Association between the early high level of serum tacrolimus and recurrence of hepatocellular carcinoma in ABO-incompatible liver transplantation

BACKGROUND Clinical factors predicting graft survival(GS)after ABO-incompatible(ABOi)liver transplantation(LT),and differences between recipients with and without hepatocellular carcinoma(HCC)are unclear.AIM To analyze the impact of serial serum tacrolimus trough concentration in recipients with or without(HCC)in ABOi living-donor liver transplantation(LDLT).METHODS We analyzed a historical cohort of 89 recipients who underwent ABOi LDLT,including 47 patients with HCC.RESULTS The 1-,3-,5-,and 10-year GS rates were 85.9%,73.3%,71.4%,and 71.4%,respectively,and there were no significant differences between HCC and non-HCC recipients.In multivariate Coxregression analyses,tacrolimus trough concentrations below 5.4 ng/mL at 24 wk post-LT,in addition to the antibody-mediated rejection(AMR)were associated with poor-graft outcomes.In HCC patients,AMR[hazard ratio(HR)=63.20,P<0.01]and HCC recurrence(HR=20.72,P=0.01)were significantly associated with poor graft outcomes.HCCs outside Milan criteria,and tacrolimus concentrations at 4 wk post-LT>7.3 ng/mL were significant predictive factors for HCC recurrence.After propensity score matching,patients with high tacrolimus concentrations at 4 wk had significantly poor recurrence-free survival.CONCLUSION Elevated tacrolimus levels at 4 wk after ABOi LDLT have been found to correlate with HCC recurrence.Therefore,careful monitoring and control of tacrolimus levels are imperative in ABOi LT recipients with HCC.

Sarcopenia in the prognosis of cirrhosis: Going beyond the MELD score

Estimating the prognosis of patients with cirrhosis remains challenging, because the natural history of cirrhosis varies according to the cause, presence of portal hypertension, liver synthetic function, and the reversibility of underlying disease. Conventional prognostic scoring systems, including the Child-Turcotte-Pugh score or model for endstage liver diseases are widely used; however, revised models have been introduced to improve prognostic performance. Although sarcopenia is one of the most common complications related to survival of patients with cirrhosis, the newly proposed prognostic models lack a nutritional status evaluation of patients. This is reflected by the lack of an optimal index for sarcopenia in terms of objectivity, reproducibility, practicality, and prognostic performance, and of a consensus definition for sarcopenia in patients with cirrhosis in whom ascites and edema may interfere with body composition analysis. Quantifying skeletal muscle mass using cross-sectional abdominal imaging is a promising tool for assessing sarcopenia. As radiological imaging provides direct visualization of body composition, it is useful to evaluate sarcopenia in patients with cirrhosis whose body mass index, anthropometric measurements, or biochemical markers are inaccurate on a nutritional assessment. Sarcopenia defined by cross-sectional imaging-based muscular assessment is prevalent and predicts mortality in patients with cirrhosis. Sarcopenia alone or in combination with conventional prognostic systems shows promise for a cirrhosis prognosis. Including an objective assessment of sarcopenia with conventional scores to optimize the outcome prediction for patients with cirrhosis needs further research.

Hepatitis B virus reactivation in patients with hepatocellular carcinoma undergoing anti-cancer therapy

Patients with hepatocellular carcinoma (HCC) often experience hepatic morbidity. Hepatitis B virus (HBV) reactivation is well documented as a serious hepatic morbidity during anti-cancer therapy. Reported rates of HBV reactivation in chronic carriers with HCC undergoing chemotherapy range from 4%-67%. Apart from chemotherapy, HBV reactivation has been increasingly identified in settings of hepatectomy and local ablation therapies. The rates of HBV reactivation vary with different levels of immunosuppression and depend on treatment, viral factors, and patient characteristics. The principal concern relating to reactivation is that a substantial proportion of patients with reactivation suffer from liver dysfunction during therapy, which often leads to disruption of planned, potentially life-prolonging treatments, adversely affecting the patients&#x02019; final outcome. The first step in the management of HBV reactivation is identification of patients at risk of reactivation by testing for HBV serology prior to commencing anti-cancer therapy. Although it is a serious complication, HBV reactivation is preventable with prophylactic anti-HBV drugs. Multiple publications have shown the benefit of prophylactic or preemptive antiviral therapy in this setting and justified such an approach before the start of therapy. Given the tumors and underlying cirrhosis, long-term use of antivirals with high potency and low risk of resistance is recommended in patients with HCC. This topic review will summarize the epidemiology, pathogenesis, and clinical issues related to HBV reactivation in HCC patients, and will discuss proper management against HBV reactivation during anti-cancer therapy for HCC.

