Conventional and machine-learning based risk score for patients with early-stage hepatocellular carcinoma.

Background/Aims: The performance of machine-learning (ML) in predicting the outcomes of patients with hepatocellular carcinoma (HCC) remains uncertain. We aimed to develop risk scores using conventional methods and ML to categorize early-stage HCC patients into distinct prognostic groups. Methods: The study retrospectively enrolled 1411 consecutive treatment-naïve patients with the Barcelona Clinic Liver Cancer (BCLC) stage 0 to A HCC from 2012 to 2021. The patients were randomly divided into a training cohort (n=988) and validation cohort (n=423). Two risk scores (CATS-IF and CATS-INF) were developed to predict overall survival (OS) in the training cohort using the conventional methods (Cox proportional hazards model) and ML-based methods (LASSO Cox regression), respectively. They were then validated and compared in the validation cohort. Results: In the training cohort, factors for the CATS-IF score were selected by the conventional method, including age, curative treatment, single large HCC, serum creatinine and alpha-fetoprotein levels, fibrosis-4 score, lymphocyte-to-monocyte ratio, and albumin bilirubin grade. The CATS-INF score, determined by ML-based methods, included the above factors and two additional ones (aspartate aminotransferase and prognostic nutritional index). In the validation cohort, both CATS-IF score and CATS-INF score outperformed other modern prognostic scores in predicting OS, with the CATS-INF score having the lowest Akaike information criterion value. A calibration plot exhibited good correlation between predicted and observed outcomes for both scores. Conclusions: Both the conventional Cox-based CATS-IF score and ML-based CATS-INF score effectively stratified patients with early-stage HCC into distinct prognostic groups, with the CATS-INF score showing slightly superior performance.

Risk factors associated with hepatitis D virus infection and preventive strategies in Mongolia.

BACKGROUND: Hepatitis D virus (HDV) infection is highly prevalent in Mongolia. We aimed to identify the risk factors associated with HDV infection, propose preventive strategies, and evaluate the outcomes of a 3-year collaborative project between Taiwan and Mongolia. METHODS: In 2016 and 2018, we conducted onsite visits to Mongolia. Mongolian investigators collected questionnaires focusing on risk factors, demographic characteristics, and serum samples for acute HDV infections. Furthermore, 19 Mongolian seed teachers participated in a 1-week workshop on infection control in Taiwan. Subsequently, these seed teachers trained more than 400 medical personnel in Mongolia. To assess secular changes in acute HDV infection, we reviewed the registration data from the National Center for Communicable Disease (NCCD) in Mongolia between 2011 and 2021. RESULTS: Among the 194 Mongolian patients, 108 had dual infection with hepatitis B virus (HBV) and HDV, while 86 had acute hepatitis B (AHB). Patients with HBV/HDV dual infections were older (28.6 vs 25.5 years, p = 0.030) and had lower rates of positive hepatitis B e antigen in their sera, lower rates of serum HBV DNA exceeding 2000 IU/mL, and higher rates of having received dental treatment (59.4% vs 40.5%, p = 0.014) and injection therapy (64.2% vs 44.0%, p = 0.009) compared with those with AHB. Analysis of NCCD data revealed that new HDV infection cases were more prevalent between 2011 and 2015 (111.20 ± 29.79 cases/y) and decreased to 54.67 ± 27.34 cases/y between 2016 and 2021 ( p = 0.010). CONCLUSION: Dental treatment and injections were associated with a higher risk of acute HDV infections in Mongolia. Through collaborative efforts, the incidence rate of HDV infection has declined in recent years.

Prognostic Nutritional Index as a Prognostic Factor for Very Early-Stage Hepatocellular Carcinoma.

