Liver transplantation for unresectable hepatocellular carcinoma in normal livers.

BACKGROUND & AIMS: The role of liver transplantation in the treatment of hepatocellular carcinoma in livers without fibrosis/cirrhosis (NC-HCC) is unclear. We aimed to determine selection criteria for liver transplantation in patients with NC-HCC. METHODS: Using the European Liver Transplant Registry, we identified 105 patients who underwent liver transplantation for unresectable NC-HCC. Detailed information about patient, tumor characteristics, and survival was obtained from the transplant centers. Variables associated with survival were identified using univariate and multivariate statistical analyses. RESULTS: Liver transplantation was primary treatment in 62 patients and rescue therapy for intrahepatic recurrences after liver resection in 43. Median number of tumors was 3 (range 1-7) and median tumor size 8 cm (range 0.5-30). One- and 5-year overall and tumor-free survival rates were 84% and 49% and 76% and 43%, respectively. Macrovascular invasion (HR 2.55, 95% CI 1.34 to 4.86), lymph node involvement (HR 2.60, 95% CI 1.28 to 5.28), and time interval between liver resection and transplantation < 12 months (HR 2.12, 95% CI 0.96 to 4.67) were independently associated with survival. Five-year survival in patients without macrovascular invasion or lymph node involvement was 59% (95% CI 47-70%). Tumor size was not associated with survival. CONCLUSIONS: This is the largest reported series of patients transplanted for NC-HCC. Selection of patients without macrovascular invasion or lymph node involvement, or patients ≥ 12months after previous liver resection, can result in 5-year survival rates of 59%. In contrast to HCC in cirrhosis, tumor size is not a predictor of post-transplant survival in NC-HCC.

Duct-to-duct biliary reconstruction in orthotopic liver transplantation for primary sclerosing cholangitis: a viable and safe alternative.

Roux-en-Y loop is considered the reconstruction method of choice in Orthotopic Liver Transplantation (OLT) for Primary Sclerosing Cholangitis (PSC). We have adopted an approach of duct-to-duct (D-D) reconstruction when recipient common bile duct is free of gross disease. Patients were divided into two groups: patients who underwent a Roux-en-Y choledochojejunostomy and patients who had a D-D anastomosis. Morbidity, mortality, disease recurrence and graft and patient survival were compared between the two groups and analyzed. Ninety-one patients had OLT for PSC. Sixty-three patients underwent a D-D biliary reconstruction, whereas 28 patients had a Roux-en-Y loop. Biliary leak complicated 8% from the D-D group, and 14% from the Roux-en-Y group (P = 0.08), whereas biliary strictures were identified in 10% vs. 7% patients from the D-D and Roux-en-Y group, respectively (P = 0.9). Actuarial 1, 3 and 10 year survival for D-D and Roux-en-Y group was (87%, 80% and 62%) and (82%, 73% and 73%), respectively (P = 0.7). The corresponding 1, 3 and 10 year graft survival was (72%, 58% and 42%) and (67%, 58% and 53%), respectively (P = 0.6). No difference was seen in disease recurrence rates. D-D biliary reconstruction in OLT for selected PSC patients remains our first option of reconstruction.

Liver transplantation for erythropoietic protoporphyria in Europe.

Liver transplantation is an established lifesaving treatment for patients with severe protoporphyric liver disease, but disease recurrence in the graft occurs for the majority of recipients. Severe burn injuries may occur when protective light filters are not used with surgical luminaires. Motor neuropathy with an unclear pathogenesis is a frequent complication. We retrospectively studied 35 transplants performed for protoporphyric liver disease in 31 European patients between 1983 and 2008. Most of the patients were male (61.3%), and the mean age at the time of primary transplantation was 39 years (range = 9-60 years). The overall patient survival rates were 77% at 1 year and 66% at 5 and 10 years. The overall rate of disease recurrence in the graft was 69%. Forty-three percent of the patients experienced recurrence within a year, but this was often a transient finding that was associated with other graft complications. Phototoxic injuries due to surgical luminaires were seen in 25.0% of the patients who were not protected by filters, but these injuries were not seen in the 9 patients who were protected by filters. Significant motor neuropathies requiring prolonged ventilation complicated the postoperative course for 5 of the 31 patients (16.1%). Hematopoietic stem cell transplantation was performed for 3 patients to prevent graft loss due to disease recurrence. Prognostic markers are needed to identify patients prone to severe protoporphyric liver disease so that curative stem cell transplantation can be offered to select patients instead of liver transplantation.

