly decrease throughout the considered period. Based on considering the information from this study, it can be concluded that the MPeM epidemic has probably already reached its peak in Italy.

RevDate: 2020-12-29

Brahim D, Mechergui N, Ben Said H, et al (2020)

Peritoneal mesothelioma associated with bladder cancer and occupational exposure to asbestos: A case report.

Clinical case reports, 8(12):3529-3532.

Mesothelioma is a rare tumor usually located on the pleura. In this typical location, it is closely linked to asbestos exposure. However, in other locations such as in peritoneal mesothelioma, the association to asbestos remains unusual.

RevDate: 2020-12-21

Re A, Shersher D, Allen A, et al (2020)

Malignant pleural neoplasm with both differentiation of epithelioid mesothelioma and squamous-cell carcinoma, a rare phenomena.

Diagnostic cytopathology [Epub ahead of print].

Malignant mesothelioma, a neoplasm arising within the serosal surfaces, has been linked closely to asbestos exposure. We present a case of 72-year-old male with a 27 year work-related history of asbestos exposure who presented with dyspnea. Chest computed tomography scan showed a large, right pleural effusion with compressive right lung atelectasis. Biopsies, subsequent pleurectomy and lung wedge resections revealed epithelioid malignant mesothelioma with associated focal non-keratinizing squamous-cell carcinoma, supported by extensive immunohistochemical stains and molecular studies. The patient was treated with 6 cycles of carboplatin/pemetrexed, showing no new metastases. Seven months post-treatment, the patient presented with progressive dyspnea and large pleural effusions. Bilateral pleural fluid was collected and showed malignant epithelioid cells, morphologically similar to the patient's pleural neoplastic cells. However, the tumor was positive for squamous cells markers and showed BAP1 loss, while negative for mesothelial markers. The findings support the diagnosis of squamous-cell carcinoma and were consistent with the patient's previously diagnosed pleural neoplastic origin. A malignant mesothelioma associated with squamous-cell carcinoma is a rare phenonmenon. To our knowledge, only two case reports are available in current literature. This unique case shows a single pleura tumor differentiating as both malignant mesothelioma and squamous-cell carcinoma. Squamous-cell carcinoma is the predominating malignancy seen within the bilateral pleural effusions, a potential pitfall for cytology specimen diagnosis.

RevDate: 2020-12-21

Fazzo L, Minelli G, Bruno C, et al (2020)

Early mortality from malignant mesothelioma in Italy as a proxy of environmental exposure to asbestos in children.

Annali dell'Istituto superiore di sanita, 56(4):478-486.

Malignant mesothelioma (MM) is a rare neoplasm caused by asbestos. Mortality from MM in ≤50 years old people, considering the long latency, is likely related to asbestos exposure in childhood. Mortality from MM (C45, ICD10 code) is described among ≤50 years (ys) old people in Italy, in 2003-2016. National and regional Standardized Rates (SRs) were computed by age-class. The North-South trend of regional SRs, increasing in >50ys age-class, showed a flat cline in ≤50ys old people. Municipal Standardized Mortality Ratios (SMRs) were computed, with respect to regional figures, for ≤50 ys old population. In Italy, 487 people ≤50 ys old died from MM, in 2003-2016 (2.5% of all MM deaths), corresponding to 35/year. The highest SMRs were observed in Northern Regions, the most industrialized areas. Exceeding SMRs were found in 10 municipalities where former asbestos-cement plants, shipyards, and a quarry contaminated by fluoro-edenite fibres were present. Early mortality from MM, proxy of childhood environmental asbestos exposure, deserves particular concern.

RevDate: 2020-12-22

Chand MT, Edens J, Lin T, et al (2020)

Benign multicystic peritoneal mesothelioma: literature review and update.

Autopsy & case reports, 10(3):e2020159.

Benign multicystic peritoneal mesothelioma (BMPM) is a rare peritoneal tumor diagnosed predominantly in pre-menopausal women. Associated risk factors include endometriosis and pelvic inflammatory disease in women, and prior abdominal surgery in both genders. To date, the pathogenesis of this disease remains controversial with possible etiologies, including a neoplastic versus a reactive process. Given the risk factors, some authors believe that this disease is secondary to a reactive process. However, because some studies describe cases where there is no prior surgical history or inflammatory milieu present, and because of this entity's predilection for recurrence, some authors believe the origin to be neoplastic. Some genetic and familial associations have also been reported. Malignant transformation is extremely rare, with only two cases reported in the literature, despite the recurrence potential. Like the etiology, the name of this entity is also controversial. Some authors prefer the term "peritoneal inclusion cyst (PCM)" instead of "benign cystic mesothelioma" and argue that the term mesothelioma should only be used when there is evidence of atypia. Most cases of BMPM are discovered incidentally. Others reflect sequela of tumor mass effect. It appears intra-operatively as large, multi-focal, cystic lesions in the peritoneal and pelvic cavity. Diagnosis is achieved through surgical sampling with histopathological examination. Immunobiologically, BMPM exhibits multiple small cystic spaces with flattened lining containing calretinin positive cells without atypical features, mitotic figures, or tissue invasion. Treatment includes cytoreductive surgery. Here we present a case of BMPM in a 60-year-old male - a rare disease in an uncommon patient population.

RevDate: 2020-12-18

Bartkowiak K, Casjens S, Andreas A, et al (2020)

Sensitive Blood-Based Detection of Asbestos-Associated Diseases Using Cysteine-Rich Angiogenic Inducer 61 as Circulating Protein Biomarker.

Clinical chemistry pii:6041272 [Epub ahead of print].

BACKGROUND: Detection of asbestos-associated diseases like asbestosis or mesothelioma is still challenging. We sought to improve the diagnosis of benign asbestos-associated disease (BAAD) by detection of the protein cysteine-rich angiogenic inducer 61 (Cyr61) in human plasma.

METHODS: Plasma Cyr61 was quantified using an enzyme-linked immunosorbent assay. Plasma samples from males diagnosed with BAAD, but without a malignant disease (n = 101), and malignant mesothelioma (n = 21; 15 males, 6 females), as well as nonasbestos-exposed healthy control participants (n = 150; 58 males, 92 females) were analyzed. Clinical sensitivity and specificity of Cyr61 were determined by receiver operating characteristic analysis.

RESULTS: The median plasma Cyr61 concentration for healthy control participants was 0.27 ng/mL. Cytoplasmic Cyr61 in peripheral blood mononuclear cells from healthy control participants was evenly distributed, as detected by immunofluorescent staining. The increase in plasma Cyr61 concentrations in the BAAD study group was statistically significant compared to the healthy control participants (P < 0.0001). For the detection of BAAD vs male healthy control participants, clinical sensitivity was 88% and clinical specificity 95% with an area under the curve of 0.924 at maximal Youden Index. For a predefined clinical specificity of 100%, the clinical sensitivity was 76%. For male mesothelioma patients vs male healthy control participants, the clinical sensitivity at maximal Youden Index was 95% with a clinical specificity of 100% (area under the curve, 0.997) and for a predefined clinical specificity of 100%, the clinical sensitivity was 93%.

CONCLUSIONS: In our study, plasma Cyr61 protein concentrations showed to be a new biomarker for asbestos-associated diseases like BAAD and mesothelioma in men, which deserves further investigation in large-scale cohort studies.

RevDate: 2020-12-18

Park EK, Johnson AR, Wilson D, et al (2020)

Follow-up of Soluble Mesothelin-Related Protein Levels in Participants With Asbestos-Related Disorders.

Safety and health at work, 11(4):425-430.

Background: Asbestos exposure is associated with the development of the cancer malignant mesothelioma (MM). Measurement of soluble mesothelin-related protein (SMRP) has been suggested as a method for detection of MM in its early stages. We prospectively examined SMRP levels in participants with asbestos exposure who are a group at a high risk of development of MM.

Methods: This study was a follow-up of our cohort of 322 asbestos-exposed participants. No further participants developed MM or malignancy over the study period. Mean follow-up time was 22.9 months.

Results: Mean (standard deviation) SMRP levels at baseline and follow-up were 0.94 (0.79) and 0.91 (0.86) nmol/L (p = 0.1033), respectively. Mean SMRP levels of the healthy individuals exposed to asbestos at baseline was significantly lower than those of participants with asbestosis and pleural plaques alone; similar patterns were found on follow-up measurements. There was a statistically significant effect of age on serial SMRP measurements. Our study confirms higher levels in participants with nonmalignant asbestos-related disorders. Levels decreased in asbestos-related disorders other than asbestosis, where a small increase was observed. We did not detect any further cases of malignancy.

Conclusion: Monitoring programs for early detection of MM need to take into account increased SMRP levels found in benign asbestos-related diseases.

RevDate: 2020-12-15

Sakai K, Inoue M, Mikami S, et al (2020)

Functional inhibition of heat shock protein 70 by VER-155008 suppresses pleural mesothelioma cell proliferation via an autophagy mechanism.

Thoracic cancer [Epub ahead of print].

BACKGROUND: Pleural mesothelioma, a devastating asbestos-associated malignancy, urgently requires a novel effective therapy. Heat shock protein 70 (HSP70), which is synthesized in the cell response to protein damage, is expected to be a new target for antitumor treatment. In addition to its well-known protein refolding function, HSP70 regulates cell proliferation through different pathways, including PI3K/AKT/mTOR, and autophagy in malignant cells. In this study, we attempted to clarify the effects of VER-155008, an HSP70 inhibitor, on pleural mesothelioma.

METHODS: Human pleural mesothelioma cell lines 211H, H2452 and H28 were cultured with VER-155008, and protein expression, cell proliferation, colony formation, cell cycle, synergistic effect with cisplatin, and autophagy induction were analyzed.

RESULTS: In mesothelioma cell lines, VER-155008 (5.0 μM or more) inhibited cell growth and colony formation, accompanied by G1 cell cycle arrest. According to western blot analysis, VER-155008 reduced p-AKT expression. However, VER-155008 failed to show a synergistic effect with cisplatin on cell growth. Mesothelioma cells transfected with the novel plasmid pMRX-IP-GFP-LC3-RFP-LC3ΔG, which was developed for the quantitative and statistical estimation of macroautophagy, showed enhanced macroautophagy upon treatment with VER-155008 and gefitinib which is an EGFR-tyrosine kinase inhibitor. In addition, fetal bovine serum deprivation induced macroautophagy was further enhanced by VER-155008.

CONCLUSIONS: On the basis of these results, functional HSP70 inhibition by VER-155008 suppressed cell growth in pleural mesothelioma cells, accompanied by enhanced macroautophagy. HSP70 inhibition is thus expected to become a new strategy for treating mesothelioma.

KEY POINTS: Significant findings of the study In pleural mesothelioma cells, inhibition of HSP70 function by VER-155008 suppressed cell proliferation accompanied by induction of autophagy which was synergistically enhanced under the starvation condition, whereas gefitinib, an EGFR-TKI, did not show the same synergistic effect in autophagy. What this study adds The inhibition of HSP70 induced autophagy and suppressed cell proliferation in mesothelioma cells.

RevDate: 2020-12-30

Bononi A, Goto K, Ak G, et al (2020)

Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma.

Proceedings of the National Academy of Sciences of the United States of America, 117(52):33466-33473.

