Immune signature and therapeutic approach of natural killer cell in chronic liver disease and hepatocellular carcinoma.

Natural killer (NK) cells are one of the key members of innate immunity that predominantly reside in the liver, potentiating immune responses against viral infections or malignant tumors. It has been reported that changes in cell numbers and function of NK cells are associated with the development and progression of chronic liver diseases (CLDs) including non-alcoholic fatty liver disease, alcoholic liver disease, and chronic viral hepatitis. Also, it is known that the crosstalk between NK cells and hepatic stellate cells plays an important role in liver fibrosis and cirrhosis. In particular, the impaired functions of NK cells observed in CLDs consequently contribute to occurrence and progression of hepatocellular carcinoma (HCC). Chronic infections by hepatitis B or C viruses counteract the anti-tumor immunity of the host by producing the sheddases. Soluble major histocompatibility complex class I polypeptide-related sequence A (sMICA), released from the cell surfaces by sheddases, disrupts the interaction and affects the function of NK cells. Recently, the MICA/B-NK stimulatory receptor NK group 2 member D (NKG2D) axis has been extensively studied in HCC. HCC patients with low membrane-bound MICA or high sMICA concentration have been associated with poor prognosis. Therefore, reversing the sMICA-mediated downregulation of NKG2D has been proposed as an attractive strategy to enhance both innate and adaptive immune responses against HCC. This review aims to summarize recent studies on NK cell immune signatures and its roles in CLD and hepatocellular carcinogenesis and discusses the therapeutic approaches of MICA/B-NKG2D-based or NK cell-based immunotherapy for HCC.

Validation of MELD 3.0 in patients with alcoholic liver cirrhosis using prospective KACLiF cohort.

BACKGROUND AND AIM: The Model for End-Stage Liver Disease (MELD) is a reliable prognostic tool for short-term outcome prediction in patients with end-stage liver disease. MELD 3.0 was introduced to enhance the predictive accuracy. This study assessed the performance of MELD 3.0, in comparison to MELD and MELD-Na, in patients with alcoholic liver cirrhosis. METHODS: This multicenter prospective cohort study comprised patients with alcoholic cirrhosis admitted for acute deterioration of liver function in the Republic of Korea between 2015 and 2019. This study compared the predictive abilities of MELD, MELD-Na, and MELD 3.0, for 30-day and 90-day outcomes, specifically death or liver transplantation, and explored the factors influencing these outcomes. RESULTS: A total of 1096 patients were included in the study, with a mean age of 53.3 ± 10.4 years, and 82.0% were male. The mean scores for MELD, MELD-Na, and MELD 3.0 at the time of admission were 18.7 ± 7.2, 20.6 ± 7.7, and 21.0 ± 7.8, respectively. At 30 and 90 days, 7.2% and 14.1% of patients experienced mortality or liver transplantation. The areas under the receiver operating characteristic curves for MELD, MELD-Na, and MELD 3.0 at 30 days were 0.823, 0.820, and 0.828; and at 90 days were 0.765, 0.772, and 0.776, respectively. Factors associated with the 90-day outcome included concomitant chronic viral hepatitis, prolonged prothrombin time, elevated levels of aspartate transaminase, bilirubin, and creatinine, and low albumin levels. CONCLUSION: MELD 3.0 demonstrated improved performance compared to previous models, although the differences were not statistically significant.

Effect of Probiotics in Stress-Associated Constipation Model in Zebrafish (Danio rerio) Larvae.