INTRODUCTION: Field factors play more important roles in predicting the outcomes of patients compared with tumor factors in early-stage hepatocellular carcinoma (HCC). However, the prognostic ability of noninvasive serum marker scores for hepatic fibrosis and liver functional reserve on very early-stage HCC is still not yet determined. We aimed to investigate the performance of these serum marker scores in predicting the prognoses of patients with very early-stage HCC. METHODS: A total of 446 patients with very early-stage HCC from 2012 to 2022 were retrospectively enrolled. Serum biomarkers and prognostic scores determining overall survival (OS) were analyzed by Cox proportional hazards model. We compared the Akaike information criterion among the prognostic nutritional index (PNI), aspartate aminotransferase-to-platelet ratio index, albumin-bilirubin (ALBI) score, EZ (easy)-ALBI score, modified ALBI score, fibrosis-4 score, and lymphocyte-to-monocyte ratio to determine the predictability on the OS. RESULTS: After a median follow-up of 41.0 months (interquartile range 36.9-45.1 months), 81 patients died, with a 5-year OS rate of 71.0%. Among the noninvasive serum marker scores, PNI had the best performance in predicting the OS with the lowest Akaike information criterion (846.407) compared with other scores. Moreover, we stratified the patients into high-risk (PNI <45) and low-risk (PNI ≥45) groups. It showed that the 5-year OS rates were 83.4% and 60.8% in the low-risk and high-risk PNI groups, respectively ( P < 0.001). DISCUSSION: PNI had the best performance in predicting the OS for patients with very early-stage HCC.

Antiviral therapy reduces hepatocellular carcinoma through suppressing hepatitis B virus replication may improve ER stress, mitochondrial and metabolic dysfunctions and decrease p62 in hybridized mice with single HBV transgene and miR-122.

Hepatitis B virus (HBV) hijacks autophagy for its replication. Nucleos(t)ide analogs (NUCs) treatment suppressed HBV replication and reduced hepatocellular carcinoma (HCC) incidence. However, the use of NUCs in chronic hepatitis B (CHB) patients with normal or minimally elevated serum alanine aminotransferase (ALT) levels is still debated. Animal models are crucial for studying the unanswered issue and evaluating new therapies. MicroRNA-122 (miR-122), which regulates fatty acid and cholesterol metabolism, is downregulated during hepatitis and HCC progression. The reciprocal inhibition of miR-122 with HBV highlights its role in HCC development as a tumor suppressor. By crossbreeding HBV-transgenic mice with miR-122 knockout mice, we generated a hybrid mouse model with a high incidence of HCC up to 89% and normal ALT levels before HCC. The model exhibited early-onset hepatic steatosis, progressive liver fibrosis, and impaired late-phase autophagy. Metabolomics and microarray analysis identified metabolic signatures, including dysregulation of lipid metabolism, inflammation, genomic instability, the Warburg effect, reduced TCA cycle flux, energy deficiency, and impaired free radical scavenging. Antiviral treatment reduced HCC incidence in hybrid mice by approximately 30-35% compared to untreated mice. This effect was linked to the activation of ER stress-responsive transcription factor ATF4, clearance of autophagosome cargo p62, and suppression of the CHOP-mediated apoptosis pathway. In summary, this study suggests that despite minimal ALT elevation, HBV replication can lead to liver injury. Endoplasmic reticulum stress, reduced miR-122 levels, mitochondrial and metabolic dysfunctions, blocking protective autophagy resulting in p62 accumulation, apoptosis, fibrosis, and HCC. Antiviral may improve the above-mentioned pathogenesis through HBV suppression.

The outcomes and prognostic factors of patients with hepatocellular carcinoma and Child-Turcotte-Pugh class B.