Rare biallelic BLM gene mutations cause Bloom syndrome. Whether BLM heterozygous germline mutations (BLM+/-) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma patients (33 familial and 122 sporadic). We found 2 deleterious germline BLM+/- mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R). Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM+/- mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM+/- mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from Blm+/- mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. Blm+/- mice injected intraperitoneally with asbestos had higher levels of proinflammatory M1 macrophages and of TNF-α, IL-1β, IL-3, IL-10, and IL-12 in the peritoneal lavage, findings linked to asbestos carcinogenesis. Blm+/- mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline BLM+/- mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.

RevDate: 2020-12-17

Kishimoto T, Fujimoto N, Mizuhashi K, et al (2020)

Retrospective investigation on diagnostic process for benign asbestos pleural effusion (BAPE) using checklist.

Journal of occupational health, 62(1):e12182.

OBJECTIVES: In Japan, benign asbestos pleural effusion (BAPE) has been eligible for industrial accident compensation since 2003 as an asbestos-related disease despite the lack of good criteria. We compiled a criteria into a checklist of essential items and for excluding other diseases inducing pleural effusion as a diagnosis process.

METHOD: Thoracentesis was performed in order to confirm the presence of pleural effusion at the initial diagnosis, and 105 suspected BAPE patients were retrospectively examined. We complied a checklist comprising the following diagnostic items: (a) occupational asbestos exposure; (b) confirmation of exudate of pleural effusion; (c) exclusion of pleural effusion with malignant tumors based on negative results of CEA and hyaluronic acid, and cytology of pleural effusion; (d) exclusion of rheumatic, bacterial, and tuberculous pleuritis; (d) radiological findings for exclusion of malignancies; and (e) histopathological findings based on thoracoscopy that exclude malignancies (when thoracoscopy was not performed, there was confirmation that no malignancies were present during 3-month follow-up observation). Cases that satisfied all items were defined as BAPE.

RESULTS: Among the 105 suspected cases, there were five cases that had no occupational asbestos exposure; six cases in which transudate of on pleural effusion; one case each of rheumatoid pleuritis and tuberculous pleuritis; and five cases of pleural mesothelioma based on chest radiography and histopathological findings within 3 months after initial diagnosis. Therefore, we excluded 18 cases from the 105 candidates and determined 87 cases of BAPE.

CONCLUSION: We consider that six items described above are suitable for diagnosing BAPE.

RevDate: 2020-12-16

Moteallemi A, Minaei M, Tahmasbizadeh M, et al (2020)

Monitoring of airborne asbestos fibers in an urban ambient air of Mashhad City, Iran: levels, spatial distribution and seasonal variations.

Journal of environmental health science & engineering, 18(2):1239-1246.

Asbestos, as with other pollutants in the air, has adverse effects on the health of human beings and animals. Today, the relationship between presence of asbestos fibers in the air breathed by humans and developing serious diseases such as lung cancer (asbestosis) and mesothelioma has been proven. The objectives of this study were to monitor the levels of asbestos fibers in ambient air of Mashhad, Iran during 2018, and to draw its Geographic Information System (GIS) distribution map for the city. In this descriptive study, 13 sampling points in Mashhad city were chosen. Sampling of asbestos was carried out for 3 hour during summer and winter at 2018. Sampling of asbestos was performed using MCE (Mixed Cellulose Ester) membrane filters (pour size 0.45 µm; diameter: 25 mm) and cassette holder and peripheral pump. The samples were the analyzed by the phase contrast microscopy (PCM) method (NIOSH7400). Also, to investigate the type of asbestos and for more accurate counting of fibers, Scanning Electron Microscopy (SEM) analysis was utilized. Meteorological parameter were recorded through portable devices. To draw the graphs, Excel, R and Arc GIS software were used. Results showed that the mean asbestos fiber concentrations were equal to 11.40 ± 2.14 and 14.38 ± 2.52 f/L in summer and winter, respectively. The maximum level of asbestos fiber was detected in the station of Baitolmoghaddas square by 26.64 ± 2.14 and 19.3 SEM f/L in winter and summer, respectively. High concentration of asbestos fiber observed in this study can be attributed to the heavy traffic, the presence of prominent industries in the vicinity of the study area, and topographic features. The results from this research recommends that suitable controlling policies should be regulated to reduce both ambient air asbestos and its adverse health endpoints in Mashhad.

RevDate: 2020-12-12

Cheng YY, Yuen ML, Rath EM, et al (2020)

CDKN2A and MTAP Are Useful Biomarkers Detectable by Droplet Digital PCR in Malignant Pleural Mesothelioma: A Potential Alternative Method in Diagnosis Compared to Fluorescence In Situ Hybridisation.

Frontiers in oncology, 10:579327.

Background: The diagnosis of malignant pleural mesothelioma (MPM) can be difficult, in part due to the difficulty in distinguishing between MPM and reactive mesothelial hyperplasia (RMH). The tumor suppressor gene, CDKN2A, is frequently silenced by epigenetic mechanisms in many cancers; in the case of MPM it is mostly silenced via genomic deletion. Co-deletion of the CDKN2A and methylthioadenosine phosphorylase (MTAP) genes has been researched extensively and discovered to be a highly specific characteristic of MPM. Most studies have used FISH to detect the deletion of CDKN2A and IHC for MTAP as a surrogate for this. In this study, we aim to investigate and validate droplet digital PCR (ddPCR) as an emerging alternative and efficient testing method in diagnosing MPM, by particularly emphasizing on the loss of MTAP and CDKN2A.

Methods: This study included 75 formalin fixed paraffin embedded (FFPE) MPM tissue, and 12 normal pleural tissue and 10 RMH as control. Additionally, primary MPM cell lines and normal pleural samples were used as biomarker detection controls, as established in our previous publication. All FFPE specimens were processed to isolate the DNA, that was subsequently used for ddPCR detection of CDKN2A and MTAP. FFPE samples were also analyzed by fluorescence in situ hybridization (FISH) for CDKN2A and MTAP deletion, and for MTAP IHC expression. Concordance of IHC and ddPCR with FISH were studied in these samples.

Results: 95% and 82% of cases showed co-deletion of both MTAP and CDKN2A when determined by FISH and ddPCR respectively. ddPCR has a sensitivity of 72% and specificity of 100% in detecting CDKN2A homozygous loss in MPM. ddPCR also has a concordance rate of 92% with FISH in detecting homozygous loss of CDKN2A. MTAP IHC was 68% sensitive and 100% specific for detecting CDKN2A homozygous loss in MPM when these losses were determined by ddPCR.

Conclusion: Our study confirms that MTAP is often co-deleted with CDKN2A in MPM. Our in-house designed ddPCR assays for MTAP and CDKN2A are useful in differentiating MPM from RMH, and is highly concordant with FISH that is currently used in diagnosing MPM. ddPCR detection of these genetic losses can potentially be utilized as an alternative method in the diagnosis of MPM and for the future development of a less-invasive MPM-specific detection technique on MPM tumor tissue DNA.

RevDate: 2020-12-12

Cheah HM, Fitzgerald D, Louw A, et al (2021)

Hyaluronic acid in viscous malignant mesothelioma pleural effusion.

Respirology case reports, 9(1):e00694.

Malignant pleural effusion (MPE) is common with mesothelioma. We report two cases of extraordinarily viscous MPEs associated with mesothelioma. The viscosity prohibited spontaneous gravity-dependent drainage via indwelling pleural catheters. Our ex vivo experiments found very high hyaluronic acid (HA) content within the fluid. Treatment of the fluid with hyaluronidase, but not with deoxyribonucleases, significantly reduced fluid viscosity. The results provide proof that HA can contribute to high viscosity of pleural fluid in mesothelioma. Research into strategies of counteracting HA properties in the management of MPEs may provide further insight.

RevDate: 2020-12-10

Dell'Anno I, Martin SA, Barbarino M, et al (2020)

Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma.

Investigational new drugs [Epub ahead of print].

Objectives Malignant pleural mesothelioma (MPM) is an occupational disease mainly due to asbestos exposure. Effective therapies for MPM are lacking, making this tumour type a fatal disease. Materials and Methods In order to meet this need and in view of a future "drug repositioning" approach, here we screened five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model, with a library of 1170 FDA-approved drugs. Results Among several potential compounds, we found that fludarabine (F-araA) and, to a lesser extent, risedronic acid (RIS) were cytotoxic in MPM cells, in comparison to the non-malignant Met-5A cells. In particular, F-araA reduced the proliferation and the colony formation ability of the MPM malignant cells, in comparison to the non-malignant control cells, as demonstrated by proliferation and colony formation assays, in addition to measurement of the phospho-ERK/total-ERK ratio. We have shown that the response to F-araA was not dependent upon the expression of DCK and NT5E enzymes, nor upon their functional polymorphisms (rs11544786 and rs2295890, respectively). Conclusion This drug repositioning screening approach has identified that F-araA could be therapeutically active against MPM cells, in addition to other tumour types, by inhibiting STAT1 expression and nucleic acids synthesis. Further experiments are required to fully investigate this.

RevDate: 2020-12-10

Tanaka T, Miyamoto Y, Sakai A, et al (2020)

Nivolumab for malignant peritoneal mesothelioma.

BMJ case reports, 13(11): pii:13/11/e237721.

Malignant peritoneal mesothelioma (MPeM) is a highly malignant neoplasm of the peritoneum, which carries a poor prognosis. A 70-year-old man, who was employed in the shipbuilding industry and exposed to asbestos for 50 years, was found to have a low-density lesion in the peritoneum around the liver and spleen, associated with multiple mediastinal and parasternal lymphadenopathy. Laparoscopic exploration was performed, and biopsy specimen analysis led to a diagnosis of MPeM. Initial systemic chemotherapy comprising cisplatin and pemetrexed yielded a modest cytoreductive effect. However, 4 months later, the patient presented with abdominal distension and anorexia. CT images revealed massive ascites, bowel obstruction and an enlarged intra-abdominal tumour, which was considered progression of the MPeM. The patient was treated with nivolumab. Bowel obstruction was improved after the first administration, and his sense of abdomen distension completely disappeared after the third administration. This case supports the utility of immunotherapy in MPeM.

RevDate: 2020-12-10

Arulananda S, Lee EF, Fairlie WD, et al (2020)

The role of BCL-2 family proteins and therapeutic potential of BH3-mimetics in malignant pleural mesothelioma.

Expert review of anticancer therapy [Epub ahead of print].

Introduction: With limited recent therapeutic changes, malignant pleural mesothelioma (MPM) is associated with poor survival and death within 12 months, making it one of the most lethal malignancies. Due to unregulated asbestos use in developing countries and home renovation exposures, cases of MPM are likely to present for decades. As MPM is largely driven by dysregulation of tumor suppressor genes, researchers have examined other mechanisms of subverting tumor proliferation and spread. Over-expression of pro-survival BCL-2 family proteins impairs cells from undergoing apoptosis, and BH3-mimetics targeting them are a novel treatment option across various cancers, though have not been widely investigated in MPM. Areas covered: This review provides an overview of MPM and its current treatment landscape. It summarizes the role of BCL-2 family proteins in tumorigenesis and the therapeutic potential of BH3-mimetics . Finally, it discusses the role of BCL-2 proteins in MPM and the pre-clinical rationale for investigating BH3-mimetics as a therapeutic strategy. Expert opinion: As a disease without readily actionable oncogene driver mutations and with modest benefit from immune checkpoint inhibition, novel therapeutic options are urgently needed for MPM. Hence, BH3-mimetics provide a promising treatment option, with evidence supporting dependence on pro-survival BCL-2 proteins for MPM cell survival.

RevDate: 2020-12-01

Cugliari G, Catalano C, Guarrera S, et al (2020)

DNA Methylation of FKBP5 as Predictor of Overall Survival in Malignant Pleural Mesothelioma.

