Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation

Oriana Miltiadous, Daniela Sia, Yujin Hoshida, Maria Isabel Fiel, Andrew N. Harrington, Swan N. Thung, Poh Seng Tan, Hui Dong, Kate Revill, Charissa Y. Chang, Sasan Roayaie, Thomas J. Byrne, Vincenzo Mazzaferro, Jorge Rakela, Sander Florman, Myron Schwartz, Josep M. Llovet

Research output: Contribution to journalArticle

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Abstract

Background & Aims 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 88 months, 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.

Original languageEnglish (US)
Pages (from-to)1368-1377
Number of pages10
JournalJournal of Hepatology
Volume63
Issue number6
DOIs
StatePublished - Dec 1 2015

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Liver Transplantation
Hepatocellular Carcinoma
Stem Cells
Keratin-19
Recurrence
Neoplasms
Survival
Survival Rate
Genes
Pathology
Transplants

Keywords

  • Gene expression
  • Gene signature
  • Prognosis
  • Stem cell
  • Survival

ASJC Scopus subject areas

  • Medicine(all)
  • Hepatology

Cite this

Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation. / Miltiadous, Oriana; Sia, Daniela; Hoshida, Yujin; Fiel, Maria Isabel; Harrington, Andrew N.; Thung, Swan N.; Tan, Poh Seng; Dong, Hui; Revill, Kate; Chang, Charissa Y.; Roayaie, Sasan; Byrne, Thomas J.; Mazzaferro, Vincenzo; Rakela, Jorge; Florman, Sander; Schwartz, Myron; Llovet, Josep M.

In: Journal of Hepatology, Vol. 63, No. 6, 01.12.2015, p. 1368-1377.

Research output: Contribution to journalArticle

Miltiadous, O, Sia, D, Hoshida, Y, Fiel, MI, Harrington, AN, Thung, SN, Tan, PS, Dong, H, Revill, K, Chang, CY, Roayaie, S, Byrne, TJ, Mazzaferro, V, Rakela, J, Florman, S, Schwartz, M & Llovet, JM 2015, 'Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation', Journal of Hepatology, vol. 63, no. 6, pp. 1368-1377. https://doi.org/10.1016/j.jhep.2015.07.025
Miltiadous, Oriana ; Sia, Daniela ; Hoshida, Yujin ; Fiel, Maria Isabel ; Harrington, Andrew N. ; Thung, Swan N. ; Tan, Poh Seng ; Dong, Hui ; Revill, Kate ; Chang, Charissa Y. ; Roayaie, Sasan ; Byrne, Thomas J. ; Mazzaferro, Vincenzo ; Rakela, Jorge ; Florman, Sander ; Schwartz, Myron ; Llovet, Josep M. / Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation. In: Journal of Hepatology. 2015 ; Vol. 63, No. 6. pp. 1368-1377.
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abstract = "Background & Aims 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 88 months, 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.",
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T1 - Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation

AU - Miltiadous, Oriana

AU - Sia, Daniela

AU - Hoshida, Yujin

AU - Fiel, Maria Isabel

AU - Harrington, Andrew N.

AU - Thung, Swan N.

AU - Tan, Poh Seng

AU - Dong, Hui

AU - Revill, Kate

AU - Chang, Charissa Y.

AU - Roayaie, Sasan

AU - Byrne, Thomas J.

AU - Mazzaferro, Vincenzo

AU - Rakela, Jorge

AU - Florman, Sander

AU - Schwartz, Myron

AU - Llovet, Josep M.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Background & Aims 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 88 months, 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.

AB - Background & Aims 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 88 months, 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.

KW - Gene expression

KW - Gene signature

KW - Prognosis

KW - Stem cell

KW - Survival

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