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Mesothelioma: HELP
Articles by Lucian R. Chirieac
Based on 21 articles published since 2008
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Between 2008 and 2019, L. Chirieac wrote the following 21 articles about Mesothelioma.
 
+ Citations + Abstracts
1 Guideline Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group. 2018

Husain, Aliya Noor / Colby, Thomas V / Ordóñez, Nelson G / Allen, Timothy Craig / Attanoos, Richard Luther / Beasley, Mary Beth / Butnor, Kelly Jo / Chirieac, Lucian R / Churg, Andrew M / Dacic, Sanja / Galateau-Sallé, Françoise / Gibbs, Allen / Gown, Allen M / Krausz, Thomas / Litzky, Leslie Anne / Marchevsky, Alberto / Nicholson, Andrew G / Roggli, Victor Louis / Sharma, Anupama K / Travis, William D / Walts, Ann E / Wick, Mark R. ·From the Department of Pathology, University of Chicago Medical Center, Chicago, Illinois (Drs Husain and Krausz) · the Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona (Dr Colby, emeritus) · the Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston (Dr Ordóñez) · the Department of Pathology, University of Texas Medical Branch, Galveston (Dr Allen) · the Department of Cellular Pathology, University Hospital of Wales and Cardiff University, Cardiff, South Glamorgan, Wales (Dr Attanoos) · the Department of Pathology, Mount Sinai Medical Center, New York, New York (Dr Beasley) · the Department of Pathology, University of Vermont College of Medicine, Burlington (Dr Butnor) · the Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (Dr Chirieac) · the Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada (Dr Churg) · the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Dr Dacic) · Centre National Référent MESOPATH Departement de Biopathologie, Lyon Cedex, France (Dr Galateau-Sallé) · the Department of Pathology, University Hospital of Wales, Penarth, South Glamorgan, Wales (Dr Gibbs) · the Department of Pathology, PhenoPath Laboratories, Seattle, Washington (Dr Gown) · the Department of Pathology & Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, (Dr Litzky) · the Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California (Drs Marchevsky and Walts) · the Department of Histopathology, Royal Brompton & Harefield National Health Service Foundation Trust and the National Heart and Lung Institute, Imperial College, Chelsea, London, England (Dr Nicholson) · the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Dr Roggli) · the Department of Pathology, University of Pittsburgh, and the VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania (Dr Sharma) · the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Travis) · and the Department of Pathology, University of Virginia Medical Center, Charlottesville (Dr Wick). ·Arch Pathol Lab Med · Pubmed #28686500.

ABSTRACT: CONTEXT: - Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: - To provide updated, practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: - Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks. CONCLUSIONS: - There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.

2 Guideline Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. 2013

Husain, Aliya N / Colby, Thomas / Ordonez, Nelson / Krausz, Thomas / Attanoos, Richard / Beasley, Mary Beth / Borczuk, Alain C / Butnor, Kelly / Cagle, Philip T / Chirieac, Lucian R / Churg, Andrew / Dacic, Sanja / Fraire, Armando / Galateau-Salle, Francoise / Gibbs, Allen / Gown, Allen / Hammar, Samuel / Litzky, Leslie / Marchevsky, Alberto M / Nicholson, Andrew G / Roggli, Victor / Travis, William D / Wick, Mark / Anonymous2710735. ·Department of Pathology, University of Chicago, Chicago, IL 60637, USA. aliya.husain@uchospitals.edu ·Arch Pathol Lab Med · Pubmed #22929121.

ABSTRACT: CONTEXT: Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: To provide updated practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: Pathologists involved in the International Mesothelioma Interest Group and others with an interest in the field contributed to this update. Reference material includes peer-reviewed publications and textbooks. CONCLUSIONS: There was consensus opinion regarding (1) distinction of benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiation of epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. It is recommended that immunohistochemical markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist.

3 Guideline Malignant pleural mesothelioma. 2012

Ettinger, David S / Akerley, Wallace / Borghaei, Hossein / Chang, Andrew / Cheney, Richard T / Chirieac, Lucian R / D'Amico, Thomas A / Demmy, Todd L / Ganti, Apar Kishor P / Govindan, Ramaswamy / Grannis, Frederic W / Horn, Leora / Jahan, Thierry M / Jahanzeb, Mohammad / Kessinger, Anne / Komaki, Ritsuko / Kong, Feng-Ming Spring / Kris, Mark G / Krug, Lee M / Lennes, Inga T / Loo, Billy W / Martins, Renato / O'Malley, Janis / Osarogiagbon, Raymond U / Otterson, Gregory A / Patel, Jyoti D / Schenck, Mary Pinder / Pisters, Katherine M / Reckamp, Karen / Riely, Gregory J / Rohren, Eric / Swanson, Scott J / Wood, Douglas E / Yang, Stephen C / Anonymous5390714. ·The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. Baltimore, MD, USA. ·J Natl Compr Canc Netw · Pubmed #22223867.

ABSTRACT: -- No abstract --

4 Guideline Guidelines for pathologic diagnosis of malignant mesothelioma: a consensus statement from the International Mesothelioma Interest Group. 2009

Husain, Aliya N / Colby, Thomas V / Ordóñez, Nelson G / Krausz, Thomas / Borczuk, Alain / Cagle, Philip T / Chirieac, Lucian R / Churg, Andrew / Galateau-Salle, Francoise / Gibbs, Allen R / Gown, Allen M / Hammar, Samuel P / Litzky, Leslie A / Roggli, Victor L / Travis, William D / Wick, Mark R. ·Department of Pathology, University of Chicago, Chicago, IL 60631, USA. ahusain@bsd.uchicago.edu ·Arch Pathol Lab Med · Pubmed #19653732.