Cancers, 12(11):.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 × 10-9) OS-related differential methylation of a single-CpG (cg03546163), located in the 5'UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm < 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm ≥ 0.45 (mean: 243 versus 534 days; p value< 0.001). Epigenetic changes at the FKBP5 gene were robustly associated with OS in MPM cases. Our results showed that blood DNA methylation levels could be promising and dynamic prognostic biomarkers in MPM.

RevDate: 2020-12-14

Jiang Z, Shen W, Ying S, et al (2020)

Overexpression of fibulin-3 in tumor tissue predicts poor survival of malignant mesothelioma patients from hand-spinning asbestos exposed area in eastern China.

Scientific reports, 10(1):20373.

Fibulin-3 is an extracellular matrix glycoprotein widely expressed in various tissues. Tissue fibulin-3 expression have never been reported in association with prognosis of mesothelioma. Hence, we sought to determine the association between fibulin-3 expression and mesothelioma survival. We made a tissue microarray, which was comprised of cancer and normal tissue from mesothelioma patients (n = 82) during the period 1998-2017 in China. Fibulin-3 and HGMB1 expression were analyzed by immunohistochemistry method. Kaplan-Meier method and Cox proportional hazard models were used for analyzing survival data. Overall, 61 cases (74.4%) were female; 90.2% were of epithelioid type; the median overall survival time was 12.5 months. Fibulin-3 and HMGB1 were highly expressed in tumor tissue rather than adjacent tissue. The expression of fibulin-3 in tissue was correlated with that of HMGB1 (r = 0.32, P = 0.003). High expression of fibulin-3 in tumor tissue could predict poor survival in patients with mesothelioma (P = 0.02). This remained true in a multivariate model, with a significant hazard ratio of 1.91. We demonstrated that fibulin-3 in tumor tissue was a novel biomarker of poor survival of mesothelioma, suggesting it may be a relevant target for therapeutic intervention.

RevDate: 2021-01-02

Xia H, Feng L, Lin L, et al (2020)

Exploration of identifying novel serum biomarkers for malignant mesothelioma using iTRAQ combined with 2D-LC-MS/MS.

Environmental research, 193:110467 pii:S0013-9351(20)31364-5 [Epub ahead of print].

Malignant mesothelioma (MM) is an aggressive cancer linked to asbestos exposure. Its poor prognosis makes early diagnosis extremely important, which would provide an opportunity for early treatment and potentially changing outcomes. This study aimed to explore the underlying mechanisms of MM and discover novel noninvasive biomarkers for the diagnosis of malignant mesothelioma. Using Isobaric tags for relative and absolute quantitation (iTRAQ) combined with two-dimensional liquid chromatography/tandem mass spectrometry (2D LC-MS/MS), a total of 145 differentially expressed serum proteins were identified between MM patients and healthy controls. The identified proteins were further analyzed by bioinformatics, out of which three candidate biomarkers (Filamin A (FLNA), Fibulin 1 (FBLN1) and Thrombospondin-1 (TSP-1)) were validated in large cohorts of patients with asbestos-related diseases including MM patients by ELISA assay. Receiver operating characteristic (ROC) curve analysis showed that serum FLNA, FBLN1 and TSP-1 had high diagnostic values in distinguishing MM patients from healthy controls, individuals with asbestos exposure (AE), and patients with pleural plaques (PP) or asbestosis. Meanwhile, serum FBLN1 and TSP-1 possessed good diagnostic values in distinguishing asbestosis patients from healthy controls and individuals with AE. The combination of FLNA, FBLN1, and TSP-1 proteins had higher sensitivity and specificity in discriminating patients with MM, PP and asbestosis. Our findings indicated that analysis of serum proteome using iTRAQ is a feasible strategy for biomarker discovery, and serum FLNA, FBLN1 and TSP-1 may be promising candidates for diagnosis of malignant mesothelioma and screening of at-risk individuals.

RevDate: 2020-11-06

Filetti V, Vitale E, Broggi G, et al (2020)

Update of in vitro, in vivo and ex vivo fluoro-edenite effects on malignant mesothelioma: A systematic review (Review).

Biomedical reports, 13(6):60.

Fluoro-edenite (FE), asbestiform fiber found in Biancavilla (Sicily, Italy), presents various characteristics similar to the asbestos group, in particular two fibrous phases tremolite and actinolite. Indeed, epidemiological studies have shown that FE fibers have similar effects to those of asbestos fibers. Such studies have reported a high incidence of malignant mesothelioma (MM), an aggressive neoplasm of the serosal membranes lining the pleural cavity, in individuals residing there due to FE exposure in Biancavilla related to environmental contamination. Evidence has led to the classification of FE as a Group 1 human carcinogen by the International Agency for Research on Cancer (IARC). The aim of this systematic review is to compare the results achieved in in vitro, in vivo and ex vivo experimental studies involving FE in order to update the current knowledge on the pathogenesis and molecular mechanisms responsible for FE-mediated MM development as well as the availability of effective biomarkers for MM prevention and diagnosis. This review is focused on the pathophysiological mechanisms mediated by inflammation induced by FE fiber exposure and which are responsible for MM development. This review also discusses the discovery of new diagnostic and prognostic biomarkers for the management of this pathology. It is known that the risk of cancer development increases with chronic inflammation, arising from enhanced reactive oxygen species (ROS) and NO• production stimulated by the body to remove exogenous agents, causing DNA damage and enhanced signal transduction that may lead to activation of oncogenes. Studies concerning MM biomarker discovery indicate that several biomarkers have been proposed for MM, but mesothelin is the only Food and Drug Administration (FDA)-approved biomarker for MM, with limitations. In recent studies, in silico analysis to identify selected miRNAs highly deregulated in cancer samples when compared with normal control have been developed. This in silico approach could represent an effort in the field of biomarker discovery for MM.

RevDate: 2020-11-06

Notue YA, Mbessoh UI, Nganwa G, et al (2020)

Sarcomatoid malignant peritoneal mesothelioma presenting as a localized mesenteric tumor with no previous asbestos exposure.

Journal of surgical case reports, 2020(10):rjaa419.

Sarcomatoid malignant peritoneal mesothelioma is the rarest and most lethal form of peritoneal mesothelioma. We present the case of a sarcomatoid malignant peritoneal mesothelioma presenting as a localized mesenteric tumor in a 54-year-old female with no previous asbestos exposure. This clinical presentation is extremely rare and is the first documented in Cameroon.

RevDate: 2020-12-31

Khaliullin TO, Kisin ER, Guppi S, et al (2020)

Differential responses of murine alveolar macrophages to elongate mineral particles of asbestiform and non-asbestiform varieties: Cytotoxicity, cytokine secretion and transcriptional changes.

Toxicology and applied pharmacology, 409:115302.

Human exposures to asbestiform elongate mineral particles (EMP) may lead to diffuse fibrosis, lung cancer, malignant mesothelioma and autoimmune diseases. Cleavage fragments (CF) are chemically identical to asbestiform varieties (or habits) of the parent mineral, but no consensus exists on whether to treat them as asbestos from toxicological and regulatory standpoints. Alveolar macrophages (AM) are the first responders to inhaled particulates, participating in clearance and activating other resident and recruited immunocompetent cells, impacting the long-term outcomes. In this study we address how EMP of asbestiform versus non-asbestiform habit affect AM responses. Max Planck Institute (MPI) cells, a non-transformed mouse line that has an AM phenotype and genotype, were treated with mass-, surface area- (s.a.), and particle number- (p.n.) equivalent concentrations of respirable asbestiform and non-asbestiform riebeckite/tremolite EMP for 24 h. Cytotoxicity, cytokines secretion and transcriptional changes were evaluated. At the equal mass, asbestiform EMP were more cytotoxic, however EMP of both habits induced similar LDH leakage and decrease in viability at s.a. and p.n. equivalent doses. DNA damage assessment and cell cycle analysis revealed differences in the modes of cell death between asbestos and respective CF. There was an increase in chemokines, but not pro-inflammatory cytokines after all EMP treatments. Principal component analysis of the cytokine secretion showed close clustering for the s.a. and p.n. equivalent treatments. There were mineral- and habit-specific patterns of gene expression dysregulation at s.a. equivalent doses. Our study reveals the critical nature of EMP morphometric parameters for exposure assessment and dosing approaches used in toxicity studies.

RevDate: 2020-11-04

Liu Y, Tong J, Ling X, et al (2020)

A Case of Systemic Lupus Erythematosus with Malignant Pleural Mesothelioma in a 42-year Woman.

Journal of the College of Physicians and Surgeons--Pakistan : JCPSP, 30(10):1099-1101.

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease characterised by inflammation. Malignant pleural mesothelioma (MPM) is a highly invasive malignant tumor derived from pleural mesothelial cells. Here, we report a case of SLE with MPM. A 42-year woman with no exposure to asbestos presented with severe left chest pain. Initially, we diagnosed her with SLE because of the clinical manifestations and high antinuclear antibody titer. Finally, a diagnosis of MPM was made, based on pleural biopsy. Her condition was under control after one cycle of chemotherapy and oral methotrexate. However, three years later, she was admitted with dyspnea, mild orthopnea, and tachycardia, and died one month later after discontinuing treatment. MPM is rare, and MPM with SLE is even rarer. We should pay attention to pleural effusion when diagnosing SLE. If possible, a pleural biopsy should be performed to reduce misdiagnosis and missed diagnosis. Key Words: Pleural effusion, Systemic lupus erythematosus (SLE), Mesothelioma.

RevDate: 2020-11-03

MacMillan M, Roy B, McLaren S, et al (2020)

Widespread pulmonary invasion by malignant pleural mesothelioma: an important diagnostic consideration.

Respirology case reports, 8(9):e00675.

We report a rare case of early and extensive pulmonary invasion of malignant pleural mesothelioma (MPM) in a 70-year-old woman. She first presented with a hydropneumothorax and subsequent workup, including video-assisted thoracoscopy (VAT), confirmed MPM. After VAT, she developed dyspnoea, cough, and widespread pulmonary infiltrates of uncertain aetiology. These infiltrates progressed over the following months, failed to respond to antibiotics, and were strongly fluorodeoxyglucose (FDG)-avid on positron emission tomography (PET). Bronchoalveolar lavage (BAL) yielded extremely viscous fluid containing mesothelioma cells. These cells were also found in the sputum when nebulized deoxyribonuclease (DNase) was trialled to enhance clearance of the pulmonary fluid. The patient deteriorated rapidly with progressive mediastinal and contralateral MPM involvement and died one month later. This case highlights the importance of including tumour invasion as a differential diagnosis of non-resolving pulmonary infiltrates in patients with MPM.

RevDate: 2020-11-03

Gesmundo I, Silvagno F, Banfi D, et al (2020)

Calcitriol Inhibits Viability and Proliferation in Human Malignant Pleural Mesothelioma Cells.

Frontiers in endocrinology, 11:559586.

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor, often associated with exposure to asbestos and characterized by poor prognosis and limited treatment options. The biologically active form of vitamin D, calcitriol, exerts anticancer effects in many cell types, both alone and in combination with chemotherapy drugs, through binding to vitamin D receptor (VDR); however, the role of calcitriol in MPM is still unknown. This study aimed to determine the potential antitumor role of calcitriol in MPM. The results showed that calcitriol reduces cell viability and proliferation in human MPM cells lines, which express both cytoplasmic and nuclear VDR; furthermore, calcitriol potentiated the inhibitory activity of the chemotherapy drug PEM. These effects were paralleled by cell cycle arrest and inhibition in expression of c-Myc and cyclins involved in cell cycle progression. Exposure of MPM cells to calcitriol also produced an alteration in mitochondrial function and inhibition in the expression of respiratory chain complex subunits. Finally, the inhibitory effects of calcitriol were also observed on viability of human primary MPM cells. Collectively, these results indicate a novel anticancer role for calcitriol in MPM, suggesting potential for vitamin D derivatives, alone or in combination with chemotherapy, in the treatment of this malignancy.