The pathophysiology of functional bowel disorders is complex, involving disruptions in gut motility, visceral hypersensitivity, gut-brain-microbiota interactions, and psychosocial factors. Light pollution, as an environmental stressor, has been associated with disruptions in circadian rhythms and the aggravation of stress-related conditions. In this study, we investigated the effects of environmental stress, particularly continuous light exposure, on intestinal motility and inflammation using zebrafish larvae as a model system. We also evaluated the efficacy of probiotics, specifically Bifidobacterium longum (B. longum), at alleviating stress-induced constipation. Our results showed that continuous light exposure in zebrafish larvae increased the cortisol levels and reduced the intestinal motility, establishing a stress-induced-constipation model. We observed increased inflammatory markers and decreased intestinal neural activity in response to stress. Furthermore, the expressions of aquaporins and vasoactive intestinal peptide, crucial for regulating water transport and intestinal motility, were altered in the light-induced constipation model. Administration of probiotics, specifically B. longum, ameliorated the stress-induced constipation by reducing the cortisol levels, modulating the intestinal inflammation, and restoring the intestinal motility and neural activity. These findings highlight the potential of probiotics to modulate the gut-brain axis and alleviate stress-induced constipation. Therefore, this study provides a valuable understanding of the complex interplay among environmental stressors, gut function, and potential therapeutic strategies.

Response-Guided Therapy With Cefotaxime, Ceftriaxone, or Ciprofloxacin for Spontaneous Bacterial Peritonitis: A Randomized Trial: A Validation Study of 2021 AASLD Practice Guidance for SBP.

INTRODUCTION: For the treatment of spontaneous bacterial peritonitis (SBP), cefotaxime, ceftriaxone, and ciprofloxacin were used as first-line agents. However, considering the increasing rate of antibiotic resistance, it is unclear which of these drugs can be initially recommended. This study aimed to compare the current efficacy of the 3 antibiotics, namely cefotaxime, ceftriaxone, and ciprofloxacin, for the treatment of SBP in patients with cirrhosis with ascites, when guided by therapeutic responses. METHODS: This study was a multicenter, prospective, randomized controlled trial. The inclusion criteria were 16- to 75-year-old patients with liver cirrhosis with ascites, having polymorphonuclear cell count of >250/mm 3 . We performed a follow-up paracentesis at 48 hours to decide continuing or changing the assigned antibiotics and then assessed the resolution rates at 120 and 168 hours of treatment. RESULTS: A total of 261 patients with cirrhosis who developed SBP were enrolled. Most of the patients were diagnosed as those with SBP within 48 hours of admission. The resolution rates at 120 hours, which is the primary endpoint, were 67.8%, 77.0%, and 73.6% in the cefotaxime, ceftriaxone, and ciprofloxacin groups, respectively ( P = 0.388), by intension-to-treat analysis. The 1-month mortality was similar among the groups ( P = 0.770). The model for end-stage liver disease score and the SBP resolution were significant factors for survival. CONCLUSION: The efficacy of empirical antibiotics, such as cefotaxime, ceftriaxone, and ciprofloxacin, against SBP was not significantly different. In addition, these antibiotics administered based on response-guided therapy were still efficacious as initial treatment for SBP, especially in those with community-acquired infections.

The clinical effect of antiviral therapy in patients with hepatitis B virus-related decompensated cirrhosis and undetectable DNA.

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.

A Novel SAVE Score to Stratify Decompensation Risk in Compensated Advanced Chronic Liver Disease (CHESS2102): An International Multicenter Cohort Study.

INTRODUCTION: In patients with compensated advanced chronic liver disease (cACLD), the invasive measurement of hepatic venous pressure gradient is the best predictor of hepatic decompensation. This study aimed at developing an alternative risk prediction model to provide a decompensation risk assessment in cACLD. METHODS: Patients with cACLD were retrospectively included from 9 international centers within the Portal Hypertension Alliance in China (CHESS) network. Baseline variables from a Japanese cohort of 197 patients with cACLD were examined and fitted a Cox hazard regression model to develop a specific score for predicting hepatic decompensation. The novel score was validated in an external cohort (n = 770) from 5 centers in China, Singapore, Korea, and Egypt, and was further assessed for the ability of predicting clinically significant portal hypertension in a hepatic venous pressure gradient cohort (n = 285). RESULTS: In the derivation cohort, independent predictors of hepatic decompensation were identified including Stiffness of liver, Albumin, Varices, and platElets and fitted to develop the novel score, termed "SAVE" score. This score performed significantly better (all P < 0.05) than other assessed methods with a time-dependent receiver operating characteristic curve of 0.89 (95% confidence interval [CI]: 0.83-0.94) and 0.83 (95% CI: 0.73-0.92) in the derivation and validation cohorts, respectively. The decompensation risk was best stratified by the cutoff values at -6 and -4.5. The 5-year cumulative incidences of decompensation were 0%, 24.9%, and 69.0% in the low-risk, middle-risk, and high-risk groups, respectively ( P < 0.001). The SAVE score also accurately predicted clinically significant portal hypertension (AUC, 0.85 95% CI: 0.80-0.90). DISCUSSION: The SAVE score can be readily incorporated into clinical practice to accurately predict the individual risk of hepatic decompensation in cACLD.

