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The IASLC Mesothelioma Staging Project: Proposals for the M Descriptors and for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Mesothelioma

Open ArchivePublished:September 26, 2016DOI:https://doi.org/10.1016/j.jtho.2016.09.124

      Abstract

      Introduction

      The M component and TNM stage groupings for malignant pleural mesothelioma (MPM) have been empirical. The International Association for the Study of Lung Cancer developed a multinational database to propose evidence-based revisions for the eighth edition of the TNM classification of MPM.

      Methods

      Data from 29 centers were submitted either electronically or by transfer of existing institutional databases. The M component as it currently stands was validated by confirming sufficient discrimination (by Kaplan-Meier analysis) with respect to overall survival (OS) between the clinical M0 (cM0) and cM1 categories. Candidate stage groups were developed by using a recursive partitioning and amalgamation algorithm applied to all cM0 cases.

      Results

      Of 3519 submitted cases, 2414 were analyzable and 84 were cM1 cases. Median OS for cM1 cases was 9.7 months versus 13.4 months (p = 0.0013) for the locally advanced (T4 or N3) cM0 cases, supporting inclusion of only cM1 in the stage IV group. Exploratory analyses suggest a possible difference in OS for single- versus multiple-site cM1 cases. A recursive partitioning and amalgamation–generated survival tree on the OS outcomes restricted to cM0 cases with the newly proposed (eighth edition) T and N components indicates that optimal stage groupings for the eighth edition will be as follows: stage IA (T1N0), stage IB (T2–3N0), stage II (T1–2N1), stage IIIA (T3N1), stage IIIB (T1–3N2 or any T4), and stage IV (any M1).

      Conclusions

      This first evidence-based revision of the TNM classification for MPM leads to substantial changes in the T and N components and the stage groupings.

      Keywords

      Introduction

      The current staging system for malignant pleural mesothelioma (MPM) was developed in 1994 at a workshop sponsored by the International Association for the Study of Lung Cancer (IASLC) and the International Mesothelioma Interest Group (IMIG), during which MPM investigators analyzed reported surgical databases and the available small clinical trials in this disease. The resulting TNM-based system was potentially applicable to the clinical, surgical and pathologic staging of MPM,
      • Rusch V.W.
      The International Mesothelioma Interest Group. A proposed new international TNM staging system for malignant pleural mesothelioma.
      and it was subsequently accepted by the Union for International Cancer Control (UICC) and the American Joint Commission on Cancer (AJCC) as the first international MPM staging system for the sixth edition of their staging manuals. Although this system was thereafter widely used in retrospective studies and in clinical trials, it has been criticized for being insufficiently evidence based and difficult to apply to clinical staging.
      To identify potential deficits in the MPM staging system, the IASLC Staging and Prognostic Factors Committee, in collaboration with members of the IMIG, initiated a large international database in 2009. This approach was modeled on the methods used by the IASLC to revise the lung cancer staging system. Data were solicited from surgeons around the world known to care for a high volume of patients with MPM and were transmitted to the statistical center, Cancer Research And Biostatistics (CRAB) in Seattle, Washington, without identifiable private patient information. Common data elements were established after review of institutional databases, and the time frame chosen for the initial analysis was 1995 to 2009. Data were submitted on 3101 patients from 15 centers on four continents, and a first analysis was published in 2012.
      • Rusch V.W.
      • Giroux D.
      • Kennedy C.
      • et al.
      Initial analysis of the International Association for the Study of Lung Cancer mesothelioma database.
      Although overall survival data largely supported continued use of the original IMIG system for the seventh editions of the staging manuals, several important areas for improvement were identified, particularly for the T and N components.
      To address controversies raised by the initial analysis, an expansion of the IASLC MPM database was started in July 2013 in anticipation of the eighth editions of the AJCC and UICC staging systems. The data dictionary was revised to provide more granular information for the T, N, and M descriptors, and a new electronic data capture (EDC) system, housed at CRAB, was developed. Additional investigators who could provide valid information on patients with tumors staged clinically and managed nonsurgically were recruited.
      • Pass H.I.
      • Giroux D.
      • Kennedy C.
      • Ruffini E.
      • Cangir A.K.
      • Rice D.
      • et al.
      The IASLC mesothelioma staging project: improving staging of a rare disease through international participation.
      The proposals for changes to the T and N components have been published previously.
      • Nowak A.K.
      • Chansky K.
      • Rice D.C.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
      • Rice D.C.
      • Chansky K.
      • Nowak A.K.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for revisions of the N descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
      Here we present the proposals for the M component and for the resultant TNM stage groupings.