Long-term follow-up of immunosuppressive monotherapy in liver transplantation: tacrolimus and microemulsified cyclosporin.

BACKGROUND: Early withdrawal of steroids after liver transplantation has benefits, but rarely is total avoidance of steroids used. We evaluated long-term results of patients with ab initio monotherapy with cyclosporin (CYA) vs. tacrolimus (TAC), in randomized and cohort studies. METHODS: We evaluated long-term outcomes in 66 adults randomized to TAC or CYA and 94 subsequent patients who received TAC. Protocol liver biopsies were performed. Rejection was treated with three 1 g/d methylprednisolone. Further rejection after two courses of methylprednisolone was defined as monotherapy failure. RESULTS: Actuarial five-yr survival was 68% in TAC and 70% CYA. Monotherapy failed in 8% TAC and 13% CYA patients; no rejection in 24% TAC and 19% CYA patients; 42% TAC and 33% CYA patients were not exposed to any steroids. Rejection episodes were less with TAC, compared to CYA: mean 1.8 vs. 2.5, p = 0.042. Chronic rejection occurred in only 4 (11%) CYA patients. During follow-up of median 97 months (range: 0.06-145), there were 16 (44%) deaths in CYA and 48 (39%) in TAC patients (p > 0.05). CONCLUSIONS: TAC monotherapy ab initio is a viable immunosuppressive strategy in liver transplantation and was associated with lower rejection rates and renal complications, compared to CYA.

Risk factors associated with early hepatic artery thrombosis after orthotopic liver transplantation - univariable and multivariable analysis.

Hepatic artery thrombosis (HAT) is a serious complication in patients undergoing orthotopic liver transplantation (OLT). It is associated with a high graft loss and mortality rate. In this study, possible risk factors associated with early HAT (occurring within the first postoperative month) were evaluated using univariable and multivariable analyses. Nine-hundred-and-fourteen consecutive OLTs in our institution were examined by univariable and multivariable analyses. Early HAT occurred in 43 patients (4.7%). Graft number, abnormal donor arterial anatomy, bench arterial reconstruction, aortic conduit use, multiple anastomoses, reperfusion time (interval between portal vein reperfusion and restoration of arterial flow) and the number of units of blood received intraoperatively were significantly associated with early HAT in the univariable analysis(P<0.1). These variables were included in a multivariable regression model which showed that bench arterial reconstruction was associated with a fourfold risk of early HAT(P<0.0001), whereas each additional 10min delay in reperfusion was associated with a 27% increase in the risk of early HAT (P<0.04). The main risk factors associated with early HAT are abnormal arterial anatomy in the graft requiring bench reconstruction and a delay in arterial reperfusion. Early recognition of these factors, strict surveillance protocols with arterial Doppler and selective anticoagulation for patients at risk need to be evaluated prospectively.

Primary liver transplantation for autoimmune hepatitis: a comparative analysis of the European Liver Transplant Registry.

