5-year Hepatocellular Carcinoma Research Articles

Clinical Utility of the aMAP Score for Predicting Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis B.

This study aimed to evaluate the efficacy of the aMAP score and compare it with other risk scores for predicting hepatocellular carcinoma (HCC) development in Thai patients with chronic hepatitis B (CHB). We retrospectively analyzed patients with CHB between 1 January 2008 and 31 December 2019. Data on demographics, clinical parameters, cirrhosis status, HCC imaging, and alpha fetoprotein surveillance were collected to calculate the aMAP score (0-100) based on age, sex, albumin-bilirubin level, and platelet count. Of the 1060 patients analyzed, 789 were eligible, of whom 51 developed HCC. The cumulative HCC incidences in the low-, moderate-, and high-risk groups at 3, 5, and 10 years were significantly different (log-rank, p < 0.0001). The area under the receiver operating characteristic curves (AUROCs) of the aMAP scores for predicting HCC at 3, 5, and 10 years were 0.748, 0.777, and 0.784, respectively. Among the risk scores, the CU-HCC score had the highest AUROCs (0.823) for predicting 5-year HCC development. The aMAP score is a valuable tool for predicting HCC risk in Thai patients with CHB and can enhance surveillance strategies. However, its performance is inferior to that of the CU-HCC score, suggesting the need for new predictive tools for HCC surveillance.

PAGE-B incorporating moderate HBV DNA levels predicts risk of HCC among patients entering into HBeAg-positive chronic hepatitis B

Recent studies reported that moderate HBV DNA levels are significantly associated with hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-positive, non-cirrhotic patients with chronic hepatitis B (CHB). We aimed to develop and validate a new risk score to predict HCC development using baseline moderate HBV DNA levels in patients entering into HBeAg-positive CHB from chronic infection. This multicenter cohort study recruited 3,585 HBeAg-positive, non-cirrhotic patients who started antiviral treatment with entecavir or tenofovir disoproxil fumarate at phase change into CHB from chronic infection in 23 tertiary university-affiliated hospitals of South Korea (2012-2020). A new HCC risk score (PAGED-B) was developed (training cohort, n= 2,367) based on multivariable Cox models. Internal validation using bootstrap sampling and external validation (validation cohort, n= 1,218) were performed. Sixty (1.7%) patients developed HCC (median follow-up, 5.4 years). In the training cohort, age, gender, platelets, diabetes and moderate HBV DNA levels (5.00-7.99 log10 IU/ml) were independently associated with HCC development; the PAGED-B score (based on these five predictors) showed a time-dependent AUROC of 0.81 for the prediction of HCC development at 5 years. In the validation cohort, the AUROC of PAGED-B was 0.85, significantly higher than for other risk scores (PAGE-B, mPAGE-B, CAMD, and REAL-B). When stratified by the PAGED-B score, the HCC risk was significantly higher in high-risk patients than in low-risk patients (sub-distribution hazard ratio= 8.43 in the training and 11.59 in the validation cohorts, all p <0.001). The newly established PAGED-B score may enable risk stratification for HCC at the time of transition into HBeAg-positive CHB. In this study, we developed and validated a new risk score to predict hepatocellular carcinoma (HCC) development in patients entering into hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) from chronic infection. The newly established PAGED-B score, which included baseline moderate HBV DNA levels (5-8 log10 IU/ml), improved on the predictive performance of prior risk scores. Based on a patient's age, gender, diabetic status, platelet count, and moderate DNA levels (5-8 log10 IU/ml) at the phase change into CHB from chronic infection, the PAGED-B score represents a reliable and easily available risk score to predict HCC development during the first 5 years of antiviral treatment in HBeAg-positive patients entering into CHB. With a scoring range from 0 to 12 points, the PAGED-B score significantly differentiated the 5-year HCC risk: low <7 points and high ≥7 points.

Distinct on-treatment HCC risks associated with different decompensation events in HBV patients with cirrhosis.

