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Mesothelioma: HELP
Articles by William D. Travis
Based on 19 articles published since 2010
(Why 19 articles?)
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Between 2010 and 2020, W. Travis wrote the following 19 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 Review The 2015 World Health Organization Classification of Tumors of the Pleura: Advances since the 2004 Classification. 2016

Galateau-Salle, Francoise / Churg, Andrew / Roggli, Victor / Travis, William D / Anonymous1300856. ·Department of Pathology, Centre Hospitalier Universitaire Caen, Caen, France; Department of Biopathology, Centre Leon Berard, Lyon, France. · Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada. · Department of Pathology, Duke University Medical Center, Durham, NC, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: travisw@mskcc.org. ·J Thorac Oncol · Pubmed #26811225.

ABSTRACT: A new World Health Organization (WHO) Classification of Tumors of the Pleura has recently been published. While the histologic classification of pleural malignant mesothelioma remains the same in the 2015 WHO classification as it was in the 2004 classification, multiple new observations have been recorded. First, more detailed study has been performed of histologic subtyping of epithelioid mesothelioma. In particular, it has been recognized that the pleomorphic subtype is associated with a poor prognosis, similar to that of sarcomatoid malignant mesothelioma. Second, there is improved understanding of the role of immunohistochemistry in distinguishing mesothelioma from carcinomas of various sites. Third, the criteria for distinguishing malignant mesothelioma from reactive mesothelial proliferations has been further refined. Fourth, additional studies of sarcomatoid mesothelioma have defined the frequency and spectrum of various histologic and immunohistochemical features, including heterologous elements. Finally, pleural well-differentiated papillary mesotheliomas are better defined and cases with invasive foci are recognized. In addition, several promising observations in mesothelioma pathology and genetics have been made in the past decade. These are now the subject of further investigation to determine if they can be validated in ways that will significantly impact clinical practice. These include a preliminary study of grading, suggesting that nuclear atypia and mitotic count are independent prognostic markers. The discovery of inactivating mutations in the BRCA1-associated protein 1 gene in sporadic and hereditary mesothelioma has opened up a variety of novel molecular, clinical, and diagnostic investigations. One possible diagnostic application includes the setting of separating mesothelioma from reactive mesothelial proliferations, where it may play a role in conjunction with p16 FISH. Another useful discovery was that the NAB2-STAT6 fusion is characteristic of solitary fibrous tumors. This led to development of a STAT6 antibody that is a reliable immunohistochemical marker for solitary fibrous tumors. Genetic studies also led to the finding that WWTR1-CAMTA1 fusions are useful diagnostic markers for epithelioid hemangioendotheliomas, which can present as pleural-based masses. Finally, desmoid type fibromatosis, a locally aggressive tumor that can present in the pleura, has been shown to frequently have CTNNB1 gene mutations and express β-catenin by immunohistochemistry.

4 Clinical Trial Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma. 2011

Kadota, Kyuichi / Suzuki, Kei / Sima, Camelia S / Rusch, Valerie W / Adusumilli, Prasad S / Travis, William D. ·Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York City, New York 10065, USA. ·J Thorac Oncol · Pubmed #21358344.

ABSTRACT: INTRODUCTION: In patients with epithelioid diffuse malignant pleural mesothelioma (DMPM), clinical stage is the current primary prognostic factor. We sought to investigate whether histologic subtyping can prognostically stratify patients with epithelioid DMPM. METHODS: Hematoxylin and eosin-stained slides of 232 patients with epithelioid DMPM (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed. We classified the tumors into five subtypes, according to the predominant histological pattern: trabecular, tubulopapillary, micropapillary, solid, and pleomorphic (≥10% of tumor). RESULTS: Median overall survival (OS) of all patients with epithelioid DMPM was 16.2 months. Patients with pleomorphic subtype (n = 34) had the worst median OS (8.1 months), followed by solid (n = 89, 13.7 months), micropapillary (n = 20, 15.8 months), tubulopapillary (n = 51, 17.9 months), and trabecular (n = 38, 24.9 months). The pleomorphic subtype was associated with lymphatic and vascular invasion (p < 0.001). The micropapillary subtype was associated with lymphatic invasion (p < 0.001). In univariate analyses, pleomorphic subtype was significantly associated with poor OS (p = 0.003). The pleomorphic subtype showed no significant difference on OS compared with biphasic and sarcomatoid DMPM. In a multivariate analysis, the pleomorphic subtype was an independent predictor of poor OS (p = 0.031). In patients who underwent R1 resection, pleomorphic subtype had the shortest median time to recurrence (13.7 months). CONCLUSION: Our finding that the pleomorphic subtype is a predictor of aggressive behavior in epithelioid DMPM with no survival difference from biphasic or sarcomatoid DMPM suggests that it may be best regarded as a sarcomatoid pattern rather than a subtype of epithelioid DMPM.

5 Clinical Trial WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer. 2010

Krug, Lee M / Dao, Tao / Brown, Andrew B / Maslak, Peter / Travis, William / Bekele, Sara / Korontsvit, Tatyana / Zakhaleva, Victoria / Wolchok, Jedd / Yuan, Jianda / Li, Hao / Tyson, Leslie / Scheinberg, David A. ·Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, 1275 York Ave, New York, NY, 10065, USA. krugl@mskcc.org ·Cancer Immunol Immunother · Pubmed #20532500.

ABSTRACT: BACKGROUND: The transcription factor, WT1, is highly overexpressed in malignant pleural mesothelioma (MPM) and immunohistochemical stains for WT1 are used routinely to aid in its diagnosis. Using computer prediction analysis we designed analog peptides derived from WT1 sequences by substituting amino acids at key HLA-A0201 binding positions. We tested the safety and immunogenicity of a WT1 vaccine comprised of four class I and class II peptides in patients with thoracic neoplasms expressing WT1. METHODS: Therapy consisted of six subcutaneous vaccinations administered with Montanide adjuvant on weeks 0, 4, 6, 8, 10, and 12, with 6 additional monthly injections for responding patients. Injection sites were pre-stimulated with GM-CSF (70 mcg). Immune responses were evaluated by DTH, CD4 T-cell proliferation, CD8 T-cell interferon gamma release, intracellular cytokine staining, WT1 peptide MHC-tetramer staining, and cytotoxicity against WT1 positive tumor cells. RESULTS: Nine patients with MPM and 3 with NSCLC were vaccinated, with 8 patients receiving at least 6 vaccinations; in total, 10 patients were evaluable for immune response. Six out of nine patients tested demonstrated CD4 T-cell proliferation to WT1 specific peptides, and five of the six HLA-A0201 patients tested mounted a CD8 T-cell response. Stimulated T cells were capable of cytotoxicity against WT-1 positive cells. Vaccination also induced polyfunctional CD8 T cell responses. CONCLUSIONS: This multivalent WT1 peptide analog vaccine induces immune responses in a high proportion of patients with thoracic malignancies with minimal toxicity. A randomized trial testing this vaccine as adjuvant therapy in MPM is planned.

