[18F]FDG PET/MRI in the follow-up of hepatocellular carcinoma after liver transplantation.

BACKGROUND: There is limited evidence regarding the application of [18F] fluorodeoxyglucose (FDG)-PET/MRI in patients with a suspected clinical recurrence, who underwent liver transplantation for hepatocellular carcinoma (HCC). Therefore, we compared the accuracy of PET/MR and standard-of-care (SOC) imaging in these patients. METHODS: We retrospectively reviewed 26 patients, whose liver were transplanted for HCC and were suspected of disease relapse based on biochemical analysis or SOC follow-up imaging, and carried out PET/MRI with diffusion-weighted imaging sequences on them. All patients underwent SOC imaging within the 2 months prior to the PET/MRI examination and had follow-up data for at least 12 months after. Reference standards were histopathology, clinical and imaging follow-up data. RESULTS: Sensitivity, specificity, positive predictive value, negative predictive value and accuracy for PET/MRI were 100, 94, 91, 100 and 96%, whereas for SOC imaging were 80, 69, 61, 85 and 73%. The accuracy of PET/MRI was higher with respect to SOC imaging, although not significantly. CONCLUSIONS: PET/MRI is useful for oncological surveillance of patients who have undergone liver transplantation for HCC, particularly in cases of allergy to contrast media, renal failure or persistently elevated alpha-fetoprotein levels, and with no identification of metastatic/relapsing foci at standard-of-care imaging.

Safe pregnancy after liver transplantation: Evidence from a multicenter Italian collaborative study.

BACKGROUND: Women who have undergone liver transplantation (LT) enjoy better health, and possibility of childbearing. However, maternal and graft risks, optimal immunosuppression, and fetal outcome is still to clarify. AIM: Aim of the study was to assess outcomes of pregnancy after LT at national level. METHODS: In 2019, under the auspices of the Permanent Transplant Committee of the Italian Association for the Study of the Liver, a multicenter survey including 14 Italian LT-centers was conducted aiming at evaluating the outcomes of recipients and newborns, and graft injury/function parameters during pregnancy in LT-recipients. RESULTS: Sixty-two pregnancies occurred in 60 LT-recipients between 1990 and 2018. Median age at the time of pregnancy was 31-years and median time from transplantation to conception was 8-years. During pregnancy, 4 recipients experienced maternal complications with hospital admission. Live-birth-rate was 100%. Prematurity occurred in 25/62 newborns, and 8/62 newborns had low-birth-weight. Cyclosporine was used in 16 and Tacrolimus in 37 pregnancies, with no different maternal or newborn outcomes. Low-birth-weight was correlated to high values of AST, ALT and GGT. CONCLUSION: Pregnancy after LT has good outcome; however, maternal complications and prematurity may occur. Compliance with the immunosuppression is fundamental to ensure the stability of graft function and prevent graft-deterioration.

Hepatocellular carcinoma and the risk of de novo malignancies after liver transplantation - a multicenter cohort study.

Patients with hepatocellular carcinoma (HCC) are at high risk of second primary malignancies. As HCC has become the leading indication of liver transplant (LT), the aim of this study was to investigate whether the presence of HCC before LT could influence the onset of de novo malignancies (DNM). A cohort study was conducted on 2653 LT recipients. Hazard ratios (HR) of DNM development for patients transplanted for HCC (HCC patients) were compared with those of patients without any previous malignancy (non-HCC patients). All models were adjusted for sex, age, calendar year at transplant, and liver disease etiology. Throughout 17 903 person-years, 6.6% of HCC patients and 7.4% of non-HCC patients developed DNM (202 cases). The median time from LT to first DNM diagnosis was shorter for solid tumors in HCC patients (2.7 vs 4.5 years for HCC and non-HCC patients, respectively, P < 0.01). HCC patients were at a higher risk of bladder cancer and skin melanoma. There were no differences in cumulative DNM-specific mortality by HCC status. This study suggests that primary HCC could be a risk factor for DNM in LT recipients, allowing for risk stratification and screening individualization.