Long-term treatment with nucleoside analog (NA) reduces the risks for decompensation and hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with compensated cirrhosis (CC). However, whether antiviral therapy has differential efficacy on the risks for decompensation and HCC is insufficiently elucidated. Therefore, we investigated the disease state transition, focusing on decompensation event-specific HCC risk in NA-treated CHB patients with CC. We prospectively followed up on 1163 NA-treated CHB patients with CC every six months for up to seven years. The cumulative incidence and risk of HCC were analyzed by the Kaplan-Meier method and competing risk model. The multistate model was used to estimate the transition probabilities to HCC from different disease states. HCC predominated the first liver-related events, with a 5-year cumulative incidence of 9.0%, followed by decompensation (8.3%, including 7.9% nonbleeding decompensation and 2.4% variceal bleeding) and 0.2% death. The decompensation stage had a significantly higher 5-year cumulative HCC incidence than the CC stage (27.6% vs. 9.1%; HR = 2.42, 95% CI: 1.24, 4.71). Furthermore, nonbleeding decompensation events had a higher 5-year transition probability to HCC than bleeding (27.6% vs. 15.8%; HR = 2.69, 95% CI: 1.41, 4.17). Viral suppression modified the on-treatment transition risk to HCC (1-year: HR = 0.45, 95% CI: 0.28, 0.73; 3-year: HR = 0.23, 95% CI: 0.14, 0.38). An online calculator was developed to facilitate HCC risk stratification. In NA-treated CHB patients with compensated cirrhosis, the risk was higher for HCC than for decompensation; more importantly, different decompensation events conferred distinct HCC risks.

Use of machine learning models for identification of predictors of survival and tumour recurrence in liver transplant recipients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading indications for liver transplantation (LT) however, selection criteria remain controversial. We aimed to identify survival factors and predictors for tumour recurrence using machine learning (ML) methods. We also compared ML models to the Cox regression model. Thirty pretransplant donor and recipient general and tumour specific parameters were analysed from 170 patients who underwent orthotopic liver transplantation for HCC between March 2013 and December 2019 at the University Hospital Merkur, Zagreb. Survival rates were calculated using the Kaplan-Meier method and multivariate analysis was performed using the Cox proportional hazards regression model. Data was also processed through Coxnet (a regularized Cox regression model), Random Survival Forest (RSF), Survival Support Vector Machine (SVM) and Survival Gradient Boosting models, which included pre-processing, variable selection, imputation of missing data, training and cross-validation of the models. The cross-validated concordance index (CI) was used as an evaluation metric and to determine the best performing model. Kaplan-Meier curves for 5-year survival time showed survival probability of 80% for recipient survival and 82% for graft survival. The 5-year HCC recurrence was observed in 19% of patients. The best predictive accuracy was observed in the RSF model with CI of 0.72, followed by the Survival SVM model (CI 0.70). Overall ML models outperform the Cox regression model with respect to their limitations. Random Forest analysis provided several relevant outcome predictors: alpha fetoprotein (AFP), donor C-reactive protein (CRP), recipient age and neutrophil to lymphocyte ratio (NLR). Cox multivariate analysis showed similarities with RSF models in identifying detrimental variables. Some variables such as donor age and number of transarterial chemoembolization treatments (TACE) were pointed out, but these were not influential in our RSF model. Using ML methods in addition to classical statistical analysis, it is possible to develop sufficient prognostic models, which, compared to established risk scores, could help us quantify survival probability and make changes in organ utilization.

Predicting Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients Receiving Finite Periods of Antiviral Therapy

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most severe complications in chronic hepatitis B virus (HBV) infection. HCC can still develop in patients with chronic HBV (CHB) infection undergoing antiviral therapy. Several effective scoring systems for the prediction of HCC risk in CHB patients have been established. However, very few of them are designed for CHB patients receiving nucleos(t)ide analogues (NAs) therapy. Furthermore, none are available for HCC risk prediction in CHB patients receiving finite periods of antiviral therapy. METHODS: This study enrolled 790 consecutive treatment-naïve patients with CHB infection who had visited our liver clinics from 2008 to 2012 for pretreatment assessment before receiving antiviral therapies. The treatments were provided at finite periods according to the National Health Insurance Policy in Taiwan. The last follow-up date was 31 December 2021. We analyzed the virological and clinical factors in these 790 CHB patients receiving finite periods of NA treatments and identified the most significant risk factors for HCC to establish a novel predictive scoring system. By using stepwise selection in a multivariate Cox proportional hazards model, we divided the patients into three risk groups. RESULTS: Our predictive scoring system included five independent variables: genotype C (adjusted HR [aHR] = 2.23), NA-withdraw-related hepatitis relapse (aHR = 6.96), male (aHR = 4.19), liver cirrhosis (aHR = 11.14), and T1768A core promoter mutation (aHR = 3.21). This model revealed significant differences in HCC incidence among the three risk groups. The 5-year cumulative HCC risk significantly differed among the three risk groups (low risk: 1.33%, moderate risk: 4.99%, and high risk: 17.46%), with log-rank test p &lt; 0.001. CONCLUSION: Our predictive scoring system is a promising tool for the prediction of HCC in CHB patients receiving finite NA treatments. Genotype C, NA-withdraw-related hepatitis relapse, male gender, liver cirrhosis, and the T1768A HBV core promoter mutation were significant independent risk factors.