ABSTRACT: CONTEXT: Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: To develop practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: A pathology panel was convened at the International Mesothelioma Interest Group biennial meeting (October 2006). Pathologists with an interest in the field also contributed after the meeting. CONCLUSIONS: There was consensus opinion regarding (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the differential diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. The International Mesothelioma Interest Group recommends that markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist.

5 Review The differential diagnosis between pleural sarcomatoid mesothelioma and spindle cell/pleomorphic (sarcomatoid) carcinomas of the lung: evidence-based guidelines from the International Mesothelioma Panel and the MESOPATH National Reference Center. 2017

Marchevsky, Alberto M / LeStang, Nolwenn / Hiroshima, Kenzo / Pelosi, Giuseppe / Attanoos, Richard / Churg, Andrew / Chirieac, Lucian / Dacic, Sanja / Husain, Aliya / Khoor, Andras / Klebe, Sonja / Lantuejoul, Silvie / Roggli, Victor / Vignaud, Jean-Michel / Weynard, Birgit / Sauter, Jennifer / Henderson, Douglas / Nabeshima, Kasuzi / Galateau-Salle, Francoise. ·Department of Pathology Cedars-Sinai Medical Center, Los Angeles, CA. Electronic address: Alberto.Marchevsky@cshs.org. · Department of Pathology, MESOPATH-MESOBANK, Centre León Bérard, Lyon, France. · Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan. · Interhospital Pathology Division, Università degli Studi di Milano and IRCCS MultiMedica Group, Milan, Italy. · Department of Pathology University of Wales and Cardiff University, Cardiff, U.K. · Department of Pathology, University of British Columbia, Vancouver, BC. · Department of Pathology, Brigham and Women's Hospital, Boston, MA. · Department of Pathology UPMC-PUH, Pittsburgh, PA. · Department of Pathology, Chicago University, Chicago, IL. · Department of Pathology, Mayo Clinic, Jacksonville, FL. · SA Pathology at Flinders Medical Cemtre, Bedord Park, SA. · Department of Pathology, Centre Hospitalier Universitaire de Grenoble, Grenoble, France. · Department of Pathology Duke University, Durham, NC. · Department of Pathology, CHU de Nancy, Nancy, France. · University Hospital Leuven, Leuven, Belgium. · Department of Pathology Sloan Kettering Memorial Cancer Center, New York, NY. · Department of Pathology Fukuoka University Hospital, Fukuoka, Japan. ·Hum Pathol · Pubmed #28782639.

ABSTRACT: Immunohistochemistry is used to distinguish sarcomatoid malignant mesotheliomas (SMM) from spindle cell and pleomorphic carcinomas (SPC) but there are no guidelines on how to interpret cases that show overlapping or equivocal immunohistochemical findings. A systematic literature review of the immunophenotype of these lesions was performed and the experience with 587 SMM and 46 SPC at MESOPATH was collected. Data were analyzed with Comprehensive Meta-Analysis 2.0 software (Biostat, Englewood, NJ). There were insufficient data to evaluate the differential diagnosis between SPC and localized SMM or peritoneal SMM. Meta-analysis showed considerable overlap in the immunophenotype of these neoplasms and significant data heterogeneity amongst many of the results. Survival data from MESOPATH patients showed no significant differences in overall survival between SMM and SPC patients. Best available evidence was used to formulate several evidence-based guidelines for the differential diagnosis between pleural SMM and SPC. These guidelines emphasize the need to correlate the histopathological findings with clinical and imaging information. Diffuse SMM can be diagnosed with certainty in the presence of malignant spindle cell pleural lesions showing immunoreactivity for cytokeratin and mesothelial markers and negative staining for epithelial markers. Criteria for the interpretation of various other combinations of immunoreactivity for cytokeratin and mesothelial and/or epithelial markers are proposed. Localized sarcomatoid mesotheliomas can only be diagnosed in the presence of spindle cell malignancies that exhibit immunoreactivity for cytokeratin and mesothelial markers and negative immunoreactivity for epithelial lesions, in patients that show no multifocal or diffuse pleural spread and no evidence for extrapleural lesions.

6 Review Pathologic evaluation of malignant pleural mesothelioma. 2009

Chirieac, Lucian R / Corson, Joseph M. ·Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. lchirieac@partners.org ·Semin Thorac Cardiovasc Surg · Pubmed #19822283.

ABSTRACT: Pathologists play an important role in the surgical management of diffuse malignant pleural mesothelioma, which relies heavily on accurate diagnosis and staging. The pathologist provides crucial input to the determination of many prognostic factors including histologic subtype, extent of local disease progression, resection margins, and nodal status. They consult with the clinical care team at multiple points along the treatment spectrum, preoperatively, intraoperatively, and postoperatively. Finally, they are increasingly called on to guide selection of chemotherapy and measure treatment response.