BACKGROUND: The Child-Turcotte-Pugh (CTP) score is widely used for assessing the liver's functional reserve in patients with advanced chronic liver disease (ACLD) and hepatocellular carcinoma (HCC). This study aims to explore the outcomes of patients with HCC and CTP class B and to investigate the prognostic accuracy of prediction models for ACLD in these patients. METHODS: We retrospectively enrolled 1143 patients with HCC and CTP class B between 2007 and 2022. We divided the patients into three subgroups based on their CTP scores: CTP-B7, CTP-B8, and CTP-B9. We compared the corrected Akaike information criterion among each mortality prediction model, including the CTP score, albumin-bilirubin (ALBI) score, modified ALBI score, the model for end-stage liver disease (MELD), and MELD 3.0. RESULTS: Among the enrolled patients, 576 (50.3%) were in the CTP-B7 group, 363 (31.8%) were in the CTP-B8 group, and 204 (17.9%) were in the CTP-B9 group. After a median follow-up of 4.6 months (interquartile range IQR 1.8-17.2 months), 963 patients died, and the 5-year overall survival (OS) rate was 11.4%. The 5-year OS rates were 11.6%, 13.6%, and 8.3% in the CTP-B7, CTP-B8, and CTP-B9 groups, respectively. Patients in the CTP-B7 group and CTP-B8 group had comparable OS ( p = 0.089), both of which were better than those in the CTP-B9 group ( p < 0.001). Furthermore, the MELD 3.0 score had the lowest corrected akaike information criteria value and provided a more accurate mortality prediction than the MELD score, ALBI grade, modified ALBI grade, and CTP score. CONCLUSION: Patients in the CTP-B7 and CTP-B8 groups had comparable OS, both of which were better than those in the CTP-B9 group. Moreover, MELD 3.0 provided the most accurate mortality prediction in patients with HCC and CTP class B.

Entecavir versus tenofovir on prognosis of hepatitis B virus-related hepatocellular carcinoma after curative hepatectomy.

BACKGROUND: There is still controversy about whether tenofovir disoproxil fumarate (TDF) and entecavir (ETV) have different effects on the outcomes of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). AIMS: The aim of this study was to compare the prognoses between ETV and TDF treatment among patients with HBV-related HCC after hepatectomy. METHODS: An analysis was done on data from the Taiwan Cancer Registry, which was linked to Taiwan National Health Insurance Research Database, for the years 2011-2016. We identified 7107 patients with HBV-related HCC after curative hepatectomy, and 25.3% of them used ETV or TDF after surgery. After propensity score overlap weighting, 1797 patients treated with ETV (n = 1365) or TDF (n = 432) were included for analyses. Cox proportional hazards models were used to compare the efficacy of ETV and TDF for recurrence and overall survival (OS). RESULTS: After hepatectomy, the recurrence rate per 100 person-years was 14.87 for the ETV group and 9.25 for the TDF group. The risk of recurrence was similar in the TDF group and the ETV group (HR [95% CI]: 0.91 [0.69-1.19; p = 0.479]), as was the risk of all-cause mortality (HR [95% CI]: 0.67 [0.42-1.07]; p = 0.091). When considering early recurrence (<2 years) and late recurrence (≧2 years), the TDF and ETV groups showed no significant differences. Subgroup analyses and sensitivity analyses demonstrated consistent results. CONCLUSION: Both TDF and ETV showed similar health benefits in terms of recurrence and OS in patients with HBV-related HCC patients after hepatectomy.

The outcomes and prognostic factors of patients with hepatocellular carcinoma and normal serum alpha fetoprotein levels.

BACKGROUND: Alpha fetoprotein (AFP) is the most widely used tumor marker for hepatocellular carcinoma (HCC). Nevertheless, few studies have investigated the prognostic factors of HCC patients with normal serum AFP levels. METHODS: We retrospectively enrolled 2198 patients with HCC and normal serum AFP levels (<20 ng/mL) from 2007 to 2020. Overall survival (OS) rates were calculated by the Kaplan-Meier method, and analyses of the prognostic factors were performed using a Cox proportional hazard model. RESULTS: Among the enrolled patients, 1385 (63%) patients were in the low-normal AFP group (serum AFP levels ≤7 ng/mL), and 813 (37%) patients were in the high-normal AFP group (serum AFP levels between 7 and 20 ng/mL). The high-normal AFP group had poorer liver functional reserve, more multiple tumors, and smaller tumor size compared to those in the low-normal AFP group. After a median follow-up of 32.4 months, 942 patients died, and the 5-year OS rate was 54.4%. The 5-year OS rates were 57.4% and 49.8% in the low-normal AFP group and high-normal AFP group, respectively (p = 0.001). A multivariate analysis showed the independent prognostic factors of poor OS were no anti-viral therapy, advanced albumin-bilirubin grades, the presence of vascular invasion, tumor size ≥5 cm, and non-curative treatment modalities. Serum AFP levels were not associated with OS according to the multivariate analysis. CONCLUSION: Liver functional reserve, anti-viral therapy, tumor size, vascular invasion, and treatment modalities, determined the outcomes of HCC patients with normal serum AFP levels, but serum AFP levels did not.

