Effect of antiviral therapy in patients with low HBV DNA level on transarterial chemoembolization for hepatocellular carcinoma.

Antiviral therapy improves survival in patients with hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC). However, the effect of antiviral therapy in patients with low-level viremia HBV-HCC receiving non-curative therapy remains unclear. We aimed to evaluate the role of antiviral therapy in patients with low-level viremia and treated with transarterial chemoembolization (TACE). This retrospective study evaluated 206 patients with HBV-HCC who underwent TACE as an initial treatment. Of those, 135 patients received antiviral therapy (antiviral group), and 71 did not (non-antiviral group). The definition of low-level viremia was an HBV DNA level <2000 IU/ml. Kaplan-Meier curves, log-rank tests and Cox regression analysis were used for statistical analyses. The median follow-up duration was 39 months (1-174 months). Overall survival (OS) did not differ between groups (P = .227). Barcelona Clinic Liver Cancer stage (BCLC), Child-Pugh (CP) class and α-fetoprotein level were independent prognostic factors for OS. Antiviral therapy (hazard ratio [HR], 0.503, P = .022) was a prognostic factor for 2-year survival. On subgroup analysis, antiviral therapy improved short-term survival in patients with BCLC stage 0 and A (P = .037) and CP class A (P = .04). In patients with low-level viremia, antiviral therapy yielded short-term survival benefits, particularly in patients with early-stage HCC.

Tenofovir-based combination therapy or monotherapy for multidrug-resistant chronic hepatitis B: Long-term data from a multicenter cohort study.

The treatment of multidrug-resistant (MDR) chronic hepatitis B (CHB) is challenging. Herein, we report a multicenter prospective cohort study for the evaluation of tenofovir disoproxil fumarate (TDF)-based therapy for MDR CHB in a real-life setting. The inclusion criteria comprised patients with resistance to more than two nucleos(t)ide analogue (NA) classes and hepatitis B virus (HBV) DNA level of ≥200 IU/mL. The primary end-point was virologic response (VR), defined as undetectable HBV DNA (<20 IU/mL) after 60 months. A total of 236 patients met the inclusion criteria. The mean HBV DNA level was 4.16 ± 1.44 log IU/mL; 26.7% of patients had liver cirrhosis. Before the initiation of TDF, 33.5%, 44.9% and 21.6% of patients had mutations resistant to L-NA + adefovir, L-NA + entecavir (ETV) and L-NA + adefovir + ETV, respectively. A total of 184 patients received TDF-based combination therapy [TDF + ETV (n = 178) or TDF + L-NA (n = 6)], and 52 patients received TDF monotherapy. In the entire cohort, the VR rates were 77.2%, 89.9% and 92.2% at 12, 36 and 60 months, respectively. The VR rates were not significantly different between the combination therapy and the monotherapy group after 12 (76.2% vs 80.4%, P = .533), 36 (89.8% vs 90.3%, P = 1.000) or 60 (92.9% vs 87.5%, P = .499) months. Also, there was no significant difference in the cumulative VR rates for 5 years between the treatment groups (P = .910). Newly developed antiviral resistance was not observed. TDF-based therapy was effective for the treatment of MDR CHB. The efficacy of TDF monotherapy was not different from that of the TDF-based combination therapy.

A Long Noncoding RNA Regulates Hepatitis C Virus Infection Through Interferon Alpha-Inducible Protein 6.