Novel, high accuracy models for hepatocellular carcinoma prediction based on longitudinal data and cell-free DNA signatures

Current hepatocellular carcinoma (HCC) risk scores do not reflect changes in HCC risk resulting from liver disease progression/regression over time. We aimed to develop and validate two novel prediction models using multivariate longitudinal data, with or without cell-free DNA (cfDNA) signatures. A total of 13,728 patients from two nationwide multicenter prospective observational cohorts, the majority of whom had chronic hepatitis B, were enrolled. aMAP score, as one of the most promising HCC prediction models, was evaluated for each patient. Low-pass whole-genome sequencing was used to derive multi-modal cfDNA fragmentomics features. A longitudinal discriminant analysis algorithm was used to model longitudinal profiles of patient biomarkers and estimate the risk of HCC development. We developed and externally validated two novel HCC prediction models with a greater accuracy, termed aMAP-2 and aMAP-2 Plus scores. The aMAP-2 score, calculated with longitudinal data on the aMAP score and alpha-fetoprotein values during an up to 8-year follow-up, performed superbly in the training and external validation cohorts (AUC 0.83-0.84). The aMAP-2 score showed further improvement and accurately divided aMAP-defined high-risk patients into two groups with 5-year cumulative HCC incidences of 23.4% and 4.1%, respectively (p=0.0065). The aMAP-2 Plus score, which incorporates cfDNA signatures (nucleosome, fragment and motif scores), optimized the prediction of HCC development, especially for patients with cirrhosis (AUC 0.85-0.89). Importantly, the stepwise approach (aMAP -> aMAP-2 -> aMAP-2 Plus) stratified patients with cirrhosis into two groups, comprising 90% and 10% of the cohort, with an annual HCC incidence of 0.8% and 12.5%, respectively (p <0.0001). aMAP-2 and aMAP-2 Plus scores are highly accurate in predicting HCC. The stepwise application of aMAP scores provides an improved enrichment strategy, identifying patients at a high risk of HCC, which could effectively guide individualized HCC surveillance. In this multicenter nationwide cohort study, we developed and externally validated two novel hepatocellular carcinoma (HCC) risk prediction models (called aMAP-2 and aMAP-2 Plus scores), using longitudinal discriminant analysis algorithm and longitudinal data (i.e., aMAP and alpha-fetoprotein) with or without the addition of cell-free DNA signatures, based on 13,728 patients from 61 centers across mainland China. Our findings demonstrated that the performance of aMAP-2 and aMAP-2 Plus scores was markedly better than the original aMAP score, and any other existing HCC risk scores across all subsets, especially for patients with cirrhosis. More importantly, the stepwise application of aMAP scores (aMAP -> aMAP-2 -> aMAP-2 Plus) provides an improved enrichment strategy, identifying patients at high risk of HCC, which could effectively guide individualized HCC surveillance.

From the Editor’s Desk...

From the Editor’s Desk...

A Lower HCC Incidence in Chronic HBV-Infected Patients Recovered from Acute-on-Chronic Liver Failure: A Prospective Cohort Study.

Activation of chronic hepatitis B virus (HBV) infection is an important cause of acute-on-chronic liver failure (ACLF). However, the effect of HBV-ACLF episode on hepatocellular carcinoma (HCC) occurrence remains largely unknown. A total of 769 HBV-ACLF patients and 2114 HBV-related chronic liver disease (HBV-CLD) patients diagnosed between August 1998 and December 2011 were enrolled in this prospective cohort study. Of the HBV-CLD patients, 380 received lifetime antiviral treatment with nucleos(t)ide analogues. Propensity score matching was applied to reduce baseline differences between HBV-ACLF and HBV-CLD cohorts. The survival rate of HBV-ACLF patients was 53.6%, 50.3%, 47.8%, and 46.2% at 90-day, 1-year, 5-year, and 10-year, respectively. The cumulative incidence of HCC was lower in HBV-ACLF cohort with 369 eligible patients survived for >90 days than in HBV-CLD cohort with the 380 patients (5.77/1,000 vs. 9.78/1,000 person-years, p = 0.0497). HBV-ACLF episode decreased HCC risk regardless of liver cirrhosis, and in patients without family history of HCC. Multivariate Cox analyses indicated that male, increasing age, liver cirrhosis, and platelet count (≤100 × 109/L) increased, whereas HBV-ACLF episode decreased, HCC risk independently. In the propensity score-matched cohorts, HBV-ACLF episode reduced HCC incidence (10.20/1,000 vs. 4.66/1,000 person-years, p = 0.0326). The area under curve of nomogram was 0.812 for 3-year HCC probability. HBV-ACLF episode decreases HCC occurrence in chronic HBV patients. Older age and liver cirrhosis independently increased HCC occurrence. A nomogram-enrolled episode of ACLF reliably predicts the occurrence of HCC.