      Methods

      This was an international, multi-institutional cohort study. The study population included patients with newly diagnosed, cytologically or histologically confirmed malignant pleural mesothelioma. Information was collected on the extent of disease, demographic characteristics, comorbidities, treatment, and survival. Disease was staged by investigators according to the seventh edition of the UICC/AJCC staging system for MPM.
      American Joint Committee on Cancer
      AJCC Cancer Staging Manual.
      International Union Against Cancer
      TNM Classification of Malignant Tumours.
      Biostatistical support was provided by CRAB.
      Data to inform this effort originated from 29 centers on four continents (see Appendix). Some of the cases from the initial surgically managed database
      • Rusch V.W.
      • Giroux D.
      • Kennedy C.
      • et al.
      Initial analysis of the International Association for the Study of Lung Cancer mesothelioma database.
      possessed sufficient detail to be incorporated into the new database, and those cases are included in the present analysis. In addition to cases entered into the EDC, several institutions contributed retrospective data outside of the EDC but with data elements that could be mapped to those of the electronic database. Cases with complete anatomical stage information, complete survival information, and a diagnosis of MPM between January 1995 and June 30, 2013, were eligible. All data were collected in compliance with applicable local legislation, and only coded, deidentified data were submitted for analysis. Each participating institution gained institutional human research ethics committee approval to collect and contribute data, with a waiver of consent from individual patients.
      For this analysis, clinical stage and pathologic stage were considered along with best stage, which was defined as pathologic stage when available and clinical stage otherwise. For cases in which chemotherapy was received before surgery (usually denoted as ypTNM), only clinical stage was considered. For analyses of the T component, which is described elsewhere,
      • Nowak A.K.
      • Chansky K.
      • Rice D.C.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
      anatomical tumor descriptors were required. For analyses of the N component,
      • Rice D.C.
      • Chansky K.
      • Nowak A.K.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for revisions of the N descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
      nodal station data were required. The M component of TNM classification as it currently stands was validated by confirming sufficient discrimination with respect to overall survival between the clinical M0 (cM0) and cM1 stage groups. Analyses regarding sites of metastasis and number of metastatic sites and lesions were restricted to exploratory examinations of overall survival prognosis (Kaplan-Meier survival estimates) owing to the small number of M1 cases in this data set. The requirements for inclusion in primary analyses of overall TNM stage groups were as follows: complete T, N, and M components; known survival status at last follow-up; presentation within the specified time frame; and complete agreement between anatomical descriptors and assigned TNM category.
      Candidate proposals for overall TNM stage groups were developed by incorporating proposed changes to the T and N components that have been reported elsewhere.
      • Nowak A.K.
      • Chansky K.
      • Rice D.C.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
      • Rice D.C.
      • Chansky K.
      • Nowak A.K.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for revisions of the N descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
      Briefly, they are to combine T1a and T1b to form a T1 category, combine N1 and N2 to form a new N1 category, and rename N3 as N2. Candidate stage group schemes were developed for consideration by using a recursive partitioning and amalgamation algorithm
      • LeBlanc M.
      • Crowley J.
      Survival trees by goodness of split.
      applied to all M0 cases. Survival was measured from the date of diagnosis and was calculated by the Kaplan-Meier method. The analysis utilized the R version 3.1.2 RPART and RLSPLIT packages.
      R Development Core Team
      R: a language and environment for statistical computing.

      Therneau T, Atkinson B, Ripley B. rpart: recursive partitioning and regression trees [computer program]. R package version 4.1-10; 2015. http://CRAN.R-project.org/package=rpart. Accessed March 1, 2016.

      Mitchell A, LeBlanc M. RLSplit: Splitting functions for censored survival data [computer program]. R package version 0.2; 2014.