Long noncoding RNAs (lncRNAs) play a critical role in the regulation of many important cellular processes. However, the mechanisms by which lncRNAs regulate viral infection and host immune responses are not well understood. We sought to explore lncRNA regulation of hepatitis C virus (HCV) infection and interferon response. We performed RNA sequencing (RNAseq) in Huh7.5.1 cells with or without interferon alpha (IFNα) treatment. Clustered regularly interspaced short palindromic repeats/Cas9 guide RNA (gRNA) was used to knock out selected genes. The promoter clones were constructed, and the activity of related interferon-stimulated genes (ISGs) were detected by the secrete-pair dual luminescence assay. We constructed the full-length and four deletion mutants of an interferon-induced lncRNA RP11-288L9.4 (lncRNA-IFI6) based on predicted secondary structure. Selected gene mRNAs and their proteins, together with HCV infection, in Huh7.5.1 cells and primary human hepatocytes (PHHs) were monitored by quantitative real-time PCR (qRT-PCR) and western blot. We obtained 7,901 lncRNAs from RNAseq. A total of 1,062 host-encoded lncRNAs were significantly differentially regulated by IFNα treatment. We found that lncRNA-IFI6 gRNA significantly inhibited HCV infection compared with negative gRNA control. The expression of the antiviral ISG IFI6 was significantly increased following lncRNA-IFI6 gRNA editing compared with negative gRNA control in Japanese fulminant hepatitis 1 (JFH1)-infected Huh7.5.1 cells and PHHs. We observed that lncRNA-IFI6 regulation of HCV was independent of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling. lncRNA-IFI6 negatively regulated IFI6 promoter function through histone modification. Overexpression of the truncated spatial domain or full-length lncRNA-IFI6 inhibited IFI6 expression and increased HCV replication. Conclusion: A lncRNA, lncRNA-IFI6, regulates antiviral innate immunity in the JFH1 HCV infection model. lncRNA-IFI6 regulates HCV infection independently of the JAK-STAT pathway. lncRNA-IFI6 exerts its regulatory function via promoter activation and histone modification of IFI6 through its spatial domain.

Prevalence, incidence and risk factors of tamoxifen-related non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND & AIMS: Tamoxifen is associated with an increased risk of developing fatty liver. The aim of this systematic review and meta-analysis was to evaluate the prevalence and incidence of fatty liver developed after tamoxifen treatment in breast cancer patients. METHODS: A systematic search of PubMed (Medline), EMBASE, OVID Medline, the Cochrane Library and other databases was performed for this review. The abstracts obtained from the search were reviewed by two investigators who chose manuscripts for full-text review. The event rates were calculated with a random-effects model and quality-effects model. RESULTS: The search yielded 165 references. Of these, 24 were included in the quantitative summary. We analysed the data of a total of 6,962 patients treated with tamoxifen and 975 patients not treated with tamoxifen. The prevalence of fatty liver among patients with breast cancer taking tamoxifen was 40.25 per 100 patients and the incidence rate was 12.37 per 100 person-years. The incidence of fatty liver was much higher in the tamoxifen group than in the control group [incidence rate ratio: 3.12, 95% CI (confidence interval): 2.05-4.75, I2  = 61%], regardless of region. The main risk factors were body mass index (BMI) [hazard ratio (HR): 1.15, 95% CI: 1.09-1.22] and hypercholesterolaemia (HR: 1.01, 95% CI: 1.00-1.02). CONCLUSION: The use of tamoxifen was associated with increased risks in the incidence and prevalence of fatty liver, especially in patients with high BMI and hypercholesterolaemia.

Estimation of renal function in patients with liver cirrhosis: Impact of muscle mass and sex.

BACKGROUND & AIMS: Accurate evaluation of renal function in patients with liver cirrhosis is critical for clinical management. However, there are still discrepancies between the measured glomerular filtration rate (mGFR) and creatinine-based estimated GFR (eGFR). In this study, we compared the performance of 2 common eGFR measurements with mGFR and evaluated the impact of low muscle mass on overestimation of renal function in patients with cirrhosis. METHODS: This study included 779 consecutive cirrhotic patients who underwent 51Cr-ethylenediamine tetra acetic acid (EDTA) (as a mGFR) and abdominal computed tomography (CT). The eGFR was calculated using creatinine or cystatin C. Muscle mass was assessed in terms of the total skeletal muscle at L3 level using CT. RESULTS: Modification of diet in renal disease (MDRD)-eGFR was overestimated in 47% of patients. A multivariate analysis showed that female sex (adjusted odds ratio [aOR] 4.91), Child B and C vs. A (aOR 1.69 and 1.84) and skeletal muscle mass (aOR 0.89) were independent risk factors associated with overestimation. Interestingly, the effect of skeletal muscle mass on overestimation varied based on sex. Decreased muscle mass significantly enhanced the risk of overestimation of MDRD-eGFR in male patients, but not in female patients. Cystatin C-based eGFR showed a better correlation with mGFR than MDRD-eGFR; it was also better at predicting overall survival and the incidence of acute kidney injury than MDRD-eGFR. CONCLUSIONS: The risk factors associated with overestimation included female sex, impaired liver function, and decreased muscle mass in males. In particular, eGFR in male patients with sarcopenia should be carefully interpreted. Creatinine-based eGFR was overestimated more often than cystatin C-based eGFR, with overestimation of eGFR closely related to poor prognostic performance. LAY SUMMARY: Overestimation of renal function frequently occurs in patients with liver cirrhosis when using serum creatinine. Decreased muscle mass has a great impact on overestimation of kidney function especially in male patients with cirrhosis. Compared with creatinine, cystatin C was more closely correlated with measured glomerular filtration rate and had a higher predictive ability for renal complications and survival than creatinine.