6 Article Comprehensive Molecular and Pathologic Evaluation of Transitional Mesothelioma Assisted by Deep Learning Approach: A Multi-Institutional Study of the International Mesothelioma Panel from the MESOPATH Reference Center. 2020

Galateau Salle, Francoise / Le Stang, Nolwenn / Tirode, Franck / Courtiol, Pierre / Nicholson, Andrew G / Tsao, Ming-Sound / Tazelaar, Henry D / Churg, Andrew / Dacic, Sanja / Roggli, Victor / Pissaloux, Daniel / Maussion, Charles / Moarii, Matahi / Beasley, Mary Beth / Begueret, Hugues / Chapel, David B / Copin, Marie Christine / Gibbs, Allen R / Klebe, Sonja / Lantuejoul, Sylvie / Nabeshima, Kazuki / Vignaud, Jean-Michel / Attanoos, Richard / Brcic, Luka / Capron, Frederique / Chirieac, Lucian R / Damiola, Francesca / Sequeiros, Ruth / Cazes, Aurélie / Damotte, Diane / Foulet, Armelle / Giusiano-Courcambeck, Sophie / Hiroshima, Kenzo / Hofman, Veronique / Husain, Aliya N / Kerr, Keith / Marchevsky, Alberto / Paindavoine, Severine / Picquenot, Jean Michel / Rouquette, Isabelle / Sagan, Christine / Sauter, Jennifer / Thivolet, Francoise / Brevet, Marie / Rouvier, Philippe / Travis, William D / Planchard, Gaetane / Weynand, Birgit / Clozel, Thomas / Wainrib, Gilles / Fernandez-Cuesta, Lynnette / Pairon, Jean-Claude / Rusch, Valerie / Girard, Nicolas. ·MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France. Electronic address: francoise.galateau@lyon.unicancer.fr. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France. · University Claude Bernard Lyon, INSERM, CNRS, Research Cancer Center of Lyon, Centre Léon Bérard, Lyon, France. · OWKIN Paris, France. · Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College, London, United Kingdom. · University Health Network, Princess Margaret Cancer Centre and University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, Ontario, Canada. · Mayo Clinic, Scottsdale, Arizona. · Columbia University and Department of Pathology Vancouver, Canada. · FISH and Developmental Laboratory at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Duke University Medical Center, Department of Pathology, Durham, North Carolina. · Department of BioPathology-FISH Laboratory, Centre Leon Berard Lyon, France. · Mount-Sinai Medical Center, Department of Pathology, New York, New York. · CHU Bordeaux, Haut Leveque Hospital, Department of Pathology, Bordeaux, France. · University of Chicago, Department of Pathology, Chicago, Illinois. · University. Lille-CHU, Department of Pathology, Lille, France. · University of Wales, Department of Cellular Pathology, Cardiff, United Kingdom. · Department of Anatomical Pathology, Flinders University, Adelaide, Australia. · Department of Pathology, Fukuoka University School of Medicine and Hospital, Fukuoka, Japan. · CHU Nancy, INSERM, University of Lorraine, Lorraine, France. · Department of Pathology, Graz, Austria. · CHU Pitié Salpétrière Paris, Department of Pathology, Paris, France. · Brigham and Women's Hospital, Boston, Massachusetts. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Bichat Department of Pathology, University Paris VII, Paris, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Cochin-Hotel Dieu, Department of Pathology, Paris, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CH Le Mans, Department of Pathology, Pays de la Loire, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Hospital Nord, Marseille, University Aix-Marseille, Marseille, France. · Tokyo Women's Medical University, Department of Pathology, Tokyo, Japan. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Mayo Clinic, Scottsdale, Arizona; CHU Nice, Department of Clinical and Experimental Pathology (LPCE), Nice, France. · Aberdeen Royal Infirmary, Department of Pathology, Aberdeen, Scotland. · Scotland Cedars-Sinai Medical Center, Department of Pathology, Los Angeles, California. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, Henri Becquerel Centre, Rouen, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; IUCT-Oncopôle, Department of Pathology, Toulouse, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Nantes, INSERM, Thorax Institute, Hôpital Laënnec CHU Nantes, Nantes, France. · Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, New York. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Hospices Civils, East Hospital Group, Department of Pathology, Lyon, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, CHU Caen, Caen, France. · UZ Leuven, Department of Pathology, Leuven, Belgium. · Genetic Cancer Susceptibility Group International Agency for Research on Cancer World Health Organization, Lyon, France. · INSERM, UPEC, Faculty of Medicine and CHI Creteil, Professional Pathologies and Environment Department, IST-PE, Creteil, France. · Memorial Sloan Kettering Cancer Center, Department of Thoracic Surgery, New York, New York. · Department of Thoracic Oncology Institute Curie Paris, France and European Reference Network EURACAN, Centre Leon Berard, France. ·J Thorac Oncol · Pubmed #32165206.

ABSTRACT: INTRODUCTION: Histologic subtypes of malignant pleural mesothelioma are a major prognostic indicator and decision denominator for all therapeutic strategies. In an ambiguous case, a rare transitional mesothelioma (TM) pattern may be diagnosed by pathologists either as epithelioid mesothelioma (EM), biphasic mesothelioma (BM), or sarcomatoid mesothelioma (SM). This study aimed to better characterize the TM subtype from a histological, immunohistochemical, and molecular standpoint. Deep learning of pathologic slides was applied to this cohort. METHODS: A random selection of 49 representative digitalized sections from surgical biopsies of TM was reviewed by 16 panelists. We evaluated BAP1 expression and CDKN2A (p16) homozygous deletion. We conducted a comprehensive, integrated, transcriptomic analysis. An unsupervised deep learning algorithm was trained to classify tumors. RESULTS: The 16 panelists recorded 784 diagnoses on the 49 cases. Even though a Kappa value of 0.42 is moderate, the presence of a TM component was diagnosed in 51%. In 49% of the histological evaluation, the reviewers classified the lesion as EM in 53%, SM in 33%, or BM in 14%. Median survival was 6.7 months. Loss of BAP1 observed in 44% was less frequent in TM than in EM and BM. p16 homozygous deletion was higher in TM (73%), followed by BM (63%) and SM (46%). RNA sequencing unsupervised clustering analysis revealed that TM grouped together and were closer to SM than to EM. Deep learning analysis achieved 94% accuracy for TM identification. CONCLUSION: These results revealed that the TM pattern should be classified as non-EM or at minimum as a subgroup of the SM type.

