Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Mesothelioma: HELP
Articles from University of Hawaii School of Medicine
Based on 41 articles published since 2008
||||

These are the 41 published articles about Mesothelioma that originated from University of Hawaii School of Medicine during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Recent insights emerging from malignant mesothelioma genome sequencing. 2015

Carbone, Michele / Gaudino, Giovanni / Yang, Haining. ·University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii. ·J Thorac Oncol · Pubmed #25695218.

ABSTRACT: -- No abstract --

2 Review Progress in the Management of Malignant Pleural Mesothelioma in 2017. 2018

McCambridge, Amanda J / Napolitano, Andrea / Mansfield, Aaron S / Fennell, Dean A / Sekido, Yoshitaka / Nowak, Anna K / Reungwetwattana, Thanyanan / Mao, Weimin / Pass, Harvey I / Carbone, Michele / Yang, Haining / Peikert, Tobias. ·Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota. · University of Hawaii Cancer Center, Honolulu, Hawaii; Medical Oncology Department, Campus Bio-Medico, University of Rome, Rome, Italy. · Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota. · Department of Genetics and Genome Biology, University of Leicester and University Hospitals of Leicester, United Kingdom. · Division of Molecular Oncology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan. · Medical School, University of Western Australia, Perth, Australia; National Center for Asbestos Related Diseases, University of Western Australia, Perth, Australia. · Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. · Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou, People's Republic of China; Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology of Zhejiang Province, Hangzhou, People's Republic of China. · Department of Cardiothoracic Surgery, New York University, Langone Medical Center, New York, New York. · University of Hawaii Cancer Center, Honolulu, Hawaii. · Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address: Peikert.Tobias@mayo.edu. ·J Thorac Oncol · Pubmed #29524617.

ABSTRACT: Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication, and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. Whereas recent epidemiological data demonstrated that the incidence of MPM-related death continued to increase in United States between 2009 and 2015, new insight into the molecular pathogenesis and the immunological tumor microenvironment of MPM, for example, regarding the role of BRCA1 associated protein 1 and the expression programmed death receptor ligand 1, are highlighting new potential therapeutic strategies. Furthermore, there continues to be an ever-expanding number of clinical studies investigating systemic therapies for MPM. These trials are primarily focused on immunotherapy using immune checkpoint inhibitors alone or in combination with other immunotherapies and nonimmunotherapies. In addition, other promising targeted therapies, including pegylated adenosine deiminase (ADI-PEG20), which focuses on argininosuccinate synthase 1-deficient tumors, and tazemetostat, an enhancer of zeste 2 polycomb repressive complex 2 subunit inhibitor of BRCA1 associated protein 1 gene (BAP1)-deficient tumors, are currently being explored.

3 Review Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies. 2015

Bononi, Angela / Napolitano, Andrea / Pass, Harvey I / Yang, Haining / Carbone, Michele. ·a 1 University of Hawai'i Cancer Center, University of Hawai'i at Mānoa, Honolulu, Hawai'i, USA. · b 2 Molecular Biosciences and Bioengineering, University of Hawai'i at Mānoa, Honolulu, Hawai'i, USA. · c 3 Department of Cardiothoracic Surgery, Division of Thoracic Surgery, Langone Medical Center, New York University, New York, USA. ·Expert Rev Respir Med · Pubmed #26308799.

ABSTRACT: Malignant mesothelioma is an aggressive cancer whose pathogenesis is causally linked to occupational exposure to asbestos. Familial clusters of mesotheliomas have been observed in settings of genetic predisposition. Mesothelioma incidence is anticipated to increase worldwide in the next two decades. Novel treatments are needed, as current treatment modalities may improve the quality of life, but have shown modest effects in improving overall survival. Increasing knowledge on the molecular characteristics of mesothelioma has led to the development of novel potential therapeutic strategies, including: molecular targeted approaches, that is the inhibition of vascular endothelial growth factor with bevacizumab; immunotherapy with chimeric monoclonal antibody, immunotoxin, antibody drug conjugate, vaccine and viruses; inhibition of asbestos-induced inflammation, that is aspirin inhibition of HMGB1 activity may decrease or delay mesothelioma onset and/or growth. We elaborate on the rationale behind new therapeutic strategies, and summarize available preclinical and clinical results, as well as efforts still ongoing.

4 Review Malignant mesothelioma: facts, myths, and hypotheses. 2012

Carbone, Michele / Ly, Bevan H / Dodson, Ronald F / Pagano, Ian / Morris, Paul T / Dogan, Umran A / Gazdar, Adi F / Pass, Harvey I / Yang, Haining. ·University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii 96813, USA. mcarbone@crch.hawaii.edu ·J Cell Physiol · Pubmed #21412769.

ABSTRACT: Malignant mesothelioma (MM) is a neoplasm arising from mesothelial cells lining the pleural, peritoneal, and pericardial cavities. Over 20 million people in the US are at risk of developing MM due to asbestos exposure. MM mortality rates are estimated to increase by 5-10% per year in most industrialized countries until about 2020. The incidence of MM in men has continued to rise during the past 50 years, while the incidence in women appears largely unchanged. It is estimated that about 50-80% of pleural MM in men and 20-30% in women developed in individuals whose history indicates asbestos exposure(s) above that expected from most background settings. While rare for women, about 30% of peritoneal mesothelioma in men has been associated with exposure to asbestos. Erionite is a potent carcinogenic mineral fiber capable of causing both pleural and peritoneal MM. Since erionite is considerably less widespread than asbestos, the number of MM cases associated with erionite exposure is smaller. Asbestos induces DNA alterations mostly by inducing mesothelial cells and reactive macrophages to secrete mutagenic oxygen and nitrogen species. In addition, asbestos carcinogenesis is linked to the chronic inflammatory process caused by the deposition of a sufficient number of asbestos fibers and the consequent release of pro-inflammatory molecules, especially HMGB-1, the master switch that starts the inflammatory process, and TNF-alpha by macrophages and mesothelial cells. Genetic predisposition, radiation exposure and viral infection are co-factors that can alone or together with asbestos and erionite cause MM. J. Cell. Physiol. 227: 44-58, 2012. © 2011 Wiley Periodicals, Inc.