      The algorithm generated a tree-based model for the survival data by using log-rank test statistics for recursive partitioning, and for selection of the important groupings, bootstrap was used to correct for the adaptive nature of the splitting algorithm. The primary tree-based analysis grouped 2307 cases on the basis of ordered representations of “best” T category (pathologic if available, otherwise clinical) and best N category restricted to M0 cases. An ordered list of groupings was constructed from the terminal nodes of the survival tree. With this as a guide, several stage grouping schemes were proposed by combining adjacent groups. Candidate TNM stage grouping schemes were evaluated in part by assessing overall survival in clinical, pathologic, and best stage. Contrasts between adjacent stage groupings were evaluated by using Cox proportional hazards regression (version 9.4 of the SAS System for Windows [SAS Institute, Inc., Cary, NC]), with stage group modeled by indicator variables and adjustment for sex and cell type (epithelioid versus nonepithelioid). Consensus for a final stage grouping proposal from among the candidates was based not only on the statistical results but also on relevance to clinical practice and implementation.

      Results

      As of January 2014, the combined databases of the EDC and individual submissions totaled 3519 cases, of which 2460 passed the initial eligibility screen. Cases that were stage I NOS (not otherwise specified), TXN3, or T4NX were then also excluded, leaving a total of 2414 cases. Screened cases presented within the prescribed time frame, with MPM histologic or cytologic features, with clinical and/or pathologic stage provided, and with known survival status at last contact. Additional requirements for inclusion were specific to the analyses conducted regarding the T component, N component, M component, and overall stage groupings. For the primary analyses of overall clinical and pathologic stage groups, anatomical descriptors were required in support of the T category, and cases staged T1 without indication of a subcategory of T1a versus T1b were generally excluded. Median follow-up in living patients for the entire group was 16 months. Full clinical stage was available in 1575 of these cases, and pathologic stage was available for 1491. Best stage was derived from all of these cases plus five additional cases in which neither full clinical nor full pathologic stage components were reported but a mix of clinical and pathologic components were available. Best stage took the pathologic stage component as the accepted standard when this was available. Patient characteristics are shown in Table 1. Surgical patients comprised 81% of cases, although 21% of these surgical cases were explored only and not resected.
      Table 1Patient Characteristics
      CharacteristicTotal“Best” Stage OnlyAvailable TNM Staging
      Clinical + PathologicClinicalPathologic
      n(%)N(%)N(%)N(%)
      Region
       Asia2240085(37%)133(59%)6(2%)
       Australia2211(<1%)0(0%)112(50%)108(48%)
       Europe8044(<1%)131(16%)361(44%)308(38%)
       North America8070(0%)395(48%)304(37%)108(13%)
       Turkey3580046(12%)8(2%)304(84%)
      Sex
       Female5321(0%)145(27%)166(31%)220(41%)
       Male18824(0%)512(27%)752(39%)614(32%)
      Histologic type
       Biphasic3490(0%)103(29%)103(29%)143(40%)
       Epithelioid17653(<1%)513(29%)643(36%)606(33%)
       Other/NOS1872(1%)30(16%)100(53%)55(30%)
       Sarcomatoid1130(0%)11(9%)72(63%)30(26%)
      Total24145(<1%)657(27%)918(38%)834(34%)
      Note: Best stage only refers to a composite of available clinical and pathologic TNM components.
      NOS, not otherwise specified.
      There were 84 patients with clinically staged M1 tumors at diagnosis. Location(s) of metastatic lesions were given in 70 of 84 cases (Table 2). Eighteen had a single lesion, 14 had multiple lesions in a single metastatic site, 21 had multiple sites of metastatic disease, and 17 had a single site but with an unspecified number of lesions. An exploratory analysis examining categories analogous to those proposed for extrathoracic metastases in lung cancer suggests a better prognosis in cases in which there is only a single lesion (Fig. 1). Median overall survival in the entire group of clinical stage M1 cases was 9.7 months, which contrasts with the median survival of the proposed eighth edition stage IIIB (T4 or N3, M0) of 13.4 months. The difference is significant (hazard ratio = 1.64, p = 0.0013), supporting the proposal to include only the M1 cases in stage IV.
      Table 2Location of Metastatic Sites in 84 Patients with M1 Disease Identified before Any Treatment
      Siten
      Contralateral pleura6
      Contralateral lung13
      Peritoneum9
      Intra-abdominal22
      Bone8
      Liver7
      Brain2
      Distant lymph node
      Includes all extrathoracic lymph nodes other than supraclavicular nodes. Specific information regarding these lymph node sites is not available in the database.
      23
      Other site7
      No descriptors14
      Note: Some patients had multiple sites of disease (see text).
      a Includes all extrathoracic lymph nodes other than supraclavicular nodes. Specific information regarding these lymph node sites is not available in the database.
      Figure thumbnail gr1
      Figure 1Overall survival according to site/number of metastatic lesions, clinical M1 cases. MST, median survival time.
