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Atezolizumab and bevacizumab show promise for treating hepatocellular carcinoma (HCC), but identifying responsive patients remains challenging, due to tumor heterogeneity. This study explores immune dynamics following this combination therapy. Between 2020 and 2023, 29 patients with advanced HCC who received atezolizumab plus bevacizumab at Severance Hospital, Seoul, were enrolled in this study. Peripheral blood mononuclear cells were analyzed using flow cytometry and statistical methods to assess immune alterations and identify biomarkers. Baseline characteristics showed a diverse HCC cohort with a mean age of 64 years and 82.8% male predominance. Absence of extrahepatic metastasis was associated with better overall survival. Immune responses revealed distinct CD4+ T-cell phenotypes between the 'partial response (PR) + stable disease (SD)' and 'progressive disease (PD)' groups, with an overall increase in CD8+ T-cell phenotypes. Patients with higher frequencies of CD8+PD-1+Ki-67+ T cells experienced significantly improved overall survival, while those with lower frequencies of CD4+Foxp3+PD-1+LAG3+ T cells also had notable survival benefits. These findings enhance the overall understanding of immune responses to this combination therapy, facilitating improved patient stratification and personalized therapeutic approaches for HCC. [ABSTRACT FROM AUTHOR]

Background: The prognosis of metabolic dysfunction‐associated steatotic liver disease (MASLD) is associated with liver fibrosis. We investigated the associations between changes in liver stiffness measurement (LSM) over 3‐year period and the development of cirrhosis or hepatocellular carcinoma (HCC) in patients with MASLD. Methods: This study involved patients with MASLD who underwent transient elastography at baseline and 3 years after baseline from 2012 to 2020. Low (L), indeterminate (I) and high (H) LSM values were classified as <8 kPa, 8–12 kPa and >12 kPa respectively. Results: Among 1738 patients, 150 (8.6%) were diagnosed with cirrhosis or HCC. The proportions of patients with L, I and H risk were 69.7%, 19.9% and 10.5% at baseline, and 78.8%, 12.8% and 8.4% at 3 years after baseline, respectively. The incidence rates of cirrhosis or HCC per 1000 person‐years were 3.7 (95% confidence interval [CI], 2.4–5.5) in the L → L + I group, 23.9 (95% CI, 17.1–32.6) in the I → L + I group, 38.3 (95% CI, 22.3–61.3) in the H → L + I group, 62.5 (95% CI, 32.3–109.2) in the I → H group, 67.8 (95% CI, 18.5–173.6) in the L → H group and 93.9 (95% CI 70.1–123.1) in the H → H group. Two risk factors for the development of cirrhosis or HCC were LSM changes and low platelet counts. Conclusion: LSM changes could predict clinical outcomes in patients with MASLD. Thus, it is important to monitor changes in the fibrotic burden by regular assessment of LSM values. [ABSTRACT FROM AUTHOR]

Summary: Background: Risk of hepatocellular carcinoma (HCC) persists after hepatitis B surface antigen (HBsAg) seroclearance in patients with chronic hepatitis B (CHB). Aims: To identify risk factors and construct a predictive model for HCC development. Methods: We retrospectively analysed patients with CHB with HBsAg seroclearance. Primary outcome was HCC development. Factors identified from a multivariate Cox model in the training cohort, consisting of 3476 patients from two Korean hospitals, were used to construct the prediction model. External validation was performed using data from 5255 patients in Hong Kong. Results: In the training cohort, HCC occurred in 102 patients during 24,019 person‐years of observation (0.43%/year). Risk scores were assigned to cirrhosis (C:3), age ≥50 years (A:2), male sex (M:3) and platelet count <150,000/mm3 (P:1); all were independently associated with an increased risk of HCC in multivariate analysis The time‐dependent area under receiver operating characteristic curves for 5, 10 and 15 years in the training and validation cohorts were 0.782, 0.817 and 0.825 and 0.785, 0.771 and 0.796, respectively. In the validation cohort, 85 patients developed HCC (0.24%/year). The corresponding incidence of HCC in the low‐, intermediate‐ and high‐risk groups were 0.07%, 0.37% and 0.90%, respectively. Conclusions: The CAMP‐B score (cirrhosis, age ≥50 years, male sex and platelet count <150,000/mm3/L) was significantly associated with HCC development after HBsAg seroclearance. CAMP‐B score can be easily implemented in real‐world clinical practice and helps stratify HCC risk in patients with CHB following HBsAg seroclearance. [ABSTRACT FROM AUTHOR]

The clinical significance of hsa_circ_0004018 and hsa_circ_0003570 in patients with hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) is unclear. We aimed to explore the clinical significance and prognostic utility of these two circular RNAs (circRNAs) in patients with HBV-HCC. Based on 86 paired tissue samples of HCC and adjacent non-HCC, the relative expression profiles of hsa_circ_0004018 and hsa_circ_0003570 were determined using quantitative real-time polymerase chain reactions. The cut-off values were the median expression of each of the two circRNAs in 86 patients with HBV-HCC. The combination group comprised patients with high levels of the two circRNAs. Clinicopathological features, body composition profiles at the L3 level, and survival rates were investigated. The expression of hsa_circ_0004018 and hsa_circ_0003570 was downregulated in HCC tissues compared with non-HCC tissues. High expression levels of hsa_circ_0003570 (hazard ratio (HR), 0.437; p = 0.009) and hsa_circ_0004018 (HR, 0.435; p = 0.005) were inversely independent risk factors for overall and progression-free survival in patients with HBV-HCC, whereas the combination group was also an inversely independent risk factor for overall (HR, 0.399; p = 0.005) and progression-free survival (HR, 0.422; p = 0.003) in patients with HBV-HCC. The combination of hsa_circ_0003570 and hsa_circ_0004018 may be a potential prognostic biomarker for HBV-HCC. [ABSTRACT FROM AUTHOR]

Background: Machine learning (ML) algorithms can be used to overcome the prognostic performance limitations of conventional hepatocellular carcinoma (HCC) risk models. We established and validated an ML‐based HCC predictive model optimized for patients with chronic hepatitis B (CHB) infections receiving antiviral therapy (AVT). Methods: Treatment‐naïve CHB patients who were started entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were enrolled. We used a training cohort (n = 960) to develop a novel ML model that predicted HCC development within 5 years and validated the model using an independent external cohort (n = 1937). ML algorithms consider all potential interactions and do not use predefined hypotheses. Results: The mean age of the patients in the training cohort was 48 years, and most patients (68.9%) were men. During the median 59.3 (interquartile range 45.8–72.3) months of follow‐up, 69 (7.2%) patients developed HCC. Our ML‐based HCC risk prediction model had an area under the receiver‐operating characteristic curve (AUC) of 0.900, which was better than the AUCs of CAMD (0.778) and REAL B (0.772) (both p <.05). The better performance of our model was maintained (AUC = 0.872 vs. 0.788 for CAMD and 0.801 for REAL B) in the validation cohort. Using cut‐off probabilities of 0.3 and 0.5, the cumulative incidence of HCC development differed significantly among the three risk groups (p <.001). Conclusions: Our new ML model performed better than models in terms of predicting the risk of HCC development in CHB patients receiving AVT. [ABSTRACT FROM AUTHOR]