Endoscopic variceal obturation and retrograde transvenous obliteration for acute gastric cardiofundal variceal bleeding in liver cirrhosis.

BACKGROUND/AIMS: We retrospectively compared the effect of endoscopic variceal obturation (EVO) and retrograde transvenous obliteration (RTO) in acute cardiofundal variceal bleeding. METHODS: Patients with acute cardiofundal variceal bleeding treated with EVO or RTO at two hospitals were included. RESULTS: Ninety patients treated with EVO and 86 treated with RTO were analyzed. The mean model for end-stage liver disease score was significantly higher in EVO group than in RTO group (13.5 vs. 11.7, P = 0.016). The bleeding control rates were high (97.8% vs. 96.5%), and the treatment-related complication rates were low in both EVO and RTO groups (2.2% vs. 3.5%). During the median follow-up of 18.0 months, gastric variceal (GV) and esophageal variceal rebleeding occurred in 34 (19.3%) and 7 (4.0%) patients, respectively. The all-variceal rebleeding rates were comparable between EVO and RTO groups (32.4% vs. 20.8% at 2-year, P = 0.150), while the GV rebleeding rate was significantly higher in EVO group than in RTO group (32.4% vs. 12.8% at 2-year, P = 0.003). On propensity score-matched analysis (71 patients in EVO vs. 71 patients in RTO group), both all-variceal and GV rebleeding rates were significantly higher in EVO group than in RTO group (all P < 0.05). In Cox regression analysis, EVO (vs. RTO) was the only significant predictor of higher GV rebleeding risk (hazard ratio 3.132, P = 0.005). The mortality rates were similar between two groups (P = 0.597). CONCLUSIONS: Both EVO and RTO effectively controlled acute cardiofundal variceal bleeding. RTO was superior to EVO in preventing all-variceal and GV rebleeding after treatment, with similar survival outcomes.

Besifovir therapy improves hepatic histology and reduces covalently closed circular DNA in chronic hepatitis B patients.

BACKGROUND AND AIM: Besifovir dipivoxil maleate (BSV) was reported to have comparable antiviral efficacy and superior renal and bone safety to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients. The present study aims to evaluate changes of liver histology and intrahepatic covalently closed circular DNA (cccDNA) levels by BSV treatment in comparison with TDF therapy. METHODS: This is a subset study of the phase 3 trial comparing BSV with TDF. Among them, only CHB patients willing to participate in a histologic evaluation study were enrolled. Liver histologic examination and intrahepatic cccDNA quantification were performed. RESULTS: A total of 46 CHB patients received liver biopsies (BSV, n = 29; TDF, n = 17). After 48 weeks of treatment, virological response rate was comparable between the groups (P = 0.707). Follow-up liver biopsies showed that necroinflammation was significantly improved in the both groups. However, the histological response rate defined as the proportion of subjects whose modified histologic activity index score decreased by ≥ 2 without deterioration in fibrosis was higher in the BSV group than in the TDF group (77.8% vs 36.4%, P = 0.048). The proportion of subjects with Ishak fibrosis score 3 or more decreased from 77.7% to 55.5% in the BSV and that decreased from 72.7% to 45.4% in the TDF group. The intrahepatic cccDNA significantly decreased from baseline after 48 weeks of BSV or TDF treatment (P < 0.001) without intergroup differences (P = 0.349). CONCLUSIONS: The BSV therapy improves hepatic histology and decreases intrahepatic cccDNA in CHB patients.

