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Mesothelioma: HELP
Articles from University of Sydney
Based on 70 articles published since 2008
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These are the 70 published articles about Mesothelioma that originated from University of Sydney during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Global Asbestos Disaster. 2018

Furuya, Sugio / Chimed-Ochir, Odgerel / Takahashi, Ken / David, Annette / Takala, Jukka. ·Japan Occupational Safety and Health Resource Center; Tokyo 136-0071, Japan. 2009aban@gmail.com. · Department of Environmental Epidemiology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu 807-0804, Japan. odgerel@med.uoeh-u.ac.jp. · Asbestos Diseases Research Institute, University of Sydney, P.O. Box 3628, Rhodes, Sydney, NSW 2138, Australia. ken.takahashi@sydney.edu.au. · Health Partners, LLC, 125 Tun Jose Toves Way, Tamuning 96931, Guam. amdavid@guam.net. · WSH Institute, MOMSC, Singapore, ICOH c/o INAIL, Monteporzio Catone, 00078 Rome, Italy. jstakala@gmail.com. ·Int J Environ Res Public Health · Pubmed #29772681.

ABSTRACT:

2 Review Malignant mesothelioma in Australia 2015: Current incidence and asbestos exposure trends. 2016

Soeberg, Matthew J / Leigh, James / van Zandwijk, Nico. ·a Asbestos Diseases Research Institute , University of Sydney , Concord , New South Wales , Australia. ·J Toxicol Environ Health B Crit Rev · Pubmed #27705544.

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

3 Review The IASLC Mesothelioma Staging Project: Improving Staging of a Rare Disease Through International Participation. 2016

Pass, Harvey / Giroux, Dorothy / Kennedy, Catherine / Ruffini, Enrico / Cangir, Ayten K / Rice, David / Asamura, Hisao / Waller, David / Edwards, John / Weder, Walter / Hoffmann, Hans / van Meerbeeck, Jan P / Nowak, Anna / Rusch, Valerie W / Anonymous19960882. ·Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, New York. Electronic address: harvey.pass@nyumc.org. · Cancer Research And Biostatistics, Seattle, Washington. · University of Sydney, Putney, New South Wales, Australia. · Thoracic Surgery, University of Turin, Chieri, Italy. · Department of Thoracic Surgery, Ankara University Faculty of Medicine, Ankara, Turkey. · Department of Thoracic Surgery, M. D. Anderson Cancer Center, Houston, Texas. · National Cancer Center, Keio University School of Medicine, Tokyo, Japan. · Glenfield Hospital, Groby Road, Leicestershire, United Kingdom. · Sheffield Teaching Hospital, Department of Cardiothoracic Surgery, Sheffield, United Kingdom. · Division of Thoracic Surgery, University Hospital, Zurich, Switzerland. · Thoraxklinik, University of Heidelberg, Heidelberg, Germany. · Department of Thoracic Oncology, Antwerp University Hospital, Edegem, Belgium. · University of Western Australia, Subiaco, Western Australia, Australia. · Thoracic Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. ·J Thorac Oncol · Pubmed #27670823.

ABSTRACT: For nearly 40 years, there was no generally accepted staging system for malignant pleural mesothelioma. In 1994, members of the International Mesothelioma Interest Group, in collaboration with the International Association for the Study of Lung Cancer, proposed a TNM staging system based on analyses of outcomes in retrospective surgical series and small clinical trials. Subsequently accepted by the American Joint Commission on Cancer and the Union for International Cancer Control for the sixth editions of their staging manuals, this system has since been the international staging standard. However, it has significant limitations, particularly with respect to clinical staging and to the categories for lymph node staging. Here we provide an overview of the development of the International Association for the Study of Lung Cancer malignant pleural mesothelioma staging database, which was designed to address these limitations through the development of a large international data set. Analyses of this database, described in papers linked to this overview, are being used to inform revisions in the eighth editions of the American Joint Commission on Cancer and Union for International Cancer Control staging systems.

4 Review Clinical development of TargomiRs, a miRNA mimic-based treatment for patients with recurrent thoracic cancer. 2016

Reid, Glen / Kao, Steven C / Pavlakis, Nick / Brahmbhatt, Himanshu / MacDiarmid, Jennifer / Clarke, Stephen / Boyer, Michael / van Zandwijk, Nico. ·Asbestos Diseases Research Institute, Concord, NSW 2139, Australia. · Sydney Medical School, The University of Sydney, Camperdown, NSW 2006, Australia. · Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, NSW 2050, Sydney, Australia. · Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW 2065, Australia. · Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · EnGeneIC Ltd, Sydney, Australia. ·Epigenomics · Pubmed #27185582.

ABSTRACT: miRNAs are responsible for post-transcriptional control of gene expression, and are frequently downregulated in cancer. It has become well established that restoring miRNA levels can inhibit tumor growth, and many studies have demonstrated this in preclinical models. This in turn has led to the first clinical trials of miRNA replacement therapy. This special report focuses on the development of TargomiRs - miRNA mimics delivered by targeted bacterial minicells - and the very first clinical experience of a miRNA replacement therapy in thoracic cancer patients in the Phase I MesomiR-1 trial.

5 Review Immunohistochemistry in the diagnosis of malignant pleural mesothelioma: trends in Australia and a literature review. 2013

Linton, Anthony / Kao, Steven / Vardy, Janette / Clarke, Stephen / van Zandwijk, Nico / Klebe, Sonja. ·Asbestos Diseases Research Institute, New South Wales, Australia. anthony.linton@sydney.edu.au ·Asia Pac J Clin Oncol · Pubmed #23167246.

ABSTRACT: AIMS: The accurate diagnosis of malignant pleural mesothelioma (MPM) is essential for therapeutic and legal reasons. In 2006 the International Mesothelioma Panel advocated the use of a panel, including two mesothelial and two non-mesothelial immunohistochemical (IHC) markers. We assessed the changing use of IHC for the diagnosis of MPM in Australia over two decades in the context of current best practice. METHODS: Patients with a confirmed clinico-pathological diagnosis of MPM who underwent extrapleural pneumonectomy or pleurectomy and/or decortication between 1988 and 2006 were identified from the cardiothoracic database at Royal Prince Alfred Hospital and combined with consecutive patients reviewed by the Dust Diseases Board between March 2007 and March 2009. Initial diagnostic pathology reports were reviewed. RESULTS: A total of 289 patients were identified. A median of six IHC stains per sample was performed (range 0-18): two (range 0-5) mesothelial markers, two (0-6) carcinoma markers and two epithelial markers. A trend to the higher usage of antibodies in epithelioid tumors versus biphasic and sarcomatoid tumors was noted (P = 0.148 and 0.389, respectively). Testing increased from a median of three stains per sample (1988-1997) to seven (2006-2009). Labeling specimens with > 2 mesothelial markers and > 2 carcinoma markers increased to 72 and 67 percent, respectively, after 2006. CONCLUSION: Reflecting the acceptance of diagnostic panels and increased availability of antibodies, an increase in the use of IHC stains for MPM diagnosis has occurred over the past two decades although uncertainty persists as to the optimal panel composition.