Ginsenoside Rg3 restores hepatitis C virus-induced aberrant mitochondrial dynamics and inhibits virus propagation.

Hepatitis C virus (HCV) alters mitochondrial dynamics associated with persistent viral infection and suppression of innate immunity. Mitochondrial dysfunction is also a pathologic feature of direct-acting antiviral (DAA) treatment. Despite the high efficacy of DAAs, their use in treating patients with chronic hepatitis C in interferon-sparing regimens occasionally produces undesirable side effects such as fatigue, migraine, and other conditions, which may be linked to mitochondrial dysfunction. Here, we show that clinically prescribed DAAs, including sofosbuvir, affect mitochondrial dynamics. To counter these adverse effects, we examined HCV-induced and DAA-induced aberrant mitochondrial dynamics modulated by ginsenoside, which is known to support healthy mitochondrial physiology and the innate immune system. We screened several ginsenoside compounds showing antiviral activity using a robust HCV cell culture system. We investigated the role of ginsenosides in antiviral efficacy, alteration of mitochondrial transmembrane potential, abnormal mitochondrial fission, its upstream signaling, and mitophagic process caused by HCV infection or DAA treatment. Only one of the compounds, ginsenoside Rg3 (G-Rg3), exhibited notable and promising anti-HCV potential. Treatment of HCV-infected cells with G-Rg3 increased HCV core protein-mediated reduction in the expression level of cytosolic p21, required for increasing cyclin-dependent kinase 1 activity, which catalyzes Ser616 phosphorylation of dynamin-related protein 1. The HCV-induced mitophagy, which follows mitochondrial fission, was also rescued by G-Rg3 treatment. CONCLUSION: G-Rg3 inhibits HCV propagation. Its antiviral mechanism involves restoring the HCV-induced dynamin-related protein 1-mediated aberrant mitochondrial fission process, thereby resulting in suppression of persistent HCV infection. (Hepatology 2017;66:758-771).

Follow-up Creatinine Level Is an Important Predictive Factor of In-hospital Mortality in Cirrhotic Patients with Spontaneous Bacterial Peritonitis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is one of the severe complications of liver cirrhosis. Early detection of high-risk patients is essential for prognostic improvement. The aim of this study is to investigate the predictive factors related to in-hospital mortality in patients with SBP. METHODS: This was a retrospective study of 233 SBP patients (181 males, 52 females) who were admitted to four tertiary referral hospitals between August 2002 and February 2013. The patients' laboratory and radiologic data were obtained from medical records. The Child-Turcotte-Pugh (CTP) score and model for end-stage liver disease sodium model (MELD-Na) scores were calculated using the laboratory data recorded at the time of the SBP episode. RESULTS: The causes of liver cirrhosis were hepatitis B (44.6%), alcohol (43.8%), hepatitis C (6.0%), and cryptogenic cirrhosis (5.6%). The mean MELD-Na and CTP scores were 27.1 and 10.7, respectively. Thirty-one of the patients (13.3%) died from SBP in hospital. Multivariate analysis revealed that maximum creatinine level during treatment was a statistically significant factor for in-hospital mortality (P = 0.005). The prognostic accuracy of the maximum creatinine level during treatment was 78.0% (P < 0.001). The optimal cutoff point for the maximum serum creatinine was 2 mg/dL (P < 0.001). CONCLUSION: The follow-up creatinine level during treatment is an important predictive factor of in-hospital mortality in cirrhotic patients with SBP. Patients with SBP and a serum creatinine level during treatment of ≥ 2.0 mg/dL might have a high risk of in-hospital mortality.

Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial.

Bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation has been suggested as an effective therapy for liver cirrhosis. The efficacy and safety of autologous BM-MSC transplantation in the treatment of alcoholic cirrhosis were investigated. Seventy-two patients with baseline biopsy-proven alcoholic cirrhosis who had been alcohol-abstinent for more than 6 months underwent a multicenter, randomized, open-label, phase 2 trial. Patients were randomly assigned to three groups: one control group and two autologous BM-MSC groups that underwent either one-time or two-time hepatic arterial injections of 5 × 107 BM-MSCs 30 days after BM aspiration. A follow-up biopsy was performed 6 months after enrollment, and adverse events were monitored for 12 months. The primary endpoint was improvement in fibrosis quantification based on picrosirius red staining. The secondary endpoints included liver function tests, Child-Pugh score, and Model for End-stage Liver Disease score. Outcomes were analyzed by per-protocol analysis. In terms of fibrosis quantification (before versus after), the one-time and two-time BM-MSC groups were associated with 25% (19.5 ± 9.5% versus 14.5 ± 7.1%) and 37% (21.1 ± 8.9% versus 13.2 ± 6.7%) reductions in the proportion of collagen, respectively (P < 0.001). In the intergroup comparison, two-time BM-MSC transplantation in comparison with one-time BM-MSC transplantation was not associated with improved results in fibrosis quantification (P > 0.05). The Child-Pugh scores of both BM-MSC groups (one-time 7.6 ± 1.0 versus 6.3 ± 1.3 and two-time 7.8 ± 1.2 versus 6.8 ± 1.6) were also significantly improved following BM-MSC transplantation (P < 0.05). The proportion of patients with adverse events did not differ among the three groups. CONCLUSION: Autologous BM-MSC transplantation safely improved histologic fibrosis and liver function in patients with alcoholic cirrhosis. (Hepatology 2016;64:2185-2197).

Clinical outcomes of patients with advanced hepatocellular carcinoma treated with sorafenib: a retrospective study of routine clinical practice in multi-institutions.

BACKGROUND: Sorafenib is an orally administered multikinase inhibitor with antiangiogenic and antiproliferative properties. The results of large clinical trials demonstrate that sorafenib prolongs survival and the time to progression of patients with advanced hepatocellular carcinoma (HCC). The aim of the present study was to determine the outcomes of such patients who were routinely treated with sorafenib at multi-institutions in Korea, in contrast to formal clinical trials. METHODS: Between August 2007 and March 2012, patients with advanced HCC in seven referral medical centers in Daejeon-Chungcheong Province of Korea were retrospectively enrolled to evaluate treatment response, survival, and tolerability following administration of sorafenib. The treatment response was assessed in accordance with the Response Evaluation Criteria in Solid Tumor 1.1 guidelines. RESULTS: Among 116 patients, 66 (57%) had undergone treatment for HCC, and 77 (66%) were accompanied with Child-Pugh A cirrhosis. The median duration of sorafenib treatment was 67 days (range 14-452 days). Median overall survival and median time to progression were 141 days and 90 days, respectively. Complete response, partial response, and stable disease were achieved for 0%, 2%, and 29% of patients, respectively. Overall median survival, but not the median time to progression, was significantly shorter for patients with Child-Pugh B cirrhosis compared with those with Child-Pugh A cirrhosis (64 days vs 168 days, P = 0.004). Child-Pugh B cirrhosis (P = 0.024) and a high level of serum alpha-fetoprotein (P = 0.039) were independent risk factors for poor overall survival. Thirty-nine (34%) patients experienced grade 3/4 adverse events such as hand-foot skin reactions and diarrhea that required dose adjustment. CONCLUSIONS: The clinical outcomes of sorafenib-treated patients with advanced HCC were comparable to those reported by formal clinical trial conducted in the Asia-Pacific region. Underlying hepatic dysfunction was the most important risk factor for shorter survival.

Clinical Features of Drug-induced Liver Injury According to Etiology.

Drug-induced liver injury (DILI) is an increasingly common cause of acute hepatitis. We examined clinical features and types of liver injury of 65 affected patients who underwent liver biopsy according DILI etiology. The major causes of DILI were the use of herbal medications (43.2%), prescribed medications (21.6%), and traditional therapeutic preparations and dietary supplements (35%). DILI from herbal medications, traditional therapeutic preparations, and dietary supplements was associated with higher elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels than was DILI from prescription medications. The types of liver injury based on the R ratio were hepatocellular (67.7%), mixed (10.8%), and cholestatic (21.5%). Herbal medications and traditional therapeutic preparations were more commonly associated with hepatocellular liver injury than were prescription medications (P = 0.002). Herbal medications and traditional therapeutic preparations induce more hepatocellular DILI and increased elevations in AST and ALT than prescribed medications.