Response to Terlipressin and Albumin Is Associated With Improved Liver Transplant Outcomes in Patients With Hepatorenal Syndrome.

BACKGROUND AND AIMS: Although terlipressin and albumin are effective at treating acute kidney injury-hepatorenal syndrome (AKI-HRS), liver transplantation (LT) is the best treatment. However, it is unclear if an effective treatment with terlipressin and albumin improves post-LT outcomes in these patients. The aim of this study was to evaluate the impact of response to treatment with terlipressin and albumin on posttransplant outcomes in patients with AKI-HRS. APPROACH AND RESULTS: We analyzed two cohorts of patients with cirrhosis listed for LT between 2012 and 2016: 82 patients who developed AKI-HRS before LT and were treated with terlipressin and albumin and 259 patients without AKI-HRS who received transplants during the study period (control group). After LT, patients were followed up until discharge, every month for the first 3 months, and every 3 months thereafter. Of the patients, 43 (52%) responded to terlipressin and albumin. Responders had a better 30-day transplant-free survival (60% vs. 33%, P = 0.006), longer LT waiting list time (37 vs. 17 days, P = 0.041), and lower Model for End-Stage Liver Disease score at the time of LT (23 vs. 29, P = 0.007). Among patients with AKI-HRS receiving transplant, nonresponders required renal replacement therapy (RRT) more frequently than responders (20% vs. 0%, P = 0.024). Nonresponders had a significantly higher incidence of chronic kidney disease (CKD) at 1 year after LT than responders (65% vs. 31%, P = 0.019). In multivariate analysis, nonresponse to terlipressin and albumin was found to be an independent predictor for CKD at 1 year after LT (subdistribution hazard ratio [SHR] = 2.76, P = 0.001), whereas responders did not have an increased risk (SHR = 1.53, P = 0.210). CONCLUSIONS: In patients with AKI-HRS, response to terlipressin and albumin reduces the need for RRT after LT and reduces the risk of CKD at 1 year after LT.

Biodegradable Biliary Stents for Percutaneous Treatment of Post-liver Transplantation Refractory Benign Biliary Anastomotic Strictures.

PURPOSE: The aim of this study was to evaluate the safety and the effectiveness of polydioxanone-made biodegradable biliary stent placement for the treatment of post-transplant benign, refractory biliary anastomotic strictures. MATERIALS AND METHODS: This was a retrospective observational study on all adult liver transplant recipients who developed a clinically significant anastomotic stricture between January 2014 and June 2017. Percutaneous transhepatic cholangioplasty with balloon dilation was performed as therapeutic approach in selected patients after multidisciplinary evaluation. Refractory strictures (defined as stricture persistence after two interventional procedures) were managed with placement of polydioxanone-made biodegradable biliary stent (SX-Ella biliary stent, Czech Republic). Patency of the common bile duct was calculated using Kaplan-Meier analysis. RESULTS: Eighteen adult liver transplant recipients who developed a refractory biliary anastomotic stricture [males/females 13/5, median (IQR) 58.2 (9.3) years] underwent biodegradable biliary stent placement after 10.4 (32) months from liver transplantation. All procedures except one were uneventful. After a median (IQR) follow-up time of 27.2 (22) months, complete resolution of anastomotic stricture was achieved in 72% of patients, with significant improvement on liver enzymes. CONCLUSIONS: Polydioxanone-made biodegradable biliary stent might be a safe and effective therapeutic option for the difficult-to-treat benign biliary anastomotic stricture after liver transplantation.

Prevalent use of combined prophylaxis of hepatitis B after liver transplantation in Italy: results of a national survey in a large cohort.

