Pre-retrieval reperfusion decreases cancer recurrence after rat ischemic liver graft transplantation.
OBJECTIVE
Liver 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.


METHODS
HCC cells were injected into the vena porta of all recipients at the end of an orthotopic liver transplantation (OLT). Control donors were standard heart-beating, ischemic ones (ISC), underwent 10 min or 30 min inflow liver clamping prior to retrieval, and ischemic/reperfused (ISC/R) donors underwent 2h liver reperfusion after the clamping.


RESULTS
I/R lesions were confirmed in the ISC group, with the presence of endothelial and hepatocyte injury, and increased liver function tests. These lesions were in part reversed by the 2h reperfusion in the ISC/R group. HCC growth was higher in the 10 min and 30 min ISC recipients (p = 0.018 and 0.004 vs. control, as assessed by MRI difference between weeks one and two), and was prevented in the ISC/Rs (p = 0.04 and 0.01 vs. ISC). These observations were associated with a stronger pro-inflammatory cytokine profile in the ISC recipients only, and the expression of hypoxia and HCC growth-enhancer genes, including Hmox1, Hif1a and Serpine1.


CONCLUSIONS
This experiment suggests that ischemia/reperfusion lesions lead to an increased risk of post-transplant HCC recurrence and growth. This observation can be reversed by graft reperfusion prior to retrieval.
Divisions of Transplant and Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Department of Surgery, University of Pavia, Italy.
Graziano
G
Oldani
Division of Radiology, Department of Medical Imaging, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Lindsey A
LA
Crowe
Divisions of Transplant and Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Lorenzo A
LA
Orci
Divisions of Transplant and Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Florence
F
Slits
Division of Clinical Pathology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Laura
L
Rubbia-Brandt
Division of Clinical Pathology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Claudio
C
de Vito
Divisions of Transplant and Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Philippe
P
Morel
Divisions of Transplant and Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Gilles
G
Mentha
Divisions of Transplant and Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Thierry
T
Berney
Division of Radiology, Department of Medical Imaging, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Jean-Paul
JP
Vallée
Divisions of Transplant and Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Stéphanie
S
Lacotte
Divisions of Transplant and Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland. Electronic address: christian.toso@hcuge.ch.
Christian
C
Toso
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000601:surgery*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000098:blood supply*; D008113:Liver Neoplasms / Q000473:pathology / Q000601:surgery*; D016031:Liver Transplantation / Q000009:adverse effects*; D008279:Magnetic Resonance Imaging; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D051381:Rats; D011916:Rats, Inbred F344; D015424:Reperfusion; D015427:Reperfusion Injury / Q000150:complications*; D012701:Serotonin / Q000097:blood
D015850:Interleukin-6; D012701:Serotonin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat
Carcinoma; Donation after cardiac death; Extracorporeal membrane oxygenation; Hepatocellular