Luciano De Carlis

Predictors of Long-Term Survival After Liver Transplantation for Hepatocellular Carcinoma

AIMS:The aim of this study was to identify predictors of both survival and tumor-free survival of a cohort of 155 patients, with hepatocellular carcinoma (HCC) and cirrhosis, who were treated by orthotopic liver transplantation (OLT).METHODS:From January 1989 to December 2002, 603 OLTs were performed in 549 patients. HCC was diagnosed in 116 patients before OLT and in 39 at histological examination of the explanted livers. Eighty-four percent of the patients met “Milan” criteria at histology. Ninety-four patients received anticancer therapies preoperatively.RESULTS:The median follow-up was 49 months (range, 0–178). Overall, 1-, 3-, 5-, and 10-yr survival were 84%, 75%, 72%, and 62%, respectively. Survival was not affected by the patients age or sex, etiology of liver disease, Child score at transplantation, rejection episodes, tumor number, total tumor burden, bilobar tumor, and pathologic Tumor, Nodes, Metastasis (pTNM) stages. There was no statistically significant difference in survival when patients were grouped according to the recently proposed simplified pTNM staging (5-yr survival, 80% in stage I, 69% in stage II, 50% in stage III, p = 0.3) or the United Network for Organ Sharing (UNOS) staging system for HCC. Encapsulation of the tumor and α-fetoprotein levels significantly affect patient survival. Five-year survival of patients with poorly differentiated (G3) HCC was significantly worse than that of patients with moderately (G2) or well-differentiated (G1) HCC (respectively, G3 44%, G2 67%, and G1 97%, p = 0.0015). Patients with micro- or macro-vascular invasion had a worse 5-yr survival than patients without vascular invasion (49% vs 77%, p = 0.04). Multivariate analysis showed that histological grade of differentiation and macroscopic vascular invasion are independent predictors of survival (HR 2.4, 95% CI 1.4–4.1, p = 0.0009 and HR 2.8, 95% CI 1.2–6.8, p = 0.022).CONCLUSION:Histological grade of differentiation and macroscopic vascular invasion, as assessed on the explanted livers, are strong predictors of both survival and tumor recurrence in patients with cirrhosis who received transplants for HCC.

Liver transplantation for HCV cirrhosis: Improved survival in recent years and increased severity of recurrent disease in female recipients: Results of a long term retrospective study

In recent years, a worsening outcome of hepatitis C virus (HCV)‐positive recipients and a faster progression of recurrent disease to overt cirrhosis has been reported. Our aims were to 1) assess patient survival and development of severe recurrent disease (Ishak fibrosis score > 3) in different transplant years; and 2) model the effects of pre‐ and post‐liver transplantation (LT) variables on the severity of recurrent disease. A multicenter retrospective analysis was conducted on 502 consecutive HCV‐positive transplant recipients between January 1990 and December 2002. Protocol liver biopsies were obtained at 1, 3, 5, 7, and 10 yr post‐LT in almost 90% of the patients. All 502 patients were included in the overall survival analysis, while only the 354 patients with a follow‐up longer than 1 yr were considered for the analysis of predictors of disease progression. The overall Kaplan–Meier survival rates were 78.7%, 66.3%, and 58.6%, at 12, 60, and 120 months, respectively, and a trend for a better patient survival over the years emerged from all 3 centers. The cumulative probability of developing HCV‐related recurrent severe fibrosis (Ishak score 4‐6) in the cohort of 354 patients who survived at least 1 yr remained unchanged over the years. Multivariate analysis indicated that older donors (P = 0.0001) and female gender of recipient (P = 0.02) were the 2 major risk factors for the development of severe recurrent disease, while the adoption of antilymphocytic preparations was associated with a less aggressive course (P = 0.03). Two of these prognostic factors, donor age and recipient gender, are easily available before LT and their combination showed an important synergy, such that a female recipient not only had a much higher probability of severe recurrent disease than a male recipient but her risk increased with the increasing age of the donor, reaching almost 100% when the age of the donor was 60 or older. In conclusion, a trend for a better patient survival was observed in more recent years but the cumulative probability of developing severe recurrent disease remained unchanged. The combination of a female recipient receiving an older graft emerged as a strong risk factor for a severe recurrence. Liver Transpl, 2007.

Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: a prospective, randomized, multicenter trial.