Expression Patterns of Tumor Markers in Liver Transplant Recipients Showing Complete Pathological Response of Hepatocellular Carcinoma.

Complete pathological response (CPR) is achieved with various pretransplant locoregional treatments for hepatocellular carcinoma (HCC). This study aimed to investigate pretransplant expression of HCC tumor markers in liver transplantation (LT) recipients showing CPR. For the CPR group, 166 patients were selected from a single-institution LT database. Two control groups of 332 patients without HCC and 184 patients with partial pathological response (PPR) were also selected. The model for end-stage liver disease score in the CPR group was 11.5 ± 7.7. The number of transcatheter arterial chemoembolization sessions before LT was one in 68 patients (14.0%), two in 38 patients (22.9%), and three or more in 60 patients (36.1%). A solitary non-viable tumor was identified in 120 (86.4%) of the explant livers and the largest tumor size was 2.4 ± 1.3 cm. Living-donor and deceased-donor LTs were performed in 152 (91.6%) and 14 (8.4%) patients, respectively. The median levels of α-fetoprotein (AFP) and protein induced by Vitamin K absence or antagonist-II (PIVKA-II) measured within two weeks before LT were 4.2 ng/mL and 20 mAU/mL, respectively. These tumor marker levels were comparable to those in the no-HCC control group, but much lower than those in the PPR group (p < 0.001). Receiver operating characteristic curve analysis of AFP and PIVKA-II showed no definite cutoff values for CPR in the cohort of CPR and no-HCC patients, but significant cutoffs of 6.5 ng/mL for AFP and 29 mAU/mL for PIVKA-II were obtained in the cohort of CPR and PPR patients. The 1-, 3- and 5-year HCC recurrence and overall patient survival rates of the CPR group were 5.1% and 93.3%, 7.6% and 89.6%, and 7.6% and 89.6%, respectively. These tumor recurrence rates were much lower than those in the PPR group (p < 0.001). In conclusion, the present study results suggest that normalizing AFP and PIVKA-II after locoregional treatment is indicative of CPR. However, some CPR patients showed high expression of tumor markers; thus, pretransplant values of HCC tumor markers should be interpreted with caution.

Metformin reduces hepatocellular carcinoma incidence after successful antiviral therapy in patients with diabetes and chronic hepatitis C in Taiwan

Diabetes mellitus (DM) is known to increase the risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis C (CHC). We aimed to evaluate whether metformin reduces HCC risk among individuals with DM and CHC after successful antiviral therapy. Individuals with CHC who achieved a sustained virological response (SVR) after interferon-based therapy were enrolled in a large-scale, multicenter cohort in Taiwan (T-COACH). Cases of HCC at least 1 year after SVR were identified through linkage to the catastrophic illness and cancer registry databases. Of 7,249 individuals with CHC enrolled in the study, 781 (10.8%) had diabetes and 647 (82.8%) were metformin users. During a median follow-up of 4.4 years, 227 patients developed new-onset HCC. The 5-year cumulative HCC incidence was 10.9% in non-metformin users and 2.6% in metformin users, compared to 3.0% in individuals without DM (adjusted hazard ratio [aHR] 2.83; 95% CI 1.57-5.08 and aHR 1.46; 95% CI 0.98-2.19, respectively). Cirrhosis was the most important factor significantly associated with higher HCC risk in Cox regression analysis, followed by DM non-metformin use, older age, male sex, and obesity; whereas hyperlipidemia with statin use was associated with a lower HCC risk. Using the two most crucial risk factors, cirrhosis and DM non-metformin use, we constructed a simple risk model that could predict HCC risk among individuals with CHC after SVR. Metformin use was shown to reduce the risk of all liver-related complications. Metformin use greatly reduced HCC risk after successful antiviral therapy in individuals with diabetes and CHC. A simple risk stratification model comprising cirrhosis and DM non-metformin use could predict long-term outcomes in individuals with CHC after SVR. The current study provides evidence that metformin could reduce hepatocellular carcinoma (HCC) incidence after successful antiviral therapy among those with diabetes and chronic hepatitis C in a large-scale nationwide cohort study. Although successful antiviral therapy greatly reduces HCC risk in individuals with chronic hepatitis C, those with cirrhosis, diabetes, obesity, and the elderly remain at high risk of HCC development. We demonstrated that a simple risk model composed of two crucial unfavorable factors, cirrhosis and diabetes without metformin use, predicts the risk of HCC and major liver-related complications after successful antiviral therapy in individuals with chronic hepatitis C. Metformin use is highly recommended for individuals with diabetes and chronic hepatitis C after viral eradication to reduce the risk of HCC.