Gene coexpression network analysis identifies hubs in hepatitis B virus-associated hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide. The molecular pathogenesis of HCC involves multiple signaling pathways. This study utilizes systems and bioinformatic approaches to investigate the pathogenesis of HCC. METHODS: Gene expression microarray data were obtained from 50 patients with chronic hepatitis B and HCC. There were 1649 differentially expressed genes inferred from tumorous and nontumorous datasets. Weighted gene coexpression network analysis (WGCNA) was performed to construct clustered coexpressed gene modules. Statistical analysis was used to study the correlation between gene coexpression networks and demographic features of patients. Functional annotation and pathway inference were explored for each coexpression network. Network analysis identified hub genes of the prognostic gene coexpression network. The hub genes were further validated with a public database. RESULT: Five distinct gene coexpression networks were identified by WGCNA. A distinct coexpressed gene network was significantly correlated with HCC prognosis. Pathway analysis of this network revealed extensive integration with cell cycle regulation. Ten hub genes of this gene network were inferred from protein-protein interaction network analysis and further validated in an external validation dataset. Survival analysis showed that lower expression of the 10-gene signature had better overall survival and recurrence-free survival. CONCLUSION: This study identified a crucial gene coexpression network associated with the prognosis of hepatitis B virus-related HCC. The identified hub genes may provide insights for HCC pathogenesis and may be potential prognostic markers or therapeutic targets.

Comparison of prognoses between cirrhotic and noncirrhotic patients with hepatocellular carcinoma and esophageal varices undergoing surgical resection.

BACKGROUND: Esophageal varices (EV) is common and is a poor prognostic factor for patients with hepatocellular carcinoma (HCC). However, the outcomes between cirrhotic and noncirrhotic HCC patients with EV is not well studied. The present study aimed to investigate the clinical manifestations and prognoses of HCC patients after surgical resection stratified by the cirrhosis status. METHODS: A total of 111 patients with HCC and EV, who underwent surgical resection, were retrospectively enrolled between July 2003 and July 2019. The diagnosis of liver cirrhosis was established using the Ishak fibrosis score F5 or F6 in the nontumor part of liver specimens. Prognostic factors were analyzed using the Cox proportional hazards model. RESULTS: There were 85 (76.6%) and 26 (23.4%) patients with and without cirrhosis, respectively. Compared with those without cirrhosis, there were more females, less seropositive rate of hepatitis B surface antigen (HBsAg), more seropositive rate of antibody against to hepatitis C virus (HCV), less albumin-bilirubin (ALBI) grade 1, lower platelet count, and more had tumor burden within the Milan criteria in cirrhotic patients. Cirrhotic patients had a higher risk of posthepatectomy decompensation compared to noncirrhotic patients (hazard ratio 9.577, p = 0.017). No difference was observed in overall survival and recurrence-free survival between patients with or without cirrhosis. CONCLUSION: Compared with patients without cirrhosis, cirrhotic patients with HCC and EV are vulnerable to posthepatectomy decompensation. However, cirrhosis is not a poor prognostic factor of overall survival and recurrence for HCC patients after surgical resection.

Surgical resection could provide better outcomes for patients with hepatocellular carcinoma and tumor rupture.