The principal aim of this study was to compare the probability of and potential risk factors for death and graft loss after primary adult and pediatric liver transplantation in patients undergoing transplantation for autoimmune hepatitis (AIH) to those in patients undergoing transplantation for primary biliary cirrhosis (PBC; used as the reference group) or alcoholic cirrhosis (used as an example of a nonautoimmune liver disease). The 5-year survival of patients undergoing transplantation for AIH (n = 827) was 0.73 [95% confidence interval (CI) = 0.67-0.77]. This was similar to that of patients undergoing transplantation for alcoholic cirrhosis (0.74, 95% CI = 0.72-0.76, n = 6424) but significantly worse than that of patients undergoing transplantation for PBC (0.83, 95% CI = 0.80-0.85, n = 1588). Fatal infectious complications occurred at an increased rate in patients with AIH (hazard ratio = 1.8, P = 0.002 with PBC as the reference). The outcome of pediatric AIH patients was similar to that of adult patients undergoing transplantation up to the age of 50 years. However, the survival of AIH patients undergoing transplantation beyond the age of 50 years (0.61 at 5 years, 95% CI = 0.51-0.70) was significantly reduced in comparison with the survival of young adult AIH patients (0.78 at 18-34 years, 95% CI = 0.70-0.86) and in comparison with the survival of patients of the same age group with PBC or alcoholic cirrhosis. In conclusion, age significantly affects patient survival after liver transplantation for AIH. The increased risk of dying of infectious complications in the early postoperative period, especially above the age of 50 years, should be acknowledged in the management of AIH patients with advanced-stage liver disease who are listed for liver transplantation. It should be noted that not all risk factors relevant to patient and graft survival could be analyzed with the European Liver Transplant Registry database.

Outcome of recurrent hepatitis C virus after liver transplantation in a randomized trial of tacrolimus monotherapy versus triple therapy.

Less potent immunosuppression is considered to reduce the severity of hepatitis C virus (HCV) recurrence after liver transplantation. An optimal regimen is unknown. We evaluated tacrolimus monotherapy versus triple therapy in a randomized trial of 103 first transplants for HCV cirrhosis. One hundred three patients who underwent transplantation for HCV were randomized to tacrolimus monotherapy (n = 54) or triple therapy with tacrolimus, azathioprine, and steroids (n = 49), which were tapered to zero by 3 to 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. The time to reach Ishak stage 4 was the predetermined endpoint. All factors documented in the literature as being associated with HCV recurrence and the allocated treatment were evaluated for reaching stage 4 and HVPG >or= 10 mm Hg. No significant preoperative, perioperative, or postoperative differences, including the frequency of biopsies between groups, were found. During a mean follow-up of 53.5 months, 9 monotherapy patients and 6 triple therapy patients died, and 5 monotherapy patients and 4 triple therapy patients underwent retransplantation. Stage 4 fibrosis was reached in 17 monotherapy patients and 10 triple therapy patients (P = 0.04), with slower fibrosis progression in the triple therapy patients (P = 0.048). Allocated therapy and histological acute hepatitis were independently associated with stage 4 fibrosis. HVPG increased to >or=10 mm Hg more rapidly in monotherapy patients versus triple therapy patients (P = 0.038). In conclusion, long-term maintenance immunosuppression with azathioprine and shorter term prednisolone with tacrolimus in HCV cirrhosis recipients resulted in a slower onset of histologically proven severe fibrosis and portal hypertension in comparison with tacrolimus alone, and this was independent of known factors affecting fibrosis.

Aprotinin and the risk of thrombotic complications after liver transplantation: a retrospective analysis of 1492 patients.

Aprotinin is an antifibrinolytic drug that reduces blood loss during orthotopic liver transplantation (OLT). Case reports have suggested that aprotinin may be associated with an increased risk of thromboembolic complications. Recent studies in cardiac surgery also have suggested a higher risk of renal failure and postoperative mortality. Despite these concerns, no large-scale safety assessment has been performed in OLT. In a retrospective observational study involving 1492 liver transplants, we studied the occurrence of postoperative thromboembolic or thrombotic events and mortality in patients who received aprotinin (n = 907) and patients who did not (n = 585). The overall incidence of hepatic artery thrombosis and central venous complications (pulmonary embolism or inferior vena cava thrombosis) was 3.2% and 0.9%, respectively. In propensity score-adjusted analyses (C-index = 0.79), aprotinin was not associated with an increased risk of hepatic artery thrombosis [odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.50-2.01, P = 0.86]. Although central venous complications were found more frequently in patients receiving aprotinin, the difference was not statistically significant (OR = 2.95, 95% CI = 0.54-16.23, P = 0.32). In addition, no significant differences were found in 1-year mortality (OR = 1.21, 95% CI = 0.86-1.71, P = 0.32). In conclusion, this study did not demonstrate an increased risk of thrombotic complications or mortality when aprotinin is used during OLT.