Clinical Effect of Hepatitis B Virus on COVID-19 Infected Patients: A Nationwide Population-Based Study Using the Health Insurance Review & Assessment Service Database.

BACKGROUND: Several studies have recently suggested that liver disease and cirrhosis were risk factors for poor outcomes in patients with coronavirus disease 2019 (COVID-19) infections. However, no large data study has reported the clinical course of COVID-19 patients with chronic hepatitis B virus (HBV) infections. This study investigated whether HBV infection had negative impacts on the clinical outcomes of COVID-19 patients. METHODS: We performed a nationwide population-based cohort study with 19,160 COVID-19-infected patients in 2020 from the Korean Health Insurance Review and Assessment database. The clinical outcomes of COVID-19 patients with chronic HBV infections were assessed and compared to those of non-HBV-infected patients. RESULTS: Of the 19,160 patients diagnosed with COVID-19, 675 (3.5%) patients had chronic HBV infections. The HBV-infected patients were older and had more commodities than the non-HBV infected COVID-19 patients. During the observation period, COVID-19-related mortality was seen in 1,524 (8.2%) of the non-HBV-infected 18,485 patients, whereas 91 (13.5%) in HBV-infected 675 patients died of COVID-19 infection. Compared to patients without HBV infections, a higher proportion of patients with chronic HBV infections required intensive care unit (ICU) admission and had organ failures. However, odds ratios for mortality, ICU admission, and organ failure were comparable between the two groups after adjusting for age, sex, and comorbid diseases including liver cirrhosis and hepatocellular carcinoma. CONCLUSION: COVID-19-infected patients with HBV infections showed worse clinical courses than non-HBV-infected COVID-19 patients. However, after adjustment, chronic HBV infection itself does not seem to affect the clinical outcomes in COVID-19 patients.

Incidence and risk factors for postoperative common bile duct stones in patients undergoing endoscopic extraction and subsequent cholecystectomy.

BACKGROUND AND AIMS: In patients who undergo cholecystectomy after endoscopic common bile duct (CBD) stone extraction, CBD stones found postoperatively could be problematic. This study aimed to investigate the incidence and risk factors of postoperative CBD stones after cholecystectomy. METHODS: A total of 278 patients (mean age, 59.2 years; 71 men [51.1%]) who underwent endoscopic removal of CBD stones followed by cholecystectomy from January 2013 to December 2017 were included. An endoscopic nasobiliary drainage (ENBD) tube was placed immediately after endoscopic clearance of the CBD stones in all patients until cholecystectomy. An ENBD tubogram was obtained in all patients to determine the presence of postoperative CBD stones. RESULTS: Postoperative CBD stones were detected in 20.1% (56/278). An ENBD tubogram was obtained after an average of 2.42 days postoperatively. Based on univariate analysis, the statistically significant risk factors for postoperative CBD stone were CBD stones >2, CBD stone size >10 mm, cholesterol stone, maximum diameter of CBD >15 mm, treatment with endoscopic sphincterotomy alone, and use of endoscopic mechanical lithotripsy (EML). In multivariate analysis, cholesterol stone, CBD stones >2, CBD stone size >10 mm, and EML were related to postoperative CBD stones after cholecystectomy. CONCLUSIONS: Based on the relatively high rate of postoperative CBD stones after cholecystectomy, careful follow-up should be considered in patients with high-risk factors to detect CBD stones early.

Natural killer cell activity is a risk factor for the recurrence risk after curative treatment of hepatocellular carcinoma.