5 Review Simian virus 40 transformation, malignant mesothelioma and brain tumors. 2011

Qi, Fang / Carbone, Michele / Yang, Haining / Gaudino, Giovanni. ·University of Hawaii Cancer Center, Honolulu, HI, USA. ·Expert Rev Respir Med · Pubmed #21955238.

ABSTRACT: Simian virus 40 (SV40) is a DNA virus isolated in 1960 from contaminated polio vaccines, that induces mesotheliomas, lymphomas, brain and bone tumors, and sarcomas, including osteosarcomas, in hamsters. These same tumor types have been found to contain SV40 DNA and proteins in humans. Mesotheliomas and brain tumors are the two tumor types that have been most consistently associated with SV40, and the range of positivity has varied about from 6 to 60%, although a few reported 100% of positivity and a few reported 0%. It appears unlikely that SV40 infection alone is sufficient to cause human malignancy, as we did not observe an epidemic of cancers following the administration of SV40-contaminated vaccines. However, it seems possible that SV40 may act as a cofactor in the pathogenesis of some tumors. In vitro and animal experiments showing cocarcinogenicity between SV40 and asbestos support this hypothesis.

6 Review Chemotherapy of malignant pleural mesothelioma. 2009

Bertino, Pietro / Carbone, Michele / Pass, Harvey. ·Cancer Research Center of Hawaii and Department of Pathology, University of Hawaii, 651 Ilalo Street, BSB Room 231, Honolulu, HI 96813, USA. ·Expert Opin Pharmacother · Pubmed #19236184.

ABSTRACT: BACKGROUND: Owing to worldwide use of asbestos during the past century, the global incidence of mesothelioma is still increasing. Although the outcome for patients remains poor, there has been definite progress in the systemic treatment of this disease within the past 5 years. OBJECTIVE: By examining the clinical trials performed and the role of novel emerging agents, this review aims to provide an 'expert opinion' on evidences that validate chemotherapy as current 'standard of care' for inoperable mesothelioma. METHODS: Relevant literature about clinical trials was reviewed using a PubMed search and other relevant data about novel therapeutic approaches both established and in development. CONCLUSION: The response rates achieved using chemotherapeutic treatments are higher than previous ones, and in the future may be improved by the use of combined and personalized therapies.

7 Review Mesothelioma epidemiology, carcinogenesis, and pathogenesis. 2008

Yang, Haining / Testa, Joseph R / Carbone, Michele. ·Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI 96813, USA. ·Curr Treat Options Oncol · Pubmed #18709470.

ABSTRACT: OPINION STATEMENT: The incidence of mesothelioma has gone from almost none to the current 2500-3000 cases per year in the USA. This estimate is an extrapolation based on information available from the Surveillance, Epidemiology and End Results (SEER) Program that collects information on approximately 12% of the US population. Mesothelioma is a cancer that is linked to exposure to carcinogenic mineral fibers. Asbestos and erionite have a proven causative role; the possible role of other mineral fibers in causing mesothelioma is being investigated. Asbestos is considered the main cause of mesothelioma in the US and in the Western world. The capacity of asbestos to induce mesothelioma has been linked to its ability to cause the release of TNF-alpha (that promotes mesothelial cells survival), other cytokines and growth factors, and of mutagenic oxygen radicals from exposed mesothelial cells and nearby macrophages. Some investigators proposed that as a consequence of the regulations to prevent exposure and to forbid and/or limit the use of asbestos, the incidence of mesothelioma in the US (and in some European countries) should have started to decline before or around the year 2000, and sharply decline thereafter. Unfortunately, there are no data available yet to support this optimistic hypothesis. Simian virus 40 (SV40) infection and radiation exposure are additional causes, although their contribution to the overall incidence of mesothelioma is unknown. Recent data from several laboratories indicate that asbestos exposure and SV40 infection are co-carcinogens in causing mesothelioma in rodents and in causing malignant transformation of human mesothelial cells in tissue culture. An exciting new development comes from the discovery that genetic susceptibility to mineral fiber carcinogenesis plays a critical role in the incidence of this cancer in certain families. It is hoped that the identification of this putative mesothelioma gene will lead to novel mechanistically driven preventive and therapeutic approaches.

8 Review The relationship between simian virus 40 and mesothelioma. 2008

Rivera, Zeyana / Strianese, Oriana / Bertino, Pietro / Yang, Haining / Pass, Harvey / Carbone, Michele. ·Cancer Research Center of Hawaii and Department of Pathology, University of Hawaii, Honolulu, Hawaii, USA . ·Curr Opin Pulm Med · Pubmed #18520265.

ABSTRACT: PURPOSE OF REVIEW: Simian virus 40 is present in some human malignant mesotheliomas. The evidence in favor and against a pathogenic role of simian virus 40 in malignant mesothelioma is discussed in this review. RECENT FINDINGS: When simian virus 40 is injected intracardially into hamsters, 60% develop and die of malignant mesothelioma. Moreover, some human malignant mesotheliomas contain and express simian virus 40 DNA and proteins. To date, over 50 laboratories have detected simian virus 40 in malignant mesotheliomas and in other tumors; however, the variability of the percentage of positivity led to a controversy about the role and significance of simian virus 40 in malignant mesotheliomas. Compared with other cell types, human mesothelial cells are unusually susceptible to simian virus 40-induced malignant transformation. The presence of simian virus 40 in malignant mesothelioma has been associated with the activation of specific oncogene pathways. Cocarcinogenesis between simian virus 40 and asbestos in causing malignant mesotheliomas has been demonstrated in three separate research laboratories using different experimental approaches. Epidemiological data possibly linking simian virus 40 and malignant mesothelioma is lacking owing to unattainable identification of infected from noninfected cohorts. SUMMARY: Available evidence appears sufficient to link simian virus 40 either alone or in conjunction with asbestos in causing malignant mesotheliomas; however, it is still insufficient to speculate about the contribution of simian virus 40 to the overall incidence of malignant mesotheliomas.