Cure of Acanthamoeba cerebral abscess in a liver transplant patient.

Acanthamoeba-related cerebral abscess and encephalitis are rare but usually fatal, being caused by free-living amoebic infections usually occurring in immunocompromised patients. In patients receiving transplants, a literature review showed that the infection is universally fatal. The diagnosis is often missed despite appropriate investigations including lumbar puncture, computerized tomography, and brain biopsy. We present the first reported liver transplant patient with Acanthamoeba cerebral abscess. The diagnosis was made in brain tissue removed at decompressive frontal lobectomy. He was successfully treated with a 3-month course of co-trimoxazole and rifampicin. There was no recurrence of the disease after 11 years of follow-up.

3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome.

BACKGROUND: Mortality after liver transplantation depends on heterogeneous recipient and donor factors. Our aim was to assess risk of death and to develop models to help predict mortality after liver transplantation. METHODS: We analysed data from 34,664 first adult liver transplants from the European Liver Transplant Registry to identify factors associated with mortality at 3-months (n=21,605 in training dataset) and 12-months (n=18,852 in training dataset) after transplantation. We used multivariable logistic regression models to generate mortality scores for each individual, and assessed model discrimination and calibration on an independent validation dataset (n=9489 for 3-month model and n=8313 for 12-month model). FINDINGS: 2540 of 21,605 (12%) individuals in the 3-month training sample had died by 3 months. Compared with those transplanted in 2000-03, those transplanted earlier had a higher risk of death. Increased mortality at 3-months post-transplantation was associated with acute liver failure (adjusted odds ratio 1.61), donor age older than 60 years (1.16), compatible (1.22) or incompatible (2.07) donor-recipient blood group, older recipient age (1.12 per 5 years), split or reduced graft (1.96), total ischaemia time of longer than 13 h (1.38), and low United Network for Organ Sharing score (score 1: 2.43; score 2: 1.67). However, cirrhosis with hepatocellular carcinoma, alcohol cirrhosis, hepatitis C or primary biliary cirrhosis, donor age 40 years or younger, or less, hepatitis B, and larger size of transplant centre (> or = 70 transplants per year) were associated with improved early outcomes. The 3-month mortality score discriminated well between those who did and did not die in the validation sample (C statistic=0.688). We noted similar findings for 12-month mortality, although deaths were generally underestimated at this timepoint. INTERPRETATION: The 3-month and 12-month mortality models can be effectively used to assess outcomes both within and between centres. Furthermore, the models provide a means of assessing the risk of post-transplantation mortality, giving clinicians important data on which to base strategic decisions about transplant policy in particular individuals or groups.

Liver transplantation and recurrent hepatocellular carcinoma: predictive value of nodule size in a retrospective and explant study.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains a major cause of post-LT death. METHODS: To assess which preoperative and postoperative variables were related to recurrence of HCC after LT in patients with cirrhosis and HCC, we evaluated 96 patients with cirrhosis (74 with known HCC and 22 with incidental HCC) who survived more than 1 month after LT. RESULTS: The median waiting list time was 36 days (range 1-370 days), and the median interval from detection to transplant was 180 days (range 14-1460 days). The size of largest nodule on imaging was strongly associated with recurrence (odds ratio 1.03; 95% confidence interval 0.99-1.06; P=0.064) when transplantation was performed for known HCC. Among postoperative variables, only the largest nodule diameter (independently of the number of smaller nodules) was multivariately associated with recurrence (odds ratio 1.05; 95% confidence interval 1.01-1.08; P=0.005). The best predictive cutoff was 35 mm in diameter, based on a receiver operating curve with 1-, 3-, and 5-year recurrence-free survival of 90%, 73%, and 49%, respectively, for patients with a nodule 35 mm in diameter or more compared with 96%, 93%, and 89% (P=0.0005), respectively, for patients with smaller nodules. CONCLUSIONS: In our cohort with a short waiting list time, only the largest nodule diameter, especially in the explant, predicted recurrence after LT independently of the number of nodules. New proposals for increasing the diameter of the largest nodule as a selection criteria for LT do not agree with our data, which on the contrary indicate the optimal nodule diameter should be 35 mm or less.