BACKGROUND: Natural killer (NK) cells have been known to contribute to surveillance and control of hepatocellular carcinoma (HCC). However, the association of NK cell activity with stage and recurrence risk of HCC have not been fully evaluated. METHODS: Untreated patients with newly diagnosed HCC were prospectively enrolled. Peripheral blood mononuclear cells were isolated at the time of diagnosis. Patients who had undergone surgery or radiofrequency ablation were classified as the curative treatment group, and their blood samples were collected again at 1 month after treatment. RESULTS: A total of 80 patients with HCC were enrolled. The mean age was 62.5 years. At baseline, interferon (IFN)-γ producing NK cell proportion was significantly lower in patients with Barcelona clinic liver cancer (BCLC) stage B, C, or D than in those with BCLC stage 0 (42.9% vs. 56.8%, P = 0.045). Among all patients, 56 patients had undergone curative treatment, and 42 patients re-visited at 1 month after curative treatment. There was no significant change in total NK cell and IFN-γ producing NK cell proportion from baseline to 1 month after treatment (all P > 0.05). During a median follow-up of 12.4 months, HCC recurred in 14 patients (33.3%). When patients were classified according to the IFN-γ producing NK cell proportion (group 1, ≥ 45%; and group 2, < 45%), HCC recurrence rate did not differ according to the IFN-γ producing NK cell proportion at baseline (log-rank test, P = 0.835). However, patients with < 45% IFN-γ producing NK cell proportion at 1 month after treatment had a significantly higher HCC recurrence rate than patients with that of ≥ 45% (log-rank test, P < 0.001). Multivariate analysis revealed that BCLC stage B (hazard ratio [HR] = 3.412, P = 0.045) and < 45% IFN-γ producing NK cell proportion at 1 month after treatment (HR = 6.934, P = 0.001) independently predicted an increased risk of HCC recurrence. CONCLUSIONS: Decreased NK cell activity is significantly associated with the advanced stage of HCC, and the increased recurrence risk of HCC after curative treatment.

Besifovir Dipivoxil Maleate 144-Week Treatment of Chronic Hepatitis B: An Open-Label Extensional Study of a Phase 3 Trial.

INTRODUCTION: Chronic hepatitis B (CHB) remains a major worldwide public health concern. Besifovir dipivoxil maleate (BSV) is a new promising treatment for CHB. However, long-term efficacy and safety have not yet been evaluated. Therefore, the goal of the study is to determine the antiviral efficacy and safety of BSV treatment over a 144-week duration (BSV-BSV) in comparison with those of a sequential treatment with tenofovir disoproxil fumarate (TDF) followed by a 96-week duration BSV administration (TDF-BSV). METHODS: After 48 weeks of a double-blind comparison between BSV and TDF treatments, patients continued the open-label BSV study. We evaluated antiviral efficacy and drug safety up to 144 weeks for BSV-BSV and TDF-BSV groups. The primary endpoint was a virological response (hepatitis B virus DNA < 69 IU/mL). RESULTS: Among the 197 patients enrolled, 170 and 158 patients entered the second-year and third-year open-label phase extensional study, respectively, whereas 153 patients completed the 144-week follow-up. The virological response rate over the 144-week period was 87.7% and 92.1% in BSV-BSV and TDF-BSV groups, respectively (P = 0.36). The rates of ALT normalization and HBeAg seroconversion were similar between the groups. No drug-resistant mutations to BSV were noted. Bone mineral density and renal function were well preserved in the BSV-BSV group and were significantly improved after switching therapy in TDF-BSV patients. DISCUSSION: This extensional study of a phase 3 trial (NCT01937806) suggests that BSV treatment is efficacious and safe for long-term use in treatment-naïve and TDF-experienced patients with CHB.

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.

Prognosis predictability of serum and urine renal markers in patients with decompensated cirrhosis: A multicentre prospective study.