RevDate: 2020-11-30

Barbieri PG, Mirabelli D, Madeo E, et al (2020)

[Asbestos exposure and related diseases among friction products workers (1971-2016)].

Giornale italiano di medicina del lavoro ed ergonomia, 42(3):145-152.

SUMMARY: Worldwide studies have been published on the mortality of workers employed in asbestos-based materials for the production of clutches and brakes. However no one of these studies is related to Italian cases. Furthermore, not even surveys have been conducted in Italy to characterize the correlation between asbestos exposures and the possible occurring of asbestos-related disease. Our objectives are the following: i) to assess and quantify the asbestos exposure cases, ii) to describe the nature and the frequency of asbestos-related diseases among blue collar employees of an important factory producing brakes and clutches with chrysotile asbestos content from 1971 to 1993 and iii) to provide preliminary data on cumulative asbestos exposure estimated using lung fibre burden analysis. Critical appraisal of airborne asbestos fibre measurements and identification of cases of asbestos-related diseases between the blue collar employees, either notified to the local health authority or recovered from the Italian national Mesothelioma registry was investigated. Lung fibre burden analysis using the lung tissue samples from two deceased blue collar employees was also performed. Airborne asbestos fibre measurements (carried out in 1982) suggested asbestos fibres average concentrations of about 0.3 f/ml, while all 1992 measurements showed results below 0.1 f/ml. Furthermore, since 1988, we identified four cases of pleural plaques, three cases of asbestosis and seven cases of lung cancer. No case of malignant mesothelioma was found. In both lung cancer cases, analysed to measure the lung fibre burden, commercial amphiboles were absent or in limited concentration but chrysotile and, especially, tremolite asbestos were present in noticeable amount. In conclusion, since 1971 and up to early 1980s, exposure to chrysotile asbestos and talc, likely contaminated by tremolite, had been significant and comparable to levels causing asbestosis long-term risk. No case of malignant mesothelioma was found, that is consistent with the absence of amphiboles and with the lower risk of mesothelioma associated with the chrysotile asbestos. However a subset of the blue collar employees, the ones employed later on, could still have not reached the full risk condition, and so being still at risk of developing malignant mesothelioma. In the two lung cancer cases studied, the lung fibre burden was essentially made of chrysotile and tremolite. Lastly, lung cancer occurrence in the population of blue collar employees has been likely underestimated and the correct determination of lung cancer risk should be done through the mortality analysis of this population.

RevDate: 2020-12-31
CmpDate: 2020-12-31

Brandi G, Deserti M, Palloni A, et al (2020)

Intrahepatic cholangiocarcinoma development in a patient with a novel BAP1 germline mutation and low exposure to asbestos.

Cancer genetics, 248-249:57-62.

BRCA1 associated protein-1 (BAP1) germline mutations define a novel hereditary cancer syndrome, namely BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by an increased susceptibility to develop different cancer types, including mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and basal cell and squamous cell carcinoma. Currently, the role of BAP1 germline mutations in intrahepatic cholangiocarcinoma (iCCA) pathogenesis is less known. Here we report the first clinical case of a female patient who developed an iCCA when she was 47-years-old and was found to carry a novel germline mutation at a splicing site of exon 4 in BAP1 gene (NM_004656.4: c.255_255+6del). An accurate anamnesis revealed the absence of risk factors linked to iCCA development, except for a low occupational exposure to asbestos. In tumor tissue, BAP1 sequencing, multiplex ligation-dependent probe amplification and immunoistochemistry showed the loss of heterozygosity and lack of nuclear expression, suggesting that BAP1 wild-type allele and functional protein were lost in cancer cells, in line with the classical two-hit model of tumor suppressor genes. Further studies are needed to confirm whether iCCA may be included into BAP1-TPDS cancer phenotypes and whether minimal asbestos exposure may facilitate the development of this malignancy in individuals carrying BAP1 germline mutations.

RevDate: 2020-10-22

Wong JYY, Rice C, Blair A, et al (2020)

Mesothelioma risk among those exposed to chrysotile asbestos only and mixtures that include amphibole: a case-control study in the USA, 1975-1980.

Occupational and environmental medicine pii:oemed-2020-106665 [Epub ahead of print].

OBJECTIVES: Occupational asbestos exposure is causally linked to mesothelioma. However, whether exposure to only chrysotile asbestos is associated with mesothelioma risk, and the heterogeneity in risk by different fibre types/lengths remains unclear. We investigated whether mesothelioma risk differs among workers exposed to only chrysotile asbestos compared with chrysotile and ≥1 amphibole (ie, amosite, tremolite, anthophyllite and crocidolite) over the working lifetime.

METHODS: We analysed next-of-kin interview data including occupational histories for 580 white men (176 cases and 404 controls) from a case-control study of mesothelioma conducted in the USA in 1975-1980. Asbestos exposure was determined by an occupational hygienist using a job-exposure matrix and exposure categories included chrysotile only and nine chrysotile-amphibole mixtures. Logistic regression models were used to estimate the ORs and 95% CIs of mesothelioma, comparing each asbestos category to the unexposed group, adjusted for age at death and data source. Analysis of contrasts was used to assess overall heterogeneity and pair-wise differences in risk.

RESULTS: Exposure to long and short chrysotile only was associated with increased mesothelioma risk compared with the unexposed (OR=3.8 (95% CI 1.3 to 11.2)). The complex mixture of extra-long amosite, short and long chrysotile, tremolite and anthophyllite was associated with the highest risk (OR=12.8 (95% CI 4.1 to 40.2)). There was evidence for overall heterogeneity among the asbestos exposure categories (p heterogeneity=0.02). However, the lower risk observed for exposure to chrysotile only compared with the complex mixture was not significant (p difference=0.10).

CONCLUSIONS: Our findings suggest that policies aimed at regulating asbestos should target both pure chrysotile and mixtures that include amphibole.

RevDate: 2020-12-01

Piber P, Vavpetic N, Goricar K, et al (2020)

The influence of genetic variability in IL1B and MIR146A on the risk of pleural plaques and malignant mesothelioma.

Radiology and oncology, 54(4):429-436.

Background Asbestos exposure is associated with the development of pleural plaques as well as malignant mesothelioma (MM). Asbestos fibres activate macrophages, leading to the release of inflammatory mediators including interleukin 1 beta (IL-1β). The expression of IL-1β may be influenced by genetic variability of IL1B gene or regulatory microRNAs (miRNAs). This study investigated the effect of polymorphisms in IL1B and MIR146A genes on the risk of developing pleural plaques and MM. Subjects and methods In total, 394 patients with pleural plaques, 277 patients with MM, and 175 healthy control subjects were genotyped for IL1B and MIR146A polymorphisms. Logistic regression was used in statistical analysis. Results We found no association between MIR146A and IL1B genotypes, and the risk of pleural plaques. MIR146A rs2910164 was significantly associated with a decreased risk of MM (OR = 0.31, 95% CI = 0.13-0.73, p = 0.008). Carriers of two polymorphic alleles had a lower risk of developing MM, even after adjustment for gender and age (OR = 0.34, 95% CI = 0.14-0.85, p = 0.020). Among patients with known asbestos exposure, carriers of at least one polymorphic IL1B rs1143623 allele also had a lower risk of MM in multivariable analysis (OR = 0.50, 95% CI = 0.28-0.92, p = 0.025). The interaction between IL1B rs1143623 and IL1B rs1071676 was significantly associated with an increased risk of MM (p = 0.050). Conclusions Our findings suggest that genetic variability of inflammatory mediator IL-1β could contribute to the risk of developing MM, but not pleural plaques.

RevDate: 2020-11-10
CmpDate: 2020-11-10

Janošíková M, Nakládalová M, Štěpánek L, et al (2020)

Occurrence of asbestos-related occupational diseases in the Czech Republic in the last 20 years.

Central European journal of public health, 28 Suppl:S37-S42.

OBJECTIVES: Asbestos-related diseases are still a current problem worldwide. What is their occurrence in the Czech Republic? The answer is the subject of this study, which aims to provide a general and regional overview of the situation over the last 20 years with a more detailed focus on mesothelioma, the development of which is highly associated with asbestos exposure and the issue of their recognition as an occupational disease.

METHODS: In its retrospective reviews, the study is based on analyses of data from the Institute of Health Information and Statistics of the Czech Republic and data from the Czech National Cancer Registry, which also interconnects.

RESULTS: In the last 20 years, 512 new cases of occupational diseases from asbestos have been reported, namely 228 cases of pleural thickening, 133 mesotheliomas, 92 asbestoses, and 59 cases of lung cancer. In the last 5 years, mesotheliomas (n = 39) predominated among the reported diseases with a 45% proportion in the total number of 86 cases. The trend in their incidence, as the only one among asbestos-related diseases, is not declining. There was a significant difference in the overall incidence of mesothelioma in a general population and the incidence of occupational mesotheliomas. At the national level, occupational aetiology was acknowledged in only 11.3% of cases of mesothelioma on average. The highest proportion of occupational mesotheliomas and the highest incidence of all asbestos-related diseases were found in regions where the largest asbestos processing plants were located.

CONCLUSION: The authors emphasize the importance of work history for the diagnostic process of asbestos-related diseases and also the need to perform follow-up examinations for their early detection.

RevDate: 2020-12-10

Fusco N, Vaira V, Righi I, et al (2020)

Characterization of the immune microenvironment in malignant pleural mesothelioma reveals prognostic subgroups of patients.

Lung cancer (Amsterdam, Netherlands), 150:53-61.

Malignant pleural mesothelioma (MPM) is a rare tumor with an extremely poor prognosis. Its pathogenesis is related to an immune response against asbestos fibers. The T-lymphocytes, including CD8POS and CD4POS cells, are an important part of the MPM immune microenvironment, and likely contribute to the therapy resistance observed in these tumors. Here, we sought to characterize the MPM-specific lymphocytes subpopulations within the tumor immune microenvironment to identify novel clinically relevant immunologic subtypes of tumors. Representative formalin-fixed, paraffin-embedded (FFPE) tissue blocks of 88 MPMs were included in tissue microarrays and subjected to tumor-infiltrating lymphocytes (TILs) quantification and subtyping by immunohistochemistry (IHC) with antibodies specific for CD4, CD8, and CD19. Further, PD-L1 (clone 22C3) expression was assessed by IHC as a combined positive score (CPS). Our data show that PD-L1 expression by tumor cells or the presence of a sarcomatoid component is related to increased stromal TILs presence in MPM. Survival analyses showed that low CD4POS and high CD8POS stromal TILs are associated with poor patients' survival. In MPMs with PD-L1 CPS > 1, stromal CD8HIGH was a poor prognostic factor, akin stromal CD4POS peritumoral TILs correlated with a worse prognosis. Furthermore, we demonstrated that a high CD4POS/CD8POS ratio in the tumor immune microenvironment is an independent prognostic factor for survival. Finally, we provided evidence that the characterization of the stromal immune landscape of MPM predicts responses to chemotherapy in subgroups of MPM. The results of this study provide novel insights into the clinical scenario of immune-related biomarkers in MPM.

