Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer.
| Title: | Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer. |
|---|---|
| Authors: | Goode EL; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Block MS; Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA; Kalli KR; Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA; Vierkant RA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Chen W; Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada; Fogarty ZC; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Gentry-Maharaj A; Gynaecological Cancer Research Centre, Department of Women’s Cancer, Institute for Women’s Health, University College London, London, UK; Tołoczko A; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; Hein A; Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg Comprehensive Cancer Center, Erlangen EMN, Germany; Bouligny AL; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Department of Health Sciences, Spelman College, Atlanta, GA, USA; Jensen A; Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Osorio A; Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Hartkopf A; Tübingen University Hospital, Department of Women’s Health, Tübingen, Germany; Ryan A; Gynaecological Cancer Research Centre, Department of Women’s Cancer, Institute for Women’s Health, University College London, London, UK; Chudecka-Głaz A; Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland; Magliocco AM; Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL, USA; Hartmann A; Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University; Jung AY; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Gao B; Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia; The Crown Princess Mary Cancer Centre, Westmead Hospital, The University of Sydney, Australia; Hernandez BY; Cancer Center, University of Hawaii, Honolulu, HI, USA; Fridley BL; Department of Biostatistics and Bioinformatics, Division of Population Sciences, Moffitt Cancer Center, Tampa, FL, USA; McCauley BM; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Kennedy CJ; Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia; Wang C; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Karpinskyj C; Gynaecological Cancer Research Centre, Department of Women’s Cancer, Institute for Women’s Health, University College London, London, UK; de Sousa CB; Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Tiezzi DG; Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Wachter DL; Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University; Herpel E; Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Germany and Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Taran FA; Tübingen University Hospital, Department of Women’s Health, Tübingen, Germany; Modugno F; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA; Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Nelson G; Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Lubiński J; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; Menkiszak J; Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland; Alsop J; Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK; Lester J; Women’s Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; García-Donas J; Medical Oncology Service, HM Hospitales – Centro Integral Oncológico HM Clara Campal, Madrid, Spain; Nation J; Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Hung; Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia; Palacios J; Pathology Department, Hospital Universitario Ramón y Cajal. IRYCIS. Universidad de Alcalá, Madrid, Spain. CIBERONC; Rothstein JH; Department of Population Health Science and Policy, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Kelley JL; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; de Andrade JM; Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Robles-Díaz L; Familial Cancer Unit and Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; Intermaggio MP; School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia; Widschwendter M; Gynaecological Cancer Research Centre, Department of Women’s Cancer, Institute for Women’s Health, University College London, London, UK; Beckmann MW; Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg Comprehensive Cancer Center, Erlangen EMN, Germany; Ruebner M; Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg Comprehensive Cancer Center, Erlangen EMN, Germany; Jimenez-Linan M; Department of Histopathology, Addenbrookes Hospital, Cambridge, UK; Singh N; Department of Pathology, Barts Health National Health Service Trust, London, UK; Oszurek O; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; Harnett PR; Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia; The Crown Princess Mary Cancer Centre, Westmead Hospital, The University of Sydney, Australia; Rambau PF; Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada; Pathology Department, Catholic University of Health and Allied Sciences-Bugando, Mwanza, Tanzania; Sinn P; Department of Pathology, Institute of Pathology, Heidelberg University