      A recursive partitioning and amalgamation–generated survival tree on the overall survival outcome restricted to M0 cases with the newly proposed T category and N category entered as ordered variables is shown in Figure 2. Terminal nodes, indicating subgroups with the specified survival prognosis, are shown. Hazard ratios are relative to the right-most terminal node, the T4 (any N) cases. There was no statistical difference between T4N0 and T4N+ (OS for T4N0 = 14.9 months versus T4N+ = 13.9 months, p = 0.94 by log-rank test), and thus there is no branching below the T4 node. The T1–T2, N3 group has a similar prognosis. Others are sufficiently different from one another to potentially warrant their own classification.
      Figure thumbnail gr2
      Figure 2Recursive partitioning and amalgamation–generated survival tree based on best stage for 2307 M0 cases. T and N categories are modeled as ordered variables. Stratified hazard ratios are given relative to the right-most terminal node, T4 any N. The N definitions refer to those used in the seventh edition of the malignant pleural mesothelioma staging classification.
      Overall survival according to TNM best stage group in the seventh edition and proposed eighth edition is shown in Figure 3A and B. The seventh edition stages IB and II have similar prognoses and are not significantly different. For the eighth edition best stage, the IIIA and IIIB groups are similar in prognosis, with no separation before 12 months. For clinical stage, however, the stage IIIB cases have a median survival of 13.4 months, which is considerably poorer than the median survival of 17.3 months in stage IIIA (Supplementary Fig. 1A and B). Survival according to pathologic seventh edition and eighth edition stage is shown in Supplementary Figure 2A and B. Formal comparisons of all adjacent stage groupings for clinical, pathologic, and best stage are shown in Table 3. On the basis of these data, the stage groupings recommended for the eighth edition of the MPM staging system include the following: T1N0M0 as stage IA, T2–3N0M0 as stage IB, T1–2N1M0 as stage II, T3N1M0 as stage IIIA, T1–3N2M0 and T4anyNM0 as stage IIIB, and anyTanyNM1 as stage IV. The proposed eighth edition descriptors for T, N, and M and the overall stage groupings are shown in Tables 4 and 5. In some comparisons, OS differences are either small or significant for clinical but not for pathologic stage (or vice versa). The new stage groupings are fundamentally guided by statistical analyses but also informed by relevance to clinical practice. Future additional data may lead to either expansion or consolidation of these stage groupings. Overall, the proposed revisions represent substantial changes from the stage groupings used in the sixth and seventh editions of the staging system.
      Figure thumbnail gr3
      Figure 3(A) Overall survival according to best stage, seventh edition. (Two stage I NOS cases are excluded.) (B) Overall survival according to best stage (proposed eighth edition).
      Table 3Formal Comparisons between Adjacent TNM Stage Groups Proposed for the Eighth Edition and Based on a Cox Regression Model Adjusted for Sex and Cell Type (Epithelioid versus Nonepithelioid)
      ComparisonClinical StagePathologic StageBest Stage
      HRp ValueHRp ValueHRp Value
      IB vs. IA1.67<0.00011.050.601.190.02
      II vs. IB1.130.221.110.321.140.11
      IIIA vs. II0.920.541.350.00831.190.072
      IIIB vs. IIIA1.360.020.970.771.120.17
      IV vs. IIIB1.640.00131.060.801.420.0047
      HR, hazard ratio.
      Table 4Definitions of TNM
      StageDefinition
      Primary tumor (T)
      TXPrimary tumor cannot be assessed
      T0No evidence of primary tumor
      T1Tumor limited to the ipsilateral parietal ± visceral ± mediastinal ± diaphragmatic pleura
      T2
      • Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
      • involvement of diaphragmatic muscle
      • extension of tumor from visceral pleura into the underlying pulmonary parenchyma
      T3Describes locally advanced but potentially resectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
      • involvement of the endothoracic fascia
      • extension into the mediastinal fat
      • solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall
      • nontransmural involvement of the pericardium
      T4Describes locally advanced technically unresectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
      • diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction
      • direct transdiaphragmatic extension of tumor to the peritoneum
      • direct extension of tumor to the contralateral pleura
      • direct extension of tumor to mediastinal organs
      • direct extension of tumor into the spine
      • tumor extending through to the internal surface of the pericardium with or without a pericardial effusion, or tumor involving the myocardium
      Regional lymph nodes (N)
      NXRegional lymph nodes cannot be assessed
      N0No regional lymph node metastases
      N1Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal lymph nodes) lymph nodes
      N2Metastases in the contralateral mediastinal, ipsilateral, or contralateral supraclavicular lymph nodes
      Distant metastasis (M)
      M0No distant metastasis
      M1Distant metastasis present
      Table 5TNM Stage Groupings Proposed for the Eighth Edition of MPM Staging System Relative to Those Used in the Seventh Edition
      StageN0N1/N2N1N3N2
      Seventh EditionEighth EditionSeventh EditionEighth EditionSeventh EditionEighth Edition
      T1I (A, B)IAIIIIIIVIIIB
      T2IIIBIIIIIIVIIIB
      T3IIIBIIIIIIAIVIIIB
      T4IVIIIBIVIIIBIVIIIB
      M1IVIVIVIVIVIV

