Digestive Diseases and Sciences

, Volume 60, Issue 9, pp 2832–2839 | Cite as

Extended Ischemia Times Promote Risk of HCC Recurrence in Liver Transplant Patients

  • Arno Kornberg
  • Ulrike Witt
  • Jennifer Kornberg
  • Helmut Friess
  • Katharina Thrum
Original Article



There is increasing evidence that ischemia–reperfusion injury (IRI) promotes vasculogenesis and tumor outgrowth in the liver. Hepatic IRI is exaggerated by prolongation of ischemia times.


The aim of this retrospective analysis was to assess the impact of ischemia times on risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). Subgroup analysis focused on patients with 18F-fluoro-deoxy-glucose (18F-FDG)-avid HCC on pretransplant positron emission tomography (PET).


A total of 103 liver transplant patients with HCC were included in this study. The impact of cold (CIT), warm (WIT), and total ischemia times (TIT) along with other prognostic variables on posttransplant outcome was analyzed in uni- and multivariate analysis.


Twenty-four patients (23.3 %) developed tumor relapse after LT. Mean durations of CIT (468.0 vs. 375.5 min; P = 0.001), WIT (58.4 vs. 45.7 min; P = 0.001), and TIT (525.8 vs. 422.0 min; P < 0.001) were significantly longer in patients with compared to those without HCC recurrence. In multivariate regression analysis, 18F-FDG-avid HCC (odds ratio [OR] 73.4), WIT >50 min (OR 52.5), alpha-fetoprotein level >400 IU/ml (OR 11.1), and Milan Out status (OR 7.4) were identified as independent predictors of HCC recurrence. In the subgroup of patients with PET-positive HCC, WIT remained the only independent variable to predict HCC recurrence (OR 15.5).


Prolongation of ischemia times promotes the risk of HCC recurrence after LT, especially in patients with unfavorable tumor biology on PET imaging.


Liver transplantation Hepatocellular carcinoma Ischemia–reperfusion injury PET Ischemia time Cold ischemia time Warm ischemia time 



Ischemia–reperfusion injury


Hepatocellular carcinoma


Liver transplantation




Positron emission tomography


Cold ischemia time


Warm ischemia time


Total ischemia time


Computed tomography


Magnetic resonance imaging




Hazard ratio


Model for end-stage liver disease


Transarterial chemoembolization


Cyclosporine A






Mycophenolate mofetil


Donor risk index


Operation time


Estimated blood loss


Red blood cell


Microvascular invasion


Lymphovascular invasion


Standard deviation


Circulating tumor cell(s)


Donor after cardiac death


Donor after brain death


Aspartate aminotransferase



The authors have no financial support to declare.

Conflict of interest

The authors have no conflicts of interest to declare.