Background and Aim: Antiviral therapy (AVT) is the mainstay of hepatitis B virus (HBV) management. We investigated whether AVT improves the outcomes of HBV‐related decompensated cirrhosis and undetectable HBV‐DNA. Methods: Between 2000 and 2017, treatment‐naïve patients with HBV‐related decompensated cirrhosis and undetectable HBV‐DNA were recruited from two tertiary hospitals. The endpoints included death and hepatocellular carcinoma (HCC). Results: A total of 429 patients were analyzed (50 and 379 patients in the AVT and non‐AVT groups, respectively). Patients in the AVT group were significantly younger and had higher alanine aminotransferase and alpha‐fetoprotein levels than those in the non‐AVT group (all P < 0.05). During follow‐up (median 49.6 months), 98 patients died and 105 developed HCC. The cumulative incidence rates of death (2.0%, 4.1%, and 6.4%, and 4.9%, 7.2%, and 10.2% at 6 months, 1 year, and 2 years, respectively) and HCC (8.6%, 15.8%, and 26.4% vs 1.6%, 7.7%, and 24.4% at 1, 2, and 5 years, respectively) were statistically comparable between the AVT and non‐AVT groups (all P > 0.05). Using Cox regression analysis, AVT was not significantly associated with death nor HCC (all P > 0.05). Similar results were observed after balancing baseline characteristics with inverse probability of treatment weighting. In the non‐AVT group, the cumulative incidence rates of HBV‐DNA detection at 6 months, 1 year, and 2 years were 2.0%, 3.1%, and 6.4%, respectively. Conclusions: Antiviral therapy did not attenuate the risk of death nor HCC in patients with HBV‐related decompensated cirrhosis and undetectable HBV‐DNA. [ABSTRACT FROM AUTHOR]

Background and Objectives: ZBTB48 is a telomere-related protein that has been renamed telomeric zinc finger-associated protein (TZAP). It favorably binds to elongated telomeres to regulate their appropriate length. However, TZAP expression has not been investigated in hepatocellular carcinomas (HCC). Materials and Methods: The clinical significance of TZAP expression in 72 HCC was investigated. Additionally, its findings were supported by open big data and cancer cell lines. Results: TZAP expression level was not associated with the clinical parameters of HCC. TZAP expression induced a poorer survival result (overall survival, p = 0.020; disease-free survival, p = 0.012). TCGA data showed TZAP expression was more frequently found in HCCs with hepatitis C infection (p = 0.023). However, TCGA data revealed that TZAP expression did not predict HCC prognosis. In a cell line study, TZAP inhibition via siRNA suppressed PLC/PRF/5 cell growth; however, cell viability was increased in HepG2 cells. Conclusions: We presented the clinical and prognostic values of TZAP expression in HCC tissues and cancer cell lines. Additionally, the TCGA results also revealed a significant role for TZAP expression. TZAP expression may involve HCC progression and its prognosis. [ABSTRACT FROM AUTHOR]

Purpose: Liquid biopsy has emerged as a promising tool for minimally invasive and accurate detection of various malignancies. We aimed to apply molecular barcode sequencing to circulating tumour DNA (ctDNA) from liquid biopsies of hepatocellular carcinoma (HCC). Study Design: Patients with HCC or benign liver disease were enrolled between 2017 and 2018. Matched tissue and serum samples were obtained from these patients. Plasma cell‐free DNA was extracted and subjected to targeted sequencing with ultra‐high coverage and molecular barcoding. Results: The study included 143 patients: 102 with HCC, 7 with benign liver tumours and 34 with chronic liver disease. No tier 1/2 or oncogenic mutations were detected in patients with benign liver disease. Among the HCC patients, 49 (48%) had tier 1/2 mutations in at least one gene; detection rates were higher in advanced stages (75%) than in early stages (26%–33%). TERT was the most frequently mutated gene (30%), followed by TP53 (16%), CTNNB1 (14%), ARID2 (5%), ARID1A (4%), NFE2L2 (4%), AXIN1 (3%) and KRAS (1%). Survival among patients with TP53 mutations was significantly worse (p = 0.007) than among patients without these mutations, whereas CTNNB1 and TERT mutations did not affect survival. ctDNA testing combined with α‐fetoprotein and prothrombin induced by vitamin K absence‐II analyses improved HCC detection, even in early stages. Conclusions: ctDNA detection using molecular barcoding technology offers dynamic and personalized information concerning tumour biology, such information can guide clinical diagnosis and management. This detection also has the potential as a minimally invasive approach for prognostic stratification and post‐therapeutic monitoring. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are potential biomarkers owing to their stability, tissue specificity, and abundance. This study aimed to evaluate the clinical significance of hsa_circ_0003570 expression and to investigate its potential as a biomarker in hepatocellular carcinoma (HCC). We evaluated hsa_circ_0003570 expression in 121 HCC tissue samples, its association with clinicopathological characteristics, and overall and progression-free survival. Hsa_circ_0003570 expression was downregulated in HCC tissues. Low hsa_circ_0003570 expression was more common in tumors larger than 5 cm (odds ratio (OR), 6.369; 95% confidence interval (CI), 2.725–14.706; p < 0.001), vessel invasion (OR, 5.128; 95% CI, 2.288–11.494; p < 0.001); advanced tumor-node metastasis stage (III/IV; OR, 4.082; 95% CI, 1.866–8.929; p < 0.001); higher Barcelona Clinic Liver Cancer stage (B/C; OR, 3.215; 95% CI, 1.475–6.993; p = 0.003); and higher AFP (>200 ng/mL; OR, 2.475; 95% CI, 1.159–5.291; p = 0.018). High hsa_circ_0003570 expression was an independent prognostic factor for overall survival (hazard ratio (HR), 0.541; 95% confidence interval (CI), 0.327–0.894; p = 0.017) and progression-free survival (HR, 0.633; 95% CI, 0.402–0.997; p = 0.048). Hsa_circ_0003570 is a potential prognostic biomarker in patients with HCC, and further validation of hsa_circ_0003570 is needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with low-glycolytic hepatocellular carcinoma (HCC) show better clinical outcomes than those with hypoxic and high-glycolytic HCC. Low-glycolytic HCCs seem to utilize carbon sources other than glucose for metabolic fuel and tumor growth. However, by increasing tumor size, its outgrowth perfusion generates hypoxic foci inside the tumor and becomes more aggressive and resistant to therapy. In this study, we found that SLC13A5/NaCT is an important solute carrier (SLC) in low-glycolytic HCCs. To adapt to hypoxic conditions, low-glycolytic cancer cells have to switch metabolism from oxidative phosphorylation to hypoxia-induced glycolysis by the upregulation of HIF1α. However, extracellular citrate treatment in HCCs with high SLC13A5/NaCT expression had reduced glucose uptake due to HIF1α degradation, inducing the failure of metabolic adaptation to hypoxia, resulting in anti-cancer effects in in vitro and in vivo animal models. HCC is well known for low glycolysis in the tumors, whereas hypoxia induces glycolytic phenotype and tumor progression. This study was conducted to evaluate the expression of SLCs in human HCCs and investigated whether extracellular nutrient administration related to SLCs in low-glycolytic HCC can prevent hypoxic tumor progression. SLCs expression was screened according to the level of glycolysis in HCCs. Then, whether extracellular nutrient treatment can affect hypoxic tumor progression, as well as the mechanisms, were evaluated in an in vitro cell line and an in vivo animal model. Low-glycolytic HCCs showed high SLC13A5/NaCT and SLC16A1/MCT1 but low SLC2A1/GLUT1 and HIF1α/HIF1α expression. Especially, high SLC13A5 expression was significantly associated with good overall survival in the Cancer Genome Atlas (TCGA) database. In HepG2 cells with the highest NaCT expression, extracellular citrate treatment upon hypoxia induced HIF1α degradation, which led to reduced glycolysis and cellular proliferation. Finally, in HepG2-animal models, the citrate-treated group showed smaller tumor with less hypoxic areas than the vehicle-treated group. In patients with HCC, SLC13A5/NaCT is an important SLC, which is associated with low glycolysis and good prognosis. Extracellular citrate treatment induced the failure of metabolic adaptation to hypoxia and tumor growth inhibition, which can be a potential therapeutic strategy in HCCs. [ABSTRACT FROM AUTHOR]