Calcineurin inhibitors (CNIs) contribute to renal dysfunction following liver transplantation. This prospective, randomized, multicenter, 6‐month study (with an additional 6 months of follow‐up) evaluated whether everolimus with CNI reduction or discontinuation would improve renal function in maintenance liver transplant recipients experiencing CNI‐related renal impairment. Patients started everolimus therapy with CNI reduction or discontinuation (n = 72) or continued receiving standard‐exposure CNI (n = 73). At month 6, 80% of the patients who had converted to everolimus had discontinued the CNI. The mean change in creatinine clearance (CrCl) from baseline to month 6 was similar between groups (everolimus, 1.0 ± 10.2 mL/minute; controls, 2.3 ± 7.8 mL/minute; P = 0.46), so the primary study endpoint (8 mL/minute difference in the change in CrCl) was not achieved. Among patients who continued everolimus according to the protocol, the mean increase in CrCl was 2.1 (n = 53) and 3.8 mL/minute (n = 38) at months 6 and 12, respectively, versus 2.4 (n = 68) and 3.5 mL/minute in controls (n = 51). The high frequency of CNI dose reductions in controls (77% of the patients) and the relatively long mean time post‐transplant (>3 years) likely contributed to the small difference in CrCl. Biopsy‐proven acute rejection occurred in 1.4% of the patients in each group, with no graft losses. Study drug discontinuation was higher in everolimus‐treated patients, and adverse events were more frequent. These data demonstrate that everolimus allows for discontinuation or a major reduction of CNI exposure in liver allograft recipients suffering CNI‐related renal dysfunction without a loss of efficacy. Trials targeting earlier conversion post‐transplantation are required to confirm the efficacy and safety of everolimus for improving renal function after liver transplantation. Liver Transpl 15:1262–1269, 2009.

Surgical treatment of hepatocellular cancer in the era of hepatic transplantation

BACKGROUND This study compares liver resection (LR) or transplantation (LTx) in an attempt to reevaluate the indications for treatment. STUDY DESIGN One hundred fifty-four LRs and 121 LTxs performed from 1985 to 1999 were considered. Survival and recurrence rate, together with age, gender, liver disease, Child-Pugh classification, alpha-fetoprotein (AFP), tumor capsule, vascular invasion, size, number of nodules, histologic grade, and pTNM were considered. Followup was completed in all cases (mean +/- SD = 3.2 +/- 2.9 years). RESULTS The 5- and 10-year actuarial survival rates were 61.7% and 59.8% in LTx and 46.9% and 28.0% in LR (p = 0.08). Recurrence-free survival was 85.9% and 85.9%, respectively, in LTx and 42.8% and 30.7% in LR (p < 0.0001). In both groups, size, capsule, AFP, vascular invasion, grade, pTNM, Child-Pugh classification, and age were all significantly related to survival and cancer recurrence. pTNM, AFP, Child-Pugh classification, and age, in LR, and capsule, AFP, and viral cirrhosis, in LTx, were significant independent variables in Coxs regression model for survival. Only AFP, vascular invasion, and grade were significant in both groups for recurrence. CONCLUSIONS LTx offers better recurrence freedom than LR, but longterm survival is not significantly different in the two series. A strict selection should be made to optimize graft allocation. Size and multifocality should not be considered absolute contraindications for LTx. AFP, vascular invasion, and grade are more likely to reflect the risk of recurrence of the disease. LR should be considered in patients who do not fulfill transplant criteria and also in some categories of patients with certain tumor characteristics (small resectable tumors in well-compensated cirrhosis).

Liver Match, a prospective observational cohort study on liver transplantation in Italy: Study design and current practice of donor-recipient matching