7 Article EURACAN/IASLC Proposals for Updating the Histologic Classification of Pleural Mesothelioma: Towards a More Multidisciplinary Approach. 2020

Nicholson, Andrew G / Sauter, Jennifer L / Nowak, Anna K / Kindler, Hedy L / Gill, Ritu R / Remy-Jardin, Martine / Armato, Samuel G / Fernandez-Cuesta, Lynnette / Bueno, Raphael / Alcala, Nicolas / Foll, Matthieu / Pass, Harvey / Attanoos, Richard / Baas, Paul / Beasley, Mary Beth / Brcic, Luka / Butnor, Kelly J / Chirieac, Lucian R / Churg, Andrew / Courtiol, Pierre / Dacic, Sanja / De Perrot, Marc / Frauenfelder, Thomas / Gibbs, Allen / Hirsch, Fred R / Hiroshima, Kenzo / Husain, Aliya / Klebe, Sonja / Lantuejoul, Sylvie / Moreira, Andre / Opitz, Isabelle / Perol, Maurice / Roden, Anja / Roggli, Victor / Scherpereel, Arnaud / Tirode, Frank / Tazelaar, Henry / Travis, William D / Tsao, Ming-Sound / van Schil, Paul / Vignaud, Jean Michel / Weynand, Birgit / Lang-Lazdunski, Loic / Cree, Ian / Rusch, Valerie W / Girard, Nicolas / Galateau-Salle, Francoise. ·Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College, London, United Kingdom. Electronic address: a.nicholson@rbht.nhs.uk. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Medical School, University of Western Australia, Perth, Australia. · Section of Hematology/Oncology, Department of Medicine, University of Chicago Medicine, Chicago, Illinois. · Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massacheusetts. · Department of Thoracic Imaging, Hospital Calmette, University Centre of Lille, France. · Department of Radiology, The University of Chicago, Chicago, Illinois. · Section of Genetics, International Agency for Research on Cancer (IARC/WHO), Lyon, France. · Division of Thoracic Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Cardiothoracic Surgery, NYU Langone Health, New York, New York. · Department of Cellular Pathology, University Hospital of Wales, School of Medicine, Cardiff University, United Kingdom. · Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Pathology, Mount Sinai Medical Center, New York, New York. · Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria. · Department of Pathology & Laboratory Medicine, The University of Vermont Medical Center, Burlington, Vermont. · Department of Pathology, Brigham and Women's Hospital, Boston, Massacheusetts. · Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada. · Owkin Inc., Paris, France. · Department of Pathology University of Pittsburgh Medical Center, Pennsylvania. · Division of Thoracic Surgery, Princess Margaret Cancer Centre, Toronto, Canada. · Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, Zurich, Switzerland. · Department of Cellular Pathology, Cardiff and Vale UHB, Cardiff, Wales, United Kingdom. · Center for Thoracic Oncology, Mount Sinai Health System, New York, New York. · Department of Pathology, Tokyo Women's Medical University, Yachiyo Medical Center, Tokyo, Japan. · Department of Pathology, University of Chicago, Chicago, Illinois. · Department of Anatomical Pathology, SA Pathology and Flinders University, Adelaide, Australia. · Department of Biopathology and of Translational Research and Innovation, CNR MESOPATH, Centre Leon Berard Lyon, and Grenoble Alpes University, France. · Department of Pathology, New York University Langone Health, New York, New York. · Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. · Department of Medical Oncology, Léon Bérard Cancer Center, Lyon, France. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. · Department of Pathology, Duke University Medical Center, Durham, North Carolina. · Pulmonary and Thoracic Oncology Department, University Lille, CHU Lille, France. · Université Lyon, Centre Léon Bérard, Cancer Research Center of Lyon, France. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona. · Department of Pathology, University Health Network, Princess Margaret Cancer Centre, Toronto, Canada. · Department of Thoracic and Vascular Surgery, Antwerp University Hospital and Antwerp University, Belgium. · CHU Nancy, Université Lorraine, Nancy, France. · Department of Pathology, UZ Leuven, Leuven, Belgium. · Cromwell Hospital, London, United Kingdom. · International Agency for Research on Cancer (IARC), Lyon, France. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. · Institut Curie, Institut du Thorax Curie Montsouris, Paris, France. · MESOPATH Centre Leon Berard, Lyon, France. ·J Thorac Oncol · Pubmed #31546041.

ABSTRACT: INTRODUCTION: Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has been essentially limited to three histologic subtypes. METHODS: A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists, and oncologists), sponsored by European Network for Rare Adult Solid Cancers/International Association for the Study of Lung Cancer, met in 2018 to critically review the current classification. RESULTS: Recommendations include: (1) classification should be updated to include architectural patterns and stromal and cytologic features that refine prognostication; (2) subject to data accrual, malignant mesothelioma in situ could be an additional category; (3) grading of epithelioid malignant pleural mesotheliomas should be routinely undertaken; (4) favorable/unfavorable histologic characteristics should be routinely reported; (5) clinically relevant molecular data (programmed death ligand 1, BRCA 1 associated protein 1 [BAP1], and cyclin dependent kinase inhibitor 2A) should be incorporated into reports, if undertaken; (6) other molecular data should be accrued as part of future trials; (7) resection specimens (i.e., extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged; (8) ideally, at least three separate areas should be sampled from the pleural cavity, including areas of interest identified on pre-surgical imaging; (9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging; (10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered; (11) all histologic subtypes should be considered potential candidates for chemotherapy; (12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first-line clinical trials unless there is a compelling reason; (13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy; and (14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome. CONCLUSIONS: These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials.

8 Article Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations. 2019

Zauderer, Marjorie G / Jayakumaran, Gowtham / DuBoff, Mariel / Zhang, Liying / Francis, Jasmine H / Abramson, David H / Cercek, Andrea / Nash, Garrett M / Shoushtari, Alexander / Chapman, Paul / D'Angelo, Sandra / Arnold, Angela G / Siegel, Beth / Fleischut, Megan Harlan / Ni, Andy / Rimner, Andreas / Rusch, Valerie W / Adusumilli, Prasad S / Travis, William / Sauter, Jennifer L / Zehir, Ahmet / Mandelker, Diana / Ladanyi, Marc / Robson, Mark. ·Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York. Electronic address: zauderem@mskcc.org. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York. · Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. ·J Thorac Oncol · Pubmed #31323388.