BACKGROUND AND AIMS: This prospective observational study aimed to evaluate the best serum and urine markers to assess predictability for the prognosis of patients with decompensated cirrhosis. METHODS: Serum creatinine and cystatin C (CysC), and urinary N-acetyl-beta-D glucosaminidase (uNAG) and neutrophil gelatinase-associated lipocalin (uNGAL) levels were measured from hospitalized patients with decompensated cirrhosis. RESULTS: In total, 328 patients (mean age, 57.2 ± 12.0 years; 237 men) with decompensated cirrhosis were included. Alcoholic liver disease was the most frequent underlying liver disease (68.0%). Acute kidney injury (AKI) was concomitantly present in 41 patients (12.5%) at baseline. INR, serum creatinine and CysC levels, and uNAG and uNGAL levels were significantly higher in patients with AKI. During hospitalization, AKI had progressed in 37 patients (11.3%). In 287 patients without AKI, the incidence of AKI at 3, 6, 9 and 12 months was 15.4%, 22.2%, 28.6% and 32.5% respectively. On multivariate analysis, serum CysC and uNAG levels were independent predictors of AKI, and their optimal cut-off values were 1.055 mg/L and 23.1 U/g urinary Cr respectively. When patients were classified into three groups with these cut-off values of serum CysC and uNAG levels (group 1, both low; group 2, one of two high; and group 3, both high), progression of AKI during hospitalization (P = .001), incidence of AKI in patients without AKI at baseline (P = .001) and mortality rate (P < .001) differed significantly according to serum CysC and uNAG levels. CONCLUSION: Serum CysC and uNAG levels are useful prognostic markers for renal outcomes and mortality in patients with decompensated cirrhosis.

Feasibility of Changing Intra-Arterial Flow Direction by Temporary Occlusion Using Retrievable Coils: Study with a Normal Pig Model.

PURPOSE: To evaluate feasibility of changing intra-arterial flow direction by temporary occlusion using retrievable coils. MATERIALS AND METHODS: In 2 healthy pig livers, injection of a lipiodol mixture (lipiodol:saline = 2:1) was performed at the segmental arteries after occluding 1 of the subsegmental arteries. This was accomplished using a retrievable coil in 5 different segmental arteries (3 in pig A and 2 in pig B). Injection of the lipiodol mixture was performed through a 3-way system using a hemostatic valve, whereas the retrievable coil delivery system was in the lumen of a microcatheter. Successful coil deployment, occlusion of the vessel, and coil retrieval were evaluated. Redistribution of flow after placement of the coil and vessel patency after coil removal were angiographically evaluated. The distribution of lipiodol mixture was evaluated using cone beam computed tomography. RESULTS: All 5 of the retrievable coils were successfully deployed and removed. Angiography revealed successful occlusion of subsegmental artery after coil placement with flow redistribution followed by restoration of flow after coil retrieval in all cases. On cone beam computed tomography, lipiodol tagging was abundant in hepatic parenchyma supplied by the hepatic artery without coils compared with that supplied by the branch with coils. CONCLUSIONS: Temporary arterial flow redistribution using a retrievable coil was feasible in the healthy pig model and could be applicable for endovascular procedures in which superselection is difficult or unavailable.

Differential Impact of Serum 25-Hydroxyvitamin D3 Levels on the Prognosis of Patients with Liver Cirrhosis According to MELD and Child-Pugh Scores.