BACKGROUND The Liver Match is an observational cohort study that prospectively enrolled liver transplantations performed at 20 out of 21 Italian Transplant Centres between June 2007 and May 2009. Aim of the study is to investigate the impact of donor/recipient matching on outcomes. In this report we describe the study methodology and provide a cross-sectional description of donor and recipient characteristics and of graft allocation. METHODS Adult primary transplants performed with deceased heart-beating donors were included. Relevant information on donors and recipients, organ procurement and allocation were prospectively entered in an ad hoc database within the National Transplant Centre web-based Network. Data were blindly analysed by an independent Biostatistical Board. RESULTS The study enrolled 1530 donor/recipient matches. Median donor age was 56 years. Female donors (n = 681, median 58, range 12-92 years) were older than males (n = 849, median 53, range 2-97 years, p < 0.0001). Donors older than 60 years were 42.2%, including 4.2% octogenarians. Brain death was due to non-traumatic causes in 1126 (73.6%) cases. Half of the donor population was overweight, 10.1% was obese and 7.6% diabetic. Hepatitis B core antibody (HBcAb) was present in 245 (16.0%) donors. The median Donor Risk Index (DRI) was 1.57 (>1.7 in 35.8%). The median cold ischaemia time was 7.3h (≥ 10 in 10.6%). Median age of recipients was 54 years, and 77.7% were males. Hepatocellular carcinoma (HCC) was the most frequent indication overall (44.4%), being a coindication in roughly 1/3 of cases, followed by viral cirrhosis without HCC (28.2%) and alcoholic cirrhosis without HCC (10.2%). Hepatitis C virus infection (with or without HCC) was the most frequent etiologic factor (45.9% of the whole population and 71.4% of viral-related cirrhosis), yet hepatitis B virus infection accounted for 28.6% of viral-related cirrhosis, and HBcAb positivity was found in 49.7% of recipients. The median Model for End Stage Liver Disease (MELD) at transplant was 12 in patients with HCC and 18 in those without. Multivariate analysis showed a slight but significant inverse association between DRI and MELD at transplant. CONCLUSIONS The deceased donor population in Italy has a high-risk profile compared to other countries, mainly due to older donor age. Almost half of the grafts are transplanted in recipients with HCC. Higher risk donors tend to be preferentially allocated to recipients with HCC, who are usually less ill and older. No other relevant allocation strategy is currently adopted at national level.

A comparative prospective study of two available solutions for kidney and liver preservation

Background. Viaspan (University of Wisconsin [UW]) solution is the gold standard for abdominal organ preservation. Celsior (CEL) is an extracellular-type, low-potassium, low-viscosity solution, initially used for heart and lung preservation. We have performed a prospective multicenter study to compare the role of these cold-storage solutions on kidney and liver recovery after transplantation. Patients and Methods. From March 15, 2000 to December 31, 2001, 441 (172 CEL and 269 UW) renal transplants (RT) and 175 (79 CEL and 96 UW) liver transplants (LT) were included in the study. Results. Perfusate volume used was significantly lower in the UW group, being 4,732±796 mL versus 5,826±834 mL in the CEL group (P <0.001). In LT, median total bilirubin serum levels were significantly higher at 5 and 7 posttransplant days in the UW group (90.6 and 92.3 μmol/L, respectively) as compared with CEL (51.3 and 63.4 μmol/L, respectively). After LT, primary nonfunction (PNF) rates in the CEL and UW groups were 3.8% and 4.2% (P =NS) respectively, with 1-year graft and patient survival being 83.3% versus 85.4% (P =NS) and 89.9% versus 90.6% (P =NS). After RT, delayed graft function (DGF) rates were 23.2% and 22.7% (P =NS), respectively; PNF rates were 1.9% and 1.7% (P =NS) respectively, with 1-year graft and patient survival being 92.3% versus 94.2% (P =NS) and 99.4% versus 97.7% (P =NS). Conclusions. CEL solution was shown to be as effective as UW in both liver and kidney preservation. In LT patients, biliary function recovery is significantly better in the CEL group. CEL solution represents an efficacious option in multiorgan harvesting.

The role of spontaneous portosystemic shunts in the course of orthotopic liver transplantation

Abstract. Spontaneous portosystemic shunts are commonly found in cirrhotic patients. Not yet established is their role after orthotopic liver transplantation (OLTx), especially when an increase in portal pressure develops, as during early acute rejection. In this study, 34 cirrhotic patients in a series of 70 OLTx are considered. Each patient had preoperative angiographic assessment, and, in 21 (62 %), large spontaneous portosystemic shunts were evident. In 12 cases the shunts were not affected by the surgical procedure and were present during the postoperative period; in 9 the hepatectomy itself involved interruption of the shunts. The patient population was divided into two groups: patients with postoperative shunts (n = 12) and those without (n= 22). The two groups were similar in age, sex. Childs stage, transplantation variables, and number and grade of rejection episodes. However, mean transaminases (AST) values in the first 2 weeks were significantly higher levels in shunt versus nonshunt patients (421 ± 335 vs 183 ± 126; P < 0.025), and this was even more evident when rejection occurred (626 + 375 vs 195 ±129; P < 0.001). Furthermore, during an acute rejection reaction, three cases showed a true “steal phenomenon” through the large reopened shunts with ischemic damage to the grafts. The data indicate a possible detrimental effect of the spontaneous shunts on graft perfusion and suggest the prophylactic surgical interruption of the residual shunts during the transplantation.

Liver transplantation for HBV-related cirrhosis in Europe: an ELTR study on evolution and outcomes.