Enhancing liver cirrhosis varices and CSPH risk prediction with spleen stiffness measurement using 100-Hz probe.

Managing complications of liver cirrhosis such as varices needing treatment (VNT) and clinically significant portal hypertension (CSPH) demands precise and non-invasive diagnostic methods. This study assesses the efficacy of spleen stiffness measurement (SSM) using a 100-Hz probe for predicting VNT and CSPH, aiming to refine diagnostic thresholds. A retrospective analysis was conducted on 257 cirrhotic patients, comparing the diagnostic performance of SSM against traditional criteria, including Baveno VII, for predicting VNT and CSPH. The DeLong test was used for statistical comparisons among predictive models. The success rate of SSM@100 Hz was 94.60%, and factors related to SSM failure were high body mass index and small spleen volume or length. In our cohort, the identified SSM cut-off of 38.9 kPa, which achieved a sensitivity of 92% and a negative predictive value (NPV) of 98% for detecting VNT, is clinically nearly identical to the established Baveno threshold of 40 kPa. The predictive capability of the SSM-based model for VNT was superior to the LSM ± PLT model (p = 0.017). For CSPH prediction, the SSM model notably outperformed existing non-invasive tests (NITs), with an AUC improvement and significant correlations with HVPG measurements (obtained from 49 patients), highlighting a correlation coefficient of 0.486 (p < 0.001) between SSM and HVPG. Therefore, incorporating SSM into clinical practice significantly enhances the prediction accuracy for both VNT and CSPH in cirrhosis patients, mainly due to the high correlation between SSM and HVPG. SSM@100 Hz can offer valuable clinical assistance in avoiding unnecessary endoscopy in these patients.

Comparison of Glecaprevir/Pibrentasvir and Sofosbuvir/Ledipasvir in Patients with Hepatitis C Virus Genotype 1 and 2 in South Korea.

Background/Aims: This study compared the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) in real-life clinical practice. Methods: The data from genotype 1 or 2 chronic hepatitis C patients treated with GLE/PIB or sofosbuvir + ribavirin or SOF/LDV in South Korea were collected retrospectively. The analysis included the treatment completion rate, sustained virologic response at 12 weeks (SVR12) test rate, treatment effectiveness, and adverse events. Results: Seven hundred and eighty-two patients with genotype 1 or 2 chronic hepatitis C who were treated with GLE/PIB (n=575) or SOF/LDV (n=207) were included in this retrospective study. The baseline demographic and clinical characteristics revealed significant statistical differences in age, genotype, ascites, liver cirrhosis, and hepatocellular carcinoma between the GLE/PIB and SOF/LDV groups. Twenty-two patients did not complete the treatment protocol. The treatment completion rate was high for both regimens without statistical significance (97.7% vs. 95.7%, p=0.08). The overall SVR12 of intention-to-treat analysis was 81.2% vs. 80.7% without statistical significance (p=0.87). The overall SVR12 of per protocol analysis was 98.7% vs. 100% without statistical significance (p=0.14). Six patients treated with GLE/PIB experienced treatment failure. They were all male, genotype 2, and showed a negative hepatitis C virus RNA level at the end of treatment. Two patients treated with GLE/PIB stopped medication because of fever and abdominal discomfort. Conclusions: Both regimens had similar treatment completion rates, effectiveness, and safety profiles. Therefore, the SOF/LDV regimen can also be considered a viable DAA for the treatment of patients with genotype 1 or 2 chronic hepatitis C.

Pre-existing YMDD mutants in treatment-naïve patients with chronic hepatitis B are not selected during lamivudine therapy.