BACKGROUND: Prophylaxis of hepatitis B after liver transplantation with antiviral(s) and immunoglobulins efficiently protect the majority of recipients; however recent experiences suggest a decline of HBsAg-positive candidates and the use of hepatitis B Immunoglobulin-free schedules. METHODS: This national survey evaluated the epidemiology and clinical results of hepatitis B prophylaxis among 10,365 liver transplants performed in 25 years in 13 Italian centers. RESULTS: With a percentage of 22, 2260 procedures were performed in HBsAg-positive recipients and 714 out of 1080 anti-HBc-positive grafts were used in HBsAg-negative recipients; a total of 2974 patients (29%) were considered at risk of hepatitis B after liver transplantation. Similar rates (18% of HBsAg-positive candidates and 15% of anti-HBc-positive grafts) were registered in the last collected year. Combined prophylaxis with Hepatitis B Immunoglobulins remained prevalent among centers and was effective in 96% of HBsAg-positive recipients and in 94% of HBsAg-negative recipients of anti-HBc-positive grafts. CONCLUSIONS: Data from this survey confirm: the excellent results of combined prophylaxis; the past and persistent use of Hepatitis B Immunoglobulin-on and only rare -off prophylactic regimens, in contrast with the newest reports; the increasing use of anti-HBc-positive grafts; the past and present high prevalence of HBsAg-positive recipients, due to an increase in candidates with either hepatocellular carcinoma and Hepatitis Delta Virus coinfection in the last years.

Risk factors for central pontine and extrapontine myelinolysis after liver transplantation: a single-center study.

BACKGROUND: Central pontine and extrapontine myelinolysis (CPM/EPM) are severe neurologic complications after liver transplantation. METHODS: The present work retrospectively evaluated single-center prevalence of CPM/EPM and associated risk factors: cause of liver disease, hepatic encephalopathy, preoperative, intraoperative, and perioperative blood components use, serum levels, and variation of Na, Cl, and K and immunosuppression were compared between CPM/EPM patients and control group of transplanted patients without neurologic complications. RESULTS: Among 997 transplants, CPM/EPM were diagnosed in 11 patients (1.1%), of whom four were CPM, one was EPM, and six were associated CPM and EPM. Control group consisted of 44 transplanted patients. Central pontine and extrapontine myelinolysis patients experienced higher intraoperative and perioperative serum Na/24 hr variations compared to controls (16.69 ± 5.17 vs. 9.8 ± 3.4 mEq/L, P = 0.001). Maximum peak of intraoperative or perioperative serum Na was significantly higher in patients compared to controls (151.5 ± 3.3 vs. 140.8 ± 6.2 mEq/L, P ≤ 0.001), but no difference in preoperative serum Na was detected. Three patients presented hypernatremia as isolated risk factor. CONCLUSION: Extrapontine myelinolysis can be found isolated or associated with CPM in up to two of three liver transplanted patients with myelinolysis. A marked variation of perioperative serum Na remains the main risk factor even in patients without preexisting hyponatremia; however, isolated hypernatremia may be solely responsible in some cases.

Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis.

BACKGROUND: There is no established management algorithm for portal vein thrombosis (PVT) in cirrhotic patients. The aim of our study was to prospectively evaluate anticoagulation and transjugular intrahepatic portosystemic shunt (TIPS) to treat PVT. METHODS: Cirrhotics with non-malignant PVT were included. Low weight molecular heparin anticoagulation was considered in all; TIPS was indicated if thrombosis progressed or anticoagulation was contraindicated. Patients who were not anticoagulated nor received TIPS served as controls. RESULTS: Fifty-six patients (of whom 21 controls) were included. PVT was occlusive in 11/35, with extension to the superior mesenteric or splenic vein in 13/35. In the study group 33 patients were anticoagulated, with a recanalization rate of 36% (12/33) compared with 1/21 among controls. A time interval between appearance of thrombosis and anticoagulation < 6 months predicted chance of repermeation. Thrombus progression occurred in 15/21 non anticoagulated patients and in 5/33 anticoagulated patients (P < 0.001). TIPS was placed in six patients. There were five variceal bleedings and two intestinal venous ischaemia episodes in the control group, compared with one variceal bleeding episode in the study group. CONCLUSIONS: In cirrhotics with PVT, a treatment algorithm using anticoagulation and TIPS achieves a good chance of complete repermeation, reduces portal hypertensive complications, and decreases the rate of thrombosis progression.