9 Article Inhibition of the spindle assembly checkpoint kinase Mps-1 as a novel therapeutic strategy in malignant mesothelioma. 2017

Szymiczek, A / Carbone, M / Pastorino, S / Napolitano, A / Tanji, M / Minaai, M / Pagano, I / Mason, J M / Pass, H I / Bray, M R / Mak, T W / Yang, H. ·Thoracic Oncology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA. · Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, Toronto, ON, Canada. · Department of Cardiothoracic Surgery, New York University, Langone Medical Center, New York, NY, USA. ·Oncogene · Pubmed #28759042.

ABSTRACT: Malignant mesothelioma (MM) is an aggressive malignancy, highly resistant to current medical and surgical therapies, whose tumor cells characteristically show a high level of aneuploidy and genomic instability. We tested our hypothesis that targeting chromosomal instability in MM would improve response to therapy. Thr/Tyr kinase (TTK)/monopolar spindle 1 kinase (Mps-1) is a kinase of the spindle assembly checkpoint that controls cell division and cell fate. CFI-402257 is a novel, selective inhibitor of Mps-1 with antineoplastic activity. We found that CFI-402257 suppresses MM growth. We found that Mps-1 is overexpressed in MM and that its expression correlates with poor patients' outcome. In vitro, CFI-402257-mediated inhibition of Mps-1 resulted in abrogation of the mitotic checkpoint, premature progression through mitosis, marked aneuploidy and mitotic catastrophe. In vivo, CFI-402257 reduced MM growth in an orthotopic, syngeneic model, when used as a single agent, and more so when used in combination with cisplatin+pemetrexed, the current standard of care. Our preclinical findings indicate that CFI-402257 is a promising novel therapeutic agent to improve the efficacy of the current chemotherapeutic regimens for MM patients.

10 Article FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model. 2017

Szymiczek, Agata / Pastorino, Sandra / Larson, David / Tanji, Mika / Pellegrini, Laura / Xue, Jiaming / Li, Shuangjing / Giorgi, Carlotta / Pinton, Paolo / Takinishi, Yasutaka / Pass, Harvey I / Furuya, Hideki / Gaudino, Giovanni / Napolitano, Andrea / Carbone, Michele / Yang, Haining. ·Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. · Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. pastorin@hawaii.edu. · Department of Morphology-Surgery-Experimental Medicine, University of Ferrara, Ferrara, Italy. · Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, NY, 10065, USA. · Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. mcarbone@cc.hawaii.edu. · Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. hyang@cc.hawaii.edu. ·J Transl Med · Pubmed #28298211.

ABSTRACT: BACKGROUND: Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet. METHODS: Cell viability and anchorage-independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy. The mechanism of action of FTY720 in MM was assessed by measuring the activity of phosphatase protein 2A (PP2A)-a major target of FTY720. The binding of the endogenous inhibitor SET to PP2A in presence of FTY720 was evaluated by immunoblotting and immunoprecipitation. Signaling and activation of programmed cell death were evaluated by immunoblotting and flow cytometry. A syngeneic mouse model was used to evaluate anti-tumor efficacy and toxicity profile of FTY720 in vivo. RESULTS: We show that FTY720 significantly suppressed MM cell viability and anchorage-independent growth without affecting normal HM cells. FTY720 inhibited the phosphatase activity of PP2A by displacement of SET protein, which appeared overexpressed in MM, as compared to HM cells. FTY720 promoted AKT dephosphorylation and Bcl-2 degradation, leading to induction of programmed cell death, as demonstrated by caspase-3 and PARP activation, as well as by cytochrome c and AIF intracellular translocation. Moreover, FTY720 administration in vivo effectively reduced tumor burden in mice without apparent toxicity. CONCLUSIONS: Our preclinical data indicate that FTY720 is a potentially promising therapeutic agent for MM treatment.

11 Article HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma. 2017

Pellegrini, Laura / Xue, Jiaming / Larson, David / Pastorino, Sandra / Jube, Sandro / Forest, Kelly H / Saad-Jube, Zeyana Salim / Napolitano, Andrea / Pagano, Ian / Negi, Vishal S / Bianchi, Marco E / Morris, Paul / Pass, Harvey I / Gaudino, Giovanni / Carbone, Michele / Yang, Haining. ·University of Hawai'i Cancer Center, University of Hawai'i at Manoa, Honolulu, HI, USA. · Leeward Community College, Mathematics and Sciences Division, University of Hawai'i System, Pearl City, HI, USA. · University of Hawai'i at Manoa, Department of Cell and Molecular Biology, John A. Burns School of Medicine, Honolulu, HI, USA. · University of Hawai'i at Manoa, Myron B. Thompson School of Social Work, Office of Public Health and Center on Aging, Honolulu, HI, USA. · University of Hawai'i at Manoa, Department of Molecular Biosciences and Bioengineering, Honolulu, HI, USA. · San Raffaele University and Research Institute, Milan, Italy. · Department of Thoracic Surgery, Queen's Medical Center, Honolulu, HI, USA. · New York University School of Medicine, Department of Cardiothoracic Surgery, New York, NY, USA. ·Oncotarget · Pubmed #28186988.

ABSTRACT: Human malignant mesothelioma (MM) is an aggressive cancer linked to asbestos and erionite exposure. We previously reported that High-Mobility Group Box-1 protein (HMGB1), a prototypic damage-associated molecular pattern, drives MM development and sustains MM progression. Moreover, we demonstrated that targeting HMGB1 inhibited MM cell growth and motility in vitro, reduced tumor growth in vivo, and prolonged survival of MM-bearing mice. Ethyl pyruvate (EP), the ethyl ester of pyruvic acid, has been shown to be an effective HMGB1 inhibitor in inflammation-related diseases and several cancers. Here, we studied the effect of EP on the malignant phenotype of MM cells in tissue culture and on tumor growth in vivo using an orthotopic MM xenograft model. We found that EP impairs HMGB1 secretion by MM cells leading to reduced RAGE expression and NF-κB activation. As a consequence, EP impaired cell motility, cell proliferation, and anchorage-independent growth of MM cells. Moreover, EP reduced HMGB1 serum levels in mice and inhibited the growth of MM xenografts.Our results indicate that EP effectively hampers the malignant phenotype of MM, offering a novel potential therapeutic approach to patients afflicted with this dismal disease.