BACKGROUND: Prognosis of patients with diverse chronic diseases is reportedly associated with 25-hydroxyvitamin D levels. In this study, we investigated the potential role of 25-hydroxyvitamin D3 (25[OH]D3) levels in improving the predictive power of conventional prognostic models for patients with liver cirrhosis. METHODS: We investigated clinical findings, including serum 25(OH)D3 levels at admission, of 155 patients with cirrhosis who were followed up for a median of 16.9 months. RESULTS: Median 25(OH)D3 levels were significantly different among patients exhibiting Child-Pugh grades A, B, and C. Mortality, including urgent transplantation, was significantly associated with 25(OH)D3 levels in univariate analysis. Severe vitamin-D deficiency (serum 25[OH]D3 level < 5.0 ng/mL) was significantly related to increased mortality, even after adjusting for Child-Pugh and Model for End-stage Liver Disease (MELD) scores. In particular, the presence of severe vitamin D deficiency clearly defined a subgroup with significantly poorer survival among patients with Child-Pugh scores of 5-10 or MELD scores ≤ 20. A new combination model of MELD score and severe vitamin D deficiency showed significantly more accurate predictive power for short- and long-term mortality than MELD scores alone. Additionally, serum 25(OH)D3 levels and new model scores were significantly associated with the development of spontaneous bacterial peritonitis, overt encephalopathy, and acute kidney injury. CONCLUSION: Serum 25(OH)D3 level is an independent prognostic factor for patients with liver cirrhosis and has a differential impact on disease outcomes according to MELD and Child-Pugh scores.

Efficacy and Safety of Besifovir Dipivoxil Maleate Compared With Tenofovir Disoproxil Fumarate in Treatment of Chronic Hepatitis B Virus Infection.

BACKGROUND & AIMS: Besifovir dipivoxil maleate (BSV) has activity against hepatitis B virus (HBV). We performed a phase 3 study to compare the antiviral efficacy and safety of BSV vs tenofovir disoproxil fumarate (TDF) in patients with chronic HBV infection in Korea. METHODS: We conducted a double-blind, non-inferiority trial of 197 patients with chronic HBV infection at 22 sites in South Korea, from November 2013 through February 2016. Patients were randomly assigned to groups given BSV (150 mg, n = 99) or TDF (300 mg, n = 98) for 48 weeks. We evaluated virologic responses to therapy (HBV DNA <69 IU/mL or 400 copies/ml), bone mineral density (BMD), and renal outcomes for safety analysis. The main efficacy endpoint was the proportion of patients with a virologic response at week 48. After 48 weeks, TDF was switched to BSV (150 mg) for an additional 48 weeks. RESULTS: After 48 weeks of treatment, 80.9% of patients given BSV and 84.9% of patients given TDF met the efficacy endpoint, indicating the non-inferiority of BSV to TDF. At week 96, 87.2% of patients in the BSV-BSV and 85.7% of patients in the TDF-BSV had a virologic response. At week 48, changes in hip and spine BMD differed significantly between the BSV and TDF groups, whereas the estimated glomerular filtration rate in the TDF group was significantly lower than that in the BSV group. However, at 96 weeks, there were no significant differences in BMD and estimated glomerular filtration rate between the BSV-BSV and TDF-BSV groups. CONCLUSIONS: BSV has antiviral efficacy comparable to that of TDF after 48 weeks of treatment, with durable effects for 96 weeks. BSV has a better safety profile than TDF, in terms of bone and renal outcomes. ClinicalTrials.gov no: NCT01937806.

Hepatic resection compared to chemoembolization in intermediate- to advanced-stage hepatocellular carcinoma: A meta-analysis of high-quality studies.

According to the American Association for the Study of Liver Diseases (AASLD) treatment guidelines for hepatocellular carcinoma (HCC), the role of surgery has been expanded beyond the Barcelona Clinic Liver Cancer (BCLC) algorithm. We compared primary hepatectomy (PH) with transarterial chemoembolization (TACE) in patients with intermediate- to advanced-stage (BCLC stage B/C) HCC to determine the current evidence. Through a database search, we included 18 high-quality studies (one randomized controlled trial [RCT], five propensity-score matching nonrandomized comparative trials [NRCTs], and 12 NRCTs) that compared survival outcomes of 5,986 patients after PH and TACE. We found significant survival benefits for PH over TACE in BCLC stage B/C patients (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.51-0.67; P < 0.00001; I2 = 84%). According to the BCLC, both stage B and stage C patients showed significantly better overall survival (OS) for PH compared to TACE (HR, 0.53; 95% CI, 0.43-0.65; P < 0.00001; I2 = 77%; HR, 0.67; 95% CI, 0.59-0.77; P < 0.00001; I2 = 79%, respectively). Five-year survival rates for PH were significantly higher than those for TACE in BCLC stage B/C, stage B, and BCLC stage C patients (odds ratio [OR], 2.71, 2.77, and 3.03, respectively; all P < 0.00001). Survival benefits persisted across subgroup, sensitivity, and metaregression analyses; interstudy heterogeneity remained constant. CONCLUSION: This meta-analysis suggests that surgical resection provides survival benefits in patients with intermediate- to advanced-stage HCC. The evidence found herein may assist in the choice of treatment modality based on diverse definitions of operability. (Hepatology 2018).