Development and validation of a questionnaire evaluating the impact of hepatitis B immune globulin prophylaxis on the quality of life of liver transplant recipients.

To date, there is still a lack of instruments for specifically assessing the impact of anti-hepatitis B virus prophylaxis after liver transplantation (LT) on health-related quality of life (HRQOL) and treatment satisfaction. Focusing on the use of hepatitis B immune globulin (HBIG), we developed and validated the Immunoglobulin Therapy After Liver Transplantation Questionnaire (ITaLi-Q), which includes 41 items and covers 5 domains (side effects, positive and negative feelings, impact on the flexibility of daily activities, support, and satisfaction). The questionnaire was tested by 177 consecutive LT patients [71.8% were male, 38.4% were more than 60 years old, 58.8% were on intramuscular (IM) HBIG, and 41.2% were on intravenous (IV) HBIG]. A factor analysis confirmed the hypothesized structure, and a multitrait, multi-item analysis showed favorable psychometric characteristics for ITaLi-Q: item-scale correlations > 0.40 for all items but 1, high scaling success rates (>90% for all scales but 1), excellent internal consistency (Cronbach's α ≥ 0.8 for all scales), and good reproducibility (test-retest coefficient > 0.70 for all scales but 2). ITaLi-Q was able to discriminate between subgroups of patients according to their clinical and sociodemographic characteristics. In comparison with patients on IV HBIG, patients on IM HBIG reported significantly better HRQOL scores on the Flexibility (81.5 ± 21.4 versus 73.1 ± 24.2, P = 0.01) and Negative Feelings scales (90.1 ± 17.3 versus 85.4 ± 20.7, P = 0.04), but they reported worse HRQOL scores on the Side Effects scale (81.8 ± 22.8 versus 95.6 ± 7.4, P < 0.001). No differences were found between the route of HBIG administration and the Satisfaction, Positive Feelings, Impact, and Support scales. In conclusion, ITaLi-Q showed adequate psychometric characteristics and revealed that the route of HBIG administration has a significant impact on specific HRQOL domains beyond a patient's satisfaction.

Continuous recurrence of type 1 hepatorenal syndrome and long-term treatment with terlipressin and albumin: a new exception to MELD score in the allocation system to liver transplantation?

BACKGROUND & AIMS: The recurrence of type 1 hepatorenal syndrome has been described in up to 20% of responders to terlipressin and albumin after the discontinuation of the treatment. Subsequent recurrence of type 1 hepatorenal syndrome may require long-term treatment with terlipressin and albumin. METHODS: We describe our experience of long-term administration of terlipressin as a bridge to LT in three patients with cirrhosis and recurrent type 1 hepatorenal syndrome. For all three patients we requested an "early transplant" which is an option recognized in our country to reduce waiting times for liver transplantation. RESULTS: All three patients were transplanted within 2 months of onset of hepatorenal syndrome. All patients are still alive and none of them have developed chronic kidney disease. CONCLUSIONS: The outcomes of these patients suggest that long-term treatment with terlipressin and albumin is effective and well tolerated in patients with continuous recurrence of type 1 hepatorenal syndrome and, therefore, should be considered an absolute priority criterion in the allocation system for liver transplantation.

Killer cell immunoglobulin-like receptor genotype and killer cell immunoglobulin-like receptor-human leukocyte antigen C ligand compatibility affect the severity of hepatitis C virus recurrence after liver transplantation.