12 Article Improving the Accuracy of Mesothelioma Diagnosis in China. 2017

Guo, Zhenying / Carbone, Michele / Zhang, Xing / Su, Dan / Sun, Wenyong / Lou, Jianlin / Gao, Zhibin / Shao, Dichu / Chen, Junqiang / Zhang, Gu / Hu, Jinlin / Chen, Kaiyan / Wang, Fang / Pass, Harvey I / Yu, Herbert / Napolitano, Andrea / Yang, Haining / Mao, Weimin. ·Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, People's Republic of China. · Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, Hawaii. Electronic address: mcarbone@cc.hawaii.edu. · Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China. · Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, People's Republic of China; Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology of Zhejiang Province, Hangzhou, People's Republic of China. · Yuyao People's Hospital, Yuyao, Zhejiang, People's Republic of China. · Yuyao Center of Disease Control and Prevention, Yuyao, Zhejiang, People's Republic of China. · Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, People's Republic of China; Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology of Zhejiang Province, Hangzhou, People's Republic of China; Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou, People's Republic of China. · Department of Radiology, Zhejiang Cancer Hospital, Hangzhou, People's Republic of China. · Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, New York. · Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii. · Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, Hawaii. ·J Thorac Oncol · Pubmed #28007630.

ABSTRACT: INTRODUCTION: In the Western world, malignant mesothelioma (MM) is most prevalent in the pleura of older males who have been professionally exposed to asbestos. Information about MM from rapidly industrializing countries such as China is minimal. There is concern that a proportion of MM diagnoses in China may be incorrect because most Chinese physicians do not have experience diagnosing this rare cancer. We recently reported an unusually high incidence of peritoneal MM among eastern Chinese female patients. Here, we review the accuracy of MM diagnoses in China and provide suggestions to improve the accuracy of diagnosis. METHODS: We reviewed 92 pathological diagnosis of MM in 2002-2015 from two reference centers in the province of Zhejiang in eastern China. We performed a large set of immunohistochemistry analyses to increase the reliability of the diagnosis. RESULTS: We confirmed the MM diagnosis in 12 of 34 of the pleural tumors (35.3%), in 38 of 56 of the peritoneal tumors (67.9%), and in two of two of the MMs of the tunica vaginalis (100%). MMs were characterized by tumor cells showing nuclear Wilms tumor 1 and calretinin staining and by strong membranous staining for cytokeratin CAM5.2. The results of staining for the epithelial markers carcinoembryonic antigen, thyroid transcription factor-1, MOC31, BerEP4, p63, p40, paired box 8, ER and PR were negative. BRCA1 associated protein 1 nuclear staining was lost in percentages similar to what has been reported for samples from Western countries. CONCLUSIONS: Our findings suggest that MM-especially in its pleural localization-is often misdiagnosed in eastern China. Identifying pitfalls and possible solutions in the pathological diagnosis of MM will affect both the standard of care and research in China.

13 Article Association of Asbestos Exposure With Malignant Mesothelioma Incidence in Eastern China. 2017

Mao, Weimin / Zhang, Xing / Guo, Zhenying / Gao, Zhibin / Pass, Harvey I / Yang, Haining / Carbone, Michele. ·Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou, China2Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology of Zhejiang Province, Hangzhou, China. · Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China. · Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, China. · Yuyao People's Hospital, Yuyao, Zhejiang, China. · Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York. · Thoracic Oncology Program, University of Hawaii Cancer Center, Honolulu. ·JAMA Oncol · Pubmed #27918607.

ABSTRACT: -- No abstract --

14 Article High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. 2016

Yoshikawa, Yoshie / Emi, Mitsuru / Hashimoto-Tamaoki, Tomoko / Ohmuraya, Masaki / Sato, Ayuko / Tsujimura, Tohru / Hasegawa, Seiki / Nakano, Takashi / Nasu, Masaki / Pastorino, Sandra / Szymiczek, Agata / Bononi, Angela / Tanji, Mika / Pagano, Ian / Gaudino, Giovanni / Napolitano, Andrea / Goparaju, Chandra / Pass, Harvey I / Yang, Haining / Carbone, Michele. ·Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo J663-8501, Japan. · Thoracic Oncology Program, University of Hawaii Cancer Center, Honolulu, HI 96813. · Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo J663-8501, Japan; tomokots@hyo-med.ac.jp mcarbone@cc.hawaii.edu. · Division of Molecular Pathology, Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo J663-8501, Japan. · Department of Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo J663-8501, Japan. · Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo J663-8501, Japan. · Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, NY 10016. · Thoracic Oncology Program, University of Hawaii Cancer Center, Honolulu, HI 96813; tomokots@hyo-med.ac.jp mcarbone@cc.hawaii.edu. ·Proc Natl Acad Sci U S A · Pubmed #27834213.