Prediction of the varices needing treatment with non-invasive tests in patients with compensated advanced chronic liver disease.

BACKGROUNDS & AIMS: The Baveno VI guidelines proposed criteria including liver stiffness (LS) and platelet count to avoid screening endoscopy in patients with compensated advanced chronic liver disease (cACLD). This study was performed to validate the Baveno IV criteria and to compare its diagnostic accuracy with other non-invasive models. METHODS: Patients with cACLD who underwent laboratory tests, upper gastrointestinal endoscopy and abdominal ultrasound within 6 months of transient elastography were included. RESULTS: A total of 1218 patients with cACLD were included. VNT occurred in 249 patients (20.4%). With the Baveno VI criteria, the VNT miss rate was 1.9% with a 25.7% saved endoscopy rate. Using two criteria of LS <20 kPa and platelet count >110 × 109  cells/L or LS <25 kPa and platelet count >120 × 109  cells/L, the saved endoscopy rate was 39.1% while maintaining the VNT miss rate <5%. The optimal LS and platelet count-based criteria for predicting VNT differed according to the underlying liver disease. The area under the receiver operating characteristic curve of LS-spleen diameter to platelet score (LSPS) was 0.780 (95% confidence interval: 0.774-0.820), which was significantly higher than other models. The optimal cut-off value of the LSPS for predicting VNT was 1.47. CONCLUSION: Liver stiffness and platelet count-based criteria are useful for discriminating patients with very low risk of having VNT among patients with cACLD and are partly affected by the type of underlying liver disease. Conversely, the LSPS is a predictor of VNT in patients with cACLD regardless of the type of underlying liver disease.

Prognostic assessment using a new substaging system for Barcelona clinic liver cancer stage C hepatocellular carcinoma: A nationwide study.

AIM & BACKGROUND: Advanced hepatocellular carcinoma (HCC) (Barcelona clinic liver cancer [BCLC] stage C) needs subclassification to more accurately predict survival. This study aims to establish a substaging system of BCLC stage C HCC patients for accurate prognosis. METHODS: Data from 564 patients with newly diagnosed BCLC stage C HCC from three tertiary-care hospitals affiliated with the Korea University (training set) were assessed retrospectively. Variables affecting overall survival (OS) were analysed, and patients were substaged according to the number of prognostic factors they fulfilled. The substaging system was validated using a nationwide database from the Korean Liver Cancer Association (validation set; n = 742). RESULTS: In the training set, tumour factors such as tumour burden ≥10 cm, major portal vein invasion and distant metastasis, as well as underlying liver function, were independently associated with OS. BCLC stage C was classified into four substages (C1-4) according to the number of prognostic factors. Substages C1, C2, C3 and C4 showed a median OS of 17.50 months (95% confidence interval [CI], 8.57-26.43), 10.13 months (95% CI, 8.17-12.09), 4.20 months (95% CI, 3.42-4.98), and 2.90 months (95% CI, 2.34-3.46) respectively (P < 0.05). This substaging system also had good discriminative ability in predicting survival in the validation set. In addition, it was considered that the BCLC substaging is better than Hong Kong liver cancer substaging in predicting the OS for patients with advanced HCC. CONCLUSION: Our substaging for BCLC stage C might help predict patients' prognosis better.