Drastic sex-dependent etiological distribution in severe liver diseases from Gabon.

Chronic liver diseases still represent a worrying public health issue in Sub-Saharan Africa. In this region, emphasis is generally made on hepatocellular carcinoma (HCC) albeit liver cirrhosis (LC) is also responsible for an important death toll. Very few studies have compared the presentation and etiologies of cancer and cirrhosis of the liver in Middle Africa. We conducted a comparative retrospective analysis of 74 and 134 cases of patients with HCC and LC treated in Libreville, Gabon. Viral or lifestyle risk factors, clinical symptoms, and biological features were compared. We observed that ages of diagnosis were 53.2 ± 15.7 years and 48.6 ± 18.6 years for HCC and LC with remarkably low M:F sex ratios (1.3–1.8). Ethanol consumption was highly prevalent in both disease types (65.0%–70.0%). Chronic viral infections with hepatitis B (HBV) or C (HCV) virus were also widespread with slight domination of the former in both diseases (43.4% vs. 34.3%, and 35.9% vs. 28.5%). Patients with HCC were presenting very late with a mean diameter of the main nodule of 84 ± 50 mm and a multifocal pattern in 72.7% of cases. HCC developed on a cirrhotic liver in 91.7% of cases. Serum AFP was frankly elevated (>400 ng/ml) in only 35.8% of HCC cases. The most striking feature of the HCC series was the contrasted contribution of distinct pathogenic etiologies involving sex, viral, metabolic, and toxic factors. A frequently dysmetabolic condition synergizing with hepatitis C (anti-HCV, 73.8% vs 22.7%, p < 0.0001) in females and a male cancer promoted by recreational toxicants and chronic hepatitis B (HBsAg, 83.5% vs 35.9%, p < 0.0001) were observed. Men with HCC were considerably younger than women (46.8 ± 14.5 years vs. 62.2 ± 12.2 years, p < 0.0001). Further studies are now warranted to identify routes of HCV transmission and if they are still fueling reservoirs of future patients. Public policies to prevent alcohol-related harm have also to be urgently implemented in Gabon.

Radiofrequency ablation is an inferior option to liver resection for solitary hepatocellular carcinoma ≤ 5 cm without cirrhosis: A population-based study with stratification by tumor size

BackgroundAbout 10%-20% of all individuals who develop hepatocellular carcinoma (HCC) do not have cirrhosis. Comparisons are rarely reported regarding the effectiveness of radiofrequency ablation (RFA) and liver resection (LR) in survival of HCC without cirrhosis and stratification by tumor size ≤ 5 cm. MethodsWe used the Surveillance, Epidemiology, and End Results (SEER) database and identified 1505 patients with a solitary HCC tumor ≤ 5 cm who underwent RFA or LR during 2004-2015. Patients were classified into non-cirrhosis and cirrhosis groups and each group was categorized into three subgroups, according to tumor size (≤ 30 mm, 31-40 mm, 41-50 mm). ResultsIn patients without cirrhosis, LR showed better 5-year HCC cancer-specific survival than RFA in all tumor size subgroups (≤ 30 mm: 82.51% vs. 56.42%; 31-40 mm: 71.31% vs. 46.83%; 41-50 mm: 74.7% vs. 37.5%; all P < 0.05). Compared with RFA, LR was an independent protective factor for HCC cancer-specific survival in multivariate Cox analysis [≤ 30 mm: hazard ratio (HR) = 0.533, 95% confidence interval (CI): 0.313-0.908; 31-40 mm: HR = 0.439, 95% CI: 0.201-0.957; 41-50 mm: HR = 0.382; 95% CI: 0.159-0.916; all P < 0.05]. In patients with cirrhosis, for both tumor size ≤ 30 mm and 31-40 mm groups, there were no significant survival differences between RFA and LR in multivariate analysis (all P > 0.05). However, in those with tumor size 41-50 mm, LR showed significantly better 5-year HCC cancer-specific survival than RFA in both univariate (54.72% vs. 23.06%; P < 0.001) and multivariate analyses (HR = 0.297; 95% CI: 0.136-0.648; P = 0.002). ConclusionsRFA is an inferior treatment option to LR for patients without cirrhosis who have a solitary HCC tumor ≤ 5 cm.

