title: Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation.
abstract: OBJECTIVE
  In patients with hepatocellular carcinoma (HCC), liver transplantation (LT) is an excellent therapy if tumor characteristics are within the Milan criteria. We aimed to define genomic features enabling to identify HCC patients beyond Milan criteria who have acceptable transplant outcomes.
  
  
  METHODS
  Among 770 consecutive HCC patients transplanted between 1990 and 2013, 132 had tumors exceeding Milan criteria on pathology and were enrolled in the study; 44% of the patients satisfied the 'up-to-7 rule' [7=sum of the size of the largest tumor and the number of tumors]. Explant tumors were assessed for genomic signatures and immunohistochemical markers associated with poor outcome.
  
  
  RESULTS
  At a median follow-up of 88months, 64 patients had died and 45 recurred; the 5-year overall survival (OS) and recurrence rates were 57% and 35%, respectively. Cytokeratin 19 (CK19) gene signature was independently associated with recurrence [Hazard ratio (HR)=2.95, p<0.001], along with tumor size (HR=3.37, p=0.023) and presence of satellites (HR=2.98, p=0.001). S2 subclass signature was independently associated with poor OS (HR=3.18, p=0.001), along with tumor size (HR=5.06, p<0.001) and up-to-7 rule (HR=2.50, p=0.002). Using the presence of progenitor cell markers (either CK19 or S2 signatures) patients were classified into poor prognosis (n=58; 5-year recurrence 53%, survival 45%) and good prognosis (n=74; 5-year recurrence 19%, survival 67%) (HR=3.16, p<0.001 for recurrence, and HR=1.72, p=0.04 for OS).
  
  
  CONCLUSIONS
  HCC patients transplanted beyond Milan criteria without gene signatures of progenitor markers (CK19 and S2) achieved survival rates similar as those within Milan criteria. Once prospectively validated, these markers may support a limited expansion of LT indications.
authors.affiliation: Mount Sinai Liver Cancer Program (Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Department of Pathology, Recanati Miller Transplantation Institute, Department of Surgical Oncology), Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Oriana
authors.initials: O
authors.lastname: Miltiadous
authors.affiliation: Mount Sinai Liver Cancer Program (Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Department of Pathology, Recanati Miller Transplantation Institute, Department of Surgical Oncology), Icahn School of Medicine at Mount Sinai, New York, USA; Gastrointestinal Surgery and Liver Transplantation Unit, Department of Surgery, National Cancer Institute, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sia
authors.affiliation: Mount Sinai Liver Cancer Program (Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Department of Pathology, Recanati Miller Transplantation Institute, Department of Surgical Oncology), Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.affiliation: Mount Sinai Liver Cancer Program (Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Department of Pathology, Recanati Miller Transplantation Institute, Department of Surgical Oncology), Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Fiel
authors.affiliation: Mount Sinai Liver Cancer Program (Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Department of Pathology, Recanati Miller Transplantation Institute, Department of Surgical Oncology), Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Harrington
authors.affiliation: Mount Sinai Liver Cancer Program (Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Department of Pathology, Recanati Miller Transplantation Institute, Department of Surgical Oncology), Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Swan N
authors.initials: SN
authors.lastname: Thung
authors.affiliation: Mount Sinai Liver Cancer Program (Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Department of Pathology, Recanati Miller Transplantation Institute, Department of Surgical Oncology), Icahn School of Medicine at Mount Sinai, New York, USA; Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Health System, Singapore.
authors.forename: Poh Seng
authors.initials: PS
authors.lastname: Tan
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Dong
authors.affiliation: Mount Sinai Liver Cancer Program (Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Department of Pathology, Recanati Miller Transplantation Institute, Department of Surgical Oncology), Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Revill
authors.affiliation: Mount Sinai Liver Cancer Program (Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Department of Pathology, Recanati Miller Transplantation Institute, Department of Surgical Oncology), Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Charissa Y
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Liver Cancer Program, Hofstra-North Shore LIJ School of Medicine, Lenox Hill Hospital, New York, USA.
authors.forename: Sasan
authors.initials: S
authors.lastname: Roayaie
authors.affiliation: Division of Hepatology, Mayo Clinic, Phoenix, AZ, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Byrne
authors.affiliation: Gastrointestinal Surgery and Liver Transplantation Unit, Department of Surgery, National Cancer Institute, Milan, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mazzaferro
authors.affiliation: Division of Hepatology, Mayo Clinic, Phoenix, AZ, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Rakela
authors.affiliation: Mount Sinai Liver Cancer Program (Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Department of Pathology, Recanati Miller Transplantation Institute, Department of Surgical Oncology), Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Sander
authors.initials: S
authors.lastname: Florman
authors.affiliation: Mount Sinai Liver Cancer Program (Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Department of Pathology, Recanati Miller Transplantation Institute, Department of Surgical Oncology), Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Myron
authors.initials: M
authors.lastname: Schwartz
authors.affiliation: Mount Sinai Liver Cancer Program (Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Department of Pathology, Recanati Miller Transplantation Institute, Department of Surgical Oncology), Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Translational Research Laboratory, Barcelona - Clínic Liver Cancer Group (Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Liver Unit, Hospital Clínic, Universitat de Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain. Electronic address: Josep.Llovet@mssm.edu.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000601:surgery*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D015331:Cohort Studies; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D053539:Keratin-19 / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000601:surgery*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011379:Prognosis
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D053539:Keratin-19
keywords: Gene expression; Gene signature; Prognosis; Stem cell; Survival