7 Guideline NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016. 2016

Ettinger, David S / Wood, Douglas E / Akerley, Wallace / Bazhenova, Lyudmila A / Borghaei, Hossein / Camidge, David Ross / Cheney, Richard T / Chirieac, Lucian R / D'Amico, Thomas A / Dilling, Thomas / Dobelbower, Michael / Govindan, Ramaswamy / Hennon, Mark / Horn, Leora / Jahan, Thierry M / Komaki, Ritsuko / Lackner, Rudy P / Lanuti, Michael / Lilenbaum, Rogerio / Lin, Jules / Loo, Billy W / Martins, Renato / Otterson, Gregory A / Patel, Jyoti D / Pisters, Katherine M / Reckamp, Karen / Riely, Gregory J / Schild, Steven E / Shapiro, Theresa A / Sharma, Neelesh / Swanson, Scott J / Stevenson, James / Tauer, Kurt / Yang, Stephen C / Gregory, Kristina / Hughes, Miranda. ·From The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; Huntsman Cancer Institute at the University of Utah; UC San Diego Moores Cancer Center; Fox Chase Cancer Center; University of Colorado Cancer Center; Roswell Park Cancer Institute; Dana-Farber/Brigham and Women's Cancer Center; Duke Cancer Institute; Moffitt Cancer Center; University of Alabama at Birmingham Comprehensive Cancer Center; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; Vanderbilt-Ingram Cancer Center; UCSF Helen Diller Family Comprehensive Cancer Center; The University of Texas MD Anderson Cancer Center; Fred & Pamela Buffett Cancer Center; Massachusetts General Hospital Cancer Center; Yale Cancer Center/Smilow Cancer Hospital; University of Michigan Comprehensive Cancer Center; Stanford Cancer Institute; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; City of Hope Comprehensive Cancer Center; Memorial Sloan Kettering Cancer Center; Mayo Clinic Cancer Center; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; and National Comprehensive Cancer Network. ·J Natl Compr Canc Netw · Pubmed #27407123.

ABSTRACT: These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Malignant Pleural Mesothelioma (MPM). These NCCN Guidelines Insights discuss systemic therapy regimens and surgical controversies for MPM. The NCCN panel recommends cisplatin/pemetrexed (category 1) for patients with MPM. The NCCN panel also now recommends bevacizumab/cisplatin/pemetrexed as a first-line therapy option for patients with unresectable MPM who are candidates for bevacizumab. The complete version of the NCCN Guidelines for MPM, available at NCCN.org, addresses all aspects of management for MPM including diagnosis, evaluation, staging, treatment, surveillance, and therapy for recurrence and metastasis; NCCN Guidelines are intended to assist with clinical decision-making.

8 Clinical Trial A phase I study of extrapleural pneumonectomy and intracavitary intraoperative hyperthermic cisplatin with amifostine cytoprotection for malignant pleural mesothelioma. 2009

Zellos, Lambros / Richards, William G / Capalbo, Leah / Jaklitsch, Michael T / Chirieac, Lucian R / Johnson, Bruce E / Bueno, Raphael / Sugarbaker, David J. ·Division of Thoracic Surgery and Department of Pathology, Brigham and Women's Hospital, Boston, Mass, USA. ·J Thorac Cardiovasc Surg · Pubmed #19185169.

ABSTRACT: OBJECTIVE: This study was undertaken to determine maximum tolerated dose and toxicity of intraoperative intracavitary hyperthermic cisplatin perfusion with amifostine after extrapleural pneumonectomy for malignant pleural mesothelioma. METHODS: Patients with mesothelioma were prospectively enrolled. Those with resectable disease received amifostine and 1-hour hyperthermic cisplatin perfusion of ipsilateral hemithorax and abdomen. Morbidity, recurrence, and survival were recorded. RESULTS: Forty-two patients were enrolled; 29 underwent resection (operative mortality 7%, 2/29). Median age was 57 years. Eighteen were in pathologic stage I or II; 11 were in stage III. Median hospitalization was 15 days. Common complications were atrial fibrillation (66%, 19 patients), deep venous thrombosis (31%, 9 patients), and grade 3+ renal toxicity (31%, 9 patients). Feasibility was determined. Renal toxicity was unrelated to cisplatin dose, with no maximum tolerated dose determined. Overall median survival was 17 months (resected 20 months, unresected 10 months). Median survivals were 26 months for patients receiving higher cisplatin doses and 16 months for those receiving lower doses (P = .35). Survival was significantly longer with negative extrapleural nodes (31 vs 14 months, P = .0115) and early stage (all resected 35 months for stage I-II vs 14 months for stage III, P = .0022, epithelial 39 months for stage I-II vs 15 months for stage III, P = .0072). CONCLUSION: Early stage and negative extrapleural lymph nodes were associated with prolonged survival. Single-dose amifostine did not protect adequately against cisplatin-induced renal toxicity. Additional cytoprotective strategies are needed to allow determination of cisplatin maximum tolerated dose.

9 Article Clinicopathologic and genetic characteristics of young patients with pleural diffuse malignant mesothelioma. 2018

Vivero, Marina / Bueno, Raphael / Chirieac, Lucian R. ·Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ·Mod Pathol · Pubmed #28884745.