ABSTRACT: INTRODUCTION: Inherited mutations are easily detected factors that influence the disease courses and optimal treatment strategies of some cancers. Germline mutations in BRCA1 associated protein 1 (BAP1) are associated with unique disease profiles in mesothelioma, atypical spitz nevi, and uveal melanoma, but the patient characteristics of an unselected population of BAP1 carriers identified by an ascertainment prevalence study are unknown. METHODS: We collected blood samples, cancer histories, and occupational exposures from 183 unselected patients with BAP1-related diseases. Clinical information for each patient was obtained from medical records. Germline DNA was extracted from blood samples and sequenced using a next-generation sequencing assay. We tested screening criteria developed to identify patients with a possible germline BAP1 mutation. RESULTS: Pathogenic or likely pathogenic germline BAP1 mutations were observed in 5 of 180 sequenced specimens and were exclusively found in patients identified by our screening criteria. Several patients with characteristics suspicious for a heritable deleterious mutation did not have a germline BAP1 mutation. The prevalence of pathogenic germline BAP1 mutations in patients with mesothelioma was 4.4% (95% confidence interval 1.1-11.1). CONCLUSIONS: Results from the first unselected prevalence ascertainment study of germline BAP1 alterations suggest that the frequency of this mutation is low among patients with mesothelioma. The proposed screening criteria successfully identified all patients with germline BAP1-mutant mesothelioma. These screening guidelines may assist physicians in selecting patients who would benefit from genetic testing. Future efforts should validate and refine these criteria and search for other germline mutations associated with mesothelioma and related diseases.

9 Article Integrative Molecular Characterization of Malignant Pleural Mesothelioma. 2018

Hmeljak, Julija / Sanchez-Vega, Francisco / Hoadley, Katherine A / Shih, Juliann / Stewart, Chip / Heiman, David / Tarpey, Patrick / Danilova, Ludmila / Drill, Esther / Gibb, Ewan A / Bowlby, Reanne / Kanchi, Rupa / Osmanbeyoglu, Hatice U / Sekido, Yoshitaka / Takeshita, Jumpei / Newton, Yulia / Graim, Kiley / Gupta, Manaswi / Gay, Carl M / Diao, Lixia / Gibbs, David L / Thorsson, Vesteinn / Iype, Lisa / Kantheti, Havish / Severson, David T / Ravegnini, Gloria / Desmeules, Patrice / Jungbluth, Achim A / Travis, William D / Dacic, Sanja / Chirieac, Lucian R / Galateau-Sallé, Françoise / Fujimoto, Junya / Husain, Aliya N / Silveira, Henrique C / Rusch, Valerie W / Rintoul, Robert C / Pass, Harvey / Kindler, Hedy / Zauderer, Marjorie G / Kwiatkowski, David J / Bueno, Raphael / Tsao, Anne S / Creaney, Jenette / Lichtenberg, Tara / Leraas, Kristen / Bowen, Jay / Anonymous6511115 / Felau, Ina / Zenklusen, Jean Claude / Akbani, Rehan / Cherniack, Andrew D / Byers, Lauren A / Noble, Michael S / Fletcher, Jonathan A / Robertson, A Gordon / Shen, Ronglai / Aburatani, Hiroyuki / Robinson, Bruce W / Campbell, Peter / Ladanyi, Marc. ·Department of Pathology and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. · Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts. · Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. · GenomeDx Biosciences, Vancouver, British Columbia, Canada. · Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada. · Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Computational Systems Biology, Memorial Sloan Kettering Cancer Center, New York, New York. · Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan. · Genome Science Division, The University of Tokyo, Tokyo, Japan. · Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, California. · Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Institute for Systems Biology, Seattle, Washington. · The University of Texas at Dallas, Richardson, Texas. · Division of Thoracic Surgery, The Lung Center and International Mesothelioma Program, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy. · Department of Pathology, Quebec Heart and Lung Institute, Quebec, Canada. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. · MESOPATH. Cancer Center Leon Berard, Lyon, France. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, University of Chicago, Chicago, Illinois. · Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Oncology, University of Cambridge, Cambridge, UK. · Department of Cardiothoracic Surgery, NYU Langone Medical Center, New York, New York. · Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center and Biological Sciences, Chicago, Illinois. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Division of Pulmonary Medicine, Brigham and Women's Hospital, Boston, Massachusetts. · School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia. · The Research Institute at Nationwide Children's Hospital, Columbus, Ohio. · National Cancer Institute, Bethesda, Maryland. · Department of Pathology and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. ladanyim@mskcc.org. ·Cancer Discov · Pubmed #30322867.

ABSTRACT: Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of

10 Article New Insights on Diagnostic Reproducibility of Biphasic Mesotheliomas: A Multi-Institutional Evaluation by the International Mesothelioma Panel From the MESOPATH Reference Center. 2018

Galateau Salle, F / Le Stang, N / Nicholson, A G / Pissaloux, D / Churg, A / Klebe, S / Roggli, V L / Tazelaar, H D / Vignaud, J M / Attanoos, R / Beasley, M B / Begueret, H / Capron, F / Chirieac, L / Copin, M C / Dacic, S / Danel, C / Foulet-Roge, A / Gibbs, A / Giusiano-Courcambeck, S / Hiroshima, K / Hofman, V / Husain, A N / Kerr, K / Marchevsky, A / Nabeshima, K / Picquenot, J M / Rouquette, I / Sagan, C / Sauter, J L / Thivolet, F / Travis, W D / Tsao, M S / Weynand, B / Damiola, F / Scherpereel, A / Pairon, J C / Lantuejoul, S / Rusch, V / Girard, N. ·MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France. Electronic address: francoise.galateau@lyon.unicancer.fr. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France. · Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College, London, United Kingdom. · Department of Pathology, British Columbia University, Vancouver, Canada. · Department of Biopathology, Centre Léon Bérard, and- INSERM U1052, Cancer Research Center of Lyon, Lyon, France. · Department of Anatomical Pathology, Flinders University, Adelaide, Australia. · Department of Pathology, Duke University Medical Center, Durham, North Carolina. · Mayo Clinic, Scottsdale, Arizona. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Nancy, INSERM U954, Université de Lorraine, Nancy, France. · Department of Cellular Pathology, University of Wales, Cardiff, United Kingdom. · Department of Pathology, Mount- Sinai Medical Center, New York, New York. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Bordeaux, Department of Pathology, Hopital Haut Leveque, Bordeaux, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, CHU Pitié Salpétrière Paris, Paris, France. · Harvard Medical School, Boston, Massachusetts. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, CHRU-Hopital Calmette, Lille, France. · FISH and Developmental Laboratory at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Bichat, Departement de Pathologie, University Paris VII, Paris, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, CH Le Mans, Le Mans, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Hopital Nord, University AIX-Marseille, Marseille, France. · Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Nice, Department of Clinical and Experimental Pathology (LPCE), Nice, France. · Department of Pathology, University of Chicago, Chicago, Illinois. · Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, Scotland. · Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California. · Department of Pathology, Fukuoka University School of Medicine and Hospital, Fukuoka, Japan. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, Centre Henri Bequerel, Rouen, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, IUCT- Oncopôle, Toulouse, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Nantes, INSERM U1087, l'institut du Thorax, Hôpital Laënnec CHU Nantes, Nantes, France. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, Hospices Civils, Groupe Hospitalier EST, Lyon, France. · Department of Pathology, University Health Network and Princess Margaret Hospital, Toronto, Ontario, Canada. · Department of Pathology, UZ Leuven, Belgium. · Pulmonary and Thoracic Oncology, Univ Lille, CHU Lille, INSERM U1019, CIIL, Institut Pasteur de Lille, MESOCLIN, F59000 Lille, France. · INSERM U955, équipe 4, UPEC, Faculté de médecine and CHI Creteil, Service de Pathologies professionnelles et de l'Environnement, IST-PE,Creteil, France. · Memorial Sloan Kettering Cancer Center, Department of Thoracic Surgery, NY, USA. · Department of Thoracic Oncology Institut Curie Paris, France and EURACAN. ·J Thorac Oncol · Pubmed #29723687.