6 Review Novel targeted therapies and vaccination strategies for mesothelioma. 2011

Bagia, Mamta / Nowak, Anna K. ·NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Sydney, Australia, mbagia@tpg.com.au. ·Curr Treat Options Oncol · Pubmed #21424750.

ABSTRACT: Novel targeted therapies have found a niche in the treatment of many cancers, although the most responsive populations, best biomarkers of response, and appropriate treatment settings are still under investigation. With few exceptions, cancer vaccination strategies have not entered into routine management. In malignant mesothelioma, combination first-line chemotherapy with a platinum and pemetrexed remains the standard of care when systemic therapy is considered. Second-line chemotherapy is used but benefits are uncertain in the absence of appropriately controlled randomized trials. Currently, there are no novel targeted therapies or vaccinations that should be used in this disease outside the context of a clinical trial.

7 Review A systematic review of extrapleural pneumonectomy for malignant pleural mesothelioma. 2010

Cao, Christopher Q / Yan, Tristan D / Bannon, Paul G / McCaughan, Brian C. ·Department of Cardiothoracic Surgery, Royal Prince Alfred Hospital, University of Sydney, Australia. ·J Thorac Oncol · Pubmed #20802345.

ABSTRACT: INTRODUCTION: The primary objective of the present systematic review was to evaluate the safety and efficacy of extrapleural pneumonectomy (EPP) for patients with malignant pleural mesothelioma. METHODS: A systematic review of relevant studies identified through five online search databases was performed. Two reviewers independently appraised each study. RESULTS: Thirty-four of 58 relevant studies from 26 institutions containing the most updated data were evaluated for survival and perioperative outcomes after EPP. The median overall survival varied from 9.4 to 27.5 months, and 1-, 2-, and 5-year survival rates ranged from 36 to 83%, 5 to 59%, and 0 to 24%, respectively. Overall perioperative mortality rates ranged from 0 to 11.8%, and the perioperative morbidity rates ranged from 22 to 82%. Quality of life assessments from three studies reported improvements in nearly all domains at 3 months postoperatively. Patients who underwent trimodality therapy involving EPP and adjuvant chemoradiotherapy had a median overall survival of 13 to 23.9 months. DISCUSSIONS: The current evidence suggests that selected patients with malignant pleural mesothelioma may benefit from EPP, especially when combined with neoadjuvant or adjuvant chemotherapy and adjuvant radiotherapy.

8 Clinical Trial Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study. 2017

van Zandwijk, Nico / Pavlakis, Nick / Kao, Steven C / Linton, Anthony / Boyer, Michael J / Clarke, Stephen / Huynh, Yennie / Chrzanowska, Agata / Fulham, Michael J / Bailey, Dale L / Cooper, Wendy A / Kritharides, Leonard / Ridley, Lloyd / Pattison, Scott T / MacDiarmid, Jennifer / Brahmbhatt, Himanshu / Reid, Glen. ·Asbestos Diseases Research Institute, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. Electronic address: nico.vanzandwijk@sydney.edu.au. · Northern Cancer Institute, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. · Asbestos Diseases Research Institute, Sydney, NSW, Australia; Chris O'Brien Lifehouse, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. · Department of Oncology, Concord Repatriation General Hospital, Sydney, NSW, Australia. · Chris O'Brien Lifehouse, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. · Asbestos Diseases Research Institute, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. · Department of Molecular Imaging (PET and Nuclear Medicine), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. · Department of Nuclear Medicine, Royal North Shore Hospital, Sydney, NSW, Australia; Faculty of Health Sciences, University of Sydney, Sydney, NSW, Australia. · Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia; School of Medicine, Western Sydney University, Sydney, NSW, Australia. · Department of Cardiology, Concord Repatriation General Hospital, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. · Department of Radiology, Concord Repatriation General Hospital, Sydney, NSW, Australia. · EnGeneIC, Sydney, NSW, Australia. ·Lancet Oncol · Pubmed #28870611.

ABSTRACT: BACKGROUND: TargomiRs are minicells (EnGeneIC Dream Vectors) loaded with miR-16-based mimic microRNA (miRNA) and targeted to EGFR that are designed to counteract the loss of the miR-15 and miR-16 family miRNAs, which is associated with unsuppressed tumour growth in preclinical models of malignant pleural mesothelioma. We aimed to assess the safety, optimal dosing, and activity of TargomiRs in patients with malignant pleural mesothelioma. METHODS: In this first-in-man, open-label, dose-escalation phase 1 trial at three major cancer centres in Sydney (NSW, Australia), we recruited adults (aged ≥18 years) with a confirmed diagnosis of malignant pleural mesothelioma, measurable disease, radiological signs of progression after previous chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 3 months or more, immunohistochemical evidence of tumour EGFR expression, and adequate bone marrow, liver, and renal function. Patients were given TargomiRs via 20 min intravenous infusion either once or twice a week (3 days apart) in a traditional 3 + 3 dose-escalation design in five dose cohorts. The dose-escalation steps planned were 5 × 10 FINDINGS: Between Sept 29, 2014, and Nov 24, 2016, we enrolled 27 patients, 26 of whom received at least one TargomiR dose (one patient died before beginning treatment). Overall, five dose-limiting toxicities were noted: infusion-related inflammatory symptoms and coronary ischaemia, respectively, in two patients given 5 × 10 INTERPRETATION: The acceptable safety profile and early signs of activity of TargomiRs in patients with malignant pleural mesothelioma support additional studies of TargomiRs in combination with chemotherapy or immune checkpoint inhibitors. FUNDING: Asbestos Diseases Research Foundation.