ABSTRACT: Pleural diffuse malignant mesothelioma typically presents during the seventh decade of life and has poor prognosis. Recent epidemiologic studies have shown differences between young and older mesothelioma patients, but the biology of pleural mesothelioma in young patients is poorly understood. We studied the clinicopathologic and genetic characteristics in pleural mesothelioma patients aged 35 years and younger. Thirty-six consecutive pleural mesothelioma patients aged 35 years and younger were compared with 48 older patients. We examined demographic and clinical characteristics, histologic type, growth patterns, mitotic index, and nuclear grade on hematoxylin and eosin-stained slides, BAP1 protein expression by immunohistochemistry, and CDKN2A and NF2 deletions by fluorescence in situ hybridization. Clinicopathologic and cytogenetic results were compared between young and older groups, and correlated with overall survival. Young patients were more frequently women, reported less asbestos exposure, and had a greater frequency of prior therapeutic radiation and family history of breast cancer than older patients (P<0.05 each). There were no histologic differences between young and older patients (all P>0.05). CDKN2A deletion was less prevalent in young patients (P=0.01), loss of BAP1 protein expression less frequent in young patients (P=0.06), and NF2 deletion rates similar between groups (P>0.05 each). Median overall survival was 40 vs 26 months (P=0.10) in young and older patients, respectively, and 47 vs 31 months (P=0.04) when comparing patients with epithelioid histology only. High mitotic index and non-epithelioid histology were the only characteristics associated with a poor overall survival in young patients. Young patients with pleural mesothelioma have an equal sex distribution and are more likely to have a history of mantle radiation, family history of breast cancer, and lower rates of CDKN2A deletion than older patients. Our results suggest that pleural mesothelioma in young patients has distinctive clinical and genetic characteristics, despite some similarities to pleural mesothelioma in older patients.

10 Article Dataset for Reporting of Malignant Mesothelioma of the Pleura or Peritoneum: Recommendations From the International Collaboration on Cancer Reporting (ICCR). 2016

Churg, Andrew / Attanoos, Richard / Borczuk, Alain C / Chirieac, Lucian R / Galateau-Sallé, Françoise / Gibbs, Allen / Henderson, Douglas / Roggli, Victor / Rusch, Valerie / Judge, Meagan J / Srigley, John R. ·From the Department of Pathology and Laboratory Medicine, University of British Columbia, and Vancouver General Hospital, Vancouver, British Columbia, Canada (Dr Churg) · the Department of Cellular Pathology, Cardiff and Vale University Health Board, University Hospital of Wales, Cardiff, United Kingdom (Drs Attanoos and Gibbs) · the Department of Pathology, Weill Cornell University Medical Center, New York, New York (Dr Borczuk) · the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Dr Chirieac) · the Department of Pathology, University Hospital Caen, and Department of Biopathology, Léon-Bérard Cancer Centre, Lyon, France (Dr Galateau-Sallé) · the Department of Surgical Pathology, SA Pathology, Flinders Medical Centre, Adelaide, South Australia, Australia (Dr Henderson) · the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Dr Roggli) · the Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York (Dr Rusch) · the Royal College of Pathologists of Australasia, Sydney, New South Wales, Australia (Ms Judge) · and the Program of Laboratory Medicine and Genetics, Trillium Health Partners, and the Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada (Dr Srigley). ·Arch Pathol Lab Med · Pubmed #27031777.

ABSTRACT: CONTEXT: -The International Collaboration on Cancer Reporting is a not-for-profit organization formed by the Royal Colleges of Pathologists of Australasia and the United Kingdom; the College of American Pathologists; the Canadian Association of Pathologists-Association Canadienne des Pathologists, in association with the Canadian Partnership Against Cancer; and the European Society of Pathology. Its goal is to produce common, internationally agreed upon, evidence-based datasets for use throughout the world. OBJECTIVE: -To describe a dataset developed by the Expert Panel of the International Collaboration on Cancer Reporting for reporting malignant mesothelioma of both the pleura and peritoneum. The dataset is composed of "required" (mandatory) and "recommended" (nonmandatory) elements. DESIGN: -Based on a review of the most recent evidence and supported by explanatory commentary. RESULTS: -Eight required elements and 7 recommended elements were agreed upon by the Expert Panel to represent the essential information for reporting malignant mesothelioma of the pleura and peritoneum. CONCLUSIONS: -In time, the widespread use of an internationally agreed upon, structured, pathology dataset for mesothelioma will lead not only to improved patient management but also provide valuable data for research and international benchmarks.

11 Article Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. 2016

Bueno, Raphael / Stawiski, Eric W / Goldstein, Leonard D / Durinck, Steffen / De Rienzo, Assunta / Modrusan, Zora / Gnad, Florian / Nguyen, Thong T / Jaiswal, Bijay S / Chirieac, Lucian R / Sciaranghella, Daniele / Dao, Nhien / Gustafson, Corinne E / Munir, Kiara J / Hackney, Jason A / Chaudhuri, Amitabha / Gupta, Ravi / Guillory, Joseph / Toy, Karen / Ha, Connie / Chen, Ying-Jiun / Stinson, Jeremy / Chaudhuri, Subhra / Zhang, Na / Wu, Thomas D / Sugarbaker, David J / de Sauvage, Frederic J / Richards, William G / Seshagiri, Somasekar. ·Division of Thoracic Surgery, The Lung Center and the International Mesothelioma Program, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA. · Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA. · Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Bioinformatics Department, MedGenome Labs, Pvt., Ltd., Narayana Health City, Bangalore, India. · Division of Thoracic Surgery, Baylor College of Medicine, Houston, Texas, USA. · Molecular Oncology Department, Genentech, Inc., South San Francisco, California, USA. ·Nat Genet · Pubmed #26928227.

ABSTRACT: We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated (q-score ≥ 0.8) in MPMs. We identified recurrent mutations in several genes, including SF3B1 (∼2%; 4/216) and TRAF7 (∼2%; 5/216). SF3B1-mutant samples showed a splicing profile distinct from that of wild-type tumors. TRAF7 alterations occurred primarily in the WD40 domain and were, except in one case, mutually exclusive with NF2 alterations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. Through integrated analyses, we identified alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs.