In 20% to 30% of infected individuals, hepatitis C virus (HCV) can cause cirrhosis and hepatocellular carcinoma, for which liver transplantation is the best treatment available. HCV re-infection is universal, and hepatitis disease recurrence occurs in most cases with a 30% probability of progression to graft cirrhosis at 5 years post-transplant. The immunological response to HCV involves natural killer (NK) cells and killer cell immunoglobulin-like receptors (KIRs), which specifically recognize human leukocyte antigen (HLA) class I antigens present on target cells. The effector functions of NK cells are influenced by inhibitory KIR interaction with self-HLA class I ligands, with HLA-C being the most predominant. This study examines the roles of KIR genotypes and their HLA ligands in both HCV disease recurrence and its progression. A total of 151 patients were included in the cohort, and their clinical details were recorded. Liver biopsies were used to define the absence/presence of recurrent hepatitis, the degree of fibrosis, and the progression to cirrhosis over a 10-year period. Mismatching of KIR-HLA-C ligands between donor-recipient pairs was associated with the recurrence of hepatitis (P = 0.008). The presence of KIR2DL3 in the recipient correlated with progression to liver fibrosis (P = 0.04). The mismatching of HLA-KIR ligands favored the progression of the recurrent hepatitis to fibrosis only in the presence of KIR2DL3 (P = 0.04). These preliminary results indicate that the KIR genotype and KIR-HLA-C ligand compatibility play roles in the recurrence and progression of hepatitis C disease in liver transplant recipients.

Heterophilic antibody interference in a non-endogenous molecule assay: an apparent elevation in the tacrolimus concentration.

BACKGROUND: In drug monitoring assays the most common interferences are due to hematocrit, other drugs or their metabolites, while the interference by heterophilic antibodies has been reported only when measuring endogenous molecules. In the present paper a heterophilic antibody interference in the tacrolimus measurement is described. METHODS: Samples from a patient treated with tacrolimus were analyzed on RxL Dimension analyzer. Ranging drug concentrations from 49 to 12.5 microg/L, even after the interruption of the treatment, confirmation analysis were performed using heterophilic blocking tubes before tacrolimus measurement on the same analyzer, then testing the samples on V-Twin System, finally incubating the samples with chlorophenol red beta-d-galactopyranoside, beta-galactosidase, polyclonal mouse IgG, protein A and Protein G resin. RESULTS: The elevated tacrolimus concentrations were due to the presence of an interference attributable to heterophilic antibodies, as confirmed by treating the samples with heterophilic blocking tubes and protein G resin. CONCLUSIONS: a) The interference caused by heterophilic antibodies can be found not only in immunoassays measuring endogenous molecules, but also in those for exogenous molecules; b) the pre-treatment sample procedure, which represent the main difference between the methods affected and unaffected by the interference, is a fundamental step in removing the antibodies responsible of the interference.

Nifedipine versus carvedilol in the treatment of de novo arterial hypertension after liver transplantation: results of a controlled clinical trial.

The aim of this study was to compare nifedipine and carvedilol in the treatment of de novo arterial hypertension after orthotopic liver transplantation (OLT). The study included 50 patients who developed arterial hypertension after OLT. Twenty-five patients received nifedipine (group A), and 25 received carvedilol (group B). Patients were defined as intolerant to nifedipine or carvedilol if severe adverse effects developed. These patients stopped the first drug and were switched to the other one. Patients were defined as full responders to monotherapy if there was normalization of blood pressure, and they were defined as partial responders by the need to add a second antihypertensive drug, ramipril. The 2 groups of patients were similar for baseline conditions. At the end of the study, patients intolerant to monotherapy were 48% of group A and 12.5% of group B (P < 0.01). Full responders were 20% of group A and 33.33% of group B (P < 0.01). Partial responders were 22% of group A and 54.1% of group B (P < 0.01). The addition of ramipril normalized blood pressure in 19% of partial responders to monotherapy (75% in partial responders to nifedipine and 30% in partial responders to carvedilol, P < 0.01). In responders to either monotherapy or combined therapy, there was a significant improvement of renal function. In responders to carvedilol, but not in responders to nifedipine, the daily dose of tacrolimus at 1 year should be reduced to 50% compared to the baseline dose to maintain the blood trough level in the therapeutic range.

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.

A randomized study comparing ligation with propranolol for primary prophylaxis of variceal bleeding in candidates for liver transplantation.

