Francesco D'Amico

Intention-to-treat analysis of liver transplantation in selected, aggressively treated HCC patients exceeding the Milan criteria.

This prospective study analyzed the dropout probability and intention‐to‐treat survival rates of patients with hepatocellular carcinoma (HCC) selected and treated according to our policy before liver transplantation (LT), with particular attention to those exceeding the Milan criteria. Exclusion criteria for LT were macroscopic vascular invasion, metastases, and poorly differentiated disease at percutaneous biopsy. A specific multi‐modal adjuvant algorithm was used to treat HCC before LT. A total of 100 HCC patients were listed for LT: 40 exceeded the Milan criteria in terms of nodule size and number (MILAN OUT) either at listing or in list, while 60 patients continued to meet the criteria (MILAN IN). The Milan criteria did not prove to be a significant predictor of dropout probability or survival rates using Coxs analysis. Cumulative dropout probability at 6 and 12 months was 0% and 4% for MILAN OUT, and 6% and 11% for MILAN IN. The intention‐to‐treat survival rates at 1 and 3 years were 95% and 85% in MILAN OUT, and 84% and 69% in MILAN IN. None of the 68 transplanted patients had recurrent HCC after a median 16‐month follow‐up (0–69 months). In conclusion, LT may be effective for selected, aggressively‐treated HCC patients exceeding the Milan criteria.

Use of N‐acetylcysteine during liver procurement: A prospective randomized controlled study

Antioxidant agents have the potential to reduce ischemia/reperfusion damage to organs for liver transplantation (LT). In this prospective, randomized study, we tested the impact of an infusion of N‐acetylcysteine (NAC) during liver procurement on post‐LT outcomes. Between December 2006 and July 2009, 140 grafts were transplanted into adult candidates with chronic liver disease who were listed for first LT, and according to a sequential, closed‐envelope, single‐blinded procedure, these patients were randomly assigned in a 1/1 ratio to an NAC protocol (69 patients) or to the standard protocol without NAC [71 patients (the control group)]. The NAC protocol included a systemic NAC infusion (30 mg/kg) 1 hour before the beginning of liver procurement and a locoregional NAC infusion (300 mg through the portal vein) just before cross‐clamping. The primary endpoint was graft survival. The graft survival rates at 3 and 12 months were 93% and 90%, respectively, in the NAC group and 82% and 70%, respectively, in the control group (P = 0.02). An adjusted Cox analysis showed a significant NAC effect on graft survival at both 3 months [hazard ratio = 1.65, 95% confidence interval (CI) = 1.01‐2.93, P = 0.04] and 12 months (hazard ratio = 1.73, 95% CI = 1.14‐2.76, P ≤ 0.01). The incidence of postoperative complications was lower in the NAC group (23%) versus the control group (51%, P < 0.01). In the subgroup of 61 patients (44%) receiving suboptimal grafts (donor risk index > 1.8), the incidence of primary dysfunction of the liver was lower (P = 0.09) for the NAC group (15%) versus the control group (32%). In conclusion, the NAC harvesting protocol significantly improves graft survival. The effect of NAC on early graft function and survival seems higher when suboptimal grafts are used. Liver Transpl 19:135–144, 2013.

Liver transplantation using suboptimal grafts: Impact of donor harvesting technique

In recent years, an increasing number of suboptimal grafts has been used to reduce the gap between the supply and demand of organs for liver transplantation (LT). In this randomized prospective study, we tested the impact of donor harvesting technique on the posttransplantation outcome of suboptimal donor livers. A modified double perfusion (MDP) technique (aortic and portal cooling with tourniquet clamping of splenomesenteric vein inflow) was compared with the single aortic perfusion (SAP) technique. Between February and November 2005, 35 suboptimal grafts were randomly assigned to either technique (18 MDP livers and 17 SAP livers). Donor and recipient variables were comparable in the 2 study groups. The SAP group had significantly higher blood transaminases and bilirubin levels after LT. The prevalence of graft primary dysfunction (PDF) was also significantly higher (P = 0.01) in the SAP group (35%) than in the MDP group (5%). In 5 cases, all in the SAP group (P = 0.02), early re‐LT (<30 days) was needed. The 6‐month patient and graft survival rates were significantly higher in the MDP (100% in both cases) than in the SAP group (68% and 58%, respectively). The study was stopped in November 2005, when the interim analysis revealed such markedly significant differences between the two groups. In conclusion, the present study showed a very low prevalence of PDF, death, and re‐LT after transplantation with suboptimal liver when a MDP technique was used to harvest the donor graft. Liver Transpl 13:1444–1450, 2007.

Laparoscopic Ablation of Hepatocellular Carcinoma in Cirrhotic Patients Unsuitable for Liver Resection or Percutaneous Treatment: A Cohort Study

The aim of this study was to demonstrate the safety and efficacy of laparoscopic ablation for cirrhotic HCC patients. Between January 2004 and December 2009, laparoscopic ablation was applied prospectively in 169 consecutive HCC patients (median age 62 years, 43% hepatitis C positive) considered ineligible for liver resection and/or percutaneous ablation. There was clinically relevant portal hypertension in 72% of cases. A significant proportion of subjects (50%) had multinodular tumors or nodules larger than 25 mm. The main ablation techniques used were radiofrequency in 103 patients (61%), microwave ablation in 8 (5%), and ethanol injection in 58 (34%). The primary endpoint was 3-year survival. There was no perioperative mortality. The overall morbidity rate was 25%. The median postoperative hospital stay was 3 days (range 1–19 days). Patients survived a median 33 months with a 3-year survival rate of 47%. Coxs multivariate analysis identified patient age, presence of diabetes, albumin ≤37 g/l, and alpha-fetoprotein >400 µg/l as significant preoperative predictors of survival, while the chance to undergo liver transplantation and postoperative ascites were the only independent postoperative predictor of survival. Laparoscopic ablation is a safe and effective therapeutic option for selected HCC patients ineligible for liver resection and/or percutaneous ablation.