Although the rate at which mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of hepatitis B virus polymerase form is high during prolonged lamivudine (LAM) therapy, these mutations sometimes occur naturally in treatment-naïve patients with chronic hepatitis B. The prevalence of natural YMDD mutants differs geographically, and its clinical significance during LAM therapy is unknown. This study aimed to investigate whether pre-existing YMDD mutants were selected during LAM therapy. It included 14 treatment-naïve patients who were treated with LAM for at least 9 months. LAM resistance was evaluated before and at 3-month intervals during treatment. Mutations were analyzed by direct sequencing, restriction fragment mass polymorphism (RFMP) assays, and a single-step multiplex polymerase chain reaction (PCR) test using dual-priming oligonucleotide (DPO) primers. DPO-based multiplex PCR showed two YMDD mutations in two patients before LAM therapy; rtM204V and rtL180M + rtM204V/I. Further, two patients had an rtL180M mutation without an accompanying rtM204V/I mutation. No mutant was detected in any patient by direct sequencing or the RFMP assay before LAM therapy. A virological response was observed at 3 months in all patients with pre-existing YMDD mutants. All mutations disappeared after 3 months of LAM therapy, and during the follow-up period, no re-emergence was detected by any of the three methods. Further, the viral load was suppressed optimally. In conclusion, pre-existing YMDD mutants were cleared early during the course of LAM therapy, which produced a consistent virological response, and the mutants were not selected by LAM therapy.

Single nucleotide polymorphisms associated with metastatic tumour antigen 1 overexpression in patients with hepatocellular carcinoma.

BACKGROUNDS/AIMS: Metastatic tumour antigen 1 (MTA1) promotes angiogenesis by stabilizing hypoxia-inducible factor-1α (HIF-1α), which is closely associated with frequent postoperative recurrence and poor survival in patients with HCC. In this study, we determined single nucleotide polymorphisms (SNPs) in angiogenesis-related genes that are associated with MTA1 overexpression in HCC tissues. METHODS: A total of 376 patients with HCC who had received curative surgical resection or liver transplantation were enrolled (312/21/43; HBV/HCV/NBNC). MTA1 expression was determined via immunohistochemistry. Thirty-three common SNPs sites (frequency ≥5%) in the angiogenic protein gene that are closely connected to one another were selected, including MTA1, VEGF, HIF-1α, FGF-2, and IGF-II. RESULTS: Expression of MTA1 was detected in 120 HCC tissues (31%). An A allele at position IVS4-81G/A of the MTA1 gene (P = 0.016) and the TT genotype at position +12916C of the VEGF gene (P = 0.023) were significantly associated with MTA1 overexpression. However, the TT genotype at position -13021C (P = 0.011) and the haplotypes CT-CT (-11228C; -13021C) of the IGF-II gene (P(cor) = 0.033) were more common in patients with MTA1-negative HCC. Using multivariate analysis, the A allele at IVS4-81G/A in MTA1 gene (P = 0.015) and a T allele (TT+CT genotype) at -13021C in IGF-II (P = 0.002) were independent risk factors in HCC recurrence after curative surgical resection. CONCLUSIONS: The genetic polymorphisms IVS4-81G/A in MTA1 and +12916C in VEGF genes were correlated with MTA1 overexpression. The SNPs in MTA1 and IGF-II genes may be important risk factors for the recurrence of HCC.

Effect of response to interferon-α therapy on the occurrence of hepatocellular carcinoma in patients with chronic hepatitis B.

OBJECTIVES: The aim of this study was to examine whether interferon-α (IFN-α) therapy may reduce the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) and to determine its effect based on responsiveness to IFN-α therapy. METHODS: A total of 641 biopsy-proven CHB patients were treated with IFN-α2b. They were followed by biochemistry and/or imaging studies at 3- to 6-month intervals for a median period of 113 months (range 6-222). RESULTS: HCC was detected in 22 patients and 5- and 10-year cumulative occurrence rates were 0.4 and 3.2%, respectively. In univariate analysis, age (p < 0.001), serum AFP levels (p < 0.001), and serum HBV-DNA levels (p = 0.002) at baseline were associated with HCC development. HCC occurred less frequently in biochemical responders at the end of treatment than in non-responders (p = 0.001). However, virologic response was not associated with HCC development. Multivariate analysis showed that poor biochemical response (p = 0.007) as well as older age (p = 0.018) and a higher serum AFP level (p < 0.001) remained independent predisposing factors of HCC development in CHB patients treated with IFN-α. CONCLUSION: The results suggest that the biochemical but not virologic response to IFN-α therapy reduces independently the occurrence of HCC in patients with CHB.

Optimal duration of proton pump inhibitor in the treatment of endoscopic submucosal dissection-induced ulcers: a retrospective analysis and prospective validation study.