Simple Summary: Activation of YAP/TAZ (mediators of Hippo signaling) is associated with the development of liver cancer. The expression level of YAP is known to relate to chemoresistance. However, the therapeutic effect of YAP/TAZ inhibition when combined with sorafenib and conventional chemotherapy in HCC is not known. Recent studies have highlighted the importance of the tumor microenvironment (TME) in chemoresistance. The multicellular tumor spheroid (MCTS) model has emerged as a promising tool for studying cancer drugs as it mimics actual TME. Here, we aimed at assessing the YAP/TAZ expression level of HCCs and identifying the therapeutic effects of CA3 (novel YAP inhibitor) when combined with sorafenib using a patient-derived MCTS model. We established patient-derived MCTS and confirmed that patient-derived MCTS with high YAP/TAZ expression responded more sensitively to the combination therapy (sorafenib with CA3) than MCTS with low or medium YAP/TAZ expression. These findings suggest that the YAP/TAZ inhibitor may serve as a potential therapeutic strategy to enhance sensitivity to sorafenib in HCCs with high YAP/TAZ expression. Purpose: To assess the expression levels of YAP and TAZ in patient-derived HCC tissue and identify the effects of YAP/TAZ inhibition depending on the baseline YAP/TAZ expression when combined with sorafenib using a patient-derived multicellular tumor spheroid (MCTS) model. Methods: Primary HCC cell lines were established from patient-derived tissue. Six patient-derived HCC cell lines were selected according to YAP/TAZ expression on Western blot: high, medium, low. Then, MCTS was generated by mixing patient-derived HCC cells and stroma cells (LX2, WI38, and HUVECs) and YAP/TAZ expression was assessed using Western blot. Cell viability of MCTS upon 48 h of drug treatment (sorafenib, sorafenib with CA3 0.1 µM, and CA3 (novel YAP1 inhibitor)) was analyzed. Results: Out of six patient-derived HCC cell lines, cell lines with high YAP/TAZ expression at the MCTS level responded more sensitively to the combination therapy (Sorafenib + CA3 0.1 μM) despite the potent cytotoxic effect of CA3 exhibited in all of the patient-derived HCCs. Conclusion: Targeting YAP/TAZ inhibition using the novel YAP1 inhibitor CA3 could be a promising therapeutic strategy to enhance sensitivity to sorafenib especially in HCCs with high YAP/TAZ expression in MCTS. [ABSTRACT FROM AUTHOR]

Cirrhosis and age (CAGE-B) and stiffness and age (SAGE-B) models assess the risk of hepatocellular carcinoma (HCC) development in white patients with chronic hepatitis B (CHB) undergoing sustained antiviral therapy (AVT). Herein, we checked the predictive performance of these models in Asian patients with CHB. We reviewed 734 treatment-naive patients with CHB who started entecavir between 2006 and 2011 and were followed up for more than 5 years without HCC development during AVT. The predictive performance of CAGE-B and SAGE-B models was calculated using area under the receiver operating characteristic curves (AUROCs). Median liver stiffness assessed using transient elastography after 5 years of AVT was 6.8 kPa. Median CAGE-B and SAGE-B models after 5 years of AVT were 7.0 and 6.0, respectively. More than 5 years after AVT initiation, 66 patients (9.0%) developed HCC. The AUROCs of the CAGE-B and SAGE-B models were 0.764 and 0.785 after 7 years and 0.799 and 0.802 after 10 years of AVT, respectively. The cumulative incidence of HCC was significantly higher in the high-risk groups according to CAGE-B and SAGE-B risk stratification than in the medium- and low-risk groups (P <.05 in all cases). The SAGE-B model showed a higher likelihood ratio (χ2) (76.2 vs 71.4) and linear trend (χ2) (74.1 vs 58.6) than the CAGE-B model, whereas the CAGE-B model showed higher Akaike information criteria (64.3 vs 50.3). Both SAGE-B and CAGE-B showed acceptable performance in predicting HCC after 5 years of AVT in Asian patients with CHB. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The necessity of antiviral therapy (AVT) for hepatitis B virus (HBV)-infected compensated cirrhosis with low-level viremia (LLV) is controversial. Herein, we evaluated its natural history. METHODS: From 3 tertiary hospitals, we enrolled untreated patients with compensated cirrhosis with persistent serum HBV-DNA levels <2,000 IU/mL; LLV was defined as having at least 1 detectable serum HBV-DNA (20-2,000 IU/mL) episode, whereas maintained virological response (MVR) was defined as having persistently undetectable serum HBV-DNA (<20 IU/mL). When serum HBV-DNA was >=2,000 IU/mL during follow-up, AVT was administered according to guidelines. Study end points were development of cirrhotic complication event (CCE) or hepatocellular carcinoma (HCC). RESULTS: Among 567 patients analyzed, cumulative HCC risk at 3, 5, and 7 years was comparable between LLV (n = 391) vs MVR (n = 176) groups (5.7%, 10.7%, and 17.3% vs 7.2%, 15.5%, and 19.4%, respectively [ P = 0.390]). CCE risk was also comparable between 2 groups (7.5%, 12.8%, and 13.7% vs 7.8%, 12.3%, and 14.6%, respectively [ P = 0.880]). By multivariate analysis, LLV (vs MVR) was not associated with HCC or CCE risks, with adjusted hazard ratios of 1.422 (95% confidence interval [CI] 0.694-2.913; P = 0.336) and 1.816 (95% CI: 0.843-3.911; P = 0.128), respectively. Inverse probability of treatment weighting analysis yielded comparable outcomes between 2 groups, regarding HCC and CCE risks with hazard ratios of 0.903 (95% CI: 0.528-1.546; P = 0.711) and 1.192 (95% CI: 0.675-2.105; P = 0.545), respectively. DISCUSSION: Episodic LLV among untreated patients with compensated cirrhosis does not increase the risk of disease progression compared with MVR status. Thus, the benefits of AVT for episodic LLV should be re-evaluated. [ABSTRACT FROM AUTHOR]

It is unclear whether tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) is more effective for preventing hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB). In this study, we compared the effectiveness of these two antiviral agents for preventing HCC. We included treatment‐naïve CHB patients undergoing antiviral therapy with TDF only (TDF group) or a TAF‐based regimen (TAF group) at three academic teaching hospitals from 2012 to 2019. The TAF group included patients receiving TAF as first‐line treatment and patients switching from TDF to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded. Cumulative probabilities of HCC were assessed using Kaplan‐Meier methodology. In total, 2,117 patients were included: 1,832 in the TDF group and 285 in the TAF group. The annual HCC incidence was not significantly different between TDF and TAF groups: 1.66 vs. 1.19 per 100 person‐years [PY], respectively (multivariate analysis: adjusted hazard ratio [HR] 0.774 [reference: TDF group]; p =.438). Male, liver cirrhosis, hepatitis B e antigen negativity, Fibrosis‐4 index>3.25 and low albumin were independently associated with a higher risk of HCC. Propensity score‐matched and inverse probability of treatment weighting analyses yielded similar results: 1.56 vs. 1.19 per 100 PY, respectively (HR 1.175; p =.708) and 1.66 vs. 1.29 per 100 PY, respectively (HR 0.888; p =.446). The risk of HCC development was not significantly different between TDF and TAF groups of CHB patients. Further studies with a larger sample size and longer follow‐up are required to validate our results. [ABSTRACT FROM AUTHOR]

The influence of hepatic steatosis on the natural history of chronic hepatitis B (CHB) virus is unclear. Therefore, we investigated whether concurrent steatosis in patients with CHB influences the probability of hepatitis B surface antigen (HBsAg) loss, fibrosis progression and hepatocellular carcinoma (HCC) development. This study enrolled treatment‐naïve patients with virologically (HBV DNA <2,000 IU/ml) and biochemically (alanine aminotransferase level <40 IU/L) quiescent CHB who underwent transient elastography between January 2004 and December 2015 and completed 3 years of follow‐up. Results: The mean age of the study population (n = 720) was 52.0 years, and there were more men than women (n = 419, 58.2%). The mean HBV DNA level was 321.6 IU/ml. During the 3‐year period, 74 (10.3%) patients achieved HBsAg seroclearance. Lower HBV DNA levels (hazard ratio = 0.995, p <.05) were independently associated with HBsAg seroclearance, while hepatic steatosis was not (p >.05). Fibrosis progressed in 89 (12.4%) patients. Male gender (odds ratio [OR] = 1.720) and higher body mass index (OR = 1.083) were independently associated with an increased probability of fibrosis progression (all p <.05), while higher total cholesterol levels (OR = 0.991) and higher liver stiffness values (OR = 0.862) were independently associated with a decreased probability of fibrosis progression (all p <.05). HCC developed in 46 (6.4%) patients. Male gender (OR = 3.917) and higher AST levels (OR = 1.036) were independently associated with an increased probability of HCC development (p <.05). Hepatic steatosis was not associated with the probability of HBsAg seroclearance, fibrosis progression or HCC development in patients quiescent CHB in our study. Further studies with longer follow‐up periods are required to validate our findings. [ABSTRACT FROM AUTHOR]