A prospective randomized trial of N-acetyl cysteine administration during cold preservation of the donor liver for transplantation.

AIMS: N-acetyl cysteine (NAC), an anti oxidant and a glutathione precursor, is effective in ameliorating liver injury of Tylenol overdose. There is experimental evidence that it also reduces ischemia reperfusion (I/R) injury. This clinical study was undertaken to study the effect of NAC administered in the donor operation. METHODS: 22 patients were randomized to receive NAC (IV & Portal flush) or no NAC (Control Group) during donor operation. Peak AST levels and 1-hour post-reperfusion biopsies were used to assess I/R injury. Episodes of acute rejection were recorded together with immunosuppressive drug levels. RESULTS: There were 4 exclusions (re-exploration for post-operative hemorrhage x3, OLT for acute liver failure x1). The two groups (n = 9 each) were matched for recipient and donor ages and sex. Viral hepatitis accounted for cirrhosis in 3 patients in NAC Group and 6 patients in Control Group. Statistically, Cold and warm ischemia times were not significantly different as was the use of blood and blood products in both groups. Serum peak AST levels were similar and post- reperfusion biopsy showed moderate to severe reperfusion injury in 3 recipients in the NAC Group and 4 in the Control Group. Excluding ones associated with low Tacrolimus levels (n = 4), there were 6 episodes of acute rejection (2- mild, 4- moderate) in the NAC Group and 5 in the Control Group (3- mild,1- moderate, 1- severe). CONCLUSION: In this pilot study, NAC administered during donor operation did not show a protective effect on I/R injury or on acute cellular rejection.

Long-term mycophenolate mofetil monotherapy in combination with calcineurin inhibitors for chronic renal dysfunction after liver transplantation.

BACKGROUND: Calcineurin inhibitors (CNIs) are the first-line immunosuppressive agents administered after liver transplantation, but they cause renal impairment. Two recent randomized trials report cellular rejection and liver graft loss when mycophenolate mofetil (MMF) monotherapy was used as a renal-sparing agent. Our experience with MMF in the same setting but with longer follow-up is described. METHODS: In 45 patients with serum creatinine more than 120 micromol/L or creatinine clearance less than 50 mL/min, 2 g MMF per day was administered (median 29 months, 1-49 months) either as monotherapy (with all other immunosuppression withdrawn in 1 month) in 16 patients (group I) or in combination with low-dose CNI (trough tacrolimus

Donor liver preservation and stimulation of adhesion molecules : cold preservation initiates the cascade.

BACKGROUND: Pro-inflammatory adhesion molecules (including ICAM-1, E-Selectin) are important in clinical hepatic ischaemia and reperfusion injury. The initiating factors remain to be fully elucidated. METHODS: Needle biopsies taken during and after donor liver preservation were studied in 28 cases by immunohistochemical methods. Human responder cell cultures were exposed to the effluent cold storage solution after liver preservation in a further 10 transplants. RESULTS: Increased ICAM-1 staining was seen at the end of cold storage compared to baseline (P less than 0.01), whilst reperfusion caused further increase (P less than 0.001). The storage solutions stimulated ICAM-1 and E-Selectin expression in responder cells in vitro as a bioassay (P less than 0.01 in each case). CONCLUSIONS: Liver harvesting and cold storage can initiate adhesion molecule expression even before reperfusion in the recipient.

Postpartum pneumoperitoneum: an important clinical lesson.

A 23-year-old primigravida presented to accident and emergency department with a 4-day history of generalised abdominal pain associated with vomiting and diarrhoea. She had previously given birth to her first child by vaginal delivery 6 days previously at another hospital and suffered a third-degree vaginal tear following prolonged labour. Shortly after birth, the patient had described the unusual symptom of soft tissue crepitations in the neck, but had been reassured and discharged without further investigation by her obstetrics team and reassured by a visiting general practitioner. At representation, the patient had obvious pneumoperitoneum, which was missed by the admitting team and underwent laparotomy for perforated duodenal ulcer.

Anticoagulation after liver transplantation: a retrospective audit and case-control study.