9 Article Upcoming epidemic of asbestos-related malignant pleural mesothelioma in Taiwan: A prediction of incidence in the next 30 years. 2019

Lin, Ro-Ting / Chang, Yu-Yin / Wang, Jung-Der / Lee, Lukas Jyuhn-Hsiarn. ·Department of Occupational Safety and Health, College of Public Health, China Medical University, No. 91 Hsueh-Shih Road, Taichung, 40402, Taiwan; National Institute of Environmental Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County, 35053, Taiwan; Asbestos Diseases Research Institute, Concord Clinical School, University of Sydney, Gate 3 Hospital Road, Concord, NSW, 2139, Australia. · National Institute of Environmental Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County, 35053, Taiwan. · Department of Public Health College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 70101, Taiwan; Departments of Internal Medicine and Occupational and Environmental Medicine, National Cheng Kung University Hospital, No. 1, University Road, Tainan, 70101, Taiwan. · National Institute of Environmental Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County, 35053, Taiwan; Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, No. 17, Xu-Zhou Road, Taipei, 100, Taiwan; Environmental and Occupational Medicine, Kaohsiung Medical University, 100, Shih-Chuan 1st Rd., Kaohsiung City, 807, Taiwan. Electronic address: lukaslee@gmail.com. ·J Formos Med Assoc · Pubmed #30072200.

ABSTRACT: BACKGROUND/PURPOSE: Globally, asbestos-related diseases (ARDs) keep rising over the coming decades. The epidemic of ARDs will be a burden on public health. We aimed to predict the malignant pleural mesothelioma (MPM) incidence in the next 30 years for Taiwan based on historical asbestos consumption. METHODS: We collected annual data on local asbestos consumption during 1939-2015 and sex-specific incidence of pleural cancer as a proxy for MPM during 1979-2013. We applied Poisson log-linear models to predict future MPM numbers under the assumption that latency periods between asbestos exposure and MPM incidence were between 25 and 45 years. RESULTS: Asbestos consumption reached a peak in the 1980s, with a total of 668 thousand metric tons during 1939-2015. The observed number of MPM incidence increased by 9- and 6-fold in males and females during 1979-2013, with a cumulative number of 907. Given a latency period of 31 years, MPM incidences were expected to peak around 2012-2016 for males and 2016-2020 for females. In 2017-2046, the predicted total number of new MPM might reach 659 cases (95% confidence interval = 579-749); and the male to female ratios ranged from 1.8 to 2.8. CONCLUSION: The MPM epidemic in Taiwan will likely peak in 2012-2020 as a result of local asbestos consumption. Approximately 659 new MPM cases in the next 30 years warrant an urgent need to implement a total asbestos ban and put more resources on a comprehensive surveillance, diagnosis, and follow-up health care system for ARDs.

10 Article Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice. 2018

Funahashi, Satomi / Okazaki, Yasumasa / Nishiyama, Takahiro / Ohyoshi, Hidekazu / Yasui, Hiroyuki / Nishida, Kazuki / Matsui, Shigeyuki / Toyokuni, Shinya. ·a Department of Pathology and Biological Responses , Nagoya University Graduate School of Medicine , Nagoya , Japan. · b Department of Food and Nutritional Environment , Kinjo Gakuin University of Human Life and Environment , Nagoya , Japan. · c Department of Hematology and Oncology , Nagoya University Graduate School of Medicine , Nagoya , Japan. · d Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Chemistry , Kyoto Pharmaceutical University , Kyoto , Japan. · e Department of Biostatistics , Nagoya University Graduate School of Medicine , Nagoya , Japan. · f Sydney Medical School , the University of Sydney , Sydney , Australia. ·Free Radic Res · Pubmed #30309285.

ABSTRACT: Exposure to asbestos fiber is central to mesothelial carcinogenesis, for which iron overload in or near mesothelial cells is a key pathogenic mechanism. Alternatively, iron chelation therapy with deferasirox or regular phlebotomy was significantly preventive against crocidolite-induced mesothelial carcinogenesis in rats. However, the role of iron transporters during asbestos-induced carcinogenesis remains elusive. Here, we studied the role of divalent metal transporter 1 (DMT1; Slc11a2), which is a Fe(II) transporter, that is present not only on the apical plasma membrane of duodenal cells but also on the lysosomal membrane of every cell, in crocidolite-induced mesothelial carcinogenesis using DMT1 transgenic (DMT1Tg) mice. DMT1Tg mice show mucosal block of iron absorption without cancer susceptibility under normal diet. We unexpectedly found that superoxide production was significantly decreased upon stimulation with crocidolite both in neutrophils and macrophages of DMT1Tg mice, and the macrophage surface revealed higher iron content 1 h after contact with crocidolite. Intraperitoneal injection of 3 mg crocidolite ultimately induced malignant mesothelioma in ∼50% of both wild-type and DMT1Tg mice (23/47 and 14/28, respectively); this effect was marginally (p = 0.069) delayed in DMT1Tg mice, promoting survival. The promotional effect of nitrilotriacetic acid was limited, and the liver showed significantly higher iron content both in DMT1Tg mice and after crocidolite exposure. The results indicate that global DMT1 overexpression causes decreased superoxide generation upon stimulation in inflammatory cells, which presumably delayed the promotional stage of crocidolite-induced mesothelial carcinogenesis. DMT1Tg mice with low-stamina inflammatory cells may be helpful to evaluate the involvement of inflammation in various pathologies.