We investigated the outcomes of patients with ruptured hepatocellular carcinoma (HCC) and identified the optimal treatment modality for such patients. We retrospectively enrolled 91 patients with treatment-naive HCC and tumor rupture at diagnosis, including 38 patients who underwent surgical resection (SR) alone, 28 patients who were treated with transarterial chemoembolization (TACE) only, 20 patients who had a sequential combination therapy of TACE and SR, and 5 patients who received best supportive care. After a median follow-up of 13.1 months, 54 patients died. The cumulative 5 years overall survival (OS) rates were 55.1% and 0% in the SR group and non-SR group, respectively (p < 0.001). Non-SR therapy was associated with poorer OS according to a multivariate analysis with a hazard ratio of 6.649 (95% confidence interval 3.581-12.344, p < 0.001). Moreover, whether patients received TACE or not did not impact the OS in both the SR group and the non-SR group. In conclusion, for patients with HCC and tumor rupture at the time of diagnosis, SR could lead to better prognoses than non-surgery treatment modalities. Moreover, a sequential combination of TACE and SR had similar clinical outcomes when compared to SR alone.

Differential prognoses among male and female patients with hepatocellular carcinoma.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) is significantly higher in men than women. Nonetheless, the impact of sex disparities on HCC outcomes remains unclear. We aimed to compare the clinical manifestations and prognoses between male and female patients with HCC. METHODS: This retrospective study enrolled 5337 consecutive patients (3976 men, 1361 women) who were diagnosed with HCC from 2007 to 2020. The prognostic factors were identified by the Cox proportional hazards model. RESULTS: Male patients were younger upon HCC diagnosis (median age 64 vs 69 years; p < 0.001) with more favorable hepatic functional reserves (39.0% vs 35.1% albumin-bilirubin grade 1; p = 0.025) but had greater tumor burdens than the female patients. Furthermore, fewer male patients underwent curative therapies for HCC compared with the female patients (49.0% vs 57.0%; p < 0.001). After a median follow-up of 20.1 months (interquartile range, 5.8-47.3 months), 3133 patients died. The cumulative 5-year overall survival rates were 37.1% and 41.9% for male and female patients, respectively (p < 0.001). From the multivariate analysis, male sex was not an independent factor predictive of poor overall survival in all patients and in the subgroup analysis stratified by treatment modalities. When stratified by age, the female sex was an independent factor associated with lower mortality in younger (≤50 years) patients but not in older patients with HCC. CONCLUSION: Sex was not an independent predictor of the outcome of patients with HCC, especially for those aged more than 50 years.

Upregulation of USP22 and ABCC1 during Sorafenib Treatment of Hepatocellular Carcinoma Contribute to Development of Resistance.

Sorafenib is a small molecule that blocks tumor proliferation by targeting the activity of multi-kinases for the treatment of advanced hepatocellular carcinoma (HCC). Increasing sorafenib resistance following long-term treatment is frequently encountered. Mechanisms underlying sorafenib resistance remain not completely clear. To further understand the mechanism of sorafenib resistance in HCC, we established sorafenib-resistant cell lines by slowly increasing sorafenib concentration in cell culture medium. Upregulation of USP22 and ABCC1 were found in Sorafenib-resistant cells. Sorafenib-resistant cells treated with USP22 siRNA showed significant reduction in endogenous mRNA and protein levels of ABCC1. During sorafenib treatment, upregulation of USP22 increases ABCC1 expression and subsequently contributes to sorafenib resistance in HCC cells. Immunohistochemical analysis revealed a positive correlation between USP22 and ABCC1 expression in tissue samples from sorafenib-resistant patients (Pearson's correlation = 0.59, p = 0.03). Our findings indicate that upregulation of USP22 and ABCC1 expression during treatment contribute to sorafenib resistance in HCC cells and that USP22 has strong potential as a therapeutic target for overcoming sorafenib resistance in HCC patients.

Hepatitis D virus dual infection increased the risk of hepatocellular carcinoma compared with hepatitis B virus mono infection: A meta-analysis.