Whether beta-blockers (BB) or banding is the best therapy for primary prophylaxis of variceal bleeding is subject to debate. A randomized comparison between the 2 treatments was performed in candidates for liver transplantation (LT). A total of 62 patients with Child-Turcotte-Pugh B-C cirrhosis and high risk varices received propranolol (31) or variceal banding (31). The primary endpoint was variceal bleeding. There were 2 variceal hemorrhages (6.5%) in the banding group, related to postbanding ulcers, and 3 (9.7%) in the propranolol group (P = not significant [n.s.]). Deaths and bleeding related deaths were 3 and 1 for banding and 3 and 2 for BB, respectively (P = n.s.). A total of 14 patients underwent LT in the banding group and 10 in the propranolol group (P = n.s.). Adverse events were 2 postbanding ulcer bleedings in ligated patients (1 fatal) and 5 were intolerant to propranolol (P = n.s.). Mean costs per patient were higher with banding than with propranolol treatment (4,289 +/- 285 vs. 1,425 +/- 460 U.S. dollars, P < 0.001). In conclusion, propranolol and banding are similarly effective in reducing the incidence of variceal bleeding in candidates for LT, but ligation can be complicated by fatal bleeding and is more expensive. Our results suggest that banding should not be utilized as primary prophylaxis in transplant candidates who can be treated with BB.

Prospective validation of the Barcelona Clinic Liver Cancer staging system.

BACKGROUND/AIMS: The Barcelona Clinic Liver Cancer (BCLC) classification offers a prognostic stratification of patients with hepatocellular carcinoma (HCC). We recently demonstrated the BCLC's peculiar prognostic ability in a retrospective cohort of HCC patients. The aim of this study was to evaluate the BCLC system prospectively in a subsequent separate group of HCC patients enrolled at the same surgically oriented liver unit. METHODS: One hundred and ninety-five consecutive HCC patients were prospectively enrolled and their liver disease was staged before therapy. Unlike the BCLC treatment protocol, nodule size and number were not used as absolute exclusion criteria for radical treatment. Predictors of survival were identified using the Cox model. RESULTS: The median survival time was 23 months overall, and 53, 16, 7 and 3 months, respectively, for BCLC categories A, B, C, and D. In our cohort, BCLC had the best independent predictive power for survival when compared with the Okuda, CLIP, UNOS-TNM, and JIS prognostic systems (linear trend chi(2)=43.01, likelihood chi(2)=57.94, AIC 885.98). Moreover, the BCLC classification showed a better prognostic ability than the AJCC-TNM 2002 system in surgical patients. CONCLUSIONS: The discriminating power of BCLC staging was prospectively assessed in an Italian cohort of HCC patients treated mainly with radical therapies.

Acute hepatic failure in pregnancy.

Severe liver dysfunction in late pregnancy is an unusual but dramatic event because it can progress very rapidly to fulminating disease and also because two lives, that of the mother and foetus, are involved. We report a descriptive study of a pregnant woman presenting with severe liver dysfunction.

Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma.

OBJECTIVE: To determine the long-term results of liver transplantation for well- or moderately differentiated hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: HCC patient selection for liver transplantation remains controversial, and deciding exclusively on the strength of criteria such as number and size of nodules appears prognostically inaccurate. METHODS: Since 1991, preoperative tumor grading has been used at our center to establish whether a patient with HCC is fit for transplantation. Poorly differentiated HCC cases were excluded, while size and number of nodules were not considered as absolute selection criteria. Thirty-three patients with moderately or well-differentiated HCC were prospectively studied after liver transplantation. A group of 15 patients with incidental HCC transplanted during the same period were also evaluated and compared with the 33 patients with preoperatively diagnosed HCC. RESULTS: On histologic examination, 38% of the entire group of 48 patients did not meet the "Milan criteria" and 42% were pTNM stages III and IV. The median follow-up was 44 months. The 5-year actuarial survival rate was 75% and recurrence-free survival was 92%. HCC recurred in only 3 patients (6%). The only histomorphologic variable differing significantly between incidental and nonincidental HCC was nodule size. The timing of diagnosis (incidental vs. nonincidental HCC), the Milan criteria, and the TNM stage revealed no statistically significant impact on overall and recurrence-free survival rates. CONCLUSIONS: The routine pre-orthotopic liver transplantation tumor grading may represent a valid tool in the selection of unresectable HCC patients for transplantation.