BACKGROUND: The optimal duration of proton pump inhibitor (PPI) use in the treatment of endoscopic submucosal dissection (ESD)-induced ulcers has not been well defined. AIMS: The aim of study was to determine the optimal duration of PPI treatment for ESD-induced gastric ulcers. METHODS: A total of 333 patients who underwent ESD were included in this retrospective analysis and prospective randomized validation. Medical records and endoscopic images for the 221 patients in our ESD-database were reviewed retrospectively. Based on the results of the retrospective analysis, 112 patients with ESD-induced ulcers over 40 mm were randomly assigned to two groups (4- or 8-week course of Lansoprazole 30 mg). Main outcome measurements were to assess the healing-related factors of post-ESD ulcers (retrospective analysis) and to compare complete mucosal healing rate in large (≥ 40 mm) ESD-induced ulcers according to the duration of PPI treatment (prospective validation). RESULTS: Multivariate logistic regression from a retrospective analysis showed that a duration of PPI treatment <8 weeks and a post-ESD ulcer ≥ 40 mm in size were associated with incomplete healing. In a prospective validation, the rate of complete healing in the 8-week PPI group was significantly higher than that of the 4-week PPI group for a large (≥ 40 mm) ESD-induced ulcer at 8 weeks follow-up (83.3 vs. 42.6%, P < 0.01). CONCLUSIONS: The optimal duration of PPI treatment varies based on the initial ulcer size. Patients with an ESD-induced ulcer over 40 mm should be treated with an 8-week course of PPIs.

Cystatin C is a good predictor of hepatorenal syndrome and survival in patients with cirrhosis who have normal serum creatinine levels.

BACKGROUND/AIMS: We evaluated the usefulness of cystatin C as a prognostic marker in patients with liver cirrhosis and normal serum creatinine. METHODOLOGY: We retrospectively analyzed prospectively enrolled patients with liver cirrhosis and normal serum creatinine from February 2007 to March 2008. We checked liver function and kidney variables including serum creatinine, cystatin C and glomerular filtration rate from 51Cr-EDTA on the same day for all patients. The endpoints of the study were either development of hepatorenal syndrome or mortality. RESULTS: In total, 112 patients with liver cirrhosis were enrolled in the study (87 men and 25 women, age 52 ± 12 years). Twelve (11%), 59 (53%) and 41 (36%) patients were in Child-Pugh class A, B and C, respectively. Cystatin C was better correlated with glomerular filtration rate from 51Cr-EDTA than creatinine. The 1-year cumulative incidence of hepatorenal syndrome and the 1-year survival rate of patients were 20.5% and 79.5%, respectively. Cystatin C, Model for End-Stage Liver Disease and serum sodium were the independent predictive factors for hepatorenal syndrome. Cystatin C, serum sodium and prothrombin time were the independent factors for predicting survival. CONCLUSIONS: In patients with liver cirrhosis and normal creatinine levels, cystatin C is a useful marker for predicting hepatorenal syndrome and survival.

Regression of liver fibrosis and hepatocellular carcinoma development after HCV eradication with oral antiviral agents.

We prospectively investigated the changes of liver stiffness (LS) and the occurrence of hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) eradication using direct antiviral agents (DAA) over three years. LS measurement using transient elastography and serum fibrosis surrogate markers before treatment and at 48, 96, 144 weeks after starting direct-acting antivirals (DAA) according to the protocol were evaluated. Patients were also compared with historical cohort treated with pegylated interferon (peg-IFN). Sustained viral response (SVR) was observed in 95.8%. LS value in the patients achieving SVR significantly decreased over time (19.4 ± 12.9 kPa [baseline], 13.9 ± 9.1 kPa [48 weeks], 11.7 ± 8.2 kPa [96 weeks], 10.09 ± 6.23 [144 weeks], all p < 0.001). With matched analysis, the decrease in LS value was significantly larger in DAA group than peg-IFN group at both 48 weeks (29% vs. 9%) and 96 weeks (39% vs. 17%). The incidence of HCC was not significantly different between DAA and peg-IFN groups (5.5% vs. 5.4%) at 144 weeks. HCV eradication with DAA can lead to improvement of liver stiffness over time. The regression of fibrosis was greater in the group with DAA than peg-IFN.Clinical trials registration: ClinicalTrials.gov (NCT02865369).

The diagnostic value of circulating tumor DNA in hepatitis B virus induced hepatocellular carcinoma: a systematic review and meta-analysis.