12 Article Gender-Specific Molecular and Clinical Features Underlie Malignant Pleural Mesothelioma. 2016

De Rienzo, Assunta / Archer, Michael A / Yeap, Beow Y / Dao, Nhien / Sciaranghella, Daniele / Sideris, Antonios C / Zheng, Yifan / Holman, Alexander G / Wang, Yaoyu E / Dal Cin, Paola S / Fletcher, Jonathan A / Rubio, Renee / Croft, Larry / Quackenbush, John / Sugarbaker, Peter E / Munir, Kiara J / Battilana, Jesse R / Gustafson, Corinne E / Chirieac, Lucian R / Ching, Soo Meng / Wong, James / Tay, Liang Chung / Rudd, Stephen / Hercus, Robert / Sugarbaker, David J / Richards, William G / Bueno, Raphael. ·The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts. aderienzo@partners.org. · The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts. · Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Center for Cancer Computational Biology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Harvard School of Public Health, Boston, Massachusetts. · Departments of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts. · Malaysian Genomics Resource Centre, Kuala Lumpur, Malaysia. · Debakey Department of Surgery, Baylor College of Medicine, Houston, Texas. ·Cancer Res · Pubmed #26554828.

ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive cancer that occurs more frequently in men, but is associated with longer survival in women. Insight into the survival advantage of female patients may advance the molecular understanding of MPM and identify therapeutic interventions that will improve the prognosis for all MPM patients. In this study, we performed whole-genome sequencing of tumor specimens from 10 MPM patients and matched control samples to identify potential driver mutations underlying MPM. We identified molecular differences associated with gender and histology. Specifically, single-nucleotide variants of BAP1 were observed in 21% of cases, with lower mutation rates observed in sarcomatoid MPM (P < 0.001). Chromosome 22q loss was more frequently associated with the epithelioid than that nonepitheliod histology (P = 0.037), whereas CDKN2A deletions occurred more frequently in nonepithelioid subtypes among men (P = 0.021) and were correlated with shorter overall survival for the entire cohort (P = 0.002) and for men (P = 0.012). Furthermore, women were more likely to harbor TP53 mutations (P = 0.004). Novel mutations were found in genes associated with the integrin-linked kinase pathway, including MYH9 and RHOA. Moreover, expression levels of BAP1, MYH9, and RHOA were significantly higher in nonepithelioid tumors, and were associated with significant reduction in survival of the entire cohort and across gender subgroups. Collectively, our findings indicate that diverse mechanisms highly related to gender and histology appear to drive MPM.

13 Article Tsc1-Tp53 loss induces mesothelioma in mice, and evidence for this mechanism in human mesothelioma. 2014

Guo, Y / Chirieac, L R / Bueno, R / Pass, H / Wu, W / Malinowska, I A / Kwiatkowski, D J. ·Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. · Department of Pathology, Harvard Medical School, Boston, MA, USA. · Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, NY, USA. ·Oncogene · Pubmed #23851502.

ABSTRACT: Mesothelioma is diagnosed in ∼2500 patients in the United States every year, most often arising in the pleural space, but also occurring as primary peritoneal mesothelioma. The vast majority of patients with mesothelioma die of their disease within 3 years. We developed a new mouse model of mesothelioma by bladder or intraperitoneal injection of adenovirus Cre into mice with conditional alleles of each of Tp53 and Tsc1. Such mice began to develop malignant ascites about 6 months after injection, which was due to peritoneal mesothelioma, on the basis of tumor morphology and immunohistochemical staining. Mesothelioma cell lines were established, which showed loss of both Tsc1 and Tp53, with mammalian target of rapamycin complex (mTORC)1 activation. Treatment of mice with malignant ascites due to mesothelioma with rapamycin led to a marked reduction in ascites, extended survival and a 95-99% reduction in the mesothelioma tumor volume, in comparison with vehicle-treated mice. To see whether TSC1/TSC2 loss was a common genetic event in human mesothelioma, we examined nine human mesothelioma cell lines, and found that four of nine showed persistent activation of mTORC1, although none had loss of TSC1 or TSC2. A tissue microarray analysis of 198 human mesothelioma specimens showed that 33% of cases had reduced TSC2 expression and 60% showed activation of mTOR, indicating that mTOR activation is common in human mesothelioma, suggesting that it is a potential therapeutic target.

14 Article Clinicopathologic characteristics of malignant mesotheliomas arising in patients with a history of radiation for Hodgkin and non-Hodgkin lymphoma. 2013

Chirieac, Lucian R / Barletta, Justine A / Yeap, Beow Y / Richards, William G / Tilleman, Tamara / Bueno, Raphael / Baldini, Elizabeth H / Godleski, John / Sugarbaker, David J. ·Lucian R. Chirieac, Justine A. Barletta, William G. Richards, Tamara Tilleman, Raphael Bueno, Elizabeth H. Baldini, John Godleski, and David J. Sugarbaker, Brigham and Women's Hospital · Beow Y. Yeap, Massachusetts General Hospital · and William G. Richards, Tamara Tilleman, Raphael Bueno, Elizabeth H. Baldini, and David J. Sugarbaker, Harvard Medical School, Boston, MA. ·J Clin Oncol · Pubmed #24248693.