      Discussion

      This is the first evidence-based revision of the TNM staging system for MPM. The original TNM classification developed in 1994 was based on the modest amount of data available at that time, predominantly from retrospective surgical series. Alternative proposed staging systems have been either not TNM based or derived from single-institution surgical data.
      • Pass H.I.
      • Giroux D.
      • Kennedy C.
      • Ruffini E.
      • Cangir A.K.
      • Rice D.
      • et al.
      The IASLC mesothelioma staging project: improving staging of a rare disease through international participation.
      The current analyses leading to substantial proposed revisions for the eighth edition of the UICC/AJCC staging system benefit from data that are multicenter and international, are submitted from high-volume centers treating this rare malignancy, are detailed with respect to T and N components, and are derived from patients managed both surgically and nonsurgically.
      Although the current proposed revisions are based on the most robust staging and survival data yet available for MPM, they also emphasize the need for continued data collection and additional analyses to inform revisions for the ninth edition of the staging system of this rare cancer. As noted in our previous reports,
      • Nowak A.K.
      • Chansky K.
      • Rice D.C.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
      • Rice D.C.
      • Chansky K.
      • Nowak A.K.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for revisions of the N descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
      additional data may ultimately lead to further revisions of the T and N components of the staging system, which could then influence stage groupings. In particular, both the IASLC MPM database analyses and other studies correlating tumor volume to outcomes in MPM
      • Gill R.R.
      • Naidich D.P.
      • Mitchell A.
      • et al.
      North American multicenter volumetric CT study for clinical staging of malignant pleural mesothelioma: feasibility and logistics of setting up a quantitative imaging study.
      • Rusch V.W.
      • Gill R.R.
      • Mitchell A.
      • et al.
      A multicenter study of volumetric computed tomography for staging malignant pleural mesothelioma.
      suggest that either pleural thickness measurements or computed tomography–based calculations of tumor volume may provide a more accurate assessment of T category than the current T descriptors. Additional studies addressing this issue could lead to substantially different T categories. Likewise, additional detailed data correlating pathologic involvement of specific nodal stations with outcome could alter the current recommendation to consider all ipsilateral intrathoracic lymph nodes as N1. The M1 data reported here are hypothesis-generating in that a single metastasis or single site of metastatic disease appears to be associated with an overall survival that is different from that seen with multiple lesions or sites. Much more data are needed to confirm these initial results and will involve continued efforts to accrue more nonsurgically treated patients to the database.
      The current proposed revisions for the stage groupings provide a better estimation of outcomes than have previously been shown. However, in the future, additional data collected from patients managed both surgically and nonsurgically will also help refine these stage groupings, potentially providing a more consistent separation of overall survival curves and resolving some of the differences found between clinical and pathologic staging.