ABSTRACT: We used a custom-made comparative genomic hybridization array (aCGH; average probe interval 254 bp) to screen 33 malignant mesothelioma (MM) biopsies for somatic copy number loss throughout the 3p21 region (10.7 Mb) that harbors 251 genes, including BRCA1 (breast cancer 1)-associated protein 1 (BAP1), the most commonly mutated gene in MM. We identified frequent minute biallelic deletions (<3 kb) in 46 of 251 genes: four were cancer-associated genes: SETD2 (SET domain-containing protein 2) (7 of 33), BAP1 (8 of 33), PBRM1 (polybromo 1) (3 of 33), and SMARCC1 (switch/sucrose nonfermentable- SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily c, member 1) (2 of 33). These four genes were further investigated by targeted next-generation sequencing (tNGS), which revealed sequence-level mutations causing biallelic inactivation. Combined high-density aCGH and tNGS revealed biallelic gene inactivation in SETD2 (9 of 33, 27%), BAP1 (16 of 33, 48%), PBRM1 (5 of 33, 15%), and SMARCC1 (2 of 33, 6%). The incidence of genetic alterations detected is much higher than reported in the literature because minute deletions are not detected by NGS or commercial aCGH. Many of these minute deletions were not contiguous, but rather alternated with segments showing oscillating copy number changes along the 3p21 region. In summary, we found that in MM: (i) multiple minute simultaneous biallelic deletions are frequent in chromosome 3p21, where they occur as distinct events involving multiple genes; (ii) in addition to BAP1, mutations of SETD2, PBRM1, and SMARCC1 are frequent in MM; and (iii) our results suggest that high-density aCGH combined with tNGS provides a more precise estimate of the frequency and types of genes inactivated in human cancer than approaches based exclusively on NGS strategy.

15 Article Investigating palygorskite's role in the development of mesothelioma in southern Nevada: Insights into fiber-induced carcinogenicity. 2016

Larson, David / Powers, Amy / Ambrosi, Jean-Paul / Tanji, Mika / Napolitano, Andrea / Flores, Erin G / Baumann, Francine / Pellegrini, Laura / Jennings, Cormac J / Buck, Brenda J / McLaurin, Brett T / Merkler, Doug / Robinson, Cleo / Morris, Paul / Dogan, Meral / Dogan, A Umran / Pass, Harvey I / Pastorino, Sandra / Carbone, Michele / Yang, Haining. ·a University of Hawai'i Cancer Center , University of Hawai'i , Honolulu , Hawai'i , USA. · b CNRS, IRD, CEREGE UM34 , Aix-Marseille Université , Aix en Provence, France. · c Department of Molecular Biosciences and Bioengineering , University of Hawai'i at Manoa , Honolulu , Hawai'i , USA. · d ERIM , Université de la Nouvelle-Calédonie , Nouméa , New Caledonia. · e Department of Geoscience , University of Nevada Las Vegas , Las Vegas , Nevada , USA. · f Department of Environmental, Geographical and Geological Sciences , Bloomsburg University of Pennsylvania , Bloomsburg , Pennsylvania , USA. · g U.S. Department of Agriculture , Natural Resources Conservation Service , Las Vegas , Nevada , USA. · h National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology , University of Western Australia, Harry Perkins Institute for Medical Research , Nedlands, Perth , Western Australia. · i Department of Thoracic Surgery , Queen's Medical Center , Honolulu , Hawai'i , USA. · j Geological Engineering Department , Hacettepe University , Beytepe , Ankara , Turkey. · k Chemical and Biochemical Engineering Department & Center for Global and Regional Environmental Research , University of Iowa , Iowa City , Iowa , USA. · l Department of Cardiothoracic Surgery , New York Langone Medical Center , New York , New York , USA. ·J Toxicol Environ Health B Crit Rev · Pubmed #27705545.

ABSTRACT: Similar to asbestos fibers, nonregulated mineral fibers can cause malignant mesothelioma (MM). Recently, increased proportions of women and young individuals with MM were identified in southern Nevada, suggesting that environmental exposure to carcinogenic fibers was causing the development of MM. Palygorskite, a fibrous silicate mineral with a history of possible carcinogenicity, is abundant in southern Nevada. In this study, our aim was to determine whether palygorskite was contributing to the development of MM in southern Nevada. While palygorskite, in vitro, displayed some cytotoxicity toward primary human mesothelial (HM) cells and reduced their viability, the effects were roughly half of those observed when using similar amounts of crocidolite asbestos. No Balb/c (0/19) or MexTAg (0/18) mice injected with palygorskite developed MM, while 3/16 Balb/c and 13/14 MexTAg mice injected with crocidolite did. Lack of MM development was associated with a decreased acute inflammatory response, as injection of palygorskite resulted in lower percentages of macrophages (p = .006) and neutrophils (p = .02) in the peritoneal cavity 3 d after exposure compared to injection of crocidolite. Additionally, compared to mice injected with crocidolite, palygorskite-injected mice had lower percentages of M2 (tumor-promoting) macrophages (p = .008) in their peritoneal cavities when exposed to fiber for several weeks. Our study indicates that palygorskite found in the environment in southern Nevada does not cause MM in mice, seemingly because palygorskite, in vivo, fails to elicit inflammation that is associated with MM development. Therefore, palygorskite is not a likely contributor to the MM cases observed in southern Nevada.

16 Article Environmental risk of mesothelioma in the United States: An emerging concern-epidemiological issues. 2016

Baumann, Francine / Carbone, Michele. ·a ERIM , University of New Caledonia , Nouméa , New Caledonia. · b Cancer Center , University of Hawaii , Honolulu , Hawaii , USA. ·J Toxicol Environ Health B Crit Rev · Pubmed #27705543.

ABSTRACT: Despite predictions of decline in mesothelioma following the ban of asbestos in most industrial countries, the incidence is still increasing globally, particularly in women. Because occupational exposure to asbestos is the main cause of mesothelioma, it occurs four- to eightfold more frequently in men than women, at a median age of 74 years. When mesothelioma is due to an environmental exposure, the M:F sex ratio is 1:1 and the median age at diagnosis is ~60 years. Studying environmental risk of mesothelioma is challenging because of the long latency period and small numbers, and because this type of exposure is involuntary and unknown. Individual-based methods cannot be used, and new approaches need to be found. To better understand the most recent trends of mesothelioma in the United States, all mesothelioma deaths reported to the Centers for Disease Control and Prevention (CDC) during 1999-2010 were analyzed. Among all mesothelioma deaths in the United States, the 1920s birth cohort significantly predominated, and the proportion of younger cohorts constantly decreased with time, suggesting a decline in occupational exposure in these cohorts. The M:F mesothelioma sex ratio fell with time, suggesting an increased proportion of environmental cases. Environmental exposures occur in specific geographic areas. At the large scale of a state, mesotheliomas related to environmental exposure are diluted among occupational cases. The spatial analysis at a smaller scale, such as county, enables detection of areas with higher proportions of female and young mesothelioma cases, thus indicating possible environmental exposure, where geological and environmental investigations need to be carried out.