Anticoagulation may in the future become a therapeutic option for the prevention of liver fibrosis, such as due to recurrent hepatitis C virus infection after liver transplantation. Currently, there are other indications for anticoagulation after liver transplantation but no data regarding its safety. The objective of the study was to audit the safety of anticoagulation after liver transplantation. Liver transplant recipients receiving anticoagulation postoperatively were compared with a matched control group with respect to bleeding complications and postoperative course. Anticoagulation did not increase the risk of bleeding complications after liver transplantation. On the basis of safety, it appears feasible to use anticoagulation in trials to assess prevention of liver fibrosis.

Clinical outcome of HCV-related graft cirrhosis and prognostic value of hepatic venous pressure gradient.

Hepatitis C virus (HCV) allograft cirrhosis may progress rapidly requiring re-transplantation but its course is little studied. We evaluated serially biopsied patients who developed HCV-related allograft cirrhosis. We assessed outcome of graft cirrhosis in 55 out of 234 consecutive patients and predictors of decompensation and mortality, including hepatic venous pressure gradient (HVPG) in 38. Allograft cirrhosis (Ishak stage 6, 60%; stage 5, 40%) was diagnosed between 12 and 172 months (median, 52) from transplantation; subsequent follow up was 22 (1-78) months. Faster development (or= 10 mmHg, Child-Pugh score >or= 7, and albumin levels or= 10 mmHg, in addition to liver dysfunction, gives independent prognostic information prior to decompensation, allowing early relisting before prognosis becomes extremely poor.

Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation.

Liver transplantation (LT) is the only therapeutic option for end-stage primary sclerosing cholangitis (PSC), but PSC can recur (rPSC) in some patients after LT. The aim of our study was to evaluate the risk factors associated with rPSC. Between 1989 and 2004, 69 patients receiving transplantation for PSC (42 male, mean age 41.9 yr). Clinical and laboratory data, activity/extension and treatment of ulcerative colitis (UC), post-LT cytomegalovirus (CMV) infection, and immunosuppression were evaluated. Determination of rPSC was made by radiological and histological findings. Exclusion criteria were ABO blood group incompatibility, hepatic artery stenosis, and biliary strictures occurring in <3 months post-LT. A total of 48 (70%) patients had PSC and UC pre-LT. rPSC occurred in 7 of 53 (13.5%, 2 patients with de novo UC) who were alive 1 yr after LT and/or met inclusion/exclusion criteria: median 60 (4-120) months. No patient without post-LT UC had rPSC: 0 of 20 vs. 7 of 26 with post-LT UC (P = 0.027). The multivariate logistic regression analysis showed that maintenance steroids for UC (>3 months) post-LT was the only risk factor significantly associated with rPSC (P = 0.025). In conclusion, the presence of UC post-LT, and the need for maintenance steroids post-LT, which is an independent factor, are associated with rPSC. These findings could help elucidate a possible mechanism of PSC pathogenesis.

Efficacy of loco-regional ablation therapy of HCC in a population of liver transplanted patients.

BACKGROUND AND OBJECTIVE: Loco-ablation therapy (LAT) has become standard treatment for patients with HCC who are candidates for liver transplantation (LT). The aim of this study was: to evaluate if LAT was able to induce complete necrosis of tumour mass; to determine the tumour recurrence rate after LT and factors associated with recurrence. PATIENTS: The percentage and the distribution of necrosis in 116 HCC nodules of 61 patients with (26 patients) and without (35 patients) previous types of LAT were examined in explanted livers. RESULTS: Total necrosis was found only in 7% of treated nodules, and 42% of these showed absence of necrosis. The amount of necrosis was significantly related to the gross appearance of HCC: a single nodule with smaller adjacent satellite nodules showed a higher percentage of necrosis. No relation was found between the amount of necrosis and the type of LAT. Recurrence was observed in 11.5% and 8.5% of patients with and without previous LAT, respectively (P = ns). CONCLUSIONS: LAT very rarely induces complete necrosis; the amount of necrosis seems to depend on the growth pattern of the tumour and not on the type of previous LAT; the tumour size, measured at explant, is the only variable significantly related to recurrence.

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.