      Acknowledgments

      Dr. Rusch’s work is supported in part by National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748 .

      Appendix

      IASLC Staging and Prognostic Factors Committee

      Peter Goldstraw, past chair, Royal Brompton Hospital and Imperial College, London, United Kingdom; Ramón Rami-Porta, chair, Hospital Universitari Mútua Terrassa, Terrassa, Spain; Hisao Asamura, chair-elect, Keio University, Tokyo, Japan; David Ball, Peter MacCallum Cancer Centre, Melbourne, Australia; David Beer, University of Michigan, Ann Arbor, Michigan; Ricardo Beyruti, University of Sao Paulo, Brazil; Vanessa Bolejack, Cancer Research And Biostatistics, Seattle, Washington; Kari Chansky, Cancer Research And Biostatistics, Seattle, Washington; John Crowley, Cancer Research And Biostatistics, Seattle, Washington; Frank C. Detterbeck, Yale University, New Haven, Connecticut; Wilfried Ernst Erich Eberhardt, West German Cancer Centre, University Hospital, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany; John Edwards, Northern General Hospital, Sheffield, United Kingdom; Françoise Galateau-Sallé, Centre Leon Berard, Lyon, France; Dorothy Giroux, Cancer Research And Biostatistics, Seattle, Washington; Fergus Gleeson, Churchill Hospital, Oxford, United Kingdom; Patti Groome, Queen’s Cancer Research Institute, Kingston, Ontario, Canada; James Huang, Memorial Sloan-Kettering Cancer Center, New York, New York; Catherine Kennedy, University of Sydney, Sydney, Australia; Jhingook Kim, Samsung Medical Center, Seoul, Republic of Korea; Young Tae Kim, Seoul National University, Seoul, Republic of Korea; Laura Kingsbury, Cancer Research And Biostatistics, Seattle, Washington; Haruhiko Kondo, Kyorin University Hospital, Tokyo, Japan; Mark Krasnik, Gentofte Hospital, Copenhagen, Denmark; Kaoru Kubota, Nippon Medical School Hospital, Tokyo, Japan; Toni Lerut, University Hospitals, Leuven, Belgium; Gustavo Lyons, British Hospital, Buenos Aires, Argentina; Mirella Marino, Regina Elena National Cancer Institute, Rome, Italy; Edith M. Marom, M. D. Anderson Cancer Center, Houston, Texas; Jan P. van Meerbeeck, Antwerp University Hospital, Edegem (Antwerp), Belgium; Alan Mitchell, Cancer Research And Biostatistics, Seattle, Washington; Takashi Nakano, Hyogo College of Medicine, Hyogo, Japan; Andrew G. Nicholson, Royal Brompton and Harefield National Health Service Foundation Trust and Imperial College, London, United Kingdom; Anna Nowak, University of Western Australia, Perth, Australia; Michael Peake, Glenfield Hospital, Leicester, United Kingdom; Thomas W. Rice, Cleveland Clinic, Cleveland, Ohio; Kenneth Rosenzweig, Mount Sinai Hospital, New York, New York; Enrico Ruffini, University of Turin, Turin, Italy; Valerie W. Rusch, Memorial Sloan-Kettering Cancer Center, New York, New York; Nagahiro Saijo, National Cancer Center Hospital East, Chiba, Japan; Paul Van Schil, Antwerp University Hospital, Edegem (Antwerp), Belgium; Jean-Paul Sculier, Institut Jules Bordet, Brussels, Belgium; Lynn Shemanski, Cancer Research And Biostatistics, Seattle, Washington; Kelly Stratton, Cancer Research And Biostatistics, Seattle, Washington; Kenji Suzuki, Juntendo University, Tokyo, Japan; Yuji Tachimori, National Cancer Center, Tokyo, Japan; Charles F. Thomas Jr., Mayo Clinic, Rochester, Minnesota; William D. Travis, Memorial Sloan-Kettering Cancer Center, New York, New York; Ming S. Tsao, The Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Andrew Turrisi, Sinai Grace Hospital, Detroit, Michigan; Johan Vansteenkiste, University Hospitals, Leuven, Belgium; Hirokazu Watanabe, National Cancer Center Hospital, Tokyo, Japan; Yi-Long Wu, Guangdong General Hospital, Guangzhou, People’s Republic of China.