17 Article Consensus Report of the 2015 Weinman International Conference on Mesothelioma. 2016

Carbone, Michele / Kanodia, Shreya / Chao, Ann / Miller, Aubrey / Wali, Anil / Weissman, David / Adjei, Alex / Baumann, Francine / Boffetta, Paolo / Buck, Brenda / de Perrot, Marc / Dogan, A Umran / Gavett, Steve / Gualtieri, Alessandro / Hassan, Raffit / Hesdorffer, Mary / Hirsch, Fred R / Larson, David / Mao, Weimin / Masten, Scott / Pass, Harvey I / Peto, Julian / Pira, Enrico / Steele, Ian / Tsao, Anne / Woodard, Gavitt Alida / Yang, Haining / Malik, Shakun. ·Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, Hawaii. Electronic address: mcarbone@cc.hawaii.edu. · Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, Hawaii; Samuel Oschin Comprehensive Cancer Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California. · Center for Global Health, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina. · Center to Reduce Cancer Health Disparities, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Respiratory Health Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia. · Mayo Clinic, Rochester, Minnesota. · ERIM, University of New Caledonia, Noumea, New Caledonia. · Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Geoscience, University of Nevada Las Vegas, Las Vegas, Nevada. · Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. · Chemical and Biochemical Engineering Department and Center for Global and Regional Environmental Research, University of Iowa, Iowa City, Iowa. · Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina. · Chemical/Earth Sciences Department, University of Modena, Modena, Italy. · Thoracic Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland. · Mesothelioma Applied Research Foundation, Alexandria, Virginia. · University of Colorado Cancer Center, Denver, Colorado. · Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, Hawaii. · Cancer Research Institute, Zhejiang Cancer Hospital and Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology of Zhejiang, Hangzhou, People's Republic of China. · National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina. · Cardiothoracic Surgery, New York University Langone Medical Center, New York, New York. · Cancer Research UK, London School of Hygiene and Tropical Medicine, London, United Kingdom. · Department of Public Health and Pediatrics, University of Turin, Turin, Italy. · Notre Dame Integrated Imaging Facility, Notre Dame University, Notre Dame, Indiana. · Department of Thoracic and Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. · Thoracic Surgery, University of California at San Francisco, San Francisco, California. · Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. ·J Thorac Oncol · Pubmed #27453164.

ABSTRACT: On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group's efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM.

18 Article Positive nuclear BAP1 immunostaining helps differentiate non-small cell lung carcinomas from malignant mesothelioma. 2016

Carbone, Michele / Shimizu, David / Napolitano, Andrea / Tanji, Mika / Pass, Harvey I / Yang, Haining / Pastorino, Sandra. ·Thoracic Oncology Program, University of Hawaii Cancer Center, Honolulu, HI, USA. · Department of Pathology, Queen Medical Center, Honolulu, HI, USA. · Department of Cardiothoracic Surgery, New York University, NYU Langone Medical Center, NY, USA. ·Oncotarget · Pubmed #27447750.

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

19 Article Plasma Biomarker Enrichment of Clinical Prognostic Indices in Malignant Pleural Mesothelioma. 2016

Pass, Harvey I / Goparaju, Chandra / Espin-Garcia, Osvaldo / Donington, Jessica / Carbone, Michele / Patel, Devalben / Chen, Zhuo / Feld, Ronald / Cho, John / Gadgeel, Shirish / Wozniak, Antoinette / Chachoua, Abraham / Leighl, Natasha / Tsao, Ming-Sound / de Perrot, Marc / Xu, Wei / Liu, Geoffrey. ·Langone Medical Center, New York University, New York, New York. Electronic address: harvey.pass@med.nyu.edu. · Langone Medical Center, New York University, New York, New York. · Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network and University of Toronto, Toronto, Ontario, Canada. · University of Hawaii Cancer Center, Honolulu, Hawaii. · Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. ·J Thorac Oncol · Pubmed #26903362.

ABSTRACT: OBJECTIVES: Prognostic models for malignant pleural mesothelioma (MPM) are needed to prevent potentially futile outcomes. We combined MPM plasma biomarkers with validated clinical prognostic indices to determine whether stratification of risk for death in 194 patients with MPM improved. METHODS: Individuals were recruited from three different centers: a discovery cohort (83 patients with MPM) created by combining patients from two U.S. centers and a separate, independent cohort from Canada (111 patients with MPM). Univariable and multivariable analyses were performed on the initial discovery and independent cohorts separately. In the multivariable analyses, prognostic factors were adjusted for the European Organisation for Research and Treatment of Cancer (EORTC) prognostic index (PI) of mesothelioma. The prognostic significance of adding plasma biomarker data to the PI was determined by using the likelihood ratio test, comparing models with and without the addition of biomarker to the clinical PI. The predictive ability of the biomarker was then assessed formally using Harrell's C-index by applying the fitted model variables of the discovery cohort to the second, independent cohort, including and not including the biomarker with the PI. RESULTS: Higher levels of osteopontin and mesothelin were individually associated with worse prognosis after adjusting for the PI. In the independent cohort, incorporating either plasma osteopontin or mesothelin into the baseline predictive PI model substantively and statistically significantly improved Harrell's C-statistic. In the final prognostic model, log-osteopontin, EORTC clinical prognostic index, and hemoglobin remained as independently significant predictors and the entire prognostic model improved the optimism-corrected Harrell's C-index significantly, from 0.718 (0.67-0.77) to 0.801 (0.77-0.84). CONCLUSIONS: These data suggest a possible role for preoperative plasma biomarkers to improve the prognostic capability of the EORTC PI of MPM.