11 Article Genomic Deletion of 2018

Sarun, Kadir Harun / Lee, Kenneth / Williams, Marissa / Wright, Casey Maree / Clarke, Candice Julie / Cheng, Ngan Ching / Takahashi, Ken / Cheng, Yuen Yee. ·Asbestos Diseases Research Institute, University of Sydney, Sydney, NSW 2139, Australia. kadir.sarun@sydney.edu.au. · Asbestos Diseases Research Institute, University of Sydney, Sydney, NSW 2139, Australia. kenneth.Lee@health.nsw.gov.au. · Anatomical Pathology Department, Concord Repatriation General Hospital, Sydney, NSW 2139, Australia. kenneth.Lee@health.nsw.gov.au. · School of Medicine, University of Sydney, Sydney, NSW 2006, Australia. kenneth.Lee@health.nsw.gov.au. · Asbestos Diseases Research Institute, University of Sydney, Sydney, NSW 2139, Australia. marissa.williams@sydney.edu.au. · School of Medicine, University of Sydney, Sydney, NSW 2006, Australia. marissa.williams@sydney.edu.au. · Asbestos Diseases Research Institute, University of Sydney, Sydney, NSW 2139, Australia. cmdodds84@gmail.com. · Anatomical Pathology Department, Concord Repatriation General Hospital, Sydney, NSW 2139, Australia. Candice.Clarke@health.nsw.gov.au. · Liver Injury and Cancer Program, Centenary Institute, Sydney, NSW 2050, Australia. ngan.cheng@gmail.com. · Asbestos Diseases Research Institute, University of Sydney, Sydney, NSW 2139, Australia. ken.takahashi@sydney.edu.au. · Asbestos Diseases Research Institute, University of Sydney, Sydney, NSW 2139, Australia. yycheng@sydney.edu.au. · School of Medicine, University of Sydney, Sydney, NSW 2006, Australia. yycheng@sydney.edu.au. ·Int J Mol Sci · Pubmed #30301262.

ABSTRACT: Malignant pleural mesothelioma (MPM) is a deadly cancer that is caused by asbestos exposure and that has limited treatment options. The current standard of MPM diagnosis requires the testing of multiple immunohistochemical (IHC) markers on formalin-fixed paraffin-embedded tissue to differentiate MPM from other lung malignancies. To date, no single biomarker exists for definitive diagnosis of MPM due to the lack of specificity and sensitivity; therefore, there is ongoing research and development in order to identify alternative biomarkers for this purpose. In this study, we utilized primary MPM cell lines and tested the expression of clinically used biomarker panels, including CK8/18, Calretinin, CK 5/6, CD141, HBME-1, WT-1, D2-40, EMA, CEA, TAG72, BG8, CD15, TTF-1, BAP1, and Ber-Ep4. The genomic alteration of

12 Article BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state. 2018

Rath, Emma M / Cheng, Yuen Yee / Pinese, Mark / Sarun, Kadir H / Hudson, Amanda L / Weir, Christopher / Wang, Yiwei D / Håkansson, Anders P / Howell, Viive M / Liu, Guo Jun / Reid, Glen / Knott, Robert B / Duff, Anthony P / Church, W Bret. ·Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia. · Asbestos Diseases Research Institute (ADRI), Concord, NSW, Australia. · University of Sydney, Sydney, NSW, Australia. · Kinghorn Cancer Centre and Garvan Institute of Medical Research, Sydney, NSW, Australia. · Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, University of Sydney, Sydney, NSW, Australia. · Northern Blood Research Centre, Kolling Institute, University of Sydney, Sydney, NSW, Australia. · Burns Research, ANZAC Research Institute, Concord Hospital, University of Sydney, Concord, NSW, Australia. · Division of Experimental Infection Medicine, Lund University, Lund, Sweden. · Australian Nuclear Science and Technology Organisation (ANSTO), New Illawarra Rd, Lucas Heights, NSW, Australia. · Brain and Mind Centre and Faculty of Health Sciences, University of Sydney, Sydney, NSW, Australia. ·PLoS One · Pubmed #30157247.

ABSTRACT: Malignant pleural mesothelioma is an aggressive cancer with poor prognosis. Here we have investigated in vitro efficacy of BAMLET and BLAGLET complexes (anti-cancer complexes consisting of oleic acid and bovine α-lactalbumin or β-lactoglobulin respectively) in killing mesothelioma cells, determined BAMLET and BLAGLET structures, and investigated possible biological mechanisms. We performed cell viability assays on 16 mesothelioma cell lines. BAMLET and BLAGLET having increasing oleic acid content inhibited human and rat mesothelioma cell line proliferation at decreasing doses. Most of the non-cancer primary human fibroblasts were more resistant to BAMLET than were human mesothelioma cells. BAMLET showed similar cytotoxicity to cisplatin-resistant, pemetrexed-resistant, vinorelbine-resistant, and parental rat mesothelioma cells, indicating the BAMLET anti-cancer mechanism may be different to drugs currently used to treat mesothelioma. Cisplatin, pemetrexed, gemcitabine, vinorelbine, and BAMLET, did not demonstrate a therapeutic window for mesothelioma compared with immortalised non-cancer mesothelial cells. We demonstrated by quantitative PCR that ATP synthase is downregulated in mesothelioma cells in response to regular dosing with BAMLET. We sought structural insight for BAMLET and BLAGLET activity by performing small angle X-ray scattering, circular dichroism, and scanning electron microscopy. Our results indicate the structural mechanism by which BAMLET and BLAGLET achieve increased cytotoxicity by holding increasing amounts of oleic acid in an active cytotoxic state encapsulated in increasingly unfolded protein. Our structural studies revealed similarity in the molecular structure of the protein components of these two complexes and in their encapsulation of the fatty acid, and differences in the microscopic structure and structural stability. BAMLET forms rounded aggregates and BLAGLET forms long fibre-like aggregates whose aggregation is more stable than that of BAMLET due to intermolecular disulphide bonds. The results reported here indicate that BAMLET and BLAGLET may be effective second-line treatment options for mesothelioma.

13 Article FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal. 2018

Schelch, Karin / Wagner, Christina / Hager, Sonja / Pirker, Christine / Siess, Katharina / Lang, Elisabeth / Lin, Ruby / Kirschner, Michaela B / Mohr, Thomas / Brcic, Luka / Marian, Brigitte / Holzmann, Klaus / Grasl-Kraupp, Bettina / Krupitza, Georg / Laszlo, Viktoria / Klikovits, Thomas / Dome, Balazs / Hegedus, Balazs / Garay, Tamas / Reid, Glen / van Zandwijk, Nico / Klepetko, Walter / Berger, Walter / Grusch, Michael / Hoda, Mir Alireza. ·Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria. · Asbestos Diseases Research Institute (ADRI), Sydney, NSW, Australia. · School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia. · Institute of Pathology, Medical University of Graz, Graz, Austria. · Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria. · Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna. · Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria. · Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary. · Department of Thoracic Surgery, National Institute of Oncology and Semmelweis University, Budapest, Hungary. · MTA-SE Molecular Oncology Research Group, Hungarian Academy of Sciences, Budapest, Hungary. · Department of Thoracic Surgery, Ruhrlandklinik, University Clinic Essen, University of Duisburg-Essen, Essen, Germany. · School of Medicine, University of Sydney, NSW, Australia. ·Carcinogenesis · Pubmed #29635378.