Update on hepatitis B virus infection

Chronic infection with hepatitis B virus (HBV) leads to the development of hepatocellular carcinoma and/or chronic liver failure. Despite extensive research, the immunopathogenesis is not completely understood. Viral persistence and clinical outcomes following HBV infection depend on viral factors and host factors; including genetic factors that determine a host&#x02019;s immune mechanisms. The primary goal of chronic hepatitis B (CHB) treatment is to eradicate HBV or to at least maintain suppression of HBV replication. Despite recent advances in anti-viral agents for chronic HBV infection, complete eradication of the virus has been difficult to achieve. Agents for the treatment of CHB are divided mainly into two groups: immunomodulating agents and antiviral nucleos(t)ide analogues (NAs). Although NAs are safe, effective and easily administered orally, their long-term use poses the risk of drug resistance. Currently, international evidence-based guidelines have been developed to support physicians in managing CHB patients. However, treatment of patients with drug resistance is still challenging, as only a few classes of anti-HBV drugs are available and cross-resistance between drugs can occur. In addition, as the currently available genotypic test for detection of drug resistance still has limitations in identifying the different substitutions present in the same viral genome, the development of a new virologic test to overcome this limitation is necessary. Among the predictive factors associated with response to pegylated interferon (PEG-IFN) therapy, hepatitis B surface antigen quantification is considered to be a surrogate marker for monitoring response to PEG-IFN. Current practice guidelines stress the importance of profound and durable HBV viral suppression in the treatment of CHB patients. To this end, it is essential to choose a potent antiviral drug with a low risk of resistance for initial treatment of CHB to achieve sustained virological response. This review highlights recent advances in the understanding of the immunopathogenesis of HBV and currently available and developing treatment strategies against HBV infection.

Outcome of transarterial chemoembolization-based multi-modal treatment in patients with unresectable hepatocellular carcinoma

AIM:To investigate the efficacy and safety of transarterial chemoembolization(TACE)-based multimodal treatment in patients with large hepatocellular carcinoma(HCC).METHODS:A total of 146 consecutive patients were included in the analysis,and their medical records and radiological data were reviewed retrospectively.RESULTS:In total,119 patients received TACE-based multi-modal treatments,and the remaining 27 received conservative management.Overall survival(P<0.001)and objective tumor response(P=0.003)were significantly better in the treatment group than in the conservative group.After subgroup analysis,survival benefits were observed not only in the multi-modal treatment group compared with the TACE-only group(P=0.002)but also in the surgical treatment group compared with the loco-regional treatment-only group(P<0.001).Multivariate analysis identified tumor stage(P<0.001)and tumor type(P=0.009)as two independent pre-treatment factors for survival.After adjusting for significant pre-treatment prognostic factors,objective response(P<0.001),surgical treatment(P=0.009),and multi-modal treatment(P=0.002)were identified as independent post-treatment prognostic factors.CONCLUSION:TACE-based multi-modal treatments were safe and more beneficial than conservative management.Salvage surgery after successful downstaging resultedin long-term survival in patients with large,unresectable HCC.

Predictive value of ^(18)F-fluorodeoxyglucose PET/CT for transarterial chemolipiodolization of hepatocellular carcinoma

AIM： To investigate the correlation of 18F-fluorodeoxy- glucose （18F-FDG） positron emission tomography （PET） with clinical features and the prediction of treatment response. METHODS： A total of 83 hepatocellular carcinoma （HCC） patients undergoing 18F-FDG PET before transar- terial chemolipiodolization with systemic chemo-infusion between October, 2006 and May, 2009 were retrospec-tively enrolled. The patients included 68 men and 15 women （mean age, 60 ~ 10.7 years）. The effect of 18F- FDG-monitored PET uptake on clinical features and on the evaluated treatment response was ascertained with modified Response Evaluation Criteria in Solid Tumors. The PET parameters of maximal standardized uptake value of the tumor （Tsuvmax）, the ratio of the tumor maximal standardized uptake value （SUV） to the liver maximal SUV （Tsuvmax/Lsuwax） and the ratio of tumor maximal SUV to the liver mean SUV （msuvmax/LSUVrnean） were tested as predictive factors. RESULTS： Among the 3 SUV parameters, the TSUV- =maxdLsuvmean ratio （cutoff value of 1.90） was significantly associated with tumor burden including tumor size, tu- mor number, α-fetoprotein levels and tumor stage （P 〈 0.001, P = 0.008, P = 0.011, P 〈 0.001, respectively）. The objective response rates in patients with a high SUV ratio （≥ 1.90） were significantly better than those with a low SUV ratio （〈 1.90） （P = 0.020）. The overall survival rates of patients exhibiting a low Tsuvmax/Lsu- Vmean ratio （〈 1.90） and those with a high SUV ratio （≥1.90） was 38.2 and 10.3 mo, respectively （P 〈 0.01）. However, the time to progression showed no significant difference between the groups （P = 0.15）. CONCLUSION： 18F-FDG PET can be an important predictor of HCC treatment. In particular, the Tsuvmax/ Lsuwean ratio （cutoff value of 1.90） can provide useful information in treatment prognosis for HCC patients treated with Iocoregional therapy.