Cirrhosis has prognostic value. We investigated whether the combined use of ultrasonography (US) and transient elastography (TE) to diagnose cirrhosis is beneficial for the risk assessment of hepatocellular carcinoma (HCC) and liver‐related events in patients with chronic hepatitis B (CHB). A total of 9300 patients with CHB who underwent US and TE in two institutions between 2006 and 2018 were enrolled. TE value ≥13 kPa was set to indicate cirrhosis. Patients were divided into four groups: US(+)TE(+) (cirrhosis by US and TE), US(+)TE(−) (cirrhosis by US, but not by TE), US(−)TE(+) (cirrhosis by TE, but not by US) and US(−)TE(−) (non‐cirrhosis by US and TE).The patients were predominantly male (n = 5474, 58.9%) with a mean age of 47.5 years. The proportions of patients with cirrhosis diagnosed by US and TE were 17.2% (n = 1595) and 13.2% (n = 1225), respectively. The proportion of patients with discordant results in diagnosing cirrhosis by US and TE was 18.7% (n = 1740). During follow‐up (median: 60.0 months), HCC and liver‐related events developed in 481 (5.2%) and 759 (8.2%) patients, respectively. The cumulative incidence rates of HCC and liver‐related events were highest in the US(+)TE(+) group, intermediate‐high in the US(−)TE(+) group, intermediate‐low in the US(+)TE(−) group and lowest in the US(−)TE(−) group (overall p <.001). Cirrhosis assessed using US and TE was a major predictor of HCC and liver‐related event development in patients with CHB. Cirrhosis assessed using TE seemed better in predicting HCC or liver‐related events than using US, when cirrhosis diagnosis was discordant by US and TE. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) represent potential biomarkers because of their highly stable structure and robust expression pattern in clinical samples. The aim of this study was to evaluate the expression of a recently identified circRNA, hsa_circ_0005986; determine its clinical significance; and evaluate its potential as a biomarker of hepatocellular carcinoma (HCC). We evaluated hsa_circ_0005986 expression in 123 HCC tissue samples, its clinical significance, and its association with patients' clinicopathological characteristics and survival. Hsa_circ_0005986 expression was downregulated in HCC tissues. Low hsa_circ_0005986 expression was more common in tumors larger than 5 cm [odds ratio (OR), 3.19; 95% confidence interval (CI), 1.51–6.76; p = 0.002], advanced TNM stage (III/IV; OR, 2.39; 95% CI, 1.16–4.95; p = 0.018), and higher BCLC stage (B/C; OR, 2.71; 95% CI, 1.30–5.65; p = 0.007). High hsa_circ_0005986 expression was associated with improved survival and was an independent prognostic factor for overall [hazard ratio (HR), 0.572; 95% CI, 0.339–0.966; p = 0.037] and progression-free (HR, 0.573; 95% CI, 0.362–0.906; p = 0.017) survival. Moreover, the circRNA–miRNA–mRNA network was constructed using RNA-seq/miRNA-seq data and clinical information from TCGA-LIHC dataset. Our findings indicate a promising role for hsa_circ_0005986 as a prognostic biomarker in patients with HCC. [ABSTRACT FROM AUTHOR]

Background and Aim: 18F‐fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is a functional image technique that can inform clinical decisions related to prognosis. We investigated the predictive role of 18F‐fluorodeoxyglucose PET/CT in patients with hepatocellular carcinoma (HCC) undergoing Yttrium‐90 (Y‐90) transarterial radioembolization (TARE). Methods: Patients with HCC treated with TARE and pre‐TARE PET/CT scan were recruited between 2009 and 2013. Maximum standardized uptake value and tumor‐to‐non‐tumorous liver uptake ratio (TLR) were measured. Tumor response was evaluated in accordance with modified RECIST criteria at 3‐month intervals after Y‐90 TARE. Results: Forty patients were included in the final analysis. The median age was 56.5 years and male predominant. Disease control in treated lesion was achieved in 82.5% (n = 33) of patients. During median 18.3‐month follow‐up, 27.5% (n = 11) of patients achieved progression‐free survival. The cutoff of TLR, which was related to the median value, did not affect disease control rate, progression‐free survival, and overall survival in patients with Y‐90 TARE. Conclusions: The TLR‐based stratification may be a simple method, but our study did not show the usefulness in predicting prognosis in HCC patients with Y‐90 TARE. Further studies with large number of patients are needed. [ABSTRACT FROM AUTHOR]

CAGE‐B and SAGE‐B scores, consisting of age and fibrotic burden as cirrhosis and/or liver stiffness, were recently proposed to predict hepatocellular carcinoma (HCC) risk among Caucasian chronic hepatitis B (CHB) patients undergoing long‐term antiviral therapy. We externally validated their predictive performances among an independent cohort from Asia, compared to other conventional prediction models. We consecutively recruited CHB patients with well‐controlled viremia (serum HBV DNA < 2000 IU/mL) receiving antiviral therapy. Patients with decompensated cirrhosis or HCC at baseline were excluded. Among 1763 patients, CAGE‐B score provided the highest Heagerty's integrated area under the curve (iAUC) (0.820), followed by SAGE‐B (0.804), mREACH‐B (0.800), CAMD (0.786), mPAGE‐B (0.748) and PAGE‐B (0.721) scores. CAGE‐B score showed a significantly better performance than SAGE‐B, CAMD, PAGE‐B and mPAGE‐B scores, but was similar to mREACH‐B. SAGE‐B score also showed significantly better performance than mPAGE‐B and PAGE‐B, but was similar to CAMD and mREACH‐B. According to CAGE‐B score 0–5, 6–10 and ≥11, the annual HCC incidences were 0.18, 1.34 and 6.03 per 100 person‐years, respectively (all p < 0.001 between each pair). Likewise, by SAGE‐B score 0–5, 6–10 and ≥11, those were 0.31, 1.49 and 8.96 per 100 person‐years, respectively (all p < 0.001 between each pair). Hence, CAGE‐B and SAGE‐B scores showed acceptable predictive performances for Asian CHB patients undergoing antiviral therapy, with the higher performance by CAGE‐B score. They show a trend towards better prognostic capability to predict HCC risk than previous models. [ABSTRACT FROM AUTHOR]

Hepatitis B core-related antigen (HBcrAg) is a composite measure of the serum levels of hepatitis B e antigen, hepatitis B core antigen, and a 22-kDa precore protein. It has been shown to reflect the level and transcriptional activity of covalently closed circular DNA in the liver. Longitudinal cohort studies have improved our understanding of the role of this novel viral marker in the natural history of chronic hepatitis B. HBcrAg kinetics reflect the response to peginterferon, and its role in defining guidelines for stopping peginterferon therapy has been evaluated. HBcrAg is a marker of intrahepatic viral activity, which may influence the risk of hepatocellular carcinoma. In this article, we review the virology and role of HBcrAg in defining phases of chronic hepatitis B. Furthermore, the function of HBcrAg in predicting treatment outcomes and its role in monitoring response to novel antiviral agents will be discussed. [ABSTRACT FROM AUTHOR]