      Advisory Board of the IASLC Mesothelioma Domain

      Paul Baas, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Jeremy Erasmus, M. D. Anderson Cancer Center, Houston, Texas; Seiki Hasegawa, Hyogo College of Medicine, Hyogo, Japan; Kouki Inai, Hiroshima University Postgraduate School, Hiroshima, Japan; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, Texas, Hedy Kindler, The University of Chicago Medical Center, Chicago, Illinois; Lee Krug, Memorial Sloan-Kettering Cancer Center, New York, New York; Kristiaan Nackaerts, University Hospitals, Leuven, Belgium; Harvey Pass, New York University, New York; David Rice, M. D. Anderson Cancer Center, Houston, Texas.

      Advisory Board of the IASLC Thymic Malignancies Domain

      Conrad Falkson, Queen’s University, Ontario, Canada; Pier Luigi Filosso, University of Turin, Italy; Giuseppe Giaccone, Georgetown University, Washington, District of Columbia; Kazuya Kondo, University of Tokushima, Tokushima, Japan; Marco Lucchi, University of Pisa, Pisa, Italy; Meinoshin Okumura, Osaka University, Osaka, Japan.

      Advisory Board of the IASLC Oesophageal Cancer Domain

      Eugene Blackstone, Cleveland Clinic, Ohio.

      Participating Institutions in the New Mesothelioma Staging Project Database

      H. Asamura, Keio University, Japan; H. Batirel, Marmara University, Turkey; A. Bille and U. Pastorino, Istituto Nazionale dei Tumori, Italy; S. Call, Mutua Terrassa University Hospital, Spain; A. Cangir, Ankara University School of Medicine, Turkey; S. Cedres, Vall d'Hebron University Hospital, Spain; J. Friedberg, University of Pennsylvania-Penn-Presbyterian Medical Center, Pennsylvania; F. Galateau-Sallé, Centre Leon Berard, Lyon, France; S. Hasagawa, Hyogo College of Medicine, Japan; K. Kernstine, University of Texas Southwestern Medical Center, Texas; H. Kindler, University of Chicago, Illinois; B. McCaughan, University of Sydney, Australia; T. Nakano, Hyogo College of Medicine, Japan; A. Nowak, Sir Charles Gairdner Hospital, Australia; C. Atinkaya Ozturk, Sureyyapasa Training and Research Hospital, Turkey; H. Pass, New York University Langone Medical Center, New York; M. de Perrot, Toronto General Hospital and Princess Margaret Hospital, University of Toronto, Canada; F. Rea, University of Padua, Italy; D. Rice, The University of Texas M. D. Anderson Cancer Center, Texas; R. Rintoul, Papworth Hospital National Health Service Foundation Trust, United Kingdom; E. Ruffini, University of Turin, Italy; V. Rusch, Memorial Sloan Kettering Cancer Center, New York; L. Spaggiari, D. Galetta, European Institute of Oncology, Italy; K. Syrigos, University of Athens Oncology Unit, Greece; C. Thomas, Mayo Clinic, Rochester, Minnesota; J.P. van Meerbeeck, P. Nafteux, Univeristy Hospital Antwerp and University Hospital Ghent, Belgium; J. Vansteenkiste, University Hospital Leuven, Belgium; W. Weder, I. Optiz, University Hospital of Zürich, Switzerland; M. Yoshimura, Hyogo Cancer Center, Japan.

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