BACKGROUND & AIMS HBV-related chronic liver disease is one of the most common indications for liver transplantation (LT) in Europe. The ELTR database was used to evaluate outcomes and evolution over 20 years (01/1988 and 12/2010). METHODS HBV transplanted patients were analysed according to indication for LT: decompensated cirrhosis (HBVdec) or hepatocellular carcinoma (HBV/HCC). These groups were compared with co-infected patients HBV/HDV (HBDV), HBV/HCV (HBCV), HBV/HDV/HCV (HBDCV); n = 16,664 and with HCV patients (n = 2452) according to LT indication. RESULTS 5912 patients were transplanted for HBV (78% HBVdec, 22% HBV/HCC), with HBV/HCC patients who increased from 15.8% in 1988-1995 to 29.6% in 2006-2010 (p < 0.001). In HBVdec patients, 1, 3, 5, and 10 year patient and graft survival was 83%, 78%, 75%, 68%, and 80%, 74%, 71%, 64%, respectively, significantly better than HBV/HCC (84%, 73%, 68%, 61%, and 81%, 70%, 65%, 58% respectively; p = 0.001 and p = 0.026). In 2006-2010 patient and graft survival significantly improved compared to 1988-1995, both for HBVdec and HBV/HCC (each p < 0.001). A better patient and graft survival was seen in HBV/HCC patients with HBV-DNA(-) compared to HBV-DNA(+) at the time of LT (p < 0.001). Disease recurrence, as cause of death/graft loss, was significantly reduced in recent years compared to the past: currently <1% for HBVdec and 3% for HBV/HCC. CONCLUSIONS Outcomes of LT for HBV have improved in recent years, with disease recurrence being no longer a significant cause of death/graft loss. HBV-DNA at the time of LT seems to influence survival only in HBV/HCC patients.

Three-year Outcomes in de Novo Liver Transplant Patients Receiving Everolimus with Reduced Tacrolimus: Follow-Up Results from a Randomized, Multicenter Study

Background Data are lacking regarding the long-term effect of preemptive conversion to everolimus from calcineurin inhibitors early after liver transplantation to avoid renal deterioration. Methods In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30 to (i) everolimus + reduced exposure tacrolimus (EVR + Reduced TAC), (ii) everolimus + tacrolimus elimination (TAC Elimination), or (iii) standard exposure tacrolimus (TAC Control). Results Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR) during TAC withdrawal. Of 370 patients who completed the 24-month core study on-treatment, 282 (76.2%) entered an additional 12-month extension phase. The composite efficacy failure endpoint (tBPAR, graft loss or death) occurred in 11.5% of EVR+Reduced TAC patients versus 14.6% TAC Controls from randomization to month 36 (difference, ‐3.2%; 95% confidence interval, ‐10.5% to 4.2%; P = 0.334). Treated BPAR occurred in 4.8% versus 9.2% of patients (P = 0.076). From randomization to month 36, mean (SD) estimated glomerular filtration rate decreased by 7.0 (31.3) mL/min per 1.73 m2 in the EVR+Reduced TAC group, and 15.5 (22.7) mL/min per 1.73 m2 in the TAC Control group (P = 0.005). Rates of adverse events, serious adverse events, and discontinuation due to adverse events were similar in both groups during the extension. Conclusions A clinically relevant renal benefit after introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation was maintained to 3 years in patients who continued everolimus therapy to the end of the core study, with comparable efficacy and no late safety concerns.

Biliary complications after living donor adult liver transplantation

The highest rate of complications characterizing the adult living donor liver transplantation (ALDLT) are due to biliary problems with a reported negative incidence of 22–64%. We performed 23 ALDLT grafting segments V–VIII without the middle hepatic vein from March 2001 to September 2005. Biliary anatomy was investigated using intraoperative cholangiography alone in the first five cases and magnetic resonance cholangiography in the remaining 18 cases. In 13 cases we found a single right biliary duct (56.5%) and in 10 we found multiple biliary ducts (43.7%). We performed single biliary anastomosis in 17 cases (73.91%) and double anastomosis in the remaining six (26%) cases. With a mean follow up of 644 days (8–1598 days), patient and graft survivals are 86.95% and 78.26%, respectively. The following biliary complications were observed: biliary leak from the cutting surface: three, anastomotic leak: two, late anastomotic strictures: five, early kinking of the choledochus: one. These 11 biliary complications (47.82%) occurred in eight patients (34.78%). Three of these patients developed two consecutive and different biliary complications. Biliary complications affected our series of ALDLT with a high percentage, but none of the grafts transplanted was lost because of biliary problems. Multiple biliary reconstructions are strongly related with a high risk of complication.