BACKGROUND: Hepatitis delta virus (HDV) is a defective virus that relies on the supply of hepatitis B surface antigen (HBsAg) from hepatitis B virus (HBV) to assemble HDV virions and infect hepatocytes. However, controversy remains in whether the presence of HDV increases the risk of hepatocellular carcinoma (HCC). Our aim is to evaluate the influence of HDV on the risk of HCC through a systematic review and meta-analysis. METHODS: A review of all English-language literature was conducted in the major medical databases using the subject search terms "hepatocellular carcinoma," "liver cancer," "hepatic tumor," and "hepatitis delta." A meta-analysis of the qualifying publications was then performed. RESULTS: The meta-analysis included 21 studies, which revealed a significantly higher risk of HCC among patients with HDV/HBV dual infection (odds ratio [OR] = 2.08, 95% confidence interval [CI], 1.37-3.14, p < 0.01) compared with those with HBV monoinfection. Those with HDV/HBV dual infection remained at higher risk of HCC in the subgroup analysis, irrespective of the status of hepatitis C virus (HCV) or human immunodeficiency virus (HIV) coinfection and in different ethnicities. The HCC risk remained higher in patients with HDV/HBV dual infection with heterogeneous fibrosis stage (OR = 2.04, 95% CI, 1.31-3.17, p < 0.01). The difference in the risk of HCC between HDV/HBV dual infection and HBV monoinfection was not statistically significant in patients with cirrhosis or advanced fibrosis (OR = 1.84, 95% CI, 0.48-7.02, p = 0.37). However, this subgroup comprised only two studies. CONCLUSION: HDV and HBV dual infection significantly increase the risk of HCC development compared with HBV monoinfection.

Bi-directional gene activation and repression promote ASC differentiation and enhance bone healing in osteoporotic rats.

Calvarial bone healing is challenging, especially for individuals with osteoporosis because stem cells from osteoporotic patients are highly prone to adipogenic differentiation. Based on previous findings that chondrogenic induction of adipose-derived stem cells (ASCs) can augment calvarial bone healing, we hypothesized that activating chondroinductive Sox Trio genes (Sox5, Sox6, Sox9) and repressing adipoinductive genes (C/ebp-α, Ppar-γ) in osteoporotic ASCs can reprogram cell differentiation and improve calvarial bone healing after implantation. However, simultaneous gene activation and repression in ASCs is difficult. To tackle this problem, we built a CRISPR-BiD system for bi-directional gene regulation. Specifically, we built a CRISPR-AceTran system that exploited both histone acetylation and transcription activation for synergistic Sox Trio activation. We also developed a CRISPR interference (CRISPRi) system that exploited DNA methylation for repression of adipoinductive genes. We combined CRISPR-AceTran and CRISPRi to form the CRISPR-BiD system, which harnessed three mechanisms (transcription activation, histone acetylation, and DNA methylation). After delivery into osteoporotic rat ASCs, CRISPR-BiD significantly enhanced chondrogenesis and in vitro cartilage formation. Implantation of the engineered osteoporotic ASCs into critical-sized calvarial bone defects significantly improved bone healing in osteoporotic rats. These results implicated the potential of the CRISPR-BiD system for bi-directional regulation of cell fate and regenerative medicine.

Risk scores to predict HCC and the benefits of antiviral therapy for CHB patients in gray zone of treatment guidelines.

BACKGROUNDS: ALT ≥ 80 U/L and HBV DNA ≥ 2000 IU/ml are treatment criteria of APASL guidelines for chronic hepatitis B (CHB) patients. The need of antiviral therapy for patients in gray zone (ALT < 80 U/L or HBV DNA < 2000 IU/ml) is controversial. This study aimed to develop a scoring system to predict hepatocellular carcinoma (HCC) and evaluate the benefit of antiviral therapy in these patients. METHODS: Seven hundred and forty-nine patients were analyzed. Significant variables were weighted to develop a scoring system for HCC prediction. The area under receiver operating curves (AUROC) were estimated and validated by REVEAL-HBV cohort (n = 3527). RESULTS: Older age (p < 0.001), male sex (p = 0.036), family history of HCC (p = 0.002) and HBV DNA ≥ 2000 IU/ml (p = 0.045) were independently associated with HCC. A 14-point risk score system predicts 3 and 5-years HCC risk to be 0.866 and 0.868 of AUROC, respectively in the derivation cohort; 0.821 and 0.820, in the REVEAL-HBV cohort. The cumulative HCC incidence was higher in the high risk (score ≥ 8) group both in derivation and validation cohorts (p < 0.001). Patients with antiviral therapy had lower HCC incidence compared to those without (p = 0.016). Of note, antiviral therapy significantly decreased HCC in the high risk group (p = 0.005), but not in the low risk group (p = 0.705). CONCLUSIONS: A risk scoring system is established and validated. Of CHB patients in gray zone of APASL guidelines, those with risk scores ≥ 8 had higher risk of HCC, but the risk could be significantly reduced by antiviral therapy.