ABSTRACT: PURPOSE: Studies have reported an association between pleural diffuse malignant mesothelioma (PDMM) and chest radiation for lymphoma. The clinicopathologic characteristics of malignant mesotheliomas arising in these patients have not been established. PATIENTS AND METHODS: We studied 1,618 consecutive patients diagnosed with pleural PDMM from July 1993 to February 2008 and identified patients with a history of radiation for Hodgkin and non-Hodgkin lymphoma. We evaluated the histology in the surgical resection specimens and compared clinicopathologic features with overall survival. RESULTS: We identified 22 patients who developed PDMM after chest radiation as part of their treatment for lymphoma (mean latency time, 21.4 years; 95% CI, 17.0 to 25.8 years). Asbestos bodies in lymphoma-associated PDMM were lower than in asbestos-associated PDMM (median count, 15 v 325 bodies, respectively; P < .001) and similar to an unexposed control group (median count, 15 v 10 bodies, respectively; P = .6). Seventeen lymphoma-associated PDMMs (77%) were epithelioid and five (23%) were biphasic. Seven PDMMs (32%) had unusual histologies (pleomorphic, myxoid, clear cell, and signet ring cell). Patients with lymphoma-associated PDMM were younger than patients with asbestos-associated PDMM (median age, 45 v 64 years, respectively; P < .001) and had a significantly longer overall survival time (median, 32.5 v 12.7 months, respectively; P = .018). In multivariate analysis, independent favorable predictors for overall survival were history of prior radiation (P = .022), female sex (P < .001), age ≤ 65 years (P = .005), cytoreductive surgery (P < .001), and epithelioid histology (P < .001). CONCLUSION: Patients with lymphoma-associated PDMM are likely to have unusual histologic features, are significantly younger, and seem to have a longer overall survival compared with patients with asbestos-associated PDMM.

15 Article p16 Deletion in sarcomatoid tumors of the lung and pleura. 2013

Tochigi, Naobumi / Attanoos, Richard / Chirieac, Lucian R / Allen, Timothy Craig / Cagle, Philip T / Dacic, Sanja. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. ·Arch Pathol Lab Med · Pubmed #23627453.

ABSTRACT: CONTEXT: The diagnosis of sarcomatoid neoplasms of the lung and pleura can be challenging. Homozygous deletion of 9p21, the locus harboring the p16 gene, has been reported as the most common genetic alteration in malignant mesotheliomas that is of potential diagnostic and prognostic significance. OBJECTIVES: To evaluate the frequency of 9p21 deletion by fluorescence in situ hybridization in the primary sarcomatoid neoplasms of the lung and pleura and to determine its potential diagnostic utility. DESIGN: Ninety-two sarcomatoid neoplasms of the lung and pleura (32 sarcomatoid mesotheliomas, 15 sarcomatoid carcinomas, 32 solitary fibrous tumors, and 13 high-grade sarcomas) were examined for 9p21 deletion by fluorescence in situ hybridization. RESULTS: Deletion of 9p21 was most frequently seen in malignant mesotheliomas (81%), followed by sarcomatoid carcinomas (53%), sarcomas (25%), and solitary fibrous tumors (12.5%). Malignant mesotheliomas showed mostly homozygous deletion, whereas sarcomatoid carcinomas showed either homozygous or hemizygous deletion. None of the sarcomas showed homozygous deletion. There was a trend toward more frequent occurrence of 9p21 deletion in recurrent solitary fibrous tumors, but this did not reach statistical difference. CONCLUSIONS: Deletion of 9p21 is common in sarcomatoid tumors of the lung and pleura. Despite statistically significant differences in the frequency of 9p21 deletion, and because of the large overlap among the study groups, this genetic abnormality cannot be used as a reliable diagnostic tool in the assessment of sarcomatoid lesions of the lung and pleura. A potential use of p16 deletion in predicting the biology of solitary fibrous tumors should be further explored.

16 Article Sequential binary gene ratio tests define a novel molecular diagnostic strategy for malignant pleural mesothelioma. 2013

De Rienzo, Assunta / Richards, William G / Yeap, Beow Y / Coleman, Melissa H / Sugarbaker, Peter E / Chirieac, Lucian R / Wang, Yaoyu E / Quackenbush, John / Jensen, Roderick V / Bueno, Raphael. ·The Thoracic Surgery Oncology Laboratory, and International Mesothelioma Program, Division of Thoracic Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA. ·Clin Cancer Res · Pubmed #23493352.

ABSTRACT: PURPOSE: To develop a standardized approach for molecular diagnostics, we used the gene expression ratio bioinformatic technique to design a molecular signature to diagnose malignant pleural mesothelioma (MPM) from among other potentially confounding diagnoses and differentiate the epithelioid from the sarcomatoid histologic subtype of MPM. In addition, we searched for pathways relevant in MPM in comparison with other related cancers to identify unique molecular features in MPM. EXPERIMENTAL DESIGN: We conducted microarray analysis on 113 specimens including MPMs and a spectrum of tumors and benign tissues comprising the differential diagnosis of MPM. We generated a sequential combination of binary gene expression ratio tests able to discriminate MPM from other thoracic malignancies. We compared this method with other bioinformatic tools and validated this signature in an independent set of 170 samples. Functional enrichment analysis was conducted to identify differentially expressed probes. RESULTS: A sequential combination of gene expression ratio tests was the best molecular approach to distinguish MPM from all the other samples. Bioinformatic and molecular validations showed that the sequential gene ratio tests were able to identify the MPM samples with high sensitivity and specificity. In addition, the gene ratio technique was able to differentiate the epithelioid from the sarcomatoid type of MPM. Novel genes and pathways specifically activated in MPM were identified. CONCLUSIONS: New clinically relevant molecular tests have been generated using a small number of genes to accurately distinguish MPMs from other thoracic samples, supporting our hypothesis that the gene expression ratio approach could be a useful tool in the differential diagnosis of cancers.