  1. 1.
    Mazzaferro V, Bhoori S, Sposito C, et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transplant. 2011;17:44–57.CrossRefGoogle Scholar
  2. 2.
    Ishizaki Y, Kawasaki S. The evolution of liver transplantation for hepatocellular carcinoma (past, present, and future). J Gastroenterol. 2008;43:18–26.CrossRefPubMedGoogle Scholar
  3. 3.
    Koschny R, Schmidt J, Ganten TM. Beyond Milan criteria–chances and risks of expanding transplantation criteria for HCC patients with liver cirrhosis. Clin Transplant. 2009;23:49–60.CrossRefPubMedGoogle Scholar
  4. 4.
    Cheah YL, Chow P. Liver transplantation for hepatocellular carcinoma: an appraisal of current controversies. Liver Cancer. 2012;1:183–189.CrossRefGoogle Scholar
  5. 5.
    Kornberg A. Liver transplantation for hepatocellular carcinoma beyond Milan criteria: multidisciplinary approach to improve outcome. ISRN Hepatology 2014, Article ID 706945.Google Scholar
  6. 6.
    Kornberg A, Freesmeyer M, Bärthel E, et al. 18F-FDG-uptake of hepatocellular carcinoma on PET predicts microvascular tumor invasion in liver transplant patients. Am J Transplant. 2009;9:592–600.CrossRefPubMedGoogle Scholar
  7. 7.
    Lee JW, Paeng JC, Kang KW, et al. Prediction of tumor recurrence by 18F-FDG PET in liver transplantation for hepatocellular carcinoma. J Nucl Med. 2009;50:682–687.CrossRefPubMedGoogle Scholar
  8. 8.
    Lee SD, Kim SH, Kim YK, et al. (18)F-FDG-PET/CT predicts early tumor recurrence in living donor liver transplantation for hepatocellular carcinoma. Transpl Int. 2013;26:50–60.CrossRefPubMedGoogle Scholar
  9. 9.
    Cho Y, Lee DH, Lee YB, et al. Does 18F-FDG positron emission tomography-computed tomography have a role in initial staging of hepatocellular carcinoma? PLoS ONE. 2014;9:e105679.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Zhang J, Shi ZL, Yang X, Yin ZF. Targeting of circulating hepatocellular carcinoma cells to prevent postoperative recurrence and metastasis. World J Gastroenterol. 2014;20:142–147.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Toso C, Mentha G, Majno P. Liver transplantation for hepatocellular carcinoma: five steps to prevent recurrence. Am J Transplant. 2011;11:2031–2035.CrossRefPubMedGoogle Scholar
  12. 12.
    van der Bilt JD, Kranenburg O, Nijkamp MW, et al. Ischemia/reperfusion accelerates the outgrowth of hepatic micrometastases in a highly standardized murine model. Hepatology. 2005;42:165–175.CrossRefPubMedGoogle Scholar
  13. 13.
    van der Bilt JD, Kranenburg O, Borren A, van Hillegersberg R, Borel RIH. Ageing and hepatic steatosis exacerbate ischemia/reperfusion-accelerated outgrowth of colorectal micrometastases. Ann Surg Oncol. 2008;15:1392–1398.CrossRefPubMedGoogle Scholar
  14. 14.
    Tsuchiya Y, Sawada S, Yoshioka I, et al. Increased surgical stress promotes tumor metastasis. Surgery. 2003;133:547–555.CrossRefPubMedGoogle Scholar
  15. 15.
    Teoh NC. Hepatic ischemia reperfusion injury: contemporary perspectives on pathogenic mechanisms and basis for hepatoprotection—the good, bad and deadly. J Gastroenterol Hepatol. 2011;26:180–187.CrossRefPubMedGoogle Scholar
  16. 16.
    Roayaie K, Feng S. Allocation policy for hepatocellular carcinoma in the MELD era: room for improvement? Liver Transplant. 2007;13:36–43.CrossRefGoogle Scholar
  17. 17.
    Kornberg A, Küpper B, Tannapfel A, et al. Patients with non-[18 F]fludeoxyglucose-avid advanced hepatocellular carcinoma on clinical staging may achieve long-term recurrence-free survival after liver transplantation. Liver Transplant. 2012;18:53–61.CrossRefGoogle Scholar
  18. 18.
    Parrilla P, Sanchez-Bueno F, Figueras J, et al. Analysis of the complications of the piggy-back technique in 1112 liver transplants. Transplantation. 1999;31:2388–2389.Google Scholar
  19. 19.