ABSTRACT: INTRODUCTION: The 2015 WHO classification of tumors categorized malignant mesothelioma into epithelioid, biphasic (BMM), and sarcomatoid (SMM) for prognostic relevance and treatment decisions. The survival of BMM is suspected to correlate with the amount of the sarcomatoid component. The criteria for a sarcomatoid component and the interobserver variability between pathologists for identifying this component are not well described. In ambiguous cases, a "transitional" (TMM) subtype has been proposed but was not accepted as a specific subtype in the 2015 WHO classification. The aims of this study were to evaluate the interobserver agreement in the diagnosis of BMM, to determine the nature and the significance of TMM subtype, and to relate the percentage of sarcomatoid component with survival. The value of staining for BRCA-1-associated protein (BAP1) and CDKN2A(p16) fluorescence in situ hybridization (FISH) were also assessed with respect to each of the tumoral components. METHODS: The study was conducted by the International Mesothelioma Panel supported by the French National Cancer Institute, the network of rare cancer (EURACAN) and in collaboration with the International Association for the Study of Lung Cancer (IASLC). The patient cases include a random group of 42 surgical biopsy samples diagnosed as BMM with evaluation of SMM component by the French Panel of MESOPATH experts was selected from the total series of 971 BMM cases collected from 1998 to 2016. Fourteen international pathologists with expertise in mesothelioma reviewed digitally scanned slides (hematoxylin and eosin - stained and pan-cytokeratin) without knowledge of prior diagnosis or outcome. Cases with at least 7 of 14 pathologists recognizing TMM features were selected as a TMM group. Demographic, clinical, histopathologic, treatment, and follow-up data were retrieved from the MESOBANK database. BAP1 (clone C-4) loss and CDKN2A(p16) homozygous deletion (HD) were assessed by immunohistochemistry (IHC) and FISH, respectively. Kappa statistics were applied for interobserver agreement and multivariate analysis with Cox regression adjusted for age and gender was performed for survival analysis. RESULTS: The 14 panelists recorded a total of 544 diagnoses. The interobserver correlation was moderate (weighted Kappa = 0.45). Of the cases originally classified as BMM by MESOPATH, the reviewers agreed in 71% of cases (385 of 544 opinions), with cases classified as pure epithelioid in 17% (93 of 544), and pure sarcomatoid in 12% (66 of 544 opinions). Diagnosis of BMM was made on morphology or IHC alone in 23% of the cases and with additional assessment of IHC in 77% (402 of 544). The median overall survival (OS) of the 42 BMM cases was 8 months. The OS for BMM was significantly different from SMM and epithelioid malignant mesothelioma (p < 0.0001). In BMM, a sarcomatoid component of less than 80% correlated with a better survival (p = 0.02). There was a significant difference in survival between BMM with TMM showing a median survival at 6 months compared to 12 months for those without TMM (p < 0.0001). BAP1 loss was observed in 50% (21 of 42) of the total cases and in both components in 26%. We also compared the TMM group to that of more aggressive patterns of epithelioid subtypes of mesothelioma (solid and pleomorphic of our large MESOPATH cohort). The curve of transitional type was persistently close to the OS curve of the sarcomatoid component. The group of sarcomatoid, transitional, and pleomorphic mesothelioma were very close to each other. We then considered the contribution of BAP1 immunostaining and loss of CDKN2A(p16) by FISH. BAP1 loss was observed in 50% (21 of 41) of the total cases and in both component in 27% of the cases (11 of 41). There was no significant difference in BAP1 loss between the TMM and non-TMM groups. HD CDKN2A(p16) was detected in 74% of the total cases with no significant difference between the TMM and non-TMM groups. In multivariate analysis, TMM morphology was an indicator of poor prognosis with a hazard ratio = 3.2; 95% confidence interval: 1.6 - 8.0; and p = 0.003 even when compared to the presence of HD CDKN2A(p16) on sarcomatoid component (hazard ratio = 4.5; 95% confidence interval: 1.2 - 16.3, p = 0.02). CONCLUSIONS: The interobserver concordance among the international mesothelioma and French mesothelioma panel suggests clinical utility for an updated definition of biphasic mesothelioma that allows better stratification of patients into risk groups for treatment decisions, systemic anticancer therapy, or selection for surgery or palliation. We also have shown the usefulness of FISH detection of CDKN2A(p16) HD compared to BAP1 loss on the spindle cell component for the separation in ambiguous cases between benign florid stromal reaction from true sarcomatoid component of biphasic mesothelioma. Taken together our results further validate the concept of transitional pattern as a poor prognostic indicator.