17 Article Clinical and pathological features of three-year survivors of malignant pleural mesothelioma following extrapleural pneumonectomy. 2011

Sugarbaker, David J / Wolf, Andrea S / Chirieac, Lucian R / Godleski, John J / Tilleman, Tamara R / Jaklitsch, Michael T / Bueno, Raphael / Richards, William G. ·Division of Thoracic Surgery and Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. dsugarbaker@partners.org ·Eur J Cardiothorac Surg · Pubmed #21310625.

ABSTRACT: OBJECTIVE: Surgery-based multimodality therapy is associated with long-term survival in a significant number of pleural mesothelioma patients. We explored factors associated with 3-year survival in patients with malignant pleural mesothelioma, who underwent extrapleural pneumonectomy, to help refine patient selection criteria for surgery and other therapies. METHODS: With Institutional Review Board approval, we reviewed records in the International Mesothelioma Program Patient Data Registry to identify all patients, who underwent extrapleural pneumonectomy for malignant pleural mesothelioma between 1 January 1988 and 31 May 2007. Vital status as of 31 May 2010 was confirmed. Fisher's exact test was used to compare dichotomous variables for patients who survived at least 3 years with those who did not. Kaplan-Meier analysis was used to estimate the cumulative survival probability for all 3-year survivors. RESULTS: Among 636 patients who underwent extrapleural pneumonectomy, 117 (18%) survived at least 3 years following surgery, including 26 remaining alive and four lost to follow-up. Of the 3-year survivors, 39 (33%) were female, 61 (52%) had left-sided disease, and the median age was 56 years (range 27-77). Relatively more 3-year survivors were younger than, or at the median age (p=0.0005), or female (p=0.0007), had epithelial tumor histology (p<0.0001) and/or had normal white blood cell count (p=0.0001), hemoglobin (p<0.0001), or platelet count (p<0.0001) preoperatively. The median survival of the 117 patients who survived 3-years was 59 months. Among these patients, a significant association between age and survival was found only for women. CONCLUSIONS: A significant proportion of patients undergoing extrapleural pneumonectomy for pleural mesothelioma experienced extended survival. Although favorable prognostic features were more common, the cohort of 3-year survivors included a substantial number of patients with late-stage disease. The longest survival (median greater than 7 years) was experienced by women under the median age of 56 years. These data support the role of macroscopic cytoreduction through extrapleural pneumonectomy in the context of multimodality therapy to extend survival for malignant pleural mesothelioma. Further efforts to treat micrometastatic disease and improve patient selection are warranted.

18 Article Characteristics of malignant pleural mesothelioma in women. 2010

Wolf, Andrea S / Richards, William G / Tilleman, Tamara R / Chirieac, Lucian / Hurwitz, Shelley / Bueno, Raphael / Sugarbaker, David J. ·Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. awolf2@partners.org ·Ann Thorac Surg · Pubmed #20732523.

ABSTRACT: BACKGROUND: The incidence of malignant pleural mesothelioma (MPM) is higher in men than in women, likely due to increased occupational asbestos exposure among men. Women also appear to experience better long-term survival. This study evaluates the role of gender in relation to established prognostic factors in MPM. METHODS: We reviewed 715 cases of MPM treated with extrapleural pneumonectomy at our institution between July 1987 and December 2008. Data for patients with epithelial and nonepithelial tumors were analyzed separately. Kaplan-Meier and Cox regression analyses were used to estimate survival for various cohorts to assess the relationship between gender and survival independent of age at surgery, stage, side, and preoperative laboratory studies. RESULTS: Of the 702 patients with complete data available, 114 out of 450 patients with epithelial tumors and 31 out of 252 patients with nonepithelial histology were women. Women with epithelial (and not nonepithelial) disease were found to differ significantly from men with respect to younger age, higher rate of thrombocytosis, and longer survival after surgery. The effect of gender on survival of patients with epithelial disease persisted when controlling for age, stage, thrombocytosis, leukocytosis, and anemia with a multivariable analysis. No significant differences in survival were seen among patients with nonepithelial disease with regard to gender, age, or anemia. CONCLUSIONS: In the absence of other negative prognostic factors, women with epithelial MPM demonstrated a survival advantage. These findings support an aggressive approach to treating MPM including extrapleural pneumonectomy in individuals with favorable prognostic predictors, particularly women with epithelial histology and no other risk factors.

19 Article Second generation sequencing of the mesothelioma tumor genome. 2010

Bueno, Raphael / De Rienzo, Assunta / Dong, Lingsheng / Gordon, Gavin J / Hercus, Colin F / Richards, William G / Jensen, Roderick V / Anwar, Arif / Maulik, Gautam / Chirieac, Lucian R / Ho, Kim-Fong / Taillon, Bruce E / Turcotte, Cynthia L / Hercus, Robert G / Gullans, Steven R / Sugarbaker, David J. ·The International Mesothelioma Program, Brigham and Women's Hospital, Boston, Massachusetts, United States of America. ·PLoS One · Pubmed #20485525.

