Reply to: “Pre-retrieval reperfusion decreases cancer recurrence after rat ischemic liver graft transplantation”
Authors: G. Oldani, S. Lacotte, L. Orci, C. Toso
Journal: Journal of Hepatology (2014)

We thank Drs Cheng and Lv [[1]Cheng J. Lv Y. Pre-retrieval reperfusion decreases cancer recurrence after rat ischemic liver graft transplantation.J Hepatol. 2014; 61: 962Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar] for their interest in our work suggesting an increased rate of hepatocellular carcinoma (HCC) recurrence/growth after transplantation of ischemic liver grafts, and the protective effect of in situ graft reperfusion prior to retrieval [[2]Oldani G. Crowe L.A. Orci L.A. Slits F. et al.Pre-retrieval reperfusion decreases cancer recurrence after rat ischemic liver graft transplantation.J Hepatol. 2014; 61: 278-285Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. Our rat transplantation model only approximates clinical reality. It used liver grafts undergoing 10 or 30 min of ischemia prior to retrieval (clamping the porta hepatis and the infra-hepatic vena cava in the donor). HCC cells were injected intra-portally, and liver HCC volumes were repeatedly assessed by magnetic resonance imaging. A two-hour donor liver reperfusion prior to retrieval was reversing the effects of ischemia/reperfusion and was associated to lower rates of post-transplant HCC growth. Normothermic extracorporeal membrane oxygenation (NECMO) is the closest clinical procedure to reproduce the studied model, as it allows restoring the perfusion of the donor organs in case of donation after cardiac death (DCD). Apart from being primed with a perfusion solution, NECMO uses the donor's own blood, with a maintained pH between 7.0 and 7.4 [[3]Fondevila C. Hessheimer A.J. Flores E. et al.Applicability and results of Maastricht type 2 donation after cardiac death liver transplantation.Am J Transplant. 2012; 12: 162-170Crossref PubMed Scopus (142) Google Scholar]. However, it is currently unknown whether NECMO can also have a protective impact on post-transplant HCC recurrence/growth, and this field deserves further assessment. Similarly, ex situ machine perfusion, either normothermic, hypothermic or sub-normothermic has confirmed protective effects on liver ischemia/reperfusion lesions, but its impact on cancer has never been tested [4Izamis M.L. Tolboom H. Uygun B. Berthiaume F. Yarmush M.L. Uygun K. Resuscitation of ischemic donor livers with normothermic machine perfusion: a metabolic flux analysis of treatment in rats.PLoS One. 2013; 8: e69758Crossref PubMed Scopus (23) Google Scholar, 5Bruinsma B.G. Berendsen T.A. Izamis M.L. Yarmush M.L. Uygun K. Determination and extension of the limits to static cold storage using subnormothermic machine perfusion.Int J Artif Organs. 2013; 36: 775-780Crossref PubMed Scopus (33) Google Scholar, 6Schlegel A. Graf R. Clavien P.A. Dutkowski P. Hypothermic oxygenated perfusion (HOPE) protects from biliary injury in a rodent model of DCD liver transplantation.J Hepatol. 2013; 59: 984-991Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 7Bruinsma B.G. Yeh H. Ozer S. et al.Subnormothermic machine perfusion for ex vivo preservation and recovery of the human liver for transplantation.Am J Transplant. 2014; 14: 1400-1409Crossref PubMed Scopus (139) Google Scholar, 8Dutkowski P. Schlegel A. de Oliveira M. Mullhaupt B. Neff F. Clavien P.A. HOPE for human liver grafts obtained from donors after cardiac death.J Hepatol. 2014; 60: 765-772Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar]. The minimal required time of liver graft reperfusion for preventing HCC growth is currently unknown. The used two-hour reperfusion matches international reports with NECMO or ex situ machine perfusion ranging between one and four hours [3Fondevila C. Hessheimer A.J. Flores E. et al.Applicability and results of Maastricht type 2 donation after cardiac death liver transplantation.Am J Transplant. 2012; 12: 162-170Crossref PubMed Scopus (142) Google Scholar, 7Bruinsma B.G. Yeh H. Ozer S. et al.Subnormothermic machine perfusion for ex vivo preservation and recovery of the human liver for transplantation.Am J Transplant. 2014; 14: 1400-1409Crossref PubMed Scopus (139) Google Scholar, 8Dutkowski P. Schlegel A. de Oliveira M. Mullhaupt B. Neff F. Clavien P.A. HOPE for human liver grafts obtained from donors after cardiac death.J Hepatol. 2014; 60: 765-772Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar]. It is also in agreement with the need for a minimal two-hour graft normothermic machine reperfusion in order to restore the function of ischemic rat livers [[4]Izamis M.L. Tolboom H. Uygun B. Berthiaume F. Yarmush M.L. Uygun K. Resuscitation of ischemic donor livers with normothermic machine perfusion: a metabolic flux analysis of treatment in rats.PLoS One. 2013; 8: e69758Crossref PubMed Scopus (23) Google Scholar]. Overall, ischemia/reperfusion may be an added factor altering post-transplant cancer recurrence. This link is likely weaker than the one between pre-transplant HCC characteristics and recurrence, but it deserves further exploration both to better understand the underlying mechanisms and the ways to prevent it. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Pre-retrieval reperfusion decreases cancer recurrence after rat ischemic liver graft transplantationJournal of HepatologyVol. 61Issue 2PreviewLiver transplantation from marginal donors is associated with ischemia/reperfusion (I/R) lesions, which may increase the risk of post-transplant hepatocellular carcinoma (HCC) recurrence. Graft reperfusion prior to retrieval (as for extracorporeal membrane oxygenation – ECMO) can prevent I/R lesions. The impact of I/R on the risk of cancer recurrence was assessed on a syngeneic Fischer-rat liver transplantation model. Full-Text PDF Open AccessPre-retrieval reperfusion decreases cancer recurrence after rat ischemic liver graft transplantationJournal of HepatologyVol. 61Issue 4PreviewWe read with great interest the article "Pre-retrieval reperfusion decreases cancer recurrence after rat ischemic liver graft transplantation" [1]. This elegant study assessed the impact of ischemic liver graft on the risk of cancer recurrence utilizing a rat liver transplantation model. Oldani et al. [1] demonstrated that ischemia/reperfusion lesions lead to an increased risk of post-transplant hepatocellular carcinoma (HCC) recurrence and growth, which can be reversed by graft reperfusion prior to retrieval. Full-Text PDF Open Access