Background/Aim: New biomarkers are urgently needed to aid in the diagnosis of early stage hepatocellular carcinoma (HCC). We performed a meta-analysis on the diagnostic utility of circulating tumor DNA (ctDNA) levels in patients with hepatitis B virus-induced HCC. Methods: We retrieved relevant articles from PubMed, Embase, and the Cochrane Library up to February 8, 2022. Two subgroups were defined; one subset of studies analyzed the ctDNA methylation status, and the other subset combined tumor markers and ctDNA assays. Pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (AUC) were analyzed. Results: Nine articles including 2,161 participants were included. The overall SEN and SPE were 0.705 (95% confidence interval [CI], 0.629-0.771) and 0.833 (95% CI, 0.769-0.882), respectively. The DOR, PLR, and NLR were 11.759 (95% CI, 7.982-17.322), 4.285 (95% CI, 3.098-5.925), and 0.336 (0.301-0.366), respectively. The ctDNA assay subset exhibited an AUC of 0.835. The AUC of the combined tumor marker and ctDNA assay was 0.848, with an SEN of 0.761 (95% CI, 0.659-0.839) and an SPE of 0.828 (95% CI, 0.692-0.911). Conclusions: Circulating tumor DNA has promising diagnostic potential for HCC. It can serve as an auxiliary tool for HCC screening and detection, especially when combined with tumor markers.

Ginsenoside Rd ameliorates muscle wasting by suppressing the signal transducer and activator of transcription 3 pathway.

BACKGROUND: The effects of some drugs, aging, cancers, and other diseases can cause muscle wasting. Currently, there are no effective drugs for treating muscle wasting. In this study, the effects of ginsenoside Rd (GRd) on muscle wasting were studied. METHODS: Tumour necrosis factor-alpha (TNF-α)/interferon-gamma (IFN-γ)-induced myotube atrophy in mouse C2C12 and human skeletal myoblasts (HSkM) was evaluated based on cell thickness. Atrophy-related signalling, reactive oxygen species (ROS) level, mitochondrial membrane potential, and mitochondrial number were assessed. GRd (10 mg/kg body weight) was orally administered to aged mice (23-24 months old) and tumour-bearing (Lewis lung carcinoma [LLC1] or CT26) mice for 5 weeks and 16 days, respectively. Body weight, grip strength, inverted hanging time, and muscle weight were assessed. Histological analysis was also performed to assess the effects of GRd. The evolutionary chemical binding similarity (ECBS) approach, molecular docking, Biacore assay, and signal transducer and activator of transcription (STAT) 3 reporter assay were used to identify targets of GRd. RESULTS: GRd significantly induced hypertrophy in the C2C12 and HSkM myotubes (average diameter 50.8 ± 2.6% and 49.9% ± 3.7% higher at 100 nM, vs. control, P ≤ 0.001). GRd treatment ameliorated aging- and cancer-induced (LLC1 or CT26) muscle atrophy in mice, which was evidenced by significant increases in grip strength, hanging time, muscle mass, and muscle tissue cross-sectional area (1.3-fold to 4.6-fold, vs. vehicle, P ≤ 0.05; P ≤ 0.01; P ≤ 0.001). STAT3 was found to be a possible target of GRd by the ECBS approach and molecular docking assay. Validation of direct interaction between GRd and STAT3 was confirmed through Biacore analysis. GRd also inhibited STAT3 phosphorylation and STAT3 reporter activity, which led to the inhibition of STAT3 nuclear translocation and the suppression of downstream targets of STAT3, such as atrogin-1, muscle-specific RING finger protein (MuRF-1), and myostatin (MSTN) (29.0 ± 11.2% to 84.3 ± 30.5%, vs. vehicle, P ≤ 0.05; P ≤ 0.01; P ≤ 0.001). Additionally, GRd scavenged ROS (91.7 ± 1.4% reduction at 1 nM, vs. vehicle, P ≤ 0.001), inhibited TNF-α-induced dysregulation of ROS level, and improved mitochondrial integrity (P ≤ 0.05; P ≤ 0.01; P ≤ 0.001). CONCLUSIONS: GRd ameliorates aging- and cancer-induced muscle wasting. Our findings suggest that GRd may be a novel therapeutic agent or adjuvant for reversing muscle wasting.