ABSTRACT: The current paradigm for elucidating the molecular etiology of cancers relies on the interrogation of small numbers of genes, which limits the scope of investigation. Emerging second-generation massively parallel DNA sequencing technologies have enabled more precise definition of the cancer genome on a global scale. We examined the genome of a human primary malignant pleural mesothelioma (MPM) tumor and matched normal tissue by using a combination of sequencing-by-synthesis and pyrosequencing methodologies to a 9.6X depth of coverage. Read density analysis uncovered significant aneuploidy and numerous rearrangements. Method-dependent informatics rules, which combined the results of different sequencing platforms, were developed to identify and validate candidate mutations of multiple types. Many more tumor-specific rearrangements than point mutations were uncovered at this depth of sequencing, resulting in novel, large-scale, inter- and intra-chromosomal deletions, inversions, and translocations. Nearly all candidate point mutations appeared to be previously unknown SNPs. Thirty tumor-specific fusions/translocations were independently validated with PCR and Sanger sequencing. Of these, 15 represented disrupted gene-encoding regions, including kinases, transcription factors, and growth factors. One large deletion in DPP10 resulted in altered transcription and expression of DPP10 transcripts in a set of 53 additional MPM tumors correlated with survival. Additionally, three point mutations were observed in the coding regions of NKX6-2, a transcription regulator, and NFRKB, a DNA-binding protein involved in modulating NFKB1. Several regions containing genes such as PCBD2 and DHFR, which are involved in growth factor signaling and nucleotide synthesis, respectively, were selectively amplified in the tumor. Second-generation sequencing uncovered all types of mutations in this MPM tumor, with DNA rearrangements representing the dominant type.

20 Article Proposed adjustments to pathologic staging of epithelial malignant pleural mesothelioma based on analysis of 354 cases. 2010

Richards, William G / Godleski, John J / Yeap, Beow Y / Corson, Joseph M / Chirieac, Lucian R / Zellos, Lambros / Mujoomdar, Aneil / Jaklitsch, Michael T / Bueno, Raphael / Sugarbaker, David J. ·Division of Thoracic Surgery, Brigham and Women's Hospital, Thoracic Surgery, 75 Francis Street, Boston, MA 02115, USA. wrichards@partners.org ·Cancer · Pubmed #20108310.

ABSTRACT: BACKGROUND: Several pathologic staging systems for malignant pleural mesothelioma (MPM) have been published, but none of them provide optimal survival stratification or stage distribution among patients treated with surgery. Interpretation of prior studies that correlate pathologic factors with outcome has been confounded by the inclusion of patients undergoing differing surgical procedures and with varied tumor histology. METHODS: We examined pathologic characteristics, previously included in published studies, and explored correlations with outcome among patients with epithelioid MPM who underwent extrapleural pneumonectomy (EPP) at Brigham and Women's Hospital (BWH). Comparisons of survival among patients with and without each tumor or lymph node feature guided adjustments to the American Joint Commission on Cancer (AJCC)/International Union Against Cancer (UICC) classification criteria. Proportional hazards modeling of TN combinations guided adjustments to stage groupings. RESULTS: Three hundred fifty-four patients were resectable by EPP and had complete pathologic data. Overall median survival was 18 months from surgery. By AJCC/UICC criteria, 233 (66%) patients were stage III, whereas by BWH criteria, 194 (55%) patients were stage III. T classification criteria were adjusted based on prevalence and relation to survival. N status correlated significantly with survival. Regrouping of TN combinations based on relative hazard and Kaplan-Meier survival analysis resulted in improved stage distribution (stage I-IV: 8%, 43%, 33%, 16%, respectively) and survival stratification (51, 26, 15, 8 months, respectively). CONCLUSIONS: Proposed adjustments to TNM staging criteria improved outcome stratification of patients with epithelial tumor histology who received surgical therapy by EPP and complete pathologic assessment. Determining relevance to other treatment or staging modalities will require verification in additional cohorts.

21 Article Transcriptome sequencing of malignant pleural mesothelioma tumors. 2008

Sugarbaker, David J / Richards, William G / Gordon, Gavin J / Dong, Lingsheng / De Rienzo, Assunta / Maulik, Gautam / Glickman, Jonathan N / Chirieac, Lucian R / Hartman, Mor-Li / Taillon, Bruce E / Du, Lei / Bouffard, Pascal / Kingsmore, Stephen F / Miller, Neil A / Farmer, Andrew D / Jensen, Roderick V / Gullans, Steven R / Bueno, Raphael. ·International Mesothelioma Program, Division of Thoracic Surgery, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. ·Proc Natl Acad Sci U S A · Pubmed #18303113.

ABSTRACT: Cancers arise by the gradual accumulation of mutations in multiple genes. We now use shotgun pyrosequencing to characterize RNA mutations and expression levels unique to malignant pleural mesotheliomas (MPMs) and not present in control tissues. On average, 266 Mb of cDNA were sequenced from each of four MPMs, from a control pulmonary adenocarcinoma (ADCA), and from normal lung tissue. Previously observed differences in MPM RNA expression levels were confirmed. Point mutations were identified by using criteria that require the presence of the mutation in at least four reads and in both cDNA strands and the absence of the mutation from sequence databases, normal adjacent tissues, and other controls. In the four MPMs, 15 nonsynonymous mutations were discovered: 7 were point mutations, 3 were deletions, 4 were exclusively expressed as a consequence of imputed epigenetic silencing, and 1 was putatively expressed as a consequence of RNA editing. Notably, each MPM had a different mutation profile, and no mutated gene was previously implicated in MPM. Of the seven point mutations, three were observed in at least one tumor from 49 other MPM patients. The mutations were in genes that could be causally related to cancer and included XRCC6, PDZK1IP1, ACTR1A, and AVEN.