Ropeginterferon alfa-2b in patients with genotype 1 chronic hepatitis C: Pharmacokinetics, safety, and preliminary efficacy.

BACKGROUND AND AIM: Ropeginterferon alfa-2b (P1101) is a novel long-acting mono-PEGylated recombinant proline interferon (IFN) conjugated to a 40 kDa branched polyethylene glycol (PEG) chain at its N-terminus, allowing every-two-week injection. It received European Medicines Agency and Taiwan marketing authorization for the treatment of polycythemia vera in 2019 and 2020, respectively. This phase 2 study aimed to evaluate the pharmacokinetics, safety, and preliminary efficacy of ropeginterferon alfa-2b as compared with PEG-IFN-α2a in patients with chronic hepatitis C virus genotype 1 infection. METHODS: One hundred six treatment naive patients were enrolled in this phase 2 study and randomized to four treatment groups: subcutaneous weekly PEG-IFN-α2a 180 µg (group 1), weekly ropeginterferon alfa-2b 180 µg (group 2), weekly ropeginterferon alfa-2b 270 µg (group 3), or biweekly ropeginterferon alfa-2b 450 µg (group 4) plus ribavirin for 48 weeks. RESULTS: After multiple weekly administration, serum exposure (AUC0-τ) in ropeginterferon alfa-2b 180 µg was approximately 41% greater and the accumulation ratio of 2-fold greater than PEG-IFN-α2a 180 µg. The incidences of flu-like symptoms were 66.7% (18/27), 53.3% (16/30), 55.0% (11/20), and 48.3% (14/29), anxiety were 14.8% (4/27), 6.7% (2/30), 0%, and 0%, and depression were 25.9% (7/27), 13.3% (4/30), 0%, and 3.4% (1/29), for groups 1-4, respectively. Two grade 2 of 3 depression were noted in PEG-IFN-α2a arm, but none in ropeginterferon arms. The SVR24 rates were 77.8% (21/27), 66.7% (20/30), 80% (16/20), and 69% (20/29), respectively. CONCLUSIONS: Ropeginterferon alfa-2b showed longer effective half-life and superior safety profile than PEG-IFN-α2a. Biweekly injection of ropeginterferon alfa-2b will be studied in larger viral hepatitis patient population.

Clinical Implications of HBV PreS/S Mutations and the Effects of PreS2 Deletion on Mitochondria, Liver Fibrosis, and Cancer Development.