RevDate: 2020-10-15

Sekine I, Yamamoto Y, Suzuki T, et al (2020)

Malignant Pleural Mesothelioma in Patients Who Previously Received Radiotherapy for their First Malignant Tumor.

Internal medicine (Tokyo, Japan) [Epub ahead of print].

RevDate: 2020-10-15

Nakashima K, Demura Y, Oi M, et al (2020)

The Association between Malignant Pleural Mesothelioma and Thoracic Radiation Therapy for Hodgkin's Lymphoma: The First Case Report in Japan.

Internal medicine (Tokyo, Japan) [Epub ahead of print].

Malignant pleural mesothelioma (MPM) is mostly observed in patients with a history of asbestos exposure. Although other causes are rare, there are several reports of MPM induced by therapeutic radiation, mainly in Europe and North America. However, no such case has been reported in Japan. We herein report a 50-year-old Japanese woman who developed MPM 25 years after thoracic radiation therapy for Hodgkin's lymphoma. The patient had no history of exposure to asbestos; therefore, her history of radiation therapy was considered to be the cause of MPM. Clinicians should consider secondary MPM in patients with a history of thoracic radiation therapy.

RevDate: 2020-11-19

Saleh DM, Alexander WT, Numano T, et al (2020)

Comparative carcinogenicity study of a thick, straight-type and a thin, tangled-type multi-walled carbon nanotube administered by intra-tracheal instillation in the rat.

Particle and fibre toxicology, 17(1):48.

BACKGROUND: Multi-walled carbon nanotubes can be divided into two general subtypes: tangled and straight. MWCNT-N (60 nm in diameter) and MWCNT-7 (80-90 nm in diameter) are straight-type MWCNTs, and similarly to asbestos, both are carcinogenic to the lung and pleura when administered to rats via the airway. Injection of straight-type MWCNTs into the peritoneal cavity also induces the development of mesothelioma, however, injection of tangled-type MWCNTs into the peritoneal cavity does not induce carcinogenesis. To investigate these effects in the lung we conducted a 2-year comparative study of the potential carcinogenicities of a straight-type MWCNT, MWCNT-A (approximately 150 nm in diameter), and a tangled-type MWCNT, MWCNT-B (7.4 nm in diameter) after administration into the rat lung. Crocidolite asbestos was used as the reference material, and rats administered vehicle were used as the controls. Test materials were administered by intra-Tracheal Intra-Pulmonary Spraying (TIPS) once a week over a 7 week period (8 administrations from day 1 to day 50), followed by a 2-year observation period without further treatment. Rats were administered total doses of 0.5 or 1.0 mg MWCNT-A and MWCNT-B or 1.0 mg asbestos.

RESULTS: There was no difference in survival between any of the groups. The rats administered MWCNT-A or asbestos did not have a significant increase in bronchiolo-alveolar hyperplasia or tumors in the lung. However, the rats administered MWCNT-B did have significantly elevated incidences of bronchiolo-alveolar hyperplasia and tumors in the lung: the incidence of bronchiolo-alveolar hyperplasia was 0/20, 6/20, and 9/20 in the vehicle, 0.5 mg MWCNT-B, and 1.0 mg MWCNT-B groups, respectively, and the incidence of adenoma and adenocarcinoma combined was 1/19, 5/20, and 7/20 in the vehicle, 0.5 mg MWCNT-B, and 1.0 mg MWCNT-B groups, respectively. Malignant pleural mesothelioma was not induced in any of the groups.

CONCLUSIONS: The results of this initial study indicate that tangled-type MWCNT-B is carcinogenic to the rat lung when administered via the airway, and that straight-type MWCNT-A did not have higher carcinogenic potential in the rat lung than tangled-type MWCNT-B.

RevDate: 2020-11-17

Hariharan A, Sun S, Wipplinger M, et al (2020)

RNA editing in mesothelioma: a look forward.

Open biology, 10(10):200112.

RNA editing is a post-transcriptional process increasing transcript diversity, thereby regulating different biological processes. We recently observed that mutations resulting from RNA editing due to hydrolytic deamination of adenosine increase during the development of mesothelioma, a rare cancer linked to chronic exposure to asbestos. This review gathers information from the published literature and public data mining to explore several aspects of RNA editing and their possible implications for cancer growth and therapy. We address possible links between RNA editing and particular types of mesothelioma genetic and epigenetic alterations and discuss the relevance of an edited substrate in the context of current chemotherapy or immunotherapy.

RevDate: 2020-11-10

Orbach D, André N, Brecht IB, et al (2020)

Mesothelioma in children and adolescents: the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) contribution.

European journal of cancer (Oxford, England : 1990), 140:63-70.

INTRODUCTION: Very little is known about the characteristics of mesothelial tumours in the paediatric population. In adults with malignant mesothelioma, the pemetrexed-based regimen with cytoreductive surgery (CRS) is a standard of care in limited tumours, but long-term survival is uncommon.

MATERIAL AND METHODS: The European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT) retrospectively reviewed children, adolescents and young adults (≤21 year) diagnosed with mesothelial tumours treated between 1987 and 2018.

RESULTS: Thirty-three patients were identified, 15 male and 18 female patients. One patient's exposure to asbestos was documented. Primary tumour was mainly in the peritoneum (23 patients). Histology was multicystic mesothelioma of the peritoneum (MCM) (six patients) or malignant mesothelioma (MM) (27 patients). Among MM, the first-line treatment comprised preoperative chemotherapy (14 cases), surgery only (three cases), chemotherapy only (five cases), adjuvant chemotherapy (three cases) or palliative treatment (two cases). The response rate to cisplatin-pemetrexed was 50% (6/12 cases). CRS with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) was performed in 19 patients (upfront in three, after neoadjuvant therapy in 12, or after tumour progression in six patients, including three twice). After a median follow-up of 6.7 years (range, 0-20), five-year overall and event-free survivals were 82.3% (95% CI, confidential interval ((CI), 67.8-99.9) and 45.1% (95% CI, 28.4-71.7), respectively. All patients with MCM are alive after surgery (five patients) and CRS-HIPEC (one patient).

CONCLUSIONS: Paediatric mesothelioma is exceptional and seems to be different from its adult counterpart with few asbestos exposures, more peritoneal primary, and a better outcome. The cisplatin-pemetrexed regimen showed promising efficacy. Relapses could be salvaged with active therapy including CRS-HIPEC.

RevDate: 2020-12-09

Duong BTV, Wu L, Green BJ, et al (2020)

A liquid biopsy for detecting circulating mesothelial precursor cells: A new biomarker for diagnosis and prognosis in mesothelioma.

EBioMedicine, 61:103031.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive cancer related to asbestos exposure. Early diagnosis is challenging due to generic symptoms and a lack of biomarkers. We previously demonstrated that mesothelial precursor cells (MPC) characterized by mesothelin (MSLN)+CD90+CD34+ could be implicated in the development of mesothelioma after asbestos exposure. Here, we aimed to determine the clinical significance of detecting MPC in blood for early-stage diagnosis and prognosis of mesothelioma.

METHODS: Due to the rarity of MPC in blood, it is challenging to identify this cell population using conventional techniques. Hence, we have developed a microfluidic liquid biopsy platform called MesoFind that utilizes an immunomagnetic, mesothelin capture strategy coupled with immunofluorescence to identify rare populations of cells at high sensitivity and precision. To validate our technique, we compared this approach to flow cytometry for the detection of MPC in murine blood and lavage samples. Upon successful validation of the murine samples, we then proceeded to examine circulating MPC in 23 patients with MPM, 23 asbestos-exposed individuals (ASB), and 10 healthy donors (HD) to evaluate their prognostic and diagnostic value.

FINDING: MPC were successfully detected in the blood of murine samples using MesoFind but were undetectable with flow cytometry. Circulating MPC were significantly higher in patients with epithelioid MPM compared to HD and ASB. The MPC subpopulation, MSLN+ and CD90+, were upregulated in ASB compared to HD suggesting an early role in pleural damage from asbestos. The MPC subpopulation, MSLN+ and CD34+, in contrast, were detected in advanced MPM and associated with markers of poor prognosis, suggesting a predominant role during cancer progression.

INTERPRETATION: The identification of circulating MPC presents an attractive solution for screening and early diagnosis of epithelioid mesothelioma. The presence of different subtypes of MPC have a prognostic value that could be of assistance with clinical decisions in patients with MPM.

FUNDING: Princess Margaret Hospital Foundation Mesothelioma Research Fund, Toronto General & Western Hospital Foundation.

RevDate: 2020-12-02

Korchevskiy A (2021)

Using benchmark dose modeling for the quantitative risk assessment: Carbon nanotubes, asbestos, glyphosate.

Journal of applied toxicology : JAT, 41(1):148-160.

Benchmark dose method is one of the most famous quantitative approaches available for toxicological risks prediction. However, it is not fully clear how occupational health professionals can use it for specific workplace scenarios requiring carcinogen risk assessment. The paper explores the hypothesis that benchmark dose method allows to effectively approximate dose-response data on carcinogenic response, providing reasonable estimations of risks in the situations when a choice between more complex models is not warranted for practical purposes. Three case studies were analyzed for the agents with different levels of scientific confidence in human carcinogenicity: carbon nanotubes, amosite asbestos, and glyphosate. For each agent, a critical study was determined, and a dose-response slope factor was quantified, based on the weighted average lower bound benchmark dose. The linear slope factors of 0.111 lifetime excess cases of lung carcinoma per mg/m3 of MWCNT-7 (in rats exposure equivalent), 0.009 cases of mesothelioma per f/cc-years of cumulative exposure to amosite asbestos, and 0.000094 cases of malignant lymphoma per mg/kg/day of glyphosate (in mice equivalent) were determined. The correlations between the proposed linear predictive models and observed data points were R = 0.96 (R2 = 0.92) for carbon nanotubes, R = 0.97 (R2 = 0.95) for amosite asbestos, and R = 0.89 (R2 = 0.79) for glyphosate. In all three cases, the linear extrapolation yielded comparable level of risk estimations with the "best fit" nonlinear model; for nanoparticles and amosite asbestos, linear estimations were more conservative. By performing a simulation study, it was demonstrated that a weighted average benchmark dose expressed the highest correlation with multistage and quantal-linear models.

RevDate: 2021-01-05

Slomovitz B, de Haydu C, Taub M, et al (2021)

Asbestos and ovarian cancer: examining the historical evidence.

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 31(1):122-128.

Asbestos recently returned to the spotlight when Johnson & Johnson halted sales of baby powder due to lawsuits claiming that the talc in baby powder may have been contaminated with asbestos, which has been linked to the risk of ovarian cancer development. Although talc and asbestos have some structural similarities, only asbestos is considered causally associated with ovarian cancer by the WHO's International Agency for Research on Cancer. While it is useful to understand the types and properties of asbestos and its oncologic biology, the history of its association with ovarian cancer is largely based on retrospective observational studies in women working in high asbestos exposure environments. In reviewing the literature, it is critical to understand the distinction between associative risk and causality, and to examine the strength of association in the context of how the diagnosis of ovarian cancer is made and how the disease should be distinguished from a similar appearing but unrelated neoplasm, malignant mesothelioma. Based on contextual misinterpretation of these factors, it is imperative to question the International Agency for Research on Cancer's assertion that asbestos has a clear causal inference to ovarian cancer. This has important clinical implications in the way patients are conceivably counseled and provides motivation to continue research to improve the understanding of the association between asbestos and ovarian cancer.