11 Article Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study. 2018

Rosen, Lauren E / Karrison, Theodore / Ananthanarayanan, Vijayalakshmi / Gallan, Alexander J / Adusumilli, Prasad S / Alchami, Fouad S / Attanoos, Richard / Brcic, Luka / Butnor, Kelly J / Galateau-Sallé, Françoise / Hiroshima, Kenzo / Kadota, Kyuichi / Klampatsa, Astero / Stang, Nolween Le / Lindenmann, Joerg / Litzky, Leslie A / Marchevsky, Alberto / Medeiros, Filomena / Montero, M Angeles / Moore, David A / Nabeshima, Kazuki / Pavlisko, Elizabeth N / Roggli, Victor L / Sauter, Jennifer L / Sharma, Anupama / Sheaff, Michael / Travis, William D / Vigneswaran, Wickii T / Vrugt, Bart / Walts, Ann E / Tjota, Melissa Y / Krausz, Thomas / Husain, Aliya N. ·Department of Pathology, The University of Chicago Medicine, Chicago, IL, USA. · Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA. · Department of Pathology, Loyola University Medical Center, Chicago, IL, USA. · Department of Thoracic Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Cellular Pathology, University Hospital of Wales, Cardiff, UK. · Department of Cellular Pathology, University Hospital of Wales and Cardiff University, Cardiff, UK. · Medical University of Graz, Institute of Pathology, Graz, Austria. · Department of Pathology, University of Vermont Medical Center, Burlington, VT, USA. · Centre Léon Bérard, BioPathologie, Lyon, France. · Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan. · Department of Diagnostic Pathology, Kagawa University, Takamatsu, Japan. · Division of Pulmonary, Allergy and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Division of Thoracic and Hyperbaric Surgery, Department of Surgery,Medical University of Graz, Graz, Austria. · ,Department of Pathology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. · Basildon & Thurrock University Hospital, Department of Pathology, Basildon, UK. · Department of Histopathology, Royal Brompton and Harefield Hospitals Imperial College of London, London, UK. · Department of Cancer Studies, University of Leicester, Leicester, UK. · Fukuoka University, Department of Pathology, Fukuoka, Japan. · Department of Pathology, Duke University Medical Center, Durham, NC, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Pathology, University of Pittsburgh Medical Center and VA Pittsburgh Healthcare System, Pittsburgh, PA, USA. · Department of Pathology, Barts Health NHS Trust, London, UK. · Department of Thoracic and Cardiovascular Surgery, Loyola University Medical Center, Chicago, IL, USA. · University Hospital Zurich, Institute for Pathology and Molecular Pathology, Zurich, Switzerland. ·Mod Pathol · Pubmed #29327706.

ABSTRACT: A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed.

12 Article Cancer antigen profiling for malignant pleural mesothelioma immunotherapy: expression and coexpression of mesothelin, cancer antigen 125, and Wilms tumor 1. 2017

Eguchi, Takashi / Kadota, Kyuichi / Mayor, Marissa / Zauderer, Marjorie G / Rimner, Andreas / Rusch, Valerie W / Travis, William D / Sadelain, Michel / Adusumilli, Prasad S. ·Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Division of Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan. · Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ·Oncotarget · Pubmed #29100432.

ABSTRACT: Background: To develop cancer antigen-targeted immunotherapeutic strategies for malignant pleural mesothelioma (MPM), we investigated the individual and coexpressions of the cancer-associated antigens mesothelin (MSLN), cancer antigen 125 (CA125), and Wilms tumor 1 (WT1) in both epithelioid and non-epithelioid MPM. Methods: All available hematoxylin and eosin-stained slides from patients who were diagnosed with MPM (1989-2010) were reviewed. We constructed tissue microarrays from 283 patients (epithelioid = 234; non-epithelioid = 49). Intensity and distribution for each antigen were assessed by immunohistochemistry. Results: Positive expression of MSLN, CA125, and WT1 were demonstrated in 93%, 75%, and 97% of epithelioid MPM cases, and 57%, 33%, and 98% of non-epithelioid MPM cases, respectively. Triple- and double-positive antigen coexpressions were demonstrated in 72% and 23% of epithelioid MPM cases and 29% and 33% of non-epithelioid MPM cases, respectively. Complete absence of expression for all three antigens was demonstrated in <2% of MPM cases. More than two-thirds of MPM cases had ≥50% distribution of MSLN-positive cells and, among the remaining third, half had ≥50% distribution of WT1-positive cells. CA125/MSLN coexpression was observed in more than two-thirds of epithelioid MPM cases and one-third of non-epithelioid MPM cases. Conclusion: A limited number of cancer-associated antigens can target almost all MPM tumors for immunotherapy.

13 Article A Subset of Malignant Mesotheliomas in Young Adults Are Associated With Recurrent EWSR1/FUS-ATF1 Fusions. 2017

Desmeules, Patrice / Joubert, Philippe / Zhang, Lei / Al-Ahmadie, Hikmat A / Fletcher, Christopher D / Vakiani, Efsevia / Delair, Deborah F / Rekhtman, Natasha / Ladanyi, Marc / Travis, William D / Antonescu, Cristina R. ·*Department of Pathology §Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY †Department of Pathology, Quebec Heart and Lung Institute, Quebec, QC, Canada ‡Department of Pathology, Brigham and Women's Hospital, Boston, MA. ·Am J Surg Pathol · Pubmed #28505004.

ABSTRACT: Malignant mesothelioma (MM) is a rare, aggressive tumor often associated with asbestos exposure and characterized by complex genetic abnormalities, including deletions of chromosome 22. A gene fusion involving EWSR1 and YY1 gene on 14q32 has been reported in 2 patients over the age of 60 with peritoneal MM. However, the incidence of EWSR1 rearrangements in MM and the spectrum of its fusion partners remain unknown. We recently encountered 2 MM cases with EWSR1-ATF1 fusions and sought to investigate the prevalence and clinicopathologic features associated with this abnormality. As both index cases occurred as intra-abdominal tumors in young adults, we searched our files for pleural and peritoneal MM occurring in adults younger than age of 40. All cases were tested by fluorescence in situ hybridization using custom bacterial artificial chromosomes probes for EWSR1, FUS, and ATF1 genes. When available, immunohistochemistry for BAP1 was performed. A total of 25 MM from patients aged 40 or less were screened, either from peritoneum (n=13) or pleura (n=12), with a median age of 31 (range: 7 to 40 y). Two additional ATF1-rearranged tumors were identified at pleural and peritoneal sites with EWSR1 and FUS as fusion partners, respectively, for a total of 4 cases (16%, 4/25). The fusion-positive cases displayed classic epithelioid morphology, immunoreactivity for cytokeratins and WT1, and negativity for S100. BAP1 expression was retained in the 3 fusion-positive cases with available material, and in 80% (12/15) of the fusion-negative cases. Our results expand the spectrum of tumor types harboring EWSR1/FUS-ATF1 gene fusions to include a subgroup of conventional epithelioid MM. Other features of this unique MM subset include young age at presentation, lack of asbestos exposure and retained BAP1 expression.