Background and Aim: T‐cell immunoglobulin and mucin‐domain containing molecule 3 (TIM3) has emerged as a promising immune checkpoint inhibitor target; however, immune checkpoint inhibitor monotherapy does not benefit a substantial percentage of patients. Therefore, this study investigated the antitumor effect of anti‐TIM3 therapy combined with radiation in a murine hepatocellular carcinoma (HCC) model. Methods: The effect of radiation on TIM3 expression was determined in murine and human HCC cells using western blotting, immunohistochemistry, and flow cytometry. Tumor growth and survival rate were measured to evaluate the antitumor effect of this combination therapy. Tumor immunological parameters were assessed using flow cytometry and histology. Results: TIM3 was upregulated in tumor‐infiltrating CD8+ and CD4+ T cells in radiation‐treated HCa‐1‐implanted mice. Combination treatment significantly delayed tumor growth compared with monotherapy (P < 0.01). Overall survival was improved in the combination group compared with that in the anti‐TIM3 or radiation monotherapy groups (median survival time: 52 days vs 26 or 38 days, respectively, P < 0.001). The antitumor effect of the combination treatment was associated with increased apoptosis and decreased proliferation of tumor cells and reinvigorated CD8+ T‐cell activation. CD8+ T‐cell depletion reversed the antitumor efficacy of the combination treatment. These findings suggest that CD8+ T cells play key roles in the therapeutic effect of the combination treatment. Conclusion: Anti‐TIM3 and radiation combination therapy significantly improved the antitumor effect in a murine HCC model, as evidenced by inhibited tumor growth and increased overall survival. This approach could be a novel combined immune‐radiotherapy strategy for HCC. [ABSTRACT FROM AUTHOR]

Aim: Risk prediction models for hepatocellular carcinoma (HCC) development are available. However, the influence of antiviral therapy (AVT) on these models in patients with chronic hepatitis B is unknown. Methods: The dynamic changes in risk prediction models during AVT and the association between risk prediction model and the risk of chronic hepatitis B‐related HCC development were investigated. Between 2005 and 2017, 4917 patients with chronic hepatitis B (3361 noncirrhotic, 1556 cirrhotic) were recruited. Results: The mean age of the study population was 49.3 years and 60.6% (n = 2980) of the patients were male. The mean Chinese University‐HCC (CU‐HCC) score was 12.7 at baseline in the overall study population, and decreased significantly (mean, 8.7) after 1 year of AVT (p < 0.001). The score was maintained throughout 5 years of AVT (mean, 8.4–8.8; p > 0.05). The proportion of high‐risk patients (CU‐HCC score ≥ 20) was 28.9% at baseline, and decreased significantly after 1 year of AVT (5.0%; p < 0.001), and remained stable through 5 years of AVT (2.2%–3.6%; p > 0.05). In addition to the score at baseline, the CU‐HCC score at 1 year of AVT independently predicted the risk of HCC development (hazard ratio = 1.072; p < 0.001), together with male gender and platelet count (all p < 0.05). Conclusions: The CU‐HCC score significantly decreased at 1 year of AVT and was maintained thereafter. The CU‐HCC score after 1 year of AVT independently predicted the risk of HCC development in patients with chronic hepatitis B. [ABSTRACT FROM AUTHOR]

The global pandemic of coronavirus disease‐2019 (COVID‐19) has led to significant disruptions in healthcare delivery. Patients with chronic liver diseases require a high level of care and are therefore particularly vulnerable to disruptions in medical services during COVID‐19. Recent data have also identified chronic liver disease as an independent risk factor for COVID‐19 related hospital mortality. In response to the pandemic, national and international societies have recommended interim changes to the management of patients with liver diseases. These modifications included the implementation of telehealth, postponement or cancelation of elective procedures, and other non‐urgent patient care‐related activities. There is concern that reduced access to diagnosis and treatment can also lead to increased morbidity in patients with liver diseases and we may witness a delayed surge of hospitalizations related to decompensated liver disease after the COVID‐19 pandemic has receded. Therefore, it is paramount that liver practices craft a comprehensive plan for safe resumption of clinical operations while minimizing the risk of exposure to patients and health‐care professionals. Here, we provide a broad roadmap for how to safely resume care for patients with chronic liver disease according to various phases of the pandemic with particular emphasis on outpatient care, liver transplantation, liver cancer care, and endoscopy. [ABSTRACT FROM AUTHOR]

• The definition of immune-tolerant phase of chronic hepatitis B and their prognosis is controversial. • Some studies suggest that early antiviral treatment are required for patients with immune-tolerant phase, but not others. • In this multi-center study from the East Asia, we used stringent criteria to define the genuine immune-tolerant phase with both age < 40 years and HBV DNA > 6 log 10 IU/mL. • The risk of hepatocellular carcinoma development during the untreated immune-tolerant phase is negligible. Background & aims: Whether chronic hepatitis B (CHB) patients during immune-tolerant (IT) phase are at low risk of hepatocellular carcinoma (HCC) is still controversial. We performed a multicenter study to determine their long-term prognosis. Methods: Untreated IT group included patients < 40 years of age, with persistently hepatitis B e antigen [HBeAg] positivity, serum HBV-DNA>6 log 10 IU/mL, and ALT level < 40 U/L, using age and HBV-DNA criteria by the American Association for the Study of Liver Diseases (AASLD) guideline. Cumulative HCC risk of untreated IT group (n =194) was compared to HBeAg-positive patients undergoing antiviral therapy according to the practice and reimbursement guidelines (treated HBeAg[+] group, n =454). Patients with history of cirrhosis or HCC at baseline were excluded. Results: During follow-up (median 62.1 months), HCC did not develop in any patient among untreated IT group, whereas the cumulative probability of HCC at 3, 5, and 9 years in the treated HBeAg(+) group was 0.5%, 0.7%, and 1.3%, respectively (p =0.203). Ninety-seven patients among untreated IT group entered immune-active phase, of whom 86 (88.7%) started antiviral treatment. A high normal ALT level (20–39 U/L) was associated with an increased risk of a phase change, compared to ALT < 20 U/L. After censoring at the time of phase change, the cumulative HCC risk was also not significantly different between two groups (p =0.258). Conclusions: No actual HCC risk during untreated IT phase defined by age and HBV-DNA criteria of the AASLD guideline exists, supporting their diagnostic validity from the perspective of long-term prognosis. Further validation studies are required. [ABSTRACT FROM AUTHOR]

Several prediction scores for the early detection of hepatocellular carcinoma (HCC) are available. We validated the predictive accuracy of age, albumin, sex, liver cirrhosis (AASL), RESCUE‐B, PAGE‐B and modified PAGE‐B (mPAGE‐B) scores in chronic hepatitis B (CHB) patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF). Between 2007 and 2014, 3171 patients were recruited (1645, ETV; 1517, TDF). The predictive accuracy of each prediction score was assessed. The mean age of the study population (1977 men; 1194 women) was 48.8 years. Liver cirrhosis was present in 1040 (32.8%) patients. During follow‐up (median, 58.2 months), 280 (8.8%) patients developed HCC; these patients were significantly older; more likely to be male; had significantly higher proportions of liver cirrhosis, hypertension and diabetes; and had significantly higher values for the four risk scores than those who did not develop HCC (all P <.05). Older age (hazard ratio [HR] = 1.048), male sex (HR = 2.142), liver cirrhosis (HR = 3.144) and prolonged prothrombin time (HR = 2.589) were independently associated with an increased risk of HCC (all P <.05), whereas a higher platelet count (HR = 0.996) was independently associated with a decreased risk of HCC (P <.05). The predictive accuracy of AASL score was the highest for 3‐ and 5‐year HCC predictions (areas under the curve [AUCs] = 0.818 and 0.816, respectively), followed by RESCUE‐B, PAGE‐B and mPAGE‐B scores (AUC = 0.780‐0.815 and 0.769‐0.814, respectively). In conclusion, four HCC prediction scores were assessed in Korean CHB patients treated with ETV or TDF. The AASL score showed the highest predictive accuracy. [ABSTRACT FROM AUTHOR]