Laparoscopic microwave thermal ablation for late recurrence of local hepatocellular carcinoma after liver transplant: case report

Liver transplant is the preferred treatment for hepatocellular carcinoma in patients with cirrhosis, as both neoplastic and cirrhotic liver tissue can be removed. Treatment of recurring neoplasms is a difficult issue, especially in long-term survivors of liver transplant. No consensus has been reached on the treatment of recurrent hepatocellular carcinoma. Although patients with extrahepatic metastases are generally not candidates for local therapy, successful multimodal salvage therapy including resection or ablation can be achieved in liver transplant recipients with local recurrence of hepatocellular carcinoma. Microwave ablation is safe and effective for treating unresectable hepatocellular carcinoma, achieving excellent results in local disease down-staging or as a “bridge” to liver transplant, with no significant differences in local recurrence and complications compared with the more commonly used radiofrequency ablation. A patient with local recurrence of hepatocellular carcinoma 36 months after liver transplant for multifocal hepatocellular carcinoma and cirrhosis due to hepatitis C was successfully treated with laparoscopic microwave ablation without any postoperative complications. The patient is disease free 24 months after microwave ablation.

Syngeneic living-donor liver transplantation for hemangioendothelioma: a clinical model for studying liver regeneration.

A 22‐year‐old Caucasian patient underwent living‐donor liver transplantation (LDLT) for hepatic hemangioendothelioma in a healthy liver. The organ donor was his monozygotic twin brother. Surgery was uneventful in both donor and recipient, who received the same postoperative treatment (i.e. no immunosuppression for the recipient). Although both donor and recipient achieved a full liver function recovery, the volume of the recipients graft increased much more than the donors residual liver in the first postoperative month (1.6‐fold vs. 1.2‐fold). This different growth rate correlated with growth hormone (GH)/insulin growth factor (IGF) axis dynamics: the donor had significantly lower insulin‐like growth factor 1 (IGF‐1), insulin‐like growth factor 2 (IGF‐2) and insulin‐like growth factor binding protein 3 (IGFBP‐3) values than the recipient on postoperative days (POD) 3–30, although they had similar GH values. Other potential regenerative factors, e.g. tumor necrosis α, interleukin 6 (IL‐6), insulin and C peptide did not correlate with liver regeneration rate. The particular endocrine picture of the graft may be explained by a modified GH‐hepatocyte interaction due to cold ischemia during preservation resulting in a higher IGF production. Whether this is a potential molecular tool by means of which transplanted partial livers promote their regeneration remains to be seen in a larger number of patients.

Modulation of Intestinal Microbiome Prevents Intestinal Ischemic Injury

Background: Butyrate protects against ischemic injury to the small intestine by reducing inflammation and maintaining the structure of the intestinal barrier, but is expensive, short-lived, and cannot be administered easily due to its odor. Lactate, both economical and more palatable, can be converted into butyrate by the intestinal microbiome. This study aimed to assess in a rat model whether lactate perfusion can also protect against intestinal ischemia. Materials and Methods: Rat intestinal segments were loaded in an in vitro bowel perfusion device, and water absorption or secretion was assessed based on fluorescence of FITC-inulin, a fluorescent marker bound to a biologically inert sugar. Change in FITC concentration was used as a measure of ischemic injury, given the tendency of ischemic cells to retain water. Hematoxylin and eosin-stained sections at light level microscopy were examined to evaluate intestinal epithelium morphology. Comparisons between the data sets were paired Student t-tests or ANOVA with p < 0.05 performed on GraphPad. Results: Lactate administration resulted in a protective effect against intestinal ischemia of similar magnitude to that observed with butyrate. Both exhibited approximately 1.5 times the secretion exhibited by control sections (p = 0.03). Perfusion with lactate and methoxyacetate, a specific inhibitor of lactate-butyrate conversion, abolished this effect (p = 0.09). Antibiotic treatment also eliminated this effect, rendering lactate-perfused sections similar to control sections (p = 0.72). Perfusion with butyrate and methoxyacetate did not eliminate the observed increased secretion, which indicates that ischemic protection was mediated by microbial conversion of lactate to butyrate (p = 0.71). Conclusions: Lactates protective effect against intestinal ischemia due to microbial conversion to butyrate suggests possible applications in the transplant setting for reducing ischemic injury and ameliorating intestinal preservation during transport.

Reply: The easiest way to improve the outcome of suboptimal liver grafts

the harvesting technique showed a relevant prognosticimpact on post-LT outcome when suboptimal liverswere used. Observations from Jeon and Ranjan, how-ever, give us the opportunity to further consider ourresults:1. Transaminase levels on the seventh postoperative dayin the single aortic perfusion (SAP) group were onlyminimally influenced by the high incidence of earlygraft losses in this group. In fact, 3 patients havingprimarydysfunction(PDF)diedwithinthefirstpost-LTweek, whereas 2 other patients were successfully re-transplantedforPDF.Thus,patientsintheSAPgroup,who were alive on the seventh postoperative day, hadtransaminase levels similar to those of patients in themodified double perfusion (MDP) group.2. The study by de Ville de Goyet et al.