Comparing Predicted Probability of Hepatocellular Carcinoma in Patients With Cirrhosis With the General Population: An Opportunity to Improve Risk Communication?

Risk scores estimating a patient's probability of a hepatocellular carcinoma (HCC) diagnosis are abundant but are difficult to interpret in isolation. We compared the predicted HCC probability for individuals with cirrhosis and cured hepatitis C with the general population (GP). All patients with cirrhosis achieving sustained viral response (SVR) in Scotland by April 2018 were included (N = 1,803). The predicted 3-year probability of HCC at time of SVR achievement was determined using the aMAP prognostic model. GP data on the total number of incident HCCs in Scotland, stratified by demographics, were obtained from Public Health Scotland. Predicted HCC risk of cirrhosis SVR patients was compared with GP incidence using 2 metrics: (i) incidence ratio: i.e., 3-year predicted probability for a given patient divided by the 3-year probability in GP for the equivalent demographic group and (ii) absolute risk difference: the 3-year predicted probability minus the 3-year probability in the GP. The mean predicted 3-year HCC probability among cirrhosis SVR patients was 3.64% (range: 0.012%-36.12%). Conversely, the 3-year HCC probability in the GP was much lower, ranging from &lt;0.0001% to 0.25% depending on demographics. The mean incidence ratio was 410, ranging from 5 to &gt;10,000. The mean absolute risk difference was 3.61%, ranging from 0.012% to 35.9%. An online HCC-GP comparison calculator for use by patients/clinicians is available at https://thrive-svr.shinyapps.io/RShiny/ . Comparing a patient's predicted HCC probability with the GP is feasible and may help clinicians communicate risk information and encourage screening uptake.

National experience with living donor liver transplantation for hepatocellular carcinoma.

Living donor liver transplantation (LDLT) is an attractive option to decrease waitlist dropout, particularly for patients with hepatocellular carcinoma (HCC) who face lengthening waiting times. Using the United Network for Organ Sharing (UNOS) national database, trends in LDLT utilization for patients with HCC were evaluated, and post-LT outcomes for LDLT versus deceased donor liver transplantation (DDLT) were compared. From 1998 to 2018, LT was performed in 20,161 patients with HCC including 726 (3.6%) who received LDLT. The highest LDLT utilization was prior to the 2002 HCC Model for End-Stage Liver Disease (MELD) exception policy (17.5%) and dropped thereafter (3.1%) with a slight increase following the 6-month wait policy in 2015 (3.8%). LDLT was more common in patients from long-wait UNOS regions with blood type O, in those with larger total tumor diameter (2.3 vs. 2.1cm, p=0.02), and higher alpha-fetoprotein at LT (11.5 vs. 9.0ng/ml, p=0.04). The 5-year post-LT survival (LDLT 77% vs. DDLT 75%), graft survival (72% vs. 72%), and HCC recurrence (11% vs. 13%) were similar between groups (all p>0.20). In conclusion, LDLT utilization for HCC has remained low since 2002 with only a slight increase after the 6-month wait policy introduction in 2015. Given the excellent post-LT survival, LDLT appears to be an underutilized but valuable option for patients with HCC, especially those at high risk for waitlist dropout.

Verification of hepatitis B-related hepatocellular carcinoma predictive models to evaluate the risk of HCC in patients with liver cirrhosis under antiviral treatment.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The development of chronic hepatitis B (CHB)-related HCC can be attributed to continuous hepatitis B virus (HBV) infection. It is crucial to identify and monitor patients with CHB at high risk of HCC occurrence so that HCC can be detected early and the patients are able to receive effective treatment promptly to increase the survival rate and improve prognosis. This study aimed to verify hepatitis B-related hepatocellular carcinoma predictive models to evaluate the risk of HCC in patients with liver cirrhosis under antiviral treatment. Patients with HBV-related compensated cirrhosis were treated with lamivudine and adefovir randomly, and then with a combination of two drugs at different time points based on the virologic response. Patients with HCC occurrence during follow-up were categorized as HCC group, whereas others as control group. They were further divided into 2-year HCC, 2-year control, 5-year HCC, and 5-year control groups according to the observation time. The operating curves of the patients were used to verify models before and after antiviral treatment. Using the baseline as a parameter, the area under the curve (AUC) of risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B) after 2 and 5 years was 0.863 and 0.797, respectively. The AUC after 2 and 5 years was 0.839 and 0.747, respectively, for guide with age, gender, HBV DNA, core promoter mutations and cirrhosis (GAG-HCC) and 0.741 and 0.748, respectively, for Taiwanese HBV cohort (TW1). Using 48 weeks as the parameter, it has an optimal critical value of 8 points. The AUC of REACH-B after 2 and 5 years was 0.738 and 0.721, respectively. REACH-B can predict the risk of HCC occurrence in patients with compensated liver cirrhosis before and after antiviral treatment. GAG-HCC and TW1 could predict the risk before antiviral treatment.