The risk of developing hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) is reduced by antiviral therapy. Here, we evaluated the chronological trends in HCC development risk starting in 2007, when entecavir reimbursement was first initiated in South Korea. Treatment‐naïve patients with chronic hepatitis B (CHB) receiving entecavir 0.5 mg/d were stratified into three groups according to entecavir start time: early (2007‐2010), middle (2011‐2012) and late (2013‐2014) cohorts Among 2442 patients, cumulative probabilities of developing HCC after 1, 3 and 5 years were, respectively, 1.7%, 5.1%, and 8.2% (early cohort; n = 672); 1.5%, 5.1% and 8.9% (middle cohort; n = 757); and 1.2%, 5.3% and 10.6% (late cohort; n = 1013; P >.05 between each pair). Older age, male, positive hepatitis B e antigen, liver cirrhosis, Child‐Pugh class B (vs A) and lower platelet count significantly predicted HCC development in univariate analysis (P <.001), whereas entecavir start time (early vs middle vs late cohorts) did not affect the risk of HCC development (P =.457). A multivariate analysis revealed that older age (adjusted hazard ratio [aHR]=1.041), male gender (aHR = 2.069), liver cirrhosis (aHR = 3.771) and Child‐Pugh class B (vs A, aHR = 1.548) were independently associated with an increased risk of HCC development, whereas higher platelet count was independently associated with a reduced risk of HCC development (aHR = 0.993; all P <.05). In conclusion, the risk of developing HCC among patients receiving entecavir in South Korea has been stable since 2007. To establish more effective HCC surveillance programs, further studies regarding the carcinogenic roles of nonviral factors are required. [ABSTRACT FROM AUTHOR]

Background and Aim: Male sex is a risk factor for hepatocellular carcinoma (HCC). Diabetes mellitus (DM) is associated with a doubled risk of HCC in patients with chronic hepatitis B (CHB). We examined the relationship between serum total testosterone and HCC risk in male CHB patients with DM. Methods: We performed a retrospective cohort study of male CHB patients with DM between 2000 and 2017 using a territory‐wide electronic health‐care database in Hong Kong. DM was defined by use of anti‐diabetic medications, hemoglobin A1c ≥ 6.5%, and/or fasting glucose ≥ 7 mmol/L in two measurements or ≥ 11.1 mmol/L in one measurement. Results: Of 928 male CHB patients with DM, 83 (8.9%) developed HCC at a median (interquartile range) of 10.7 (6.1–14.6) years. Higher testosterone was associated with an elevated risk of HCC (adjusted hazard ratio [aHR] per 1 SD increase 1.23, 95% confidence interval [CI] 1.03–1.46, P = 0.024). The upper tertile of testosterone (aHR 1.86, 95% CI 1.02–3.39, P = 0.043), but not middle tertile (aHR 0.84, 95% CI 0.41–1.69 P = 0.620), was associated with a higher risk of HCC than the lower tertile. The cumulative incidence (95% CI) of HCC at 5, 10, and 15 years was 4.4% (2.5–7.2%), 12.4% (8.7–16.7%), and 19.1% (14.2–24.5%), respectively, in patients in the upper tertile of testosterone. By subgroup analysis, the association between testosterone and HCC was stronger in patients aged ≥ 50 years and those not receiving antiviral therapy. Conclusion: Higher serum testosterone is associated with a higher incidence of HCC in male CHB patients with DM. [ABSTRACT FROM AUTHOR]

The use of tenofovir disoproxil fumarate (TDF) is associated with a risk of renal dysfunction. We investigated whether TDF is associated with the deterioration of renal function in patients with hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) requiring frequent computed tomography (CT) evaluations and transarterial chemoembolization (TACE) sessions, when compared to entecavir (ETV). Between 2007 and 2017, 493 patients with HBV‐related HCC were enrolled. The number of CT evaluations and TACE sessions were collected through 3 years of follow‐up. The median age of the study population (373 men and 120 women; 325 with ETV and 168 with TDF) was 56.5 years. TDF was significantly associated with a serum creatinine increase (≥25% from the baseline; unadjusted hazard ratio [uHR] = 1.620) and an estimated glomerular filtration rate (eGFR) reduction (<20% from the baseline) (uHR = 1.950) (all P <.05), when compared to ETV. In addition, CT evaluations ≥4 times/year were significantly associated with a serum creatinine increase (uHR = 2.709), eGFR reduction (uHR = 3.274) and chronic kidney disease (CKD) progression (≥1 CKD stage from the baseline) (uHR = 1.980) (all P <.05). In contrast, TACE was not associated with all renal dysfunction parameters (all P >.05). After adjustment, TDF use was independently associated with the increased risk of eGFR reduction (adjusted HR [aHR] = 1.945; P =.023), whereas CT evaluation ≥4 times/year was independently associated with the increased risk of serum creatinine increase (aHR = 2.898), eGFR reduction (aHR = 3.484) and CKD progression (aHR = 1.984) (all P <.01). In conclusion, patients with HBV‐related HCC treated with TDF and frequent CT evaluations should be closely monitored for the detection of associated renal dysfunction. [ABSTRACT FROM AUTHOR]

Thiazolidinediones (TZDs) improve glycaemic control and ameliorate liver steatosis, inflammation and fibrosis in patients with fatty liver disease. We aimed to study the impact of TZD and glycaemic control on the risk of hepatocellular carcinoma (HCC) and hepatic events in diabetic patients with chronic hepatitis B (CHB). We performed a retrospective cohort study on diabetic patients with CHB in 2000‐2017 using a territory‐wide electronic healthcare database in Hong Kong. Diabetes mellitus was identified by use of any antidiabetic medication, haemoglobin A1c (HbA1c) ≥6.5%, fasting glucose ≥7 mmol/L in two measurements or ≥11.1 mmol/L in one measurement and/or diagnosis codes. Use of antidiabetic medications was modelled as time‐dependent covariates. Of 28 999 diabetic patients with CHB, 3963 (13.7%) developed liver‐related events (a composite endpoint of HCC and hepatic events) at a median (interquartile range) follow‐up of 7.1 (3.7‐11.8) years; 1153 patients received TZD during follow‐up. After adjusted for important confounders, TZD use was associated with a reduced risk of liver‐related events (adjusted hazard ratio [aHR] 0.46, 95% confidence interval [CI] 0.24‐0.88; P =.019). Similar trends were observed in HCC (aHR 0.57) and hepatic events (aHR 0.35) separately. Compared to HbA1c of 6.5% at baseline, patients with HbA1c ≥7% had an increased risk of liver‐related events; the risk further increased in 5795 (20.0%) patients with HbA1c ≥9% at baseline (aHR 1.14, 95% CI 1.04‐1.26; P =.006). TZD use is associated with a lower risk of liver‐related events in diabetic patients with CHB. Liver‐related events are more common in patients with high HbA1c levels. [ABSTRACT FROM AUTHOR]

It is important to identify patients at high risk for alcohol-associated HCC and to assess the HCC risk continuously in these patients. Further validation in a greater number of patients with alcohol-associated cirrhosis is needed.[8] The above-mentioned scores are useful for assessing the HCC risk in cirrhotic patients. Promoting compliance with hepatocellular carcinoma (HCC) surveillance in alcoholic patients is challenging. [Extracted from the article]