RevDate: 2020-11-09
CmpDate: 2020-11-09

Song PP, Sun XW, Zhang SQ, et al (2020)

[Clinical analysis of 30 cases with asbestos-related occupational tumors].

Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases, 38(9):693-695.

Asbestos is classified as a Class 1 carcinogen by the International Cancer Organization (IARC) , and almost all types of asbestos are carcinogenic. The clinical data of 30 asbestos-induced occupational tumor patients in Qingdao city from January 2002 to May 2019 were analyzed, including 24 cases of asbestos-induced lung cancer and 6 cases of asbestos-induced malignant mesothelioma. Mesothelioma was significantly worse than lung cancer in terms of malignancy, the survival time of patients is shorter, and the mortality rate was higher. Both its diagnostic methods and treatment methods should be improved. The high incidence of asbestos-caused tumors is coming. It is recommended that workers exposed to asbestos dust should undergo regular chest CT examinations for early detection, early diagnosis and early treatment.

RevDate: 2020-11-09
CmpDate: 2020-11-09

Jiang ZQ, Shao DC, Cheng YR, et al (2020)

[Detection and comparison of fiber count concentration in processing environment of asbestos and man-made mineral fiber].

Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases, 38(9):675-678.

Objective: To connect with the measurement data of asbestos dust fiber concentration in foreign countries, improve the accuracy of asbestos fiber detection in China, and understand the dust exposure in the working environment of asbestos and man-made mineral fiber production and processing sites in Zhejiang Province. The fiber count concentrations of working environment in glass fiber, ceramic fiber and asbestos processing plants were measured and compared. Methods: The dust concentration in the working environment of two glass fiber factories, one ceramic fiber factory and eight asbestos products processing factories was measured. The total dust mass concentration was measured according to GBZ/T 192.1-2007, and the fiber count concentration was measured by phase contrast microscope. Kruskal Wallis was used to test and compare the dust concentration in the working environment of each post. The correlation between asbestos mass concentration and fiber count concentration was analyzed by Spearman correlation. Results: Under the phase contrast microscope, there were many short and fine asbestos fibers in the field of vision, and there were many impurities around. The average dust concentration of asbestos processing plant was 3.2 f/ml, and the dust concentration of cotton ginning was the highest (6.68 f/ml) . There was a significantly positive correlation between asbestos fiber count concentration and mass concentration (r=0.535, P=0.033) . The average fiber count concentration of glass fiber factory was 0.001 f/ml, and the highest was 0.005 f/ml. The average fiber count concentration of ceramic fiber factory was 0.001 f/ml, and the highest was 0.006 f/ml. Conclusion: The fiber count concentration in the working environment of asbestos factory in Zhejiang Province is obviously over the standard, which is one of the important reasons for the high incidence of mesothelioma in this area. Short and small asbestos fibers are easy to be ignored when counting. It is necessary to improve the actual operation process of fiber counting to form a laboratory standard in China.

RevDate: 2020-12-18
CmpDate: 2020-10-21

Kumagai-Takei N, Nishimura Y, Maeda M, et al (2020)

Effect of asbestos exposure on differentiation and function of cytotoxic T lymphocytes.

Environmental health and preventive medicine, 25(1):59.

Asbestos exposure is known to cause malignant mesothelioma, which is associated with poor prognosis. We focused on and examined the effect of asbestos exposure on the differentiation and function of cytotoxic T lymphocytes (CTLs). CTLs have the ability to specifically attack tumor cells after being differentiated from naïve CD8+ T cells following antigen stimulation. Exposure to chrysotile B asbestos suppressed the differentiation of CTLs during the mixed lymphocyte reaction (MLR) and was associated with a decrease in proliferation of CD8+ T cells. Additionally, in an effort to investigate the mechanism associated with suppressed CTL differentiation upon exposure to asbestos, we focused on IL-2, a cytokine involved in T cell proliferation. Our findings indicated that insufficient levels of IL-2 are not the main cause for the suppressed induction of CTLs by asbestos exposure, although they suggest potential improvement in the suppressed CTL function. Furthermore, the functional properties of peripheral blood CD8+ lymphocytes from asbestos-exposed individuals with pleural plaque (PP) and patients with malignant mesothelioma (MM) were examined. MM patients showed lower perforin levels in CD8+ lymphocytes following stimulation compared with PP-positive individuals. The production capacity of IFN-γ in the MM group tended to be lower compared with healthy volunteers or PP-positive individuals. In an effort to determine whether chronic and direct asbestos exposure affected the function of CD8+ T cells, cultured human CD8+ T cells were employed as an in vitro model and subjected to long-term exposure to chrysotile (CH) asbestos. This resulted in decreased levels of intracellular perforin and secreted IFN-γ. Those findings underlie the possibility that impaired CD8+ lymphocyte function is caused by asbestos exposure, which fail to suppress the development of MM. Our studies therefore reveal novel effects of asbestos exposure on CTLs, which might contribute towards the development and implementation of an effective strategy for the prevention and cure of malignant mesothelioma.

RevDate: 2020-12-04

Zhang X, Yang L, Chen W, et al (2020)

Identification of Potential Hub Genes and Therapeutic Drugs in Malignant Pleural Mesothelioma by Integrated Bioinformatics Analysis.

Oncology research and treatment, 43(12):656-671.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is closely linked to asbestos exposure and is an extremely aggressive tumor with poor prognosis.

OBJECTIVE: Our study aimed to elucidate hub genes and potential drugs in MPM by integrated bioinformatics analysis.

METHODS: GSE42977 was download from the Gene Expression Omnibus (GEO) database; the differentially expressed genes (DEGs) with adj.p value <0.05 and |logFC| ≥2 were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed by DAVID database. The STRING database was used to construct a protein-protein interaction network, and modules analysis and hub genes acquisition were performed by Cytoscape. The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to assess the impact of hub genes on the prognosis of MPM patients. The Drug-Gene Interaction database (DGIdb) was used to select the related drugs.

RESULTS: A total of 169 upregulated and 70 downregulated DEGs were identified. These DEGs are enriched in the pathway of extracellular matrix-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, and PPAR signaling pathway. Finally, 10 hub genes (CDC20, CDK1, UBE2C, TOP2A, CCNB2, NUSAP1, KIF20A, AURKA, CEP55, and ASPM) were identified, which are considered to be closely related to the poor prognosis of MPM. In addition, 119 related drugs that may have a therapeutic effect on MPM were filtered out.

CONCLUSION: These discovered genes and small-molecule drugs provide some new ideas for further research on MPM.

RevDate: 2020-10-29

Iannuzzi CA, Indovina P, Forte IM, et al (2020)

Pharmacological Inhibition of WEE1 Potentiates the Antitumoral Effect of the dl922-947 Oncolytic Virus in Malignant Mesothelioma Cell Lines.

International journal of molecular sciences, 21(19):.

Malignant mesothelioma (MM) is a very aggressive asbestos-related cancer, for which no therapy proves to be effective. We have recently shown that the oncolytic adenovirus dl922-947 had antitumor effects in MM cell lines and murine xenografts. Previous studies demonstrated that dl922-947-induced host cell cycle checkpoint deregulation and consequent DNA lesions associated with the virus efficacy. However, the cellular DNA damage response (DDR) can counteract this virus action. Therefore, we assessed whether AZD1775, an inhibitor of the G2/M DNA damage checkpoint kinase WEE1, could enhance MM cell sensitivity to dl922-947. Through cell viability assays, we found that AZD1775 synergized with dl922-947 selectively in MM cell lines and increased dl922-947-induced cell death, which showed hallmarks of apoptosis (annexinV-positivity, caspase-dependency, BCL-XL decrease, chromatin condensation). Predictably, dl922-947 and/or AZD1775 activated the DDR, as indicated by increased levels of three main DDR players: phosphorylated histone H2AX (γ-H2AX), phospho-replication protein A (RPA)32, phospho-checkpoint kinase 1 (CHK1). Dl922-947 also increased inactive Tyr-15-phosphorylated cyclin-dependent kinase 1 (CDK1), a key WEE1 substrate, which is indicative of G2/M checkpoint activation. This increase in phospho-CDK1 was effectively suppressed by AZD1775, thus suggesting that this compound could, indeed, abrogate the dl922-947-induced DNA damage checkpoint in MM cells. Overall, our data suggest that the dl922-947-AZD1775 combination could be a feasible strategy against MM.

RevDate: 2020-10-06

Rozitis E, Johnson B, Cheng YY, et al (2020)

The Use of Immunohistochemistry, Fluorescence in situ Hybridization, and Emerging Epigenetic Markers in the Diagnosis of Malignant Pleural Mesothelioma (MPM): A Review.

Frontiers in oncology, 10:1742.

Malignant pleural mesothelioma (MPM) is an aggressive asbestos related disease that is generally considered to be difficult to diagnose, stage and treat. The diagnostic process is continuing to evolve and requires highly skilled pathology input, and generally an extensive list of biomarkers for definitive diagnosis. Diagnosis of MPM requires histological evidence of invasion by malignant mesothelial cells often confirmed by various immunohistochemical biomarkers in order to separate it from pleural metastatic carcinoma. Often when invasion of neoplastic mesothelial cells into adjacent tissue is not apparent, further immunohistochemical testing - namely BAP1 and MTAP, as well as FISH testing for loss of p16 (CDKN2A) are used to separate reactive mesothelial proliferation due to benign processes, from MPM. Various combinations of these markers, such as BAP1 and/or MTAP immunohistochemistry alongside FISH testing for loss of p16, have shown excellent sensitivity and specificity in the diagnosis of MPM. Additionally, over the recent years, research into epigenetic marker use in the diagnosis of MPM has gained momentum. Although still in their research stages, various markers in DNA methylation, long non-coding RNA, micro RNA, circular RNA, and histone modifications have all been found to support diagnosis of MPM with generally good sensitivity and specificity. Many of these studies are however, limited by small sample sizes or other study limitations and further research into the area would be beneficial. Epigenetic markers show promise for use in the future to facilitate the diagnosis of MPM.

RevDate: 2020-10-05

Ripley RT (2020)

Extended Pleurectomy and Decortication for Malignant Pleural Mesothelioma.

Thoracic surgery clinics, 30(4):451-460.

Extended pleurectomy and decortication (ePD) is a difficult operation performed for the surgical resection of malignant pleural mesothelioma that can achieve a macroscopic complete resection with preservation of the lung. With lower perioperative mortality, similar long-term survival, and better tolerance in patients with lower performance status, ePD has become the preferred operation rather than extrapleural pneumonectomy despite lack of a direct comparison. As ePD has become more popular, international collaboration is underway to create surgical guidelines based on collection of operative data. These efforts will improve the safety and standardization of this operation.

RevDate: 2020-10-05

Pass HI, Alimi M, Carbone M, et al (2020)

Mesothelioma Biomarkers: Discovery in Search of Validation.

Thoracic surgery clinics, 30(4):395-423.

Malignant pleural mesothelioma (MPM) is an asbestos-related neoplasm that can only be treated successfully when correctly diagnosed and treated early. The asbestos-exposed population is a high-risk group that could benefit from sensitive and specific blood- or tissue-based biomarkers. We review recent work with biomarker development in MPM and literature of the last 20 years on the most promising blood- and tissue-based biomarkers. Proteomic, genomic, and epigenomic platforms are covered. SMRP is the only validated blood-based biomarker with diagnostic, monitoring and prognostic value. To strengthen development and testing of MPM biomarkers, cohorts for validation must be established by enlisting worldwide collaborations.