Tenofovir is superior to entecavir in reducing HCC for patients with HBV-related compensated cirrhosis at high HCC risk scores.

Background:Both tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are known to reduce the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to compare the difference in HCC risk reduction between TDF and ETV in treatment-naïve patients with CHB-related compensated cirrhosis.Methods:Patients with compensated cirrhosis initially treated with TDF or ETV at nine Chinese hospitals between June 2014 and March 2021 were enrolled in this retrospective study. The cumulative HCC incidence rates for the two drugs were compared for the entire cohort, and a subgroup analysis was performed according to the HCC risk scores. Propensity score matching (PSM) was used to control confounding biases.Results:The analysis included 1453 patients (TDF group, n = 188; ETV group, n = 1265). Ninety-five patients developed HCC, with a median follow-up period of 26.1 months. The 3-year HCC incidence was 2.0% in the TDF group and 7.5% in the ETV group (log-rank p = 0.005). TDF treatment was associated with a lower risk of HCC than ETV treatment [hazard ratio (HR) = 0.222, 95% confidence interval (CI), 0.070–0.702, p = 0.010] but was similar after PSM (HR = 0.483, 95% CI, 0.144–1.626, p = 0.240; log-rank p = 0.230). However, subgroup analysis showed that the cumulative HCC incidence was lower in the TDF group than in the ETV group among patients with a modified PAGE-B score (mPAGE-B) ⩾9, either before or after PSM (log-rank p = 0.048 and p = 0.023, respectively).Conclusion:Among patients with an mPAGE-B score ⩾9, TDF is associated with a lower HCC incidence than ETV in patients with CHB-related compensated cirrhosis.

Association of Serum Hepatitis B Virus RNA With Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients Under Nucleos(t)ide Analogues Therapy.

Whether serum hepatitis B virus (HBV) RNA associates with hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) patients has not been fully elucidated. We enrolled 2974 patients receiving nucleos(t)ide analogues (NAs) from a prospective, observational CHB cohort to investigate the effect of serum HBV RNA, measured at study entry (baseline), on HCC development, using Cox regression analyses. During median follow-up of 4.4 years, 90 patients developed HCC. Patients with detectable baseline HBV RNA (n = 2072) exhibited significantly higher HCC risk than those with undetectable level (5-year HCC incidence estimated by Kaplan-Meier method: 4.1% versus 1.8%, P = .009; adjusted hazard ratio [aHR] = 2.21, P = .005). HBV RNA levels of 609-99999 and ≥100000 copies/mL were associated with incrementally increasing HCC risk (aHR = 2.15 and 3.05, respectively; P for trend = .003), compared to undetectable level (<609 copies/mL). Moreover, patients with single-detectable either HBV DNA or RNA and double-detectable DNA and RNA had 1.57- and 4.02-fold higher HCC risk, respectively, than those with double-undetectable DNA and RNA (P for trend = .001). High-level HBV RNA is associated with increased HCC risk in NAs-treated patients. Achieving undetectable HBV RNA may contribute to better clinical outcomes, indicating it could be a valuable endpoint of anti-HBV treatment.

Golgi protein 73 colorimetric biosensor based on reduced graphene oxide-trimanganese tetroxide nanozyme

Golgi protein 73 (GP73) is a new type of marker discovered in recent years for Hepatocellular carcinoma (HCC) detection. Herein, a sandwich colorimetric sensor was constructed for detection GP73 based on the good catalytic activity of reduced graphene oxide-trimanganese tetroxide (RGO-Mn3O4) nanozyme labeling GP73 aptamer, GP73 antibody and GP73. RGO-Mn3O4 with good peroxidase-like activity could catalyze the oxidation of TMB by H2O2 to produce a blue oxidation product (oxTMB) with an absorption peak at 652 nm. In the range of 10-250 ng/mL, different concentrations of GP73 have a linear relationship with absorbance. The catalytic enhancement allows for sensitive colorimetric detection of GP73. The linear regression equation is Y=0.3648+0.0013X with R2 of 0.9926 and LOD of 5.41 ng/mL. All the experimental results show that the detection system has a lower detection limit and good specificity for the detection of GP73, which provides a new method for the detection of HCC.