Background and Aims: The modified PAGE‐B (mPAGE‐B) score comprising age, gender, platelet count and albumin was recently proposed to predict hepatocellular carcinoma (HCC) risk among chronic hepatitis B (CHB) patients undergoing antivirals. Here, in the independent cohort, we externally validated the predictive performance of the mPAGE‐B score and compared it with those of conventional HCC prediction models. Methods: We consecutively recruited CHB patients treated with lamivudine, entecavir or tenofovir as the first‐line antiviral regimen. Patients with decompensated cirrhosis or HCC at baseline were excluded. Predictive performances of the mPAGE‐B score and other models were assessed with comparison. Results: Among 1330 patients, 9.6% developed HCC during follow‐up. The mPAGE‐B score provided the highest Harrell's c‐index (0.769), followed by the GAG‐HCC (0.751), PAGE (0.744), REACH‐B (0.686) and CU‐HCC (0.618) scores. The mPAGE‐B score showed the similar performance to the PAGE‐B and GAG‐HCC scores and the better performance than the REACH‐B and CU‐HCC scores. Cumulative HCC probabilities at 5‐ and 7‐years were 0.0% and 0.0% in low‐risk group (mPAGE‐B score ≤ 8), 6.1% and 10.8% in intermediate‐risk group (mPAGE‐B score 9‐12) and 18.7% and 26.7% in high‐risk group (mPAGE‐B score ≥ 13) respectively (both P < 0.001 between adjacent two groups). C‐indices of the mPAGE‐B score were 0.785 and 0.724 among subgroups treated with entecavir or tenofovir (n = 1011) and with lamivudine (n = 319), respectively, which are overall similar to those of the PAGE‐B score. Conclusion: The mPAGE‐B score showed acceptable predictive performances. Compared to the PAGE‐B score, addition of albumin as a constituent provided the marginal benefit. [ABSTRACT FROM AUTHOR]

Background: There are large variations in prognosis among hepatocellular carcinoma (HCC) patients undergoing radiofrequency ablation (RFA). However, current staging or scoring systems hardly discriminate the outcome of HCC patients treated with RFA. Methods: A total of 757 treatment‐naïve HCC patients undergoing RFA (derivation cohort) were analyzed to establish a nomogram for disease‐free survival (DFS) based on Cox proportional hazard regression model. Accuracy of the nomogram was assessed and compared with conventional staging or scoring systems. Furthermore, external validation was performed in an independent cohort including 208 patients (validation cohort). Results: Tumor size, tumor number, alpha‐fetoprotein, prothrombin induced by vitamin K absence‐II, lymphocyte count, albumin, and presence of ascites were adopted to construct the prognostic nomogram from the derivation cohort. Calibration curves to predict probability of DFS at 3 and 5 years after RFA showed good agreements between the nomogram and actual observations. The concordance index of the present nomogram was 0.759 (95% confidence interval 0.728‐0.790), which was superior to those of conventional staging or scoring systems (range 0.505‐0.683, all P < .001). These results were also reproduced in the validation cohort. Conclusion: Our simple‐to‐use nomogram optimized for treatment‐naïve HCC patients undergoing RFA provided better prognostic performance than conventional staging or scoring systems. [ABSTRACT FROM AUTHOR]

Exosomal noncoding RNAs (ncRNAs) have unique expression profiles reflecting the characteristics of a tumor, and their role in tumor progression and metastasis is emerging. However, the significance of circulating exosomal ncRNAs in the prognosis of hepatocellular carcinoma (HCC) remains to be elucidated. We therefore determined the prognostic significance of circulating exosomal ncRNAs (miRNA‐21 and lncRNA‐ATB) for human HCC. This prospective study enrolled 79 HCC patients between October 2014 and September 2015. Exosomes were extracted from serum samples using the ExoQuick Exosome Precipitation Solution. To validate the isolation of the exosomes from serum, immunoblotting for exosome markers and characterization of nanoparticle using NanoSight were performed. NcRNAs were isolated from exosomes using the miRNeasy serum/plasma micro kit. Both circulating exosomal miRNA‐21 and lncRNA‐ATB were related to TNM stage and other prognostic factors, including the T stage and portal vein thrombosis. Multivariate analysis using the Cox regression test identified that both higher miRNA‐21 and higher lncRNA‐ATB were independent predictors of mortality and disease progression, along with larger tumor size and higher C‐reactive protein (all p < 0.05). The overall survival and progression‐free survival were significantly lower in patients with higher circulating levels of exosomal miRNA‐21 (≥0.09) and lncRNA‐ATB (≥0.0016) (log‐rank test: p < 0.05). In conclusion, our study has provided strong evidence that circulating exosomal ncRNAs (miRNA‐21 and lncRNA‐ATB) are novel prognostic markers and therapeutic targets for HCC. What's new? A growing body of evidence indicates that noncoding RNAs (ncRNAs), such as miRNAs and lncRNAs, play an important role in tumor progression and metastasis. Could particular ncRNAs also serve as serum biomarkers for cancer prognosis? In our study, the authors found that two specific ncRNAs in circulating exosomes were independent predictors of overall survival and disease progression in human hepatocellular carcinoma (HCC). These molecules might therefore provide valuable biomarkers to improve the clinical management of HCC, as well as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Background & Aims: We compared the risk of hepatocellular carcinoma (HCC) development between patients with chronic hepatitis B (CHB) who achieved virological response (VR; HBV‐DNA < 2000 IU/mL) with nucleos(t)ide analogues (NUCs) treatment (NUC‐VR group) and patients with inactive CHB phase (ICHBP group). Methods: To adjust for imbalances between NUC‐VR and ICHBP groups, propensity score matching (PSM) models with 1:1 ratios were performed. Results: This study included 2032 patients (n = 1291 in NUC‐VR group and n = 741 in ICHBP group). Before PSM, NUC‐VR group was at higher risk of HCC development than ICHBP group at 7 years (9.4% in NUC‐VR group vs 3.3% in ICHBP group; P < 0.001). However, after PSM, the cumulative HCC development rates at 7 years were similar in NUC‐VR and ICHBP groups using the three PSM models [2.0% vs 4.3%, PSM model‐1 (612 pairs); 3.7% vs 4.4%, PSM model‐2 (618 pairs); and 2.4% vs 4.3%, PSM model‐3 (610 pairs)] (all P > 0.05). Conclusions: After adjusting heavier hepatic fibrosis burden in NUC‐VR group, overall clinical outcomes between 2 groups had become comparable. Therefore, if appropriate, NUCs to prevent viral replication and hepatic inflammation are required for achieving better prognosis. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Several risk prediction models for hepatocellular carcinoma (HCC) development are available. We explored whether the use of risk prediction models can dynamically predict HCC development at different time points in chronic hepatitis B (CHB) patients. Methods: Between 2006 and 2014, 1397 CHB patients were recruited. All patients underwent serial transient elastography at intervals of >6 months. Results: The median age of this study population (931 males and 466 females) was 49.0 years. The median CU‐HCC, REACH‐B, LSM‐HCC and mREACH‐B score at enrolment were 4.0, 9.0, 10.0 and 8.0 respectively. During the follow‐up period (median, 68.0 months), 87 (6.2%) patients developed HCC. All risk prediction models were successful in predicting HCC development at both the first liver stiffness (LS) measurement (hazard ratio [HR] = 1.067‐1.467 in the subgroup without antiviral therapy [AVT] and 1.096‐1.458 in the subgroup with AVT) and second LS measurement (HR = 1.125‐1.448 in the subgroup without AVT and 1.087‐1.249 in the subgroup with AVT). In contrast, neither the absolute nor percentage change in the scores from the risk prediction models predicted HCC development (all P > .05). The mREACH‐B score performed similarly or significantly better than did the other scores (AUROCs at 5 years, 0.694‐0.862 vs 0.537‐0.875). Conclusions: Dynamic prediction of HCC development at different time points was achieved using four risk prediction models, but not using the changes in the absolute and percentage values between two time points. The mREACH‐B score was the most appropriate prediction model of HCC development among four prediction models. [ABSTRACT FROM AUTHOR]