14 Article The tumoral and stromal immune microenvironment in malignant pleural mesothelioma: A comprehensive analysis reveals prognostic immune markers. 2015

Ujiie, Hideki / Kadota, Kyuichi / Nitadori, Jun-Ichi / Aerts, Joachim G / Woo, Kaitlin M / Sima, Camelia S / Travis, William D / Jones, David R / Krug, Lee M / Adusumilli, Prasad S. ·Thoracic Service; Department of Surgery; Memorial Sloan Kettering Cancer Center ; New York, NY, USA ; Department of Clinical Molecular Biology; Graduate School of Medicine; Chiba University ; Chiba, Japan. · Thoracic Service; Department of Surgery; Memorial Sloan Kettering Cancer Center ; New York, NY, USA ; Department of Pathology; Memorial Sloan Kettering Cancer Center ; New York, NY, USA. · Thoracic Service; Department of Surgery; Memorial Sloan Kettering Cancer Center ; New York, NY, USA. · Department of Pulmonary Medicine; Erasmus MC Cancer Institute ; Rotterdam, the Netherlands. · Department of Epidemiology & Biostatistics; Memorial Sloan Kettering Cancer Center ; New York, NY, USA. · Department of Pathology; Memorial Sloan Kettering Cancer Center ; New York, NY, USA. · Thoracic Oncology Service; Division of Solid Tumor Oncology; Department of Medicine; Memorial Sloan Kettering Cancer Center ; New York, NY, USA. · Thoracic Service; Department of Surgery; Memorial Sloan Kettering Cancer Center ; New York, NY, USA ; Center of Cell Engineering; Memorial Sloan Kettering Cancer Center ; New York, NY, USA. ·Oncoimmunology · Pubmed #26155428.

ABSTRACT: Antitumor immune responses against solid malignancies correlate with improved patient survival. We conducted a comprehensive investigation of immune responses in tumor and tumor-associated stroma in epithelioid malignant pleural mesothelioma with the goal of characterizing the tumor immune microenvironment and identifying prognostic immune markers. We investigated 8 types of tumor-infiltrating immune cells within the tumor nest and tumor-associated stroma, as well as tumor expression of 5 cytokine/chemokine receptors in 230 patients. According to univariate analyses, high densities of tumoral CD4- and CD20-expressing lymphocytes were associated with better outcomes. High expression of tumor interleukin-7 (IL-7) receptor was associated with worse outcomes. According to multivariate analyses, stage and tumoral CD20 detection were independently associated with survival. Analysis of single immune cell infiltration for CD163

15 Article Tumoral CD10 expression correlates with aggressive histology and prognosis in patients with malignant pleural mesothelioma. 2015

Kadota, Kyuichi / Villena-Vargas, Jonathan / Nitadori, Jun-Ichi / Sima, Camelia S / Jones, David R / Travis, William D / Adusumilli, Prasad S. ·Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ·Ann Surg Oncol · Pubmed #25608772.

ABSTRACT: BACKGROUND: Currently, tumor-node-metastasis stage and histologic type are the established prognostic factors for malignant pleural mesothelioma, whereas no prognostic markers have been established for clinical practice. We investigated the prognostic value of CD10, a metalloproteinase that can promote cancer aggressiveness through enzymatic degradation and intracellular signaling crosstalk, in malignant pleural mesothelioma. METHODS: CD10 immunostaining was performed for 176 cases of malignant pleural mesothelioma (epithelioid, 148; biphasic, 14; sarcomatoid, 14), and its expression was dichotomized as negative (no staining) or positive (any staining). Epithelioid tumors were classified as pleomorphic subtype when cytologic pleomorphism was ≥10 % of the tumor. Overall survival (OS) was analyzed by log-rank tests and Cox proportional hazard models. RESULTS: Tumoral CD10 expression was identified in 42 % of epithelioid non-pleomorphic tumors, 57 % of epithelioid pleomorphic tumors, 79 % of biphasic tumors, and 93 % of sarcomatoid tumors (p < 0.001). Positive CD10 expression was correlated with higher mitotic count (p = 0.002). Overall survival for patients with positive CD10 expression was significantly shorter than that for patients with negative CD10 expression in all patients (p = 0.001) and in patients with epithelioid tumor (p = 0.04). On multivariate analysis, CD10 expression was an independent prognostic factor for all patients (hazard ratio 1.48; p = 0.019). CONCLUSIONS: Tumoral CD10 expression correlated with aggressive histologic types and higher mitotic activity and is an independent prognostic factor for patients with malignant pleural mesothelioma.

16 Article High SUVmax on FDG-PET indicates pleomorphic subtype in epithelioid malignant pleural mesothelioma: supportive evidence to reclassify pleomorphic as nonepithelioid histology. 2012

Kadota, Kyuichi / Kachala, Stefan S / Nitadori, Jun-Ichi / Suzuki, Kei / Dunphy, Mark P S / Sima, Camelia S / Travis, William D / Rusch, Valerie W / Adusumilli, Prasad S. ·Division of Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. ·J Thorac Oncol · Pubmed #22617244.

ABSTRACT: BACKGROUND: We have recently proposed to reclassify the pleomorphic subtype of epithelioid malignant pleural mesothelioma (MPM) as nonepithelioid (biphasic/sarcomatoid) histology because of its similarly poor prognosis. We sought to investigate whether preoperative maximum standardized uptake value (SUVmax) on F-fluorodeoxyglucose (FDG) positron emission tomography (PET) correlates with histologic subtype in MPM. METHODS: Clinical data were collected for 78 patients with MPM who underwent preoperative FDG-PET. We retrospectively classified the epithelioid tumors into five subtypes: trabecular, tubulopapillary, micropapillary, solid, and pleomorphic. Tumors were categorized by SUVmax into two groups: low (<10.0) and high (≥10.0). RESULTS: The median overall survival of epithelioid tumors with high SUVmax (n = 12) was significantly shorter (7.1 months) than that of epithelioid tumors with low SUVmax (n = 54, 18.9 months, p < 0.001) and comparable to nonepithelioid tumors (n = 12, 7.2 months). Epithelioid tumors with pleomorphic subtype (n = 9) had marginally higher SUVmax (mean ± SD: 10.6 ± 5.9) than epithelioid nonpleomorphic subtype (n = 57, 6.5 ± 3.2, p = 0.050), and were comparable to that of nonepithelioid tumors (n = 12, 9.1 ± 4.8). Among the epithelioid tumors with high SUVmax (n = 12), 50% (n = 6) showed pleomorphic subtype. In contrast, among epithelioid tumors with low SUVmax (n = 54), 6% (n = 3) showed epithelioid pleomorphic subtypes (p = 0.001). A positive correlation between mitotic count and SUVmax was observed (r = 0.30, p = 0.010). CONCLUSIONS: Pleomorphic subtype of epithelioid MPM showed higher SUVmax than the epithelioid nonpleomorphic subtype and was similar to nonepithelioid histology. Preoperative SUVmax on FDG-PET in epithelioid MPM can indicate patients with pleomorphic subtype with poor prognosis, supporting their reclassification as nonepithelioid.