RevDate: 2020-10-12

Wadowski B, De Rienzo A, R Bueno (2020)

The Molecular Basis of Malignant Pleural Mesothelioma.

Thoracic surgery clinics, 30(4):383-393.

Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural lining associated with asbestos exposure in greater than 80% of cases. It is characterized by molecular heterogeneity both between patients and within individual tumors. Next-generation sequencing technology and novel computational techniques have resulted in a greater understanding of the epigenetic, genetic, and transcriptomic hallmarks of MPM. This article reviews these features and discusses the implications of advances in MPM molecular biology in clinical practice.

RevDate: 2020-11-30
CmpDate: 2020-11-30

Xue J, Patergnani S, Giorgi C, et al (2020)

Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy.

Proceedings of the National Academy of Sciences of the United States of America, 117(41):25543-25552.

Asbestos causes malignant transformation of primary human mesothelial cells (HM), leading to mesothelioma. The mechanisms of asbestos carcinogenesis remain enigmatic, as exposure to asbestos induces HM death. However, some asbestos-exposed HM escape cell death, accumulate DNA damage, and may become transformed. We previously demonstrated that, upon asbestos exposure, HM and reactive macrophages releases the high mobility group box 1 (HMGB1) protein that becomes detectable in the tissues near asbestos deposits where HMGB1 triggers chronic inflammation. HMGB1 is also detectable in the sera of asbestos-exposed individuals and mice. Searching for additional biomarkers, we found higher levels of the autophagy marker ATG5 in sera from asbestos-exposed individuals compared to unexposed controls. As we investigated the mechanisms underlying this finding, we discovered that the release of HMGB1 upon asbestos exposure promoted autophagy, allowing a higher fraction of HM to survive asbestos exposure. HMGB1 silencing inhibited autophagy and increased asbestos-induced HM death, thereby decreasing asbestos-induced HM transformation. We demonstrate that autophagy was induced by the cytoplasmic and extracellular fractions of HMGB1 via the engagement of the RAGE receptor and Beclin 1 pathway, while nuclear HMGB1 did not participate in this process. We validated our findings in a novel unique mesothelial conditional HMGB1-knockout (HMGB1-cKO) mouse model. Compared to HMGB1 wild-type mice, mesothelial cells from HMGB1-cKO mice showed significantly reduced autophagy and increased cell death. Autophagy inhibitors chloroquine and desmethylclomipramine increased cell death and reduced asbestos-driven foci formation. In summary, HMGB1 released upon asbestos exposure induces autophagy, promoting HM survival and malignant transformation.

RevDate: 2020-12-21

Cattaneo M, Mendogni P, Damarco F, et al (2020)

Spontaneous diaphragmatic rupture following neoadjuvant chemotherapy and cytoreductive surgery in malignant pleural mesothelioma: A case report and review of the literature.

International journal of surgery case reports, 77S:S85-S87.

INTRODUCTION: Diaphragmatic rupture (DR) is an acquired diaphragmatic defect that can cause herniation of abdominal organs into the chest. It is usually a trauma-related lesion, but rarely it can occur spontaneously. Every DR with abdominal herniation should be considered a surgical emergency.

PRESENTATION OF CASE: A 61-year-old male patient, with previous exposure to asbestos, was diagnosed of Stage Ib malignant pleural mesothelioma (MPM). He underwent neo-adjuvant chemotherapy (three cycle of cisplatin-pemetrexed combination) and a cytoreductive surgery with pleurectomy/decortication. Post-operative course was characterized by prolonged air-leakage (PAL). After three months, during a follow-up CT-scan, a spontaneous diaphragmatic rupture (SDR) with gastric herniation was detected and treated by a laparascopic diaphragmatic repair and suture.

DISCUSSION: Spontaneous diaphragmatic rupture (SDR) is an extremely rare injury of the diaphragm (less than 1% of all DR). In this case, potential predisposing factors for SDR could be: presence of diaphragmatic "locus minoris resistentiae" due to thinning of the diaphragm and increase tissue fragility after neo-adjuvant chemotherapy and diaphragmatic pleural stripping; increased thoraco-abdominal pressure gradient due to PAL and residual pleural space. Thus, we confirmed the feasibility and safety of the laparoscopic approach.

CONCLUSION: We highlight the multifactor etiopathology, the challenging diagnosis and the importance of a prompt treatment of SDR.

RevDate: 2020-10-30

Kumagai-Takei N, Lee S, Srinivas B, et al (2020)

The Effects of Asbestos Fibers on Human T Cells.

International journal of molecular sciences, 21(19):.

Asbestos exposure causes malignant tumors such as lung cancer and malignant mesothelioma. The effects of asbestos fibers on immunocompetent cells, however, have not been well studied. Asbestos physically comprises a fibrous substance, which differs from silica particles which are a particulate substance, although chemically it is a mineral silicate. Since silicosis patients previously exposed to silica particles often suffer from lung and autoimmune diseases, it is clear that silica exposure impairs immune tolerance. Similarly, asbestos may alter the immune system in asbestos-exposed individuals. Given that malignant tumors can result following exposure to asbestos, the attenuation of anti-tumor immunity in cases of asbestos exposure is an important area of investigation. We observed the effect of asbestos fibers on T lymphocytes, such as CD8+ cytotoxic T lymphocytes (CTLs), CD4+ helper T (Th), and regulatory T (Treg) cells, and showed that anti-tumor immunity was attenuated, as demonstrated in a system that stimulates fresh cells isolated from peripheral blood in vitro and a system that is continuously exposed to a cell line. In this manuscript, we introduce the experiments and results of studies on CTLs, as well as Th and Treg cells, and discuss how future changes in immunocompetent cells induced by asbestos fibers can be clinically linked.

RevDate: 2020-11-10

Lysaniuk B, Cely-García MF, Mazzeo A, et al (2020)

Where are the landfilled zones? Use of historical geographic information and local spatial knowledge to determine the location of underground asbestos contamination in Sibaté (Colombia).

Environmental research, 191:110182.

INTRODUCTION: Sibaté is a municipality located in the central region of Colombia, where the first asbestos-cement facility of the country has been in operation since 1942. Both a malignant pleural mesothelioma cluster and landfilled zones with the presence of an underground friable asbestos layer have been identified in Sibaté. There is still limited knowledge regarding the history of the construction of landfilled zones, and what kinds of materials were deposited. The current study aims to improve our understanding of the history and characteristics of the landfilled zones present in Sibaté.

METHODS: Two participatory workshops with inhabitants of Sibaté were conducted to determine when the landfilled zones were built and their location. Information collected in participatory workshops was crossed with both topographic maps and aerial photographs, giving special attention to zones within the urban area of the municipality that in the past were inundated with water from El Muña Reservoir. An opportunistic soil sampling campaign was conducted in suspected landfilled zones that had not been previously sampled, during the replacement of pipelines of the drainage system ordered by the municipality.

RESULTS: The analysis of historical topographic maps, combined with the interpretation of aerial photographs, confirmed the disposal of residues in areas that were previously inundated with water from El Muña Reservoir, creating landfilled zones in the urban area of Sibaté. On top of these landfilled zones, a football stadium and a football field with an athletic track were built. The location of landfilled zones identified using geographic analysis was similar to the location identified analyzing maps constructed by inhabitants of Sibaté in participatory workshops. The four soil samples collected during an opportunistic sampling campaign confirmed the presence in new locations of the underground friable asbestos layer discovered in previous studies.

DISCUSSION: Based on the extension of the landfilled zones, the presence of friable asbestos in these areas, and the close proximity to a school and residential dwellings, there could have been major dispersion events of asbestos fibers in the urban area of Sibaté during the disposal of residue materials and the construction of the landfilled zones. Thus, important asbestos exposures may have occurred among residents of Sibaté, which is aggravated by the fact that during those years, more than 50% of the population of Sibaté was 25 years old or younger. Although the results of the current study improved our understanding of the processes and chronology associated with the landfilled zones, the uncertainty regarding their exact location remains significant. It is important to continue investigating the adverse health effects resulting from this potential asbestos exposure source.

RevDate: 2020-12-14
CmpDate: 2020-12-14

Chimed-Ochir O, Arachi D, Driscoll T, et al (2020)

Burden of Mesothelioma Deaths by National Income Category: Current Status and Future Implications.

International journal of environmental research and public health, 17(18):.

Background: This study compares estimates of the global-level mesothelioma burden with a focus on how existing national mortality data were utilized and further assesses the interrelationship of country-level mesothelioma burden and asbestos use with national income status. Methods: Country-level mesothelioma deaths in the WHO Mortality Database as of December 2019 were analyzed by national income category of countries in terms of data availability and reliability. Numbers of mesothelioma deaths from the study of Odgerel et al. were reanalyzed to assess country-level mesothelioma death burdens by national income status. Results: Among 80 high-income countries, 54 (68%) reported mesothelioma to the WHO and 26 (32%) did not, and among 60 upper middle-income countries, the respective numbers (proportions) were 39 (65%) countries and 21 (35%) countries, respectively. In contrast, among 78 low- and lower middle-income countries, only 11 (14%) reported mesothelioma deaths while 67 (86%) did not. Of the mesothelioma deaths, 29,854 (78%) were attributed to high- and upper middle-income countries, and 8534 (22%) were attributed to low- and lower middle- income countries. Conclusions: The global mesothelioma burden, based on reported numbers, is currently shouldered predominantly by high-income countries; however, mesothelioma burdens will likely manifest soon in upper middle-income and eventually in low and lower middle-income countries.

RevDate: 2020-09-23

Cheng TJ, More SL, Maddaloni MA, et al (2020)

Evaluation of potential gastrointestinal carcinogenicity associated with the ingestion of asbestos.

Reviews on environmental health pii:/j/reveh.ahead-of-print/reveh-2020-0061/reveh-2020-0061.xml [Epub ahead of print].

The inhalation of asbestos, depending on the fiber type and dose, may be associated with the development of mesothelioma and other asbestos-related diseases. However, little is known about the potential adverse effects associated with the ingestion of asbestos. Evidence of asbestos fibers released from asbestos-cement pipes used in water distribution systems has led to concerns of potentially contaminated drinking water. The purpose of this study is to determine whether ingestion of asbestos fibers may lead to cancerous effects on the gastrointestinal (GI) tract. Data from animal and human studies were analyzed using a weight-of-evidence approach to evaluate the potential risk of GI cancers associated with asbestos ingestion. Seventeen human and 23 animal studies were identified and evaluated in this study. Animal studies were conducted in multiple species with inconsistent dosing protocols. Overall, animal studies reported that the asbestos fibers, irrespective of fiber type and dose, failed to produce any definitive GI carcinogenic effect. The 17 identified human epidemiological studies reported the ingestion of asbestos-contaminated water with concentrations from 1 to 71,350 million fibers per liter (MFL). A majority of the epidemiology studies reported statistically significant increases in multiple GI-specific cancers. However, these findings are confounded due to several critical study limitations including flawed study design, small sample size, selection bias, lack of individual exposure history, lack of adequate latency, and the inability to account for confounders including occupational history, diet, and smoking history. Based on our weight-of-evidence assessment, there is insufficient evidence of causality between the ingestion of asbestos and an increased incidence of GI cancers.

RevDate: 2020-09-28

Ohnishi Y, Fujii T, Sakamoto T, et al (2020)

Malignant mesothelioma metastatic to the oral region and latest topics (Review).

Molecular and clinical oncology, 13(5):61.