We investigated whether baseline and on-treatment alanine aminotransferase (ALT) levels during entecavir (ETV) therapy are associated with achieving subcirrhotic liver stiffness (LS) and hepatocellular carcinoma (HCC) development in patients with hepatitis B virus (HBV)–related cirrhosis. We analyzed data from 347 treatment-naïve patients with HBV-related cirrhosis, who started ETV between 2006 and 2011 and were followed up for >5 years without developing HCC. The study outcomes were achieving subcirrhotic LS at 5 years of ETV, and risk of HCC development beyond 5 years of ETV. Subcirrhotic LS was defined as <12 kPa by transient elastography. After 5 years of ETV, 227 (65.4%) patients achieved subcirrhotic LS. During a median follow-up of 9.2 years, 49 (14.1%) patients developed HCC beyond 5 years of ETV. ALT levels at baseline, at 1 year of ETV therapy, and 5 years of ETV therapy were not associated with the probability of achieving subcirrhotic LS at 5 years of ETV therapy or risk of HCC development beyond 5 years of ETV therapy (all P >.05). Patients achieving subcirrhotic LS at 5 years of ETV therapy had significantly lower risk of HCC development than those who did not (adjusted hazard ratio, 0.33; 95% confidence interval, 0.17–0.64; P =.001). Baseline and on-treatment ALT levels were not associated with achieving subcirrhotic LS at 5 years of ETV therapy or with risk of HCC development beyond 5 years of ETV therapy in patients with HBV-related cirrhosis. Achieving subcirrhotic LS at 5 years of ETV therapy was independently associated with lower risk of HCC development beyond 5 years of ETV therapy. ▪ [ABSTRACT FROM AUTHOR]

Background: The clinical features of hepatocellular carcinoma (HCC) differ in patients with and without cirrhosis. Objective: We aimed to investigate the long-term outcomes of noncirrhotic HCC patients after curative resection. Methods: We retrospectively examined 649 consecutive patients with HCC who underwent curative resection from 1996 to 2012; 387 (59.6%) were cirrhotic and 262 (40.4%) were noncirrhotic. Results: The mean age was 54.7 years, and 511 (78.7%) of the study participants were men. The most common cause of HCC was hepatitis B virus (n = 419, 64.6%). Noncirrhotic tumors were larger and more advanced than cirrhotic tumors. However, the noncirrhotic group showed better disease-free survival (DFS) and overall survival (OS) after resection than the cirrhotic group (median 64.0 vs. 56.0 months for OS and 48.0 vs. 31.0 months for DFS, p < 0.05). The predictors for HCC recurrence were cirrhosis, tumor number, portal vein invasion, and major surgery. Conclusions: Noncirrhotic HCC showed better DFS and OS after resection than cirrhotic HCC, although noncirrhotic HCC presented more aggressively. [ABSTRACT FROM AUTHOR]

Simple Summary: Sorafenib (Nexavar@) is the only currently approved anti-cancer drug for patients with advanced hepatocellular carcinoma (HCC). However, despite the development of strategies combining sorafenib with other cytotoxic chemotherapeutic agents to overcome sorafenib resistance, clinical trial results are still disappointing. In this study, we examined the enhancement of tumor responses to sorafenib by exogenous histidine treatment. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib, a multi-kinase inhibitor, is the first-line therapy for advanced HCC. However, long-term exposure to sorafenib often results in reduced sensitivity and the development of resistance. Although various amino acids have been shown to contribute to cancer initiation and progression, little is known about the effects of histidine, a dietary essential amino acid that is partially taken up via histidine/large neutral amino acid transporter (LAT1), on cancer cells. In this study, we evaluated the effects of histidine on HCC cells and sensitivity to sorafenib. Remarkably, we found that exogenous histidine treatment induced a reduction in the expression of tumor markers related to glycolysis (GLUT1 and HK2), inflammation (STAT3), angiogenesis (VEGFB and VEGFC), and stem cells (CD133). In addition, LAT1 expression was downregulated in HCC tumor regions with high expression of GLUT1, CD133, and pSTAT3, which are known to induce sorafenib resistance. Finally, we demonstrated that combined treatment with sorafenib and histidine could be a novel therapeutic strategy to enhance the sensitivity to sorafenib, thereby improving long-term survival in HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Transarterial chemoembolization (TACE) is used to treat patients with intermediate stage hepatocellular carcinoma (HCC). However, models to accurately predict survival are lacking. The aim of our retrospective study was to attempt to validate the prognostic performance of the newly proposed Pre- and Post-TACE-Predict models with Korean patients. In our study of 187 patients with HCC who underwent TACE, there was no significant difference between the Pre- and Post-TACE prediction models in HCC patients. Additionally, simple scoring prognosis prediction models performed similarly to or better than the Pre- and Post-TACE-Predict models in our study. Thus, simple scoring prognosis prediction models such as modified hepatoma arterial embolization prognostic (mHAP)-II and SNACOR may be useful in assessing the TACE treatment survival over the Pre- and Post-TACE-Predict models in patients with HCC. This study attempted to validate the prognostic performance of the proposed Pre- and Post-TACE (transarterial chemoembolization)-Predict models, in comparison with other models for prognostication. One-hundred-and-eighty-seven patients with HCC who underwent TACE were recruited. Regarding overall survival (OS), the predictive performance of the Pre-TACE-Predict model (one-year integrated area under the curve (iAUC) 0.685 (95% confidence interval (CI) 0.593–0.772)) was better than that of the Post-TACE-Predict model (iAUC 0.659 (95% CI 0.580–0.742)). However, there was no significant statistical difference between two models at any time point. For comparison between models using pre-treatment factors, the modified hepatoma arterial embolization prognostic (mHAP)-II model demonstrated significantly better predictive performance at one year (iAUC 0.767 (95% CI 0.683–0.847)) compared with Pre-TACE-Predict. For comparison between models using first TACE response, the SNACOR model was significantly more predictive at one year (iAUC 0.778 (95% CI 0.687–0.866) vs. 0.659 (95% CI 0.580–0.742), respectively) and three years (iAUC 0.707 (95% CI 0.646–0.770) vs. 0.624 (95% CI 0.564–0.688), respectively) than the Post-TACE-Predict model. mHAP-II and SNACOR may be preferred over the Pre- and Post-TACE-Predict models, respectively, considering their similar or better performance and the ease of application. [ABSTRACT FROM AUTHOR]

Simple Summary: We developed a novel risk-scoring model for hepatocellular carcinoma development in treatment-naïve patients with chronic hepatitis B virus infection who are starting antiviral therapy with entecavir or tenofovir. The model reflects age, platelet count, hepatitis B e antigen positivity, serum albumin and total bilirubin levels, cirrhosis development, and liver stiffness values measured by transient elastography. Our new model showed better performance for predicting hepatocellular carcinoma development (Harrell's c-index: 0.799) than the PAGE-B, modified PAGE-B, and modified REACH-B models in Asian patients with chronic hepatitis B receiving potent antiviral therapy. Hepatocellular carcinoma (HCC) risk prediction is important to developing individualized surveillance approaches. We designed a novel HCC prediction model using liver stiffness on transient elastography for patients receiving antiviral therapy against hepatitis B virus (HBV) infection. We recruited 2037 patients receiving entecavir or tenofovir as first-line antivirals and used the Cox regression analysis to determine key variables for model construction. Within 58.1 months (median), HCC developed in 182 (8.9%) patients. Patients with HCC showed a higher prevalence of cirrhosis (90.7% vs. 45.9%) and higher liver stiffness values (median 13.9 vs. 7.2 kPa) than those without. A novel nomogram (score 0–304) was established using age, platelet count, cirrhosis development, and liver stiffness values, which were independently associated with increased HCC risk, along with hepatitis B e antigen positivity and serum albumin and total bilirubin levels. Cumulative HCC probabilities were 0.7%, 5.0%, and 22.7% in the low- (score ≤87), intermediate- (88–222), and high-risk (≥223) groups, respectively. The c-index value was 0.799 (internal validity: 0.805), higher than that of the PAGE-B (0.726), modified PAGE-B (0.756), and modified REACH-B (0.761) models (all p < 0.05). Our nomogram showed acceptable performance in predicting HCC in Asian HBV-infected patients receiving potent antiviral therapy. [ABSTRACT FROM AUTHOR]