Risk factors of biliary intervention by imaging after livingdonor liver transplantation

AIM:To determine the risk factors of biliary intervention using magnetic resonance cholangiopancreatography(MRCP) after living donor liver transplantation(LDLT).METHODS: We retrospectively enrolled 196 patients who underwent right lobe LDLT between 2006 and 2010 at a single liver transplantation center. Direct duct-to-duct biliary anastomosis was performed in all 196 patients. MRCP images routinely taken 1 mo after LDLT were analyzed to identify risk factors for biliary intervention during follow-up, such as retrograde cholangiopancreatography or percutaneous transhepatic biliary drainage. Two experienced radiologists evaluated the MRCP findings, including the anastomosis site angle on three-dimensional images, the length of the filling defect on maximum intensity projection, bile duct dilatation, biliary stricture, and leakage.RESULTS: Eighty-nine patients underwent biliary intervention during follow-up. The anastomosis site angle [hazard ratio(HR) = 0.48; 95% confidence interval(CI), 0.30-0.75, P < 0.001], a filling defect in the anastomosis site(HR = 2.18, 95%CI: 1.41-3.38,P = 0.001), and biliary leakage(HR = 2.52, 95%CI: 1.02-6.20, P = 0.048) on MRCP were identified in the multivariate analysis as significant risk factors for biliary intervention during follow-up. Moreover, a narrower anastomosis site angle(i.e., below the median angle of 113.3°) was associated with earlier biliary intervention(38.5 ± 4.2 mo vs 62. 1 ± 4.1 mo, P < 0.001). Kaplan-Meier analysis comparing biliary intervention-free survival according to the anastomosis site angle revealed that lower survival was associated with a narrower anastomosis site angle(36.3% vs 62.0%, P < 0.001).CONCLUSION: The biliary anastomosis site angle in MRCP after LDLT may be associated with the need for biliary intervention.

Hepatocellular carcinoma,decompensation,and mortality based on hepatitis C treatment:A prospective cohort study

BACKGROUND Prospective studies of the long-term outcomes of patients with hepatitis C virus(HCV)infection after treatment with interferon-based therapy(IBT)or directacting antivirals(DAA)are limited in many Asian countries.AIM To elucidate the incidences of hepatocellular carcinoma(HCC)and death/transplantation based on treatment with IBT or DAA,to compare the outcomes of the sustained virologic response(SVR)to IBT and DAA,and to investigate outcome-determining factors after SVR.METHODS This cohort included 2054 viremic patients(mean age,57 years;46.5%male;27.4%with cirrhosis)prospectively enrolled at seven hospitals between 2007 and 2019.They were classified as the untreated group(n=619),IBT group(n=578),and DAA group(n=857).Outcomes included the incidences of HCC and death/transplantation.The incidences of the outcomes for each group according to treatment were calculated using an exact method based on the Poisson distribution.A multivariate Cox regression analysis was performed to determine the factors associated with HCC or death/transplantation,followed by propensity score matching to confirm the results.RESULTS During a median of 4.1 years of follow-up,HCC and death/transplantation occurred in 113 and 206 patients,respectively,in the entire cohort.Compared with the untreated group,the incidences of HCC and death/transplantation were significantly lower in the IBT group[adjusted hazard ratio(aHR)0.47,95%CI:0.28-0.80 and aHR 0.28,95%CI:0.18-0.43,respectively]and the DAA group(aHR 0.58,95%CI:0.35-0.96,and aHR 0.19,95%CI:0.20-0.68,respectively).Among 1268 patients who attained SVR with IBT(n=451)or DAA(n=816),the multivariable-adjusted analysis showed no differences in the risks of HCC(HR 2.03;95%CI:0.76-5.43)and death/transplantation(HR 1.38;95%CI:0.55-3.49)between the two groups.This was confirmed by a propensity score-matching analysis.Independent factors for HCC after SVR were age,genotype 1,and the presence of cirrhosis.CONCLUSION Treatment and achieving SVR with either IBT or DAA significantly reduced the incidences of HCC and mortality in the Asian patients with HCV infection.The risks of HCC and mortality were not significantly different regardless of whether SVR was induced by IBT or DAA.