ABSTRACT: Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells, respectively. The biphasic subtype contains a mixture of both. The sarcomatoid subtype expresses markers of epithelial-mesenchymal transition (EMT) and confers the worst prognosis, but the signals and pathways controlling EMT in MPM are not well understood. We demonstrate that treatment with FGF2 or EGF induced a fibroblastoid morphology in several cell lines from biphasic MPM, accompanied by scattering, decreased cell adhesion and increased invasiveness. This depended on the MAP-kinase pathway but was independent of TGFβ or PI3-kinase signaling. In addition to changes in known EMT markers, microarray analysis demonstrated differential expression of MMP1, ESM1, ETV4, PDL1 and BDKR2B in response to both growth factors and in epithelioid versus sarcomatoid MPM. Inhibition of MMP1 prevented FGF2-induced scattering and invasiveness. Moreover, in MPM cells with sarcomatoid morphology, inhibition of FGF/MAP-kinase signaling induced a more epithelioid morphology and gene expression pattern. Our findings suggest a critical role of the MAP-kinase axis in the morphological and behavioral plasticity of mesothelioma.

14 Article Australia's Ongoing Legacy of Asbestos: Significant Challenges Remain Even after the Complete Banning of Asbestos Almost Fifteen Years Ago. 2018

Soeberg, Matthew / Vallance, Deborah A / Keena, Victoria / Takahashi, Ken / Leigh, James. ·Asbestos Diseases Research Institute, P.O. Box 3628, Rhodes, NSW 2138, Australia. matthew.soeberg@sydney.edu.au. · Australian Manufacturing Workers' Union, P.O. Box 160, Granville, NSW 2142, Australia. Deb.Vallance@amwu.org.au. · Asbestos Diseases Research Institute, P.O. Box 3628, Rhodes, NSW 2138, Australia. victoria.keena@sydney.edu.au. · Asbestos Diseases Research Institute, P.O. Box 3628, Rhodes, NSW 2138, Australia. ken.takahashi@sydney.edu.au. · Asbestos Diseases Research Institute, P.O. Box 3628, Rhodes, NSW 2138, Australia. jleigh@bigpond.com. ·Int J Environ Res Public Health · Pubmed #29473898.

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

15 Article Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. 2018

Ohara, Yuuki / Chew, Shan-Hwu / Shibata, Takahiro / Okazaki, Yasumasa / Yamashita, Kyoko / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. ·Cancer Sci · Pubmed #29193587.

ABSTRACT: Malignant mesothelioma (MM) is a rare but socially important neoplasm due to its association with asbestos exposure. Malignant mesothelioma is difficult to diagnose at an early stage, yet there are no particularly effective treatments available at the advanced stage, thus necessitating efficient strategies to prevent MM in individuals already exposed to asbestos. We previously showed that persistent oxidative damage caused by foreign body reaction and affinity of asbestos both to hemoglobin and histones is one of the major pathogeneses. Accordingly, as an effective strategy to prevent asbestos-induced MM, we undertook the use of an iron chelator, deferasirox, which decreased the epithelial-mesenchymal transition in a crocidolite-induced rat MM model. However, this agent may show adverse effects. Here, we studied the effects of iron removal by phlebotomy as a realistic measure on the same rat model. We injected a total of 5 mg crocidolite i.p. to F1 hybrid rats between the Fischer-344 and Brown-Norway strains at the age of 6 weeks. We repeated weekly or biweekly phlebotomy of 6-8 mL/kg/time from 10 to 60 weeks of age. The animals were observed until 120 weeks. In male rats, phlebotomy significantly decreased the weight and nuclear grade of MM, and modestly reduced the associated ascites and the fraction of more malignant sarcomatoid subtype. Weekly phlebotomy prolonged long-term survival. Our results indicate that appropriate phlebotomy may be a practical preventive measure to attenuate the initiation and promotion capacity of asbestos towards MM by reducing iron in individuals exposed to asbestos.

16 Article Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma. 2018

Johnson, Thomas G / Schelch, Karin / Cheng, Yuen Y / Williams, Marissa / Sarun, Kadir H / Kirschner, Michaela B / Kao, Steven / Linton, Anthony / Klebe, Sonja / McCaughan, Brian C / Lin, Ruby C Y / Pirker, Christine / Berger, Walter / Lasham, Annette / van Zandwijk, Nico / Reid, Glen. ·Asbestos Diseases Research Institute, Sydney, Australia. · Asbestos Diseases Research Institute, Sydney, Australia; School of Medicine, University of Sydney, Sydney, Australia. · Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. · Asbestos Diseases Research Institute, Sydney, Australia; School of Medicine, University of Sydney, Sydney, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia. · Asbestos Diseases Research Institute, Sydney, Australia; School of Medicine, University of Sydney, Sydney, Australia; Concord Cancer Centre, Concord Repatriation General Hospital, Sydney, Australia. · Department of Anatomical Pathology, Flinders University; Department of Anatomical Pathology, SA Pathology at Flinders Medical Centre, Adelaide, Australia. · Department of Anatomical Pathology, SA Pathology at Flinders Medical Centre, Adelaide, Australia; Sydney Cardiothoracic Surgeons, RPAH Medical Centre, Sydney, Australia. · Asbestos Diseases Research Institute, Sydney, Australia; School of Medical Sciences, University of New South Wales, Sydney, Australia. · Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria. · Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand. · Asbestos Diseases Research Institute, Sydney, Australia; School of Medicine, University of Sydney, Sydney, Australia. Electronic address: glen.reid@sydney.edu.au. ·J Thorac Oncol · Pubmed #29113949.