Hospital, Germany; Wagner P; Tübingen University Hospital, Department of Women’s Health, Tübingen, Germany; Ghatage P; Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Sharma R; Pathology West ICPMR Westmead, Westmead Hospital, The University of Sydney, Sydney, Australia; University of Western Sydney at Westmead Hospital, Westmead, New South Wales, Australia; Edwards RP; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Ness RB; The University of Texas School of Public Health, Houston, TX, USA; Orsulic S; Women’s Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Brucker SY; Tübingen University Hospital, Department of Women’s Health, Tübingen, Germany; Johnatty SE; Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia; Longacre TA; Department of Pathology, Stanford University, Stanford, CA, USA; Ursula E; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; McGuire V; Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA; Sieh W; Department of Population Health Science and Policy, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Natanzon Y; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Li Z; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Department of Gynecologic Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming, China; Whittemore AS; Department of Health Research and Policy, Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA; Anna A; Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia; Staebler A; Tübingen University Hospital, Institute of Pathology, Tübingen, Germany; Karlan BY; Women’s Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Gilks B; Genetic Pathology Evaluation Centre, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia,Canada; Bowtell DD; Cancer Genomics Program, Research Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, the University of Melbourne, Parkville, Victoria, Australia; The Garvan Institute, Sydney, New South Wales, Australia; Høgdall E; Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; Candido dos Reis FJ; Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Steed H; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Royal Alexandra Hospital, Edmonton, Alberta, Canada; Campbell IG; Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Australia; Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia; Gronwald J; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; Benítez J; Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Koziak JM; Alberta Health Services-Cancer Care, Calgary, Alberta, Canada; Chang-Claude J; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Moysich KB; Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA; Kelemen LE; Department of Public Health Sciences, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC, USA; Cook LS; Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, NM, USA; Goodman MT; Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA; García MJ; Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Fasching PA; Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg Comprehensive Cancer Center, Erlangen EMN, Germany; David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, CA, USA; Kommoss S; Tübingen University Hospital, Department of Women’s Health, Tübingen, Germany; Deen S; Department of Histopathology, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; Kjaer SK; Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Menon U; Gynaecological Cancer Research Centre, Department of Women’s Cancer, Institute for Women’s Health, University College London, London, UK; Brenton JD; Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, UK; Cambridge Experimental Cancer Medicine Centre, Cambridge, UK; Pharoah PDP; Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK; Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK; Chenevix-Trench G; Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia; Huntsman DG; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Winham SJ; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Köbel M; Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada; Ramus SJ; School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia; The Garvan Institute, Sydney, New South Wales, Australia |
| Corporate Authors: | Ovarian Tumor Tissue Analysis (OTTA) Consortium |
| Source: | JAMA oncology [JAMA Oncol] 2017 Dec 01; Vol. 3 (12), pp. e173290. |
| Publication Type: | Journal Article; Multicenter Study; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Medical Association Country of Publication: United States NLM ID: 101652861 Publication Model: Print Cited Medium: Internet ISSN: 2374-2445 (Electronic) Linking ISSN: 23742437 NLM ISO Abbreviation: JAMA Oncol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Chicago, Il : American Medical Association, [2015]- |
| MeSH Terms: | CD8 Antigens/*metabolism ; Carcinoma, Ovarian Epithelial/*drug therapy ; Cystadenocarcinoma, Serous/*immunology ; Lymphocytes, Tumor-Infiltrating/*immunology ; Ovarian Neoplasms/*immunology; BRCA2 Protein/genetics ; Carcinoma, Ovarian Epithelial/immunology ; Carcinoma, Ovarian Epithelial/pathology ; Cystadenocarcinoma, Serous/genetics ; Cystadenocarcinoma, Serous/pathology ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Cohort Studies ; Female ; Humans ; Middle Aged ; Mutation ; Neoplasm Grading ; Prospective Studies ; Survival Analysis ; Treatment Outcome |