BACKGROUND AND AIMS: PreS mutants of HBV have been reported to be associated with HCC. We conducted a longitudinal study of the role of HBV preS mutations in the development of HCC, particularly in patients with chronic hepatitis B (CHB) having low HBV DNA or alanine aminotransferase (ALT) levels, and investigated the effects of secretion-defective preS2 deletion mutant (preS2ΔMT) on hepatocyte damage in vitro and liver fibrosis in vivo. APPROACH AND RESULTS: Association of preS mutations with HCC in 343 patients with CHB was evaluated by a retrospective case-control follow-up study. Effects of preS2ΔMT on HBsAg retention, endoplasmic reticulum (ER) stress, calcium accumulation, mitochondrial dysfunction, and liver fibrosis were examined. Multivariate analysis revealed a significant association of preS mutations with HCC (HR, 3.210; 95% CI, 1.072-9.613; P = 0.037) including cases with low HBV DNA or ALT levels (HR, 2.790; 95% CI, 1.133-6.873; P = 0.026). Antiviral therapy reduced HCC risk, including cases with preS mutations. PreS2ΔMT expression promoted HBsAg retention in the ER and unfolded protein response (UPR). Transmission electron microscopic examination, MitoTracker staining, real-time ATP assay, and calcium staining of preS2ΔMT-expressing cells revealed aberrant ER and mitochondrial ultrastructure, reduction of mitochondrial membrane potential and ATP production, and calcium overload. Serum HBV secretion levels were ~100-fold lower in preS2ΔMT-infected humanized Fah-/-/ Rag2-/-/Il2rg-/- triple knockout mice than in wild-type HBV-infected mice. PreS2ΔMT-infected mice displayed up-regulation of UPR and caspase-3 and enhanced liver fibrosis. CONCLUSIONS: PreS mutations were significantly associated with HCC development in patients with CHB, including those with low HBV DNA or ALT levels. Antiviral therapy reduced HCC occurrence in patients with CHB, including those with preS mutations. Intracellular accumulation of mutated HBsAg induced or promoted ER stress, calcium overload, mitochondrial dysfunction, impaired energy metabolism, liver fibrosis, and HCC.

The role of albumin-bilirubin grade in determining the outcomes of patients with very early-stage hepatocellular carcinoma.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) and with a single tumor <2 cm in size are classified as having Barcelona Clinic Liver Cancer (BCLC) stage 0 HCC. We aimed to investigate the role of the albumin-bilirubin (ALBI) grade in predicting outcomes in patients with BCLC stage 0 HCC. METHODS: We retrospectively enrolled patients with BCLC stage 0 HCC in Taipei Veterans General Hospital from 2007 to 2015. Prognostic factors were analyzed using a Cox proportional hazards model and propensity score matching (PSM) analysis. RESULTS: There were 420 patients enrolled, including 207 with ALBI grade 1, and 213 with ALBI grade 2 or 3. After a median follow-up of 60.0 months (interquartile range, 37.2-84.6 months), 179 patients died. The cumulative 5-year overall survival (OS) rates were 80.6% in patients with ALBI grade 1 and 53.7% in those with ALBI grade 2 or 3, respectively (p < 0.001). Multivariate analysis showed that age >65 years, negative hepatitis B surface in serum, creatinine >1.0 mg/dL, platelet count ≤105/mm3, tumor size >1.5 cm, nonsurgical resection (SR) therapy, and higher ALBI grade were independent risk factors related to poor OS. Patients who underwent SR had a better OS and recurrence-free survival than those who received radiofrequency ablation, which was confirmed by a multivariate analysis and PSM analysis. CONCLUSION: The ALBI grade can determine OS for patients with BCLC stage 0 HCC. SR can also provide a better outcome than nonsurgical treatment.

A comparison of prognoses between surgical resection and radiofrequency ablation therapy for patients with hepatocellular carcinoma and esophagogastric varices.

There has been insufficient investigation of the differences in long-term outcomes between surgical resection (SR) and radiofrequency ablation (RFA) among patients with hepatocellular carcinoma (HCC) and esophagogastric varices (EGV). We retrospectively enrolled 251 patients with treatment-naïve HCC and EGV who underwent SR or RFA as a first-line treatment. Prognostic factors were analyzed using a Cox proportional hazards model. A total of 68 patients underwent SR, and the remaining 183 patients received RFA. Patients who underwent SR were younger, had better liver functional reserves, and had larger tumors. After a median follow-up duration of 45.1 months, 151 patients died. The cumulative 5-year overall survival (OS) rate was significantly higher among patients who underwent SR than those treated with RFA (66.7% vs. 36.8%, p < 0.001). Multivariate analysis showed that age > 65 years, multiple tumors, RFA, albumin bilirubin grade > 1, and the occurrence of major peri-procedural morbidity were the independent risk factors that are predictive of poor OS. In conclusion, SR could be recommended as a first-line treatment modality for HCC patients with EGV if the patients are carefully selected and liver function is well preserved.