    Ijtsma AJ, van der Hilst CS, de Boer MT, et al. The clinical relevance of the anhepatic phase during liver transplantation. Liver Transplant. 2009;15:1050–1055.CrossRefGoogle Scholar
  20. 20.
    Klune JR, Tsung A. Molecular biology of liver ischemia/reperfusion injury: established mechanisms and recent advancements. Surg Clin N Am. 2010;90:665–677.CrossRefPubMedGoogle Scholar
  21. 21.
    Zhai Y, Petrowsky H, Hong JC, Busuttil RW, Kupiec-Weglinski JW. Ischemia-reperfusion injury in liver transplantation—from bench to bedside. Nat Rev Gastroenterol Hepatol. 2013;10:79–89.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Lim C, Broqueres-You D, Brouland JP, et al. Hepatic ischemia-reperfusion increases circulating bone-marrow-derived progenitor cells and tumor growth in a mouse model of colorectal liver metastases. J Surg Res. 2013;184:888–897.CrossRefPubMedGoogle Scholar
  23. 23.
    Doi K, Horiuchi T, Uchinami M, et al. Hepatic ischemia-reperfusion injury promotes liver metastasis of colon cancer. J Surg Res. 2002;105:243–247.CrossRefPubMedGoogle Scholar
  24. 24.
    Shih KC, Man K. Small-for-size liver graft injury—impact on tumor behaviour. Transplant Rev. 2010;24:1–10.CrossRefGoogle Scholar
  25. 25.
    Oldani G, Crowe LA, Orci LA, et al. Pre-retrieval reperfusion decreases cancer recurrence after rat ischemic liver graft transplantation. J Hepatol. 2014;61:278–285.CrossRefPubMedGoogle Scholar
  26. 26.
    Xia F, Lau WY, Xu Y, Wu L, Qian C, Bie P. Does hepatic ischemia–reperfusion injury induced by hepatic pedicle clamping affect survival after partial hepatectomy for hepatocellular carcinoma? World J Surg. 2013;37:192–201.CrossRefPubMedGoogle Scholar
  27. 27.
    Giuliante F, Ardito F, Pulitano C, et al. Does hepatic pedicle camping affect disease-free survival following liver resection for colorectal metastases? Ann Surg. 2010;252:1020–1026.CrossRefPubMedGoogle Scholar
  28. 28.
    Lo CM, Fan ST, Liu CL, Chan SC, Ng IO, Wong J. Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. Br J Surg. 2007;94:78–86.CrossRefPubMedGoogle Scholar
  29. 29.
    Fisher RA, Kulik LM, Freise CE, et al. Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation. Am J Transplant. 2007;7:1601–1608.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Ling C, Ng KTP, Shao Y, et al. Posttransplant endothelial progenitor cell mobilization via CXCL10/CXCR3 signaling promotes liver tumor growth. J Hepatol. 2014;60:103–109.CrossRefPubMedGoogle Scholar
  31. 31.
    Liang W, Wu L, Ling X, et al. Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl. 2012;18:1226–1236.CrossRefPubMedGoogle Scholar
  32. 32.
    Monbaliu D, Pirenne J, Talbot D. Liver transplantation using Donation after Cardiac Death donors. J Hepatol. 2012;56:474–485.CrossRefPubMedGoogle Scholar
  33. 33.
    Croome KP, Wall W, Chandok N, Beck G, Marotta P, Hernandez-Alejandro R. Inferior survival in liver transplant recipients with hepatocellular carcinoma receiving donation after cardiac death liver allografts. Liver Transpl. 2013;19:1214–1223.CrossRefPubMedGoogle Scholar
  34. 34.
    Nagai S, Yoshida A, Facciuto M, et al. Ischemia time impacts recurrence of hepatocellular carcinoma following liver transplantation. Hepatology. 2014. doi: 10.1002/hep.27358.PubMedGoogle Scholar
  35. 35.
    Xu W, Cao L, Chen L, et al. Isolation of circulating tumor cells in patients with hepatocellular carcinoma using a novel cell separation strategy. Clin Cancer Res. 2011;17:3783–3793.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Arno Kornberg
    • 1
  • Ulrike Witt
    • 1
  • Jennifer Kornberg
    • 2
  • Helmut Friess
    • 1
  • Katharina Thrum
    • 3
  1. 1.Department of Surgery, Klinikum rechts der IsarTechnical University MunichMunichGermany
  2. 2.Department of Anaesthesiology, Klinikum GroßhadernLMU MunichMunichGermany
  3. 3.Institute of PathologyHelios Klinikum BerlinBerlinGermany

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