20 Article HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients. 2016

Napolitano, Andrea / Antoine, Daniel J / Pellegrini, Laura / Baumann, Francine / Pagano, Ian / Pastorino, Sandra / Goparaju, Chandra M / Prokrym, Kirill / Canino, Claudia / Pass, Harvey I / Carbone, Michele / Yang, Haining. ·University of Hawaii Cancer Center, Honolulu, Hawaii. Department of Molecular Biosciences and Bioengineering, University of Hawaii at Mānoa, Honolulu, Hawaii. · MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom. · University of Hawaii Cancer Center, Honolulu, Hawaii. · Department of Cardiothoracic Surgery, New York University, NYU Langone Medical Center, New York, New York. · Department of Cardiothoracic Surgery, New York University, NYU Langone Medical Center, New York, New York. hyang@cc.hawaii.edu mcarbone@cc.hawaii.edu Harvey.Pass@nyumc.org. · University of Hawaii Cancer Center, Honolulu, Hawaii. hyang@cc.hawaii.edu mcarbone@cc.hawaii.edu Harvey.Pass@nyumc.org. ·Clin Cancer Res · Pubmed #26733616.

ABSTRACT: PURPOSE: To determine whether serum levels of high mobility group box protein 1 (HMGB1) could differentiate malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls. EXPERIMENTAL DESIGN: Hyperacetylated and nonacetylated HMGB1 (together referred to as total HMGB1) were blindly measured in blood collected from malignant mesothelioma patients (n = 22), individuals with verified chronic asbestos exposure (n = 20), patients with benign pleural effusions (n = 13) or malignant pleural effusions not due to malignant mesothelioma (n = 25), and healthy controls (n = 20). Blood levels of previously proposed malignant mesothelioma biomarkers fibulin-3, mesothelin, and osteopontin were also measured in nonhealthy individuals. RESULTS: HMGB1 serum levels reliably distinguished malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls. Total HMGB1 was significantly higher in malignant mesothelioma patients and asbestos-exposed individuals compared with healthy controls. Hyperacetylated HMGB1 was significantly higher in malignant mesothelioma patients compared with asbestos-exposed individuals and healthy controls, and did not vary with tumor stage. At the cut-off value of 2.00 ng/mL, the sensitivity and specificity of serum hyperacetylated HMGB1 in differentiating malignant mesothelioma patients from asbestos-exposed individuals and healthy controls was 100%, outperforming other previously proposed biomarkers. Combining HMGB1 and fibulin-3 provided increased sensitivity and specificity in differentiating malignant mesothelioma patients from patients with cytologically benign or malignant non-mesothelioma pleural effusion. CONCLUSIONS: Our results are significant and clinically relevant as they provide the first biomarker of asbestos exposure and indicate that hyperacetylated HMGB1 is an accurate biomarker to differentiate malignant mesothelioma patients from individuals occupationally exposed to asbestos and unexposed controls. A trial to independently validate these findings will start soon. Clin Cancer Res; 22(12); 3087-96. ©2016 AACR.

21 Article Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. 2016

Napolitano, A / Pellegrini, L / Dey, A / Larson, D / Tanji, M / Flores, E G / Kendrick, B / Lapid, D / Powers, A / Kanodia, S / Pastorino, S / Pass, H I / Dixit, V / Yang, H / Carbone, M. ·University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA. · Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI, USA. · Department of Discovery Oncology, Genentech, South San Francisco, CA, USA. · Department of Biomedical Sciences and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. · Department of Cardiothoracic Surgery, New York University, New York, NY, USA. ·Oncogene · Pubmed #26119930.

ABSTRACT: Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated with professional exposure to asbestos. However, to date, we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after minimal exposure. Using a BAP1(+/-) mouse model, we found that, compared with their wild-type littermates, BAP1(+/-) mice exposed to low-dose asbestos fibers showed significant alterations of the peritoneal inflammatory response, including significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1(+/-) mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild-type mice. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.

22 Article Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s. 2015

Carbone, Michele / Flores, Erin G / Emi, Mitsuru / Johnson, Todd A / Tsunoda, Tatsuhiko / Behner, Dusty / Hoffman, Harriet / Hesdorffer, Mary / Nasu, Masaki / Napolitano, Andrea / Powers, Amy / Minaai, Michael / Baumann, Francine / Bryant-Greenwood, Peter / Lauk, Olivia / Kirschner, Michaela B / Weder, Walter / Opitz, Isabelle / Pass, Harvey I / Gaudino, Giovanni / Pastorino, Sandra / Yang, Haining. ·Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America. · Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan. · Genealogy from the Hart, Honolulu, Hawai'i, United States of America. · Mesothelioma Applied Research Foundation, Alexandria, Virginia, United States of America. · Klinik für Thoraxchirurgie Universitätsspital, Zürich, Switzerland. · Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, New York, United States of America. ·PLoS Genet · Pubmed #26683624.

ABSTRACT: We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies).

23 Article Frequent genomic rearrangements of BRCA1 associated protein-1 (BAP1) gene in Japanese malignant mesothelioma-characterization of deletions at exon level. 2015

Emi, Mitsuru / Yoshikawa, Yoshie / Sato, Chika / Sato, Ayuko / Sato, Hidenori / Kato, Takeo / Tsujimura, Tohru / Hasegawa, Seiki / Nakano, Takashi / Hashimoto-Tamaoki, Tomoko. ·Department of Genetics, Hyogo College of Medicine, Hyogo, Japan. · Thoracic Oncology Program, University of Hawaii Cancer Center, Honolulu, HI, USA. · Department of Clinical Genetics, Hyogo College of Medicine, Hyogo, Japan. · Department of Molecular Pathology, Hyogo College of Medicine, Hyogo, Japan. · Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University Faculty of Medicine, Yamagata, Japan. · Department of General Thoracic Surgery, Hyogo College of Medicine, Hyogo, Japan. · Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan. ·J Hum Genet · Pubmed #26246155.