ABSTRACT: INTRODUCTION: Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure. On a genomic level, MPM is characterized by frequent chromosomal deletions of tumor suppressors, including microRNAs. MiR-137 plays a tumor suppressor role in other cancers, so the aim of this study was to characterize it and its target Y-box binding protein 1 (YBX1) in MPM. METHODS: Expression, methylation, and copy number status of miR-137 and its host gene MIR137HG were assessed by polymerase chain reaction. Luciferase reporter assays confirmed a direct interaction between miR-137 and Y-box binding protein 1 gene (YBX1). Cells were transfected with a miR-137 inhibitor, miR-137 mimic, and/or YBX1 small interfering RNA, and growth, colony formation, migration and invasion assays were conducted. RESULTS: MiR-137 expression varied among MPM cell lines and tissue specimens, which was associated with copy number variation and promoter hypermethylation. High miR-137 expression was linked to poor patient survival. The miR-137 inhibitor did not affect target levels or growth, but interestingly, it increased miR-137 levels by means of mimic transfection suppressed growth, migration, and invasion, which was linked to direct YBX1 downregulation. YBX1 was overexpressed in MPM cell lines and inversely correlated with miR-137. RNA interference-mediated YBX1 knockdown significantly reduced cell growth, migration, and invasion. CONCLUSIONS: MiR-137 can exhibit a tumor-suppressive function in MPM by targeting YBX1. YBX1 knockdown significantly reduces tumor growth, migration, and invasion of MPM cells. Therefore, YBX1 represents a potential target for novel MPM treatment strategies.

17 Article A link between the fibroblast growth factor axis and the miR-16 family reveals potential new treatment combinations in mesothelioma. 2018

Schelch, Karin / Kirschner, Michaela B / Williams, Marissa / Cheng, Yuen Y / van Zandwijk, Nico / Grusch, Michael / Reid, Glen. ·Asbestos Diseases Research Institute, Sydney, Australia. · Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Austria. · Division of Thoracic Surgery, University Hospital Zurich, Switzerland. · School of Medicine, University of Sydney, Australia. ·Mol Oncol · Pubmed #29094504.

ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with very limited therapeutic options. Fibroblast growth factor (FGF) signals play important roles in mesothelioma cell growth. Several FGFs and FGF receptors (FGFRs) are predicted targets of the miR-15/16 family, which is downregulated in MPM. The aim of this study was to explore the link between the miR-15/16 family and the FGF axis in MPM. Expression analyses via RT-qPCR showed downregulation of the FGF axis after transfection with miR-15/16 mimics. Direct interaction was confirmed by luciferase reporter assays. Restoration of miR-15/16 led to dose-dependent growth inhibition in MPM cell lines, which significantly correlated with their sensitivity to FGFR inhibition. Treatment with recombinant FGF2 prevented growth inhibition and further reduced the levels of FGF/R-targeting microRNAs, indicating a vicious cycle between miR-15/16 down- and FGF/FGFR signaling upregulation. Combined inhibition of two independent miR-15/16 targets, the FGF axis and Bcl-2, resulted in additive or synergistic activity. Our data indicate that post-transcriptional repression of FGF-mediated signals contributes to the tumor suppressor function of the microRNA-15/16 family. Inhibiting hyperactivated FGF signals and Bcl-2 might serve as a novel therapeutic combination strategy in MPM.

18 Article Pseudoprogression Associated with Clinical Deterioration and Worsening Quality of Life in Malignant Pleural Mesothelioma. 2018

Barnet, Megan B / Zielinski, Robert R / Warby, Anne / Lewis, Craig R / Kao, Steven. ·Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; University of New South Wales, Kensington, New South Wales, Australia. Electronic address: m.barnet@garvan.org.au. · Western Sydney University, Penrith, New South Wales, Australia; Central West Cancer Care Centre, Orange, New South Wales, Australia. · University of Sydney, Camperdown, New South Wales, Australia. · University of New South Wales, Kensington, New South Wales, Australia; Prince of Wales Hospital, Randwick, New South Wales, Australia. · University of Sydney, Camperdown, New South Wales, Australia; Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia. ·J Thorac Oncol · Pubmed #28919393.

ABSTRACT: -- No abstract --

19 Article The epithelioid BAP1-negative and p16-positive phenotype predicts prolonged survival in pleural mesothelioma. 2018

Chou, Angela / Toon, Christopher W / Clarkson, Adele / Sheen, Amy / Sioson, Loretta / Gill, Anthony J. ·Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia. · University of Sydney, Sydney, NSW, Australia. · Department of Anatomical Pathology, SYDPATH, St Vincent's Hospital, Darlinghurst, NSW, Australia. · The Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. · Histopath Pathology, Macquarie Park, NSW, Australia. · NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia. ·Histopathology · Pubmed #28889523.

ABSTRACT: AIMS: Mesothelioma is a relatively uncommon but highly malignant neoplasm. Most patients die of disease within 1 year of diagnosis, but some have prolonged survival. Prospective identification of these longer-term survivors may help to guide treatment. We therefore sought to investigate the role of p16 immunohistochemistry (IHC) both alone and in combination with other markers as a potential predictor of prolonged survival in mesothelioma. METHODS AND RESULTS: P16 IHC was performed on unselected pleural mesotheliomas biopsied from 1991 to 2014; 153 of 208 (74%) cases were p16-negative, which correlated significantly with poor overall survival in both univariate (median survival 7.6 versus 13.6 months; P = 0.001) and multivariate analysis [hazard ratio (HR): 1.632; 95% confidence interval (CI): 1.103-2.415; P = 0.014]. Other independent factors associated with prolonged survival included loss of expression of BAP1 and epithelioid morphology. We therefore stratified patients further based on these three independent prognostic variables and demonstrated an unusually prolonged survival in mesotheliomas which were epithelioid, BAP1 IHC negative and p16 IHC positive (12% of cases, median survival 31.7 months, P < 0.0001). CONCLUSIONS: In conclusion, p16 IHC is an independent prognostic biomarker in pleural mesothelioma. When used in combination with BAP1 IHC and morphological subtyping, patients with exceptionally prolonged survival can potentially be identified.

20 Article None 2017

Cheng, Yuen Yee / Mok, Ellie / Tan, Sarah / Leygo, Catherine / McLaughlin, Chris / George, A M / Reid, Glen. ·Asbestos Diseases Research Institute (ADRI), University of Sydney, Sydney, NSW, Australia. · School of Life Sciences, University of Technology Sydney, Sydney, NSW, Australia. ·Dis Markers · Pubmed #29386699.

ABSTRACT: Malignant pleural mesothelioma (MPM) is associated with asbestos exposure. Asbestos can induce chronic inflammation which in turn can lead to silencing of tumour suppressor genes. Wnt signaling pathway can be affected by chronic inflammation and is aberrantly activated in many cancers including colon and MPM.