| Abstract: | Importance: Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.; Objective: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer.; Design, Setting, and Participants: This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.; Exposures: Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.; Main Outcomes and Measures: Overall survival time.; Results: The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form.; Conclusions and Relevance: This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer. |
| References: | Gynecol Oncol. 2008 Feb;108(2):415-20. (PMID: 18037158); N Engl J Med. 2003 Jan 16;348(3):203-13. (PMID: 12529460); Ann Oncol. 2013 Dec;24 Suppl 10:x16-21. (PMID: 24265397); Ann Oncol. 2017 Mar 1;28(3):651-657. (PMID: 27864219); Clin Cancer Res. 2008 Jun 1;14(11):3372-9. (PMID: 18519766); Int J Gynecol Pathol. 2016 Sep;35(5):430-41. (PMID: 26974996); Mod Pathol. 2009 Mar;22(3):393-402. (PMID: 19060844); Oncotarget. 2016 Mar 22;7(12):13587-98. (PMID: 26871470); Ann Oncol. 2015 Nov;26(11):2351. (PMID: 26347098); Nat Genet. 2017 May;49(5):680-691. (PMID: 28346442); Cancer Causes Control. 2017 May;28(5):487-495. (PMID: 28283879); Br J Cancer. 2014 Dec 9;111(12):2297-307. (PMID: 25349970); Lancet Oncol. 2013 Aug;14(9):853-62. (PMID: 23845225); Science. 2015 Apr 3;348(6230):124-8. (PMID: 25765070); N Engl J Med. 2012 Jun 28;366(26):2455-65. (PMID: 22658128); N Engl J Med. 2010 Sep 2;363(10):943-53. (PMID: 20818904); Int J Mol Sci. 2013 Mar 06;14(3):5367-79. (PMID: 23466883); Cancer Epidemiol Biomarkers Prev. 2013 Oct;22(10):1677-86. (PMID: 23880734); JAMA. 2012 Jan 25;307(4):382-90. (PMID: 22274685); J Clin Oncol. 2013 Mar 1;31(7):860-7. (PMID: 23341518); J Transl Med. 2012 Oct 03;10:205. (PMID: 23034130); Clin Cancer Res. 2008 Dec 1;14(23):7667-73. (PMID: 19047092); Gynecol Oncol. 2012 Feb;124(2):192-8. (PMID: 22040834); Lancet Oncol. 2011 Oct;12(11):1071-80. (PMID: 21616717); PLoS One. 2013 Nov 14;8(11):e80063. (PMID: 24244610); Histopathology. 2016 Aug;69(2):288-97. (PMID: 26799366); PLoS One. 2012;7(12):e51862. (PMID: 23251644); Gynecol Oncol. 2016 Mar;140(3):457-62. (PMID: 26807488); Mod Pathol. 2016 Oct;29(10):1155-64. (PMID: 27363491); Histopathology. 2014 Jun;64(7):1004-13. (PMID: 24329781); Clin Cancer Res. 2015 Feb 1;21(3):652-7. (PMID: 25398451); Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18538-43. (PMID: 16344461); Obstet Gynecol. 2013 Aug;122(2 Pt 1):225-232. (PMID: 23969788); Br J Cancer. 2005 Aug 22;93(4):387-91. (PMID: 16106245); Clin Cancer Res. 2016 Jun 15;22(12):3005-15. (PMID: 26763251); Gynecol Oncol. 2016 Nov;143(2):236-240. (PMID: 27612977); Science. 2016 Mar 25;351(6280):1463-9. (PMID: 26940869); Oncology (Williston Park). 2016 Feb;30(2):166-76. (PMID: 26892153); Annu Rev Immunol. 2013;31:443-73. (PMID: 23298205); PLoS Med. 2008 Dec 2;5(12):e232. (PMID: 19053170); Cancer Epidemiol Biomarkers Prev. 2018 Apr;27(4):395-404. (PMID: 28615364); J Gynecol Oncol. 2016 May;27(3):e31. (PMID: 27029752); CA Cancer J Clin. 2017 Jan;67(1):7-30. (PMID: 28055103); Curr Opin Oncol. 2015 Sep;27(5):412-9. (PMID: 26241347); Clin Cancer Res. 2014 Dec 15;20(24):6618-30. (PMID: 25316818); Nature. 2013 May 2;497(7447):67-73. (PMID: 23636398); Clin Cancer Res. 2008 Aug 15;14(16):5198-208. (PMID: 18698038); J Clin Oncol. 2016 Sep 1;34(25):3062-8. (PMID: 27325856); PLoS One. 2014 May 01;9(5):e95285. (PMID: 24788697); J Natl Cancer Inst. 2014 Sep 30;106(10):. (PMID: 25269487); J Clin Oncol. 2015 Dec 1;33(34):4015-22. (PMID: 26351349); J Clin Invest. 2013 Jan;123(1):517-25. (PMID: 23257362) |
| Grant Information: | U01 CA069417 United States CA NCI NIH HHS; P30 CA016056 United States CA NCI NIH HHS; UL1 TR000124 United States TR NCATS NIH HHS; P30 CA138313 United States CA NCI NIH HHS; K07 CA080668 United States CA NCI NIH HHS; R01 CA188900 United States CA NCI NIH HHS; R01 CA122443 United States CA NCI NIH HHS; 10119 United Kingdom CRUK_ Cancer Research UK; P50 CA136393 United States CA NCI NIH HHS; R25 CA092049 United States CA NCI NIH HHS; P50 CA159981 United States CA NCI NIH HHS; M01 RR000056 United States RR NCRR NIH HHS; R01 CA095023 United States CA NCI NIH HHS; K07 CA143047 United States CA NCI NIH HHS; R01 CA160669 United States CA NCI NIH HHS; 16561 United Kingdom CRUK_ Cancer Research UK; 10124 United Kingdom CRUK_ Cancer Research UK |
| Substance Nomenclature: | 0 (BRCA2 Protein); 0 (BRCA2 protein, human); 0 (CD8 Antigens) |
| Entry Date(s): | Date Created: 20171020 Date Completed: 20190513 Latest Revision: 20260302 |
| Update Code: | 20260302 |
| PubMed Central ID: | PMC5744673 |
| DOI: | 10.1001/jamaoncol.2017.3290 |
| PMID: | 29049607 |
| Database: | MEDLINE |
Journal Article; Multicenter Study; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't