17 Article A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma. 2012

Kadota, Kyuichi / Suzuki, Kei / Colovos, Christos / Sima, Camelia S / Rusch, Valerie W / Travis, William D / Adusumilli, Prasad S. ·Division of Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. ·Mod Pathol · Pubmed #21983936.

ABSTRACT: Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant pleural mesothelioma in which only staging is prognostic for survival. In this study of epithelioid diffuse malignant pleural mesothelioma, we investigate the prognostic utility of nuclear features. The slides of 232 epithelioid diffuse malignant pleural mesothelioma patients (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed for the following seven nuclear features: nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, intranuclear inclusions, prominence of nucleoli, mitotic count, and atypical mitoses. MIB-1 immunohistochemistry was performed using tissue microarray, and MIB-1 labeling index was recorded as the percentage of positive tumor cells. Median overall survival of all patients was 16 months and correlated with nuclear atypia (P<0.001), chromatin pattern (P=0.031), prominence of nucleoli (P<0.001), mitotic count (P<0.001), and atypical mitoses (P<0.001) by univariate analysis. Multivariate analysis revealed nuclear atypia (P=0.012) and mitotic count (P<0.001) as independent prognostic factors, and these two factors were utilized to create a three-tier nuclear grade score. The resulting nuclear grade stratified patients into three distinct prognostic groups: grade I (n=107, median overall survival=28 months), grade II (n=91, 14 months), and grade III (n=34, 5 months). Not only was nuclear grade an independent predictor of overall survival (P<0.001), but it was also a stronger discriminator of survival than all currently available factors. Furthermore, nuclear grade was associated with time to recurrence (P=0.004) in patients who underwent complete surgical resection (n=159). MIB-1 labeling index correlated with mitotic count (P<0.001) and nuclear atypia (P=0.037) and stratified overall survival (P<0.001) and time to recurrence (P=0.048), confirming the prognostic value of the nuclear grade. Nuclear grading in epithelioid mesothelioma provides a simple, practical, and cost-effective prognostic tool that better stratifies clinical outcome and time to recurrence than currently available clinicopathologic factors.

18 Article The fake fat phenomenon in organizing pleuritis: a source of confusion with desmoplastic malignant mesotheliomas. 2011

Churg, Andrew / Cagle, Philip / Colby, Thomas V / Corson, Joseph M / Gibbs, Allen R / Hammar, Samuel / Ordonez, Nelson / Roggli, Victor L / Tazelaar, Henry D / Travis, William D / Wick, Mark / Anonymous3630706. ·Department of Pathology, University of British Columbia, Vancouver, BC, Canada. achurg@interchange.ubc.ca ·Am J Surg Pathol · Pubmed #21959310.

ABSTRACT: We report 9 patients with pleural biopsies referred because of concern about infiltration of what appeared to be chest wall fat by pan-keratin-positive spindled cells, a finding that led to a consideration of desmoplastic mesothelioma. All patients showed pleural effusions/pleural thickening on computed tomographic scan. Pleural biopsy showed a greatly thickened and fibrotic paucicellular pleura with circular fat-like spaces and, sometimes, adjacent oblate spaces mostly deep in the fibrotic area. Indistinct, keratin-positive, spindle cells arranged parallel to the pleural surface coursed between these fat-like spaces. S-100 stains were negative around the fat-like spaces. Vimentin stains showed that the spaces did not have a cellular lining of any kind. Sometimes the spaces contained faintly hematoxyphilic material that was Alcian blue positive, and similar material was seen in the fibrotic stroma. Follow-up with periods ranging from 6 to 30 months revealed that 8 cases had stable disease on chest imaging or by clinical findings. One case had slowly progressive pleural thickening. These observations suggest that spaces resembling fat may be encountered in fibrotic pleurae and that horizontally oriented keratin-positive spindled cells between the fat-like spaces deep in the fibrotic portion of a thickened pleura represent a benign finding seen in some cases of organizing pleuritis/fibrothorax. The spaces themselves are probably artifacts derived from the biopsy procedure and/or cutting artifacts. In contrast, in true desmoplastic mesotheliomas there is downward, rather than horizontal, growth of keratin-positive spindled cells running between clearly definable fat cells.

19 Article Chronic inflammation in tumor stroma is an independent predictor of prolonged survival in epithelioid malignant pleural mesothelioma patients. 2011

Suzuki, Kei / Kadota, Kyuichi / Sima, Camelia S / Sadelain, Michel / Rusch, Valerie W / Travis, William D / Adusumilli, Prasad S. ·Division of Thoracic Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. ·Cancer Immunol Immunother · Pubmed #21769693.

ABSTRACT: This study aims to determine whether a semi-quantitative assessment of inflammatory response in tumor and stroma on routine hematoxylin and eosin-stained (H&E) slides can predict survival in patients with epithelioid malignant pleural mesothelioma (MPM). H&E sections of 175 epithelioid MPM specimens from a single institution (1989-2009) were reviewed. Patients who received neoadjuvant chemotherapy were excluded from analysis. Each tumor was histologically assessed for acute and chronic inflammatory response both within the tumor and the stromal component. Inflammatory response was graded: low (none to mild infiltrate) or high (moderate to severe infiltrate). Log-rank test and Cox proportional hazards regression were used to investigate the association between the degree of inflammation (acute/tumor, acute/stroma, chronic/tumor, and chronic/stroma) and overall survival (OS). Patients with high chronic inflammatory response in stroma (n = 59) had improved survival compared to low (n = 116) (median OS = 19.4 vs. 15.0 months, P = 0.01). This prognostic stratification remained significant in stage III patients (median OS = 16.0 vs. 9.3 months, P = 0.03). In multivariate analysis, chronic inflammation in stroma was an independent predictor of survival (HR = 0.659, 95% CI 0.464-0.937, P = 0.02). While high degree of chronic inflammatory cell infiltration in the stromal component was associated with improved overall survival, degree of other inflammatory responses did not show significant correlation with OS. Our study for the first time investigates inflammatory response in tumor and stroma and not only suggests the prognostic value of inflammatory response in epithelioid MPM but also provides rationale for investigation of immunotherapy to benefit epithelioid MPM patients.