21 Article The analysis of novel microRNA mimic sequences in cancer cells reveals lack of specificity in stem-loop RT-qPCR-based microRNA detection. 2017

Winata, Patrick / Williams, Marissa / McGowan, Eileen / Nassif, Najah / van Zandwijk, Nico / Reid, Glen. ·Asbestos Diseases Research Institute, Sydney, NSW, 2139, Australia. · School of Medicine, University of Sydney, Sydney, NSW, 2006, Australia. · University of Technology Sydney, Sydney, NSW, 2007, Australia. · Asbestos Diseases Research Institute, Sydney, NSW, 2139, Australia. glen.reid@sydney.edu.au. · School of Medicine, University of Sydney, Sydney, NSW, 2006, Australia. glen.reid@sydney.edu.au. · University of Technology Sydney, Sydney, NSW, 2007, Australia. glen.reid@sydney.edu.au. ·BMC Res Notes · Pubmed #29149911.

ABSTRACT: OBJECTIVE: MicroRNAs are frequently downregulated in cancer, and restoring expression has tumour suppressive activity in tumour cells. Our recent phase I clinical trial investigated microRNA-based therapy in patients with malignant pleural mesothelioma. Treatment with TargomiRs, microRNA mimics with novel sequence packaged in EGFR antibody-targeted bacterial minicells, revealed clear signs of clinical activity. In order to detect delivery of microRNA mimics to tumour cells in future clinical trials, we tested hydrolysis probe-based assays specific for the sequence of the novel mimics in transfected mesothelioma cell lines using RT-qPCR. RESULTS: The custom assays efficiently and specifically amplified the consensus mimics. However, we found that these assays gave a signal when total RNA from untransfected and control mimic-transfected cells were used as templates. Further investigation revealed that the reverse transcription step using stem-loop primers appeared to introduce substantial non-specific amplification with either total RNA or synthetic RNA templates. This suggests that reverse transcription using stem-loop primers suffers from an intrinsic lack of specificity for the detection of highly similar microRNAs in the same family, especially when analysing total RNA. These results suggest that RT-qPCR is unlikely to be an effective means to detect delivery of microRNA mimic-based drugs to tumour cells in patients.

22 Article Estimation of the global burden of mesothelioma deaths from incomplete national mortality data. 2017

Odgerel, Chimed-Ochir / Takahashi, Ken / Sorahan, Tom / Driscoll, Tim / Fitzmaurice, Christina / Yoko-O, Makoto / Sawanyawisuth, Kittisak / Furuya, Sugio / Tanaka, Fumihiro / Horie, Seichi / Zandwijk, Nico van / Takala, Jukka. ·Department of Environmental Epidemiology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan. · Asbestos Diseases Research Institute, Concord Clinical School, University of Sydney, Sydney, Australia. · Institute of Applied Health Research, University of Birmingham, Birmingham, UK. · School of Public Health, University of Sydney, Sydney, Australia. · Department of Medicine, Division of Hematology, Institute for Health Metrics and Evaluation, University of Washington, Seattle, WA, USA. · Department of Medicine, Faculty of Medicine, Sleep Apnea Research Group, Khon Kaen University, Khon Kaen, Thailand. · Japan Occupational Safety and Health Resource Center, Tokyo, Japan. · Department of Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan. · Department of Health Policy and Management, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan. · Workplace Safety and Health Institute, Ministry of Manpower, Singapore, Singapore. ·Occup Environ Med · Pubmed #28866609.

ABSTRACT: BACKGROUND: Mesothelioma is increasingly recognised as a global health issue and the assessment of its global burden is warranted. OBJECTIVES: To descriptively analyse national mortality data and to use reported and estimated data to calculate the global burden of mesothelioma deaths. METHODS: For the study period of 1994 to 2014, we grouped 230 countries into 59 countries with quality mesothelioma mortality data suitable to be used for reference rates, 45 countries with poor quality data and 126 countries with no data, based on the availability of data in the WHO Mortality Database. To estimate global deaths, we extrapolated the gender-specific and age-specific mortality rates of the countries with quality data to all other countries. RESULTS: The global numbers and rates of mesothelioma deaths have increased over time. The 59 countries with quality data recorded 15 011 mesothelioma deaths per year over the 3 most recent years with available data (equivalent to 9.9 deaths per million per year). From these reference data, we extrapolated the global mesothelioma deaths to be 38 400 per year, based on extrapolations for asbestos use. CONCLUSIONS: Although the validity of our extrapolation method depends on the adequate identification of quality mesothelioma data and appropriate adjustment for other variables, our estimates can be updated, refined and verified because they are based on commonly accessible data and are derived using a straightforward algorithm. Our estimates are within the range of previously reported values but higher than the most recently reported values.

23 Article Pathological complete response in malignant pleural mesothelioma patients following induction chemotherapy: Predictive factors and outcomes. 2017

Lau, Brandon / Kumar, Sanjeev / Yan, Tristan / Burn, Juliet / Kennedy, Catherine / McLean, Jocelyn / Boyer, Michael / McCaughan, Brian / Kao, Steven. ·Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia. · Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. · Sydney Medical School, The University of Sydney, Sydney, Australia; Department of Cardiothoracic Surgery, Royal Prince Alfred Hospital, Sydney, Australia. · Douglas Hanly Moir Pathology, Sydney, Australia. · Sydney Medical School, The University of Sydney, Sydney, Australia; Strathfield Private Hospital, Sydney, Australia. · Asbestos Diseases Research Institute, Sydney, Australia. · Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia. · Sydney Medical School, The University of Sydney, Sydney, Australia; Sydney Cardiothoracic Surgeons, Sydney, Australia. · Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia; Asbestos Diseases Research Institute, Sydney, Australia. Electronic address: steven.kao@lh.org.au. ·Lung Cancer · Pubmed #28838403.

ABSTRACT: A small proportion of patients with malignant pleural mesothelioma (MPM) achieve pathological complete response (CR) following treatment with current practice induction chemotherapy. Our analysis of 58 patients with MPM treated with platinum-based chemotherapy showed 4 patients (7%) attained pathological CR at subsequent extrapleural pneumonectomy (EPP). Patient and tumour factors such as age, gender, smoking habit, histological subtype, and clinical stage were not found to be associated with pathological CR. Patients with pathological CR had longer disease-free survival (29.2 vs. 13.8 months; p=0.08) and overall survival (76.4 vs. 23.4 months; p=0.06) but this did not reach statistical significance. Our study suggests that patients who achieve pathological CR after chemotherapy may have improved survival in MPM.