ABSTRACT: Malignant mesothelioma (MM) is an asbestos-related malignancy arising from surface serosal cells of pleural and peritoneal cavities. Somatic mutations of BRCA1 associated protein-1 (BAP1) gene were recently found in MM as well as in uveal melanoma and kidney cancer among the Caucasian and Japanese people. However, frequency of mutations varies among the reported studies, which might be due to presence of undetected gross rearrangements of BAP1 gene that might escape detection by sequencing strategy. We investigated the presence and frequency of gross genomic rearrangements in the BAP1 gene by multiplex ligation-dependent probe amplification (MLPA) in 17 Japanese cases of MM tumors. We found five tumors with partial deletion of BAP1 gene; each tumors displayed partial deletion of exons 1-4 (MM39), exons 1-5 (MM48), exons 11-17 (MM57), exons 1-15 (MM19) and exons 1-16 (MM21). Two tumors (MM34, MM14) had biallelic deletion and four tumors (MM29, MM35, MM45 and MM56) had monoallelic deletion of entire BAP1 gene. Therefore, MLPA analysis revealed large gene rearrangements of BAP1 gene in 65% of MM (11/17). Unusually high frequency of large deletions indicates that the 3p21 chromosomal region surrounding BAP1 gene is structurally unstable. MLPA was useful in characterizing both monoallelic and biallelic deletion of BAP1 gene precisely at exon level.

24 Article Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression. 2015

Yang, H / Pellegrini, L / Napolitano, A / Giorgi, C / Jube, S / Preti, A / Jennings, C J / De Marchis, F / Flores, E G / Larson, D / Pagano, I / Tanji, M / Powers, A / Kanodia, S / Gaudino, G / Pastorino, S / Pass, H I / Pinton, P / Bianchi, M E / Carbone, M. ·University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA. · 1] University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA [2] Department of Molecular Biosciences and Bioengineering, University of Hawaii, Honolulu, HI 96813, USA. · Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy. · San Raffaele University and Scientific Institute, Milan 20132, Italy. · Samuel Oschin Comprehensive Cancer Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · Department of Cardiothoracic Surgery, New York Langone Medical Center, New York, NY 10016, USA. ·Cell Death Dis · Pubmed #26068794.

ABSTRACT: High-mobility group box 1 (HMGB1) is an inflammatory molecule that has a critical role in the initiation and progression of malignant mesothelioma (MM). Aspirin (acetylsalicylic acid, ASA) is the most widely used nonsteroidal anti-inflammatory drug that reduces the incidence, metastatic potential and mortality of many inflammation-induced cancers. We hypothesized that ASA may exert anticancer properties in MM by abrogating the carcinogenic effects of HMGB1. Using HMGB1-secreting and -non-secreting human MM cell lines, we determined whether aspirin inhibited the hallmarks of HMGB1-induced MM cell growth in vitro and in vivo. Our data demonstrated that ASA and its metabolite, salicylic acid (SA), inhibit motility, migration, invasion and anchorage-independent colony formation of MM cells via a novel HMGB1-mediated mechanism. ASA/SA, at serum concentrations comparable to those achieved in humans taking therapeutic doses of aspirin, and BoxA, a specific inhibitor of HMGB1, markedly reduced MM growth in xenograft mice and significantly improved survival of treated animals. The effects of ASA and BoxA were cyclooxygenase-2 independent and were not additive, consistent with both acting via inhibition of HMGB1 activity. Our findings provide a rationale for the well documented, yet poorly understood antitumorigenic activity of aspirin, which we show proceeds via HMGB1 inhibition. Moreover, the use of BoxA appears to allow a more efficient HMGB1 targeting while eluding the known gastrointestinal side effects of ASA. Our findings are directly relevant to MM. Given the emerging importance of HMGB1 and its tumor-promoting functions in many cancer types, and of aspirin in cancer prevention and therapy, our investigation is poised to provide broadly applicable information.

25 Article Preclinical development of HIvax: Human survivin highly immunogenic vaccines. 2015

Hoffmann, Peter R / Panigada, Maddalena / Soprana, Elisa / Terry, Frances / Bandar, Ivo Sah / Napolitano, Andrea / Rose, Aaron H / Hoffmann, Fukun W / Ndhlovu, Lishomwa C / Belcaid, Mahdi / Moise, Lenny / De Groot, Anne S / Carbone, Michele / Gaudino, Giovanni / Matsui, Takashi / Siccardi, Antonio / Bertino, Pietro. ·a Department of Cell and Molecular Biology; John A. Burns School of Medicine ; University of Hawai'i ; Honolulu , HI , USA. ·Hum Vaccin Immunother · Pubmed #26042612.

ABSTRACT: Our previous work involved the development of a recombinant fowlpox virus encoding survivin (FP-surv) vaccine that was evaluated for efficacy in mesothelioma mouse models. Results showed that FP-surv vaccination generated significant immune responses, which led to delayed tumor growth and improved animal survival. We have extended those previous findings in the current study, which involves the pre-clinical development of an optimized version of FP-surv designed for human immunization (HIvax). Survivin-derived peptides for the most common haplotypes in the human population were identified and their immunogenicity confirmed in co-culture experiments using dendritic cells and T cells isolated from healthy donors. Peptides confirmed to induce CD8(+) and CD4(+) T cells activation in humans were then included in 2 transgenes optimized for presentation of processed peptides on MHC-I (HIvax1) and MHC-II (HIvax2). Fowlpox vectors expressing the HIvax transgenes were then generated and their efficacy was evaluated with subsequent co-culture experiments to measure interferon-γ and granzyme B secretion. In these experiments, both antigen specific CD4(+) and CD8(+) T cells were activated by HIvax vaccines with resultant cytotoxic activity against survivin-overexpressing mesothelioma cancer cells. These results provide a rationale for clinical testing of HIvax1 and HIvax2 vaccines in patients with survivin-expressing cancers.

Next