Comparative performance of risk prediction models for hepatitis B-related hepatocellular carcinoma in the United States

Guidelines recommend hepatocellular carcinoma (HCC) surveillance in patients with chronic HBV infection. Several HCC risk prediction models are available to guide surveillance decisions, but their comparative performance remains unclear. Using a retrospective cohort of patients with HBV treated with nucleos(t)ide analogues at 130 Veterans Administration facilities between 9/1/2008 and 12/31/2018, we calculated risk scores from 10 HCC risk prediction models (REACH-B, PAGE-B, m-PAGE-B, CU-HCC, HCC-RESCUE, CAMD, APA-B, REAL-B, AASL-HCC, RWS-HCC). We estimated the models' discrimination and calibration. We calculated HCC incidence in risk categories defined by the reported cut-offs for all models. Of 3,101 patients with HBV (32.2% with cirrhosis), 47.0% were treated with entecavir, 40.6% tenofovir, and 12.4% received both. During a median follow-up of 4.5 years, 113 patients developed HCC at an incidence of 0.75/100 person-years. AUC values for 3-year HCC risk were the highest for RWS-HCC, APA-B, REAL-B, and AASL-HCC (all >0.80). Of these, 3 (APA-B, RWS-HCC, REAL-B) incorporated alpha-fetoprotein. AUC values for the other models ranged from 0.73 for PAGE-B to 0.79 for CAMD and HCC-RESCUE. Of the 7 models with AUC >0.75, only APA-B was poorly calibrated. In total, 10-20% of the cohort was deemed low-risk based on the published cut-offs. None of the patients in the low-risk groups defined by PAGE-B, m-PAGE-B, AASL-HCC, and REAL-B developed HCC during the study timeframe. In this national cohort of US-based patients with HBV on antiviral treatment, most models performed well in predicting HCC risk. A low-risk group, in which no cases of HCC occurred within a 3-year timeframe, was identified by several models (PAGE-B, m-PAGE-B, CAMD, AASL-HCC, REAL-B). Further studies are warranted to examine whether these patients could be excluded from HCC surveillance. Risk prediction models for hepatocellular carcinoma (HCC) in patients infected with hepatitis B virus (HBV) could guide HCC surveillance decisions. In this large cohort of US-based patients receiving treatment for HBV, most published models discriminated between those who did or did not develop HCC, although the RWS-HCC, REAL-B, and AASL-HCC performed the best. If confirmed in future studies, these models could help identify a low-risk subset of patients on antiviral treatment who could be excluded from HCC surveillance.

Long-term assessment of recurrence of hepatocellular carcinoma in patients with chronic hepatitis C after viral cure by direct-acting antivirals.

Background and AimEarly hepatocellular carcinoma (HCC) recurrence is common, even after achieving hepatitis C virus (HCV) cure. This study was carried out to assess the long‐term trends and predictors of recurrence after HCV cure by direct‐acting antivirals (DAAs).MethodsThis retrospective, multicenter cohort study enrolled 365 consecutive patients with chronic hepatitis C who required HCC treatment following sustained viral response (SVR) by DAA administration. Patients with HCC recurrence before SVR were excluded. Late HCC recurrence and its predictors beyond the post‐treatment early phase (24 weeks after SVR) were evaluated.ResultsThe data of 326 patients were available for the final analysis. The median follow‐up duration from SVR determination was 2.7 years. Median age was 74, and 220 (67.5%) were 70 or over. The corresponding 5‐year cumulative HCC recurrence rates of previous curative and palliative treatment groups were 45.4% and 65.7%, respectively (log‐rank test: P < 0.001). Cox regression multivariable analysis revealed that cirrhosis (hazard ratio [HR] 1.85, P = 0.021), the number of HCC nodules (≥ 2) (HR 1.52, P = 0.031), and previous palliative HCC treatment (HR 1.71, P = 0.012) were independent predictors of late recurrence, in addition to the predictors of early recurrence; AFP > 7 ng/mL at 12 weeks after DAA administration, time from HCC complete response (CR) to DAA initiation (< 1 year), and the number of HCC treatments necessary to achieve CR (≥ 2).ConclusionsThe evaluation of fibrosis and characteristics of the previous HCC would allow for better HCC recurrence stratification, which would be helpful for developing long‐term surveillance strategies.