24 Article Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma. 2017

Kao, Steven C / Cheng, Yuen Yee / Williams, Marissa / Kirschner, Michaela B / Madore, Jason / Lum, Trina / Sarun, Kadir H / Linton, Anthony / McCaughan, Brian / Klebe, Sonja / van Zandwijk, Nico / Scolyer, Richard A / Boyer, Michael J / Cooper, Wendy A / Reid, Glen. ·Asbestos Diseases Research Institute, Sydney, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia. · Asbestos Diseases Research Institute, Sydney, Australia. · Asbestos Diseases Research Institute, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia. · Sydney Medical School, The University of Sydney, Sydney, Australia; Melanoma Institute Australia, Sydney, Australia. · Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia. · Asbestos Diseases Research Institute, Sydney, Australia; Department of Medical Oncology, Concord Cancer Centre, Sydney, Australia. · Sydney Medical School, The University of Sydney, Sydney, Australia; Sydney Cardiothoracic Surgeons, RPAH Medical Centre, Sydney, Australia. · Department of Anatomical Pathology, Flinders University and SA Pathology at Flinders Medical Centre, Adelaide Australia. · Sydney Medical School, The University of Sydney, Sydney, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia; Department of Medical Oncology, Concord Cancer Centre, Sydney, Australia. · Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia. · Sydney Medical School, The University of Sydney, Sydney, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia; School of Medicine, Western Sydney University, Sydney, Australia. · Asbestos Diseases Research Institute, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia. Electronic address: glen.reid@sydney.edu.au. ·J Thorac Oncol · Pubmed #28629895.

ABSTRACT: INTRODUCTION: The upregulation of programmed death ligand 1 (PD-L1) is found in many cancers and contributes to evasion of the host's immune defense. In malignant pleural mesothelioma (MPM), PD-L1 expression is associated with the nonepithelioid histological subtype and poor prognosis, but the pathways involved in control of PD-L1 expression in MPM are poorly understood. To address one possible means of PD-L1 regulation we investigated the relationship between dysregulated microRNA levels and PD-L1 expression. METHODS: PD-L1 expression was analyzed by immunohistochemistry in tissue microarrays prepared from samples from patients undergoing an operation (pleurectomy with or without decortication). MicroRNA expression was analyzed by reverse-transcriptase quantitative polymerase chain reaction. Regulation of PD-L1 expression in cell lines was assessed after transfection with microRNA mimics and small interfering RNAs. Interaction between microRNAs and PD-L1 was analyzed by using argonaute-2 immunoprecipitation and a luciferase reporter assay. RESULTS: In a series of 72 patients with MPM, 18 (25%) had positive PD-L1 staining, and this was more common in patients with the nonepithelioid subtype (p = 0.01). PD-L1 expression was associated with poor survival (median overall survival 4.0 versus 9.2 months with positive versus negative PD-L1 expression [p < 0.001]), and in multivariate analyses, PD-L1 expression remained a significant adverse prognostic indicator (hazard ratio = 2.2, 95% confidence interval: 1.2-4.1, p < 0.01). In the same patient series, PD-L1 expression was also associated with downregulation of microRNAs previously shown to have tumor suppressor activity in MPM. The median microRNA expression levels of miR-15b, miR-16, miR-193a-3p, miR-195, and miR-200c were significantly lower in the PD-L1-positive samples. Transfecting MPM cell lines with mimics corresponding to miR-15a and miR-16, both of which are predicted to target PD-L1, led to downregulation of PD-L1 mRNA and protein. In addition, miR-193a-3p, with an alternative G-U-containing target site, also caused PD-L1 downregulation. CONCLUSIONS: Together, these data suggest that tumor suppressor microRNAs contribute to the regulation of PD-L1 expression in MPM.

25 Article Non-thermal plasma induces a stress response in mesothelioma cells resulting in increased endocytosis, lysosome biogenesis and autophagy. 2017

Shi, Lei / Ito, Fumiya / Wang, Yue / Okazaki, Yasumasa / Tanaka, Hiromasa / Mizuno, Masaaki / Hori, Masaru / Hirayama, Tasuku / Nagasawa, Hideko / Richardson, Des R / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. · Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan. · Plasma Nanotechnology Research Center, Nagoya University, Nagoya 464-8603, Japan. · The Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Gifu, Japan. · Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: d.richardson@med.usyd.edu.au. · Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: toyokuni@med.nagoya-u.ac.jp. ·Free Radic Biol Med · Pubmed #28465262.

ABSTRACT: Non-thermal plasma (NTP) is a potential new therapeutic modality for cancer. However, its mechanism of action remains unclear. Herein, we studied the effect of NTP on mesothelioma cells and fibroblasts to understand its anti-proliferative efficacy. Interestingly, NTP demonstrated greater selective anti-proliferative activity against mesothelioma cells relative to fibroblasts than cisplatin, which is used for mesothelioma treatment. The anti-proliferative effect of NTP was enhanced by pre-incubation with the cellular iron donor, ferric ammonium citrate (FAC), and inhibited by iron chelation using desferrioxamine (DFO). Three oxidative stress probes (CM-H2DCFDA, MitoSOX and C11-BODIPY) demonstrated reactive oxygen species (ROS) generation by NTP, which was inhibited by DFO. Moreover, NTP decreased transferrin receptor-1 and increased ferritin-H and -L chain expression that was correlated with decreased iron-regulatory protein expression and RNA-binding activity. This regulation was potentially due to increased intracellular iron in lysosomes, which was demonstrated via the Fe(II)-selective probe, HMRhoNox-M, and was consistent with autophagic-induction. Immunofluorescence using LysoTracker and Pepstatin A probes demonstrated increased cellular lysosome content, which was confirmed by elevated LAMP1 expression. The enhanced lysosomal biogenesis after NTP could be due to the observed increase in fluid-phase endocytosis and early endosome formation. These results suggest NTP acts as a stressor, which results in increased endocytosis, lysosome content and autophagy. In fact, NTP rapidly increased autophagosome formation, as judged by increased LC3B-II expression, which co-localized with LAMP1, indicating autophagolysosome formation. Autophagic-induction by NTP was confirmed using electron microscopy. In summary, NTP acts as a cellular stressor to rapidly induce fluid-phase endocytosis, lysosome biogenesis and autophagy.

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