Malignant mesothelioma (MM) is a rare neoplasm with poor prognosis that usually develops after exposure to asbestos, and is characterised by aggressive local invasion and metastatic spread. While metastasis to the oral cavity is very rare, a total of 23 cases of MM metastasising to the oral cavity were identifed. Among those, the tongue was the most common site of metastasis (39.1%), and frequently involved the epithelioid MM cell type. Recent studies have elucidated the mechanisms underlying the development of MM. Chronic inflammation has been implicated in promoting MM growth and was shown to play a key role by driving the release of high mobility group box protein 1 following asbestos deposition. Inherited heterozygous germline mutations in the deubiquitylase BRCA-associated protein 1 were shown to increase the incidence of MM in some families. Infection by the simian virus 40 was also found to be associated with the occurrence of MM. Moreover, the increasing incidence rates of MM, together with its propensity to metastasise to the oral cavity, indicate that clinicians and pathologists should be highly aware of this disease. Furthermore, identification of novel serum biomarkers would enable better screening and treatment of MM, and improve the survival outcomes.

RevDate: 2020-09-28

Wahlbuhl E, Liehr T, Rincic M, et al (2020)

Cytogenomic characterization of three murine malignant mesothelioma tumor cell lines.

Molecular cytogenetics, 13:43.

Background: Malignant mesothelioma (MM) is a rare aggressive cancer primary located in pleura and lung. MMs can be divided into biphasic, epithelioid and sarcomatoid subtypes. In majority of cases MMs are induced by asbestos fiber exposure. As latency period after asbestos exposure ranges between ~ 10 and 60 years MMs are mainly observed in elder people. Human MM, being a rare tumor type, lacks detailed cytogenetic data, while molecular genetic studies have been undertaken more frequently. However, murine MM cell lines are also regularly applied to get more insight into MM biology and to test new therapy strategies.

Results: Here the murine MM cell lines AB1, AB22 and AC29 were studied by molecular cytogenetics and molecular karyotyping. Interestingly, yet there were no genetic or genomic studies undertaken for these already in 1992 established cell lines. The obtained data on genomic imbalances in these murine cell lines was translated into the human genome as previously reported based on human and murine genomic browsers.

Conclusions: It turned out that all three cell lines showed high similarities in copy number variants as observed typically in human MM. Also, all three cell lines were most similar to human epithelioid MMs, and should be used as models therefore.

RevDate: 2020-10-01

Fisher SA, Peddle-McIntyre CJ, Burton K, et al (2020)

Voluntary exercise in mesothelioma: effects on tumour growth and treatment response in a murine model.

BMC research notes, 13(1):435.

OBJECTIVE: There is substantial evidence that exercise can safely reduce the risk of cancer and improve survival in different human cancer populations. Long latency periods associated with carcinogen-induced cancers like asbestos induced mesothelioma provide an opportunity to implement exercise as an intervention to delay or prevent disease development. However, there are limited studies investigating the ability of exercise to prevent or delay cancer, and exercise as a preventive strategy has never been assessed in models with a known carcinogen. We investigated the potential of voluntary exercise (VE) to delay development of asbestos related disease (ARD) in our well-characterised, asbestos induced MexTAg model of mesothelioma.

RESULTS: Asbestos exposed MexTAg mice were given continuous or delayed access to VE and ARD assessed over time. We found that the addition of VE did not affect ARD development in asbestos exposed MexTAg mice. However, non-asbestos exposed, aged matched control mice participated in significantly more VE behaviours, suggesting subclinical development of ARD after asbestos exposure had a greater impact on VE participation than age alone. These data highlight the importance of model choice and the potential limitation that some pre-clinical studies may not accurately represent the clinical paradigm, particularly in the context of prevention studies.

RevDate: 2020-12-29

Costa C, Indovina P, Mattioli E, et al (2020)

P53-regulated miR-320a targets PDL1 and is downregulated in malignant mesothelioma.

Cell death & disease, 11(9):748 pii:10.1038/s41419-020-02940-w.

Malignant pleural mesothelioma (MPM) is an aggressive cancer, related to asbestos exposure, which has a dismal prognosis. MPM diagnosis is late and often challenging, suggesting the need to identify more reliable molecular biomarkers. Here, we set out to identify differentially expressed miRNAs in epithelioid, biphasic, and sarcomatoid MPMs versus normal mesothelium and explored specific miRNA contribution to mesothelial tumorigenesis. We screened an LNA™-based miRNA-microrray with 14 formalin-fixed paraffin-embedded (FFPE) MPMs and 6 normal controls. Through real-time qRT-PCR we extended the analysis of a miRNA subset and further investigated miR-320a role through state-of-the-art techniques. We identified 16 upregulated and 32 downregulated miRNAs in MPMs versus normal tissue, including the previously identified potential biomarkers miR-21, miR-126, miR-143, miR-145. We showed in an extended series that miR-145, miR-10b, and miR-320a levels can discriminate tumor versus controls with high specificity and sensitivity. We focused on miR-320a because other family members were found downregulated in MPMs. However, stable miR-320a ectopic expression induced higher proliferation and migration ability, whereas miR-320a silencing reduced these processes, not supporting a classic tumor-suppressor role in MPM cell lines. Among putative targets, we found that miR-320a binds the 3'-UTR of the immune inhibitory receptor ligand PDL1 and, consistently, miR-320a modulation affects PDL1 levels in MPM cells. Finally, we showed that p53 over-expression induces the upregulation of miR-320a, along with miR-200a and miR-34a, both known to target PDL1, and reduces PDL1 levels in MPM cells. Our data suggest that PDL1 expression might be due to a defective p53-regulated miRNA response, which could contribute to MPM immune evasion or tumorigenesis through tumor-intrinsic roles.

RevDate: 2021-01-05

Reardon ES, Shukla V, Xi S, et al (2021)

UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 16(1):89-103.

INTRODUCTION: Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) encodes a master regulator of DNA methylation that has emerged as an epigenetic driver in human cancers. To date, no studies have evaluated UHRF1 expression in malignant pleural mesothelioma (MPM). This study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM.

METHODS: Microarray, real-time quantitative reverse transcription-polymerase chain reaction, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMCs) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. The impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-sequencing, proliferation, invasion, and colony formation assays, and murine xenograft experiments were performed to evaluate gene expression and growth of MPM cells after biochemical or pharmacologic inhibition of UHRF1 expression.

RESULTS: UHRF1 expression was significantly higher in MPM lines and specimens relative to NMC and normal pleura. Asbestos induced UHRF1 expression in NMC. The overexpression of UHRF1 was associated with decreased overall survival in patients with MPM. UHRF1 knockdown reversed genomewide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, and growth of MPM xenografts. These effects were phenocopied by the repurposed chemotherapeutic agent, mithramycin. Biochemical or pharmacologic up-regulation of p53 significantly reduced UHRF1 expression in MPM cells. RNA-sequencing experiments exhibited the pleiotropic effects of UHRF1 down-regulation and identified novel, clinically relevant biomarkers of UHRF1 expression in MPM.

CONCLUSIONS: UHRF1 is an epigenetic driver in MPM. These findings support the efforts to target UHRF1 expression or activity for mesothelioma therapy.

RevDate: 2020-09-28

Tada Y, Tagawa M, Yusa T, et al (2020)

Diffuse pleural thickening and thoracic contraction: An indistinguishable case from malignant pleural mesothelioma.

SAGE open medical case reports, 8:2050313X20948716.

The differential diagnosis of reactive mesothelial hyperplasia and mesothelioma is difficult. We present a rare case of diffuse pleural thickening with thoracic contraction that was indistinguishable from mesothelioma. A 66-year-old woman with no history of asbestos exposure visited our hospital with a complaint of dyspnea. The clinical findings included circumferential pleural thickening on chest computed tomography image and a high concentration of hyaluronic acid in the pleural fluid. Pleural biopsies obtained by thoracoscopy under local anesthesia were pathologically consistent with mesothelioma, but the patient refused to take any kind of mesothelioma treatments. Four months later, she consented to a surgical pleural biopsy under general anesthesia to obtain larger tissue samples, which included typical proliferating polygonal cells positive for CAM5.2, calretinin, WT-1, D2-40, CK5/6, epithelial membrane antigen, and glucose transporter-1 and negative for carcinoembryonic antigen, BerEP4, and MOC31. The analysis was consistent with diagnosis of epithelioid mesothelioma. Fluorescence in situ hybridization, however, showed the presence of p16 gene, and the expression of BRCA1-associated protein-1 was detected by immunohistochemistry. Our final diagnosis was diffuse pleural thickening unrelated to asbestos exposure. Differential diagnosis of diffuse pleural thickening and malignant mesothelioma is thus difficult and routine immunohistochemical examinations are often insufficient for accurate diagnosis. Multiple diagnostic methods are required for correct diagnosis in a clinically marginal case.

RevDate: 2020-11-04

Lam SK, Yan S, Xu S, et al (2020)

Targeting polyamine as a novel therapy in xenograft models of malignant pleural mesothelioma.

Lung cancer (Amsterdam, Netherlands), 148:138-148.

INTRODUCTION: Inhalation of asbestos fibers is the key culprit in malignant pleural mesothelioma (MPM). Although the import and use of asbestos have been restricted, the incidence of MPM continues to increase globally due to the prolonged lag time in malignant transformation. The development of a novel adjuvant therapy for the minority of individuals with resectable early-stage disease and effective treatment for those with unresectable MPM are urgently needed. Our preliminary data revealed that ornithine decarboxylase (ODC) is highly expressed in MPM xenografts. This study aimed to determine the treatment effects of α-difluoromethylornithine (DFMO), a specific ODC inhibitor, in MPM xenografts.

RESULTS: In an "extended adjuvant DFMO treatment" setting, nude mice were fed with DFMO for 7 days prior to inoculation of 200,000 cells. DFMO suppressed tumor growth and increased median survival in both xenografts. In H226 xenograft, 43 % of treated mice had not reached the humane endpoint by day 132, mimicking long-term survival. DFMO decreased spermidine, increased nitrotyrosine and activated apoptosis in both xenografts. Furthermore, increase in nitrosocysteine, intratumoral IL-6, keratinocyte chemoattractant and TNFα, DNA lesion and inhibition of the Akt/mTOR pathway were induced by DFMO in H226 xenograft. In "DFMO treatment" setting, 107 cells were inoculated into nude mice and DFMO treatment commenced when tumor size reached ∼50-100 mm3. DFMO also suppressed tumor growth by similar mechanisms. Supplementation with spermidine reversed the therapeutic effect of DFMO. DFMO increased actin nitration at tyrosine 53 and inhibited actin polymerization.

CONCLUSION: DFMO is preclinically effective in treating MPM.

RevDate: 2020-12-14
CmpDate: 2020-12-07

Fuso Nerini I, Roca E, Mannarino L, et al (2020)

Is DNA repair a potential target for effective therapies against malignant mesothelioma?.

Cancer treatment reviews, 90:102101.

Malignant pleural mesothelioma (MPM) is a rare malignancy mainly caused by asbestos exposure. Germinal and acquired mutations in genes of DNA repair pathways, in particular of homologous recombination repair, are frequent in MPM. Here we overview the available experimental data suggesting that an impaired DNA repair system affects MPM pathogenesis by leaving lesions through the genome unresolved. DNA repair defects represent a vulnerability of MPM, and it seems plausible to propose that leveraging these deficiencies could have therapeutic potential for patients with MPM, for whom there is an urgent need of more effective therapies.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

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Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

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Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

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Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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