Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study.

BACKGROUND & AIMS: Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy. METHODS: We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization. RESULTS: Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC. CONCLUSIONS: Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease. GOV NUMBER: NCT01761266. IMPACT AND IMPLICATIONS: This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival.

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.

Applications of molecular barcode sequencing for the detection of low-frequency variants in circulating tumour DNA from hepatocellular carcinoma.

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

Direct-Acting Antivirals Improve Treatment Outcomes in Patients with Hepatitis C Virus-Related Hepatocellular Carcinoma Treated with Transarterial Chemoembolization: A Nationwide, Multi-center, Retrospective Cohort Study.

BACKGROUND AND AIMS: The influence of direct-acting antivirals (DAAs) on chronic hepatitis C (CHC)-related hepatocellular carcinoma (HCC) remains controversial. We investigated the effect of eradicating CHC using DAAs on treatment outcomes in patients with CHC-related HCC treated with transarterial chemoembolization (TACE). METHODS: This nationwide, multi-center, retrospective study recruited patients with CHC-related HCC treated with TACE as the first-line anti-cancer treatment, and who achieved a sustained virological response (SVR) using DAAs (DAA group) between 2006 and 2017. Patients achieving an SVR following interferon-based treatment (IFN group) and those without treatment (control group) were also recruited for comparison. RESULTS: A total of 425 patients were eligible for the study. Of these, 356 (83.8%), 26 (6.1%), and 43 (10.1%) were allocated to the control, IFN, and DAA groups, respectively. A multivariate analysis showed that liver cirrhosis, segmental portal vein thrombosis, and larger maximal tumor size independently predicted an increased risk of progression (all p < 0.05), whereas, the DAA group (vs. IFN and control groups) independently predicted a reduced risk of progression (hazard ratio (HR) = 0.630, 95% confidence interval 0.411-0.966, p = 0.034). The cumulative incidence rate of HCC progression in the DAA group was significantly lower than that in the IFN and control groups (p = 0.033, log-rank test). In addition, the DAA group (vs. IFN and control groups) was independently associated with a reduced risk of mortality (p = 0.042). CONCLUSIONS: DAA treatment provided significantly prolonged progression-free survival in patients with CHC-related HCC treated with TACE compared to that in patients administered IFN or no treatment.

Revised Korean Antiviral Guideline Reduces the Hepatitis B-related Hepatocellular Carcinoma Risk in Cirrhotic Patients.

BACKGROUND: Since September 2015, the initiation of antiviral therapy (AVT) for patients with chronic hepatitis B (CHB)-related cirrhosis has been reimbursed according to the revised Korean Association for the Study of Liver (KASL) guideline, if the patient had hepatitis B virus DNA level ≥ 2,000 IU/L, regardless of aminotransferase or alanine aminotransferase levels. This study investigated whether the KASL guideline implementation reduced the risk of CHB-related hepatocellular carcinoma (HCC) in patients with cirrhosis in South Korea. METHODS: A total of 429 patients with CHB-related cirrhosis who initiated AVT between 2014 and 2016 were recruited. The risk of HCC development was compared between patients who initiated AVT before and after September 2015 (pre-guideline [n = 196, 45.7%] vs. post-guideline implementation [n = 233, 54.3%]). RESULTS: Univariate analysis showed that AVT initiation before guideline implementation, older age, male gender, and diabetes significantly predicted increased risk of HCC development (all P < 0.05). Subsequent multivariate analysis showed that AVT initiation before guideline implementation (HR = 1.941), older age (HR = 5.762), male gender (HR = 2.555), and diabetes (HR = 1.568) independently predicted increased risk of HCC development (all P < 0.05). Additionally, multivariate analysis showed that AVT initiation before guideline implementation (HR = 2.309), male gender (HR = 3.058), and lower platelet count (HR = 0.989) independently predicted mortality (P < 0.05). The cumulative incidences of HCC and mortality were significantly higher in patients who initiated AVT before guideline implementation than in those who initiated AVT after guideline implementation (all P < 0.05, log-rank test). CONCLUSION: The prognosis of patients with CHB-related cirrhosis who initiated AVT improved after guideline implementation according to the revised KASL guideline.

A nomogram based on liver stiffness predicts postoperative complications in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Liver stiffness measurement (LSM), assessed by transient elastography (Fibroscan), has been demonstrated to predict post-hepatectomy liver failure in patients who undergo hepatic resection for hepatocellular carcinoma (HCC). However, other complications are also likely to be related to the underlying grade of liver fibrosis. Herein, we aimed to identify predictors of postoperative complications and to build and develop a novel nomogram able to identify patients at risk of developing severe complications. METHODS: Data from patients who underwent hepatectomy for HCC between 2006 and 2016 at 2 referral centres were retrospectively reviewed. All surgical complications were recorded and scored using the comprehensive complication index (CCI), ranging from 0 (uneventful course) to 100 (death). A CCI ≥26.2 was used as a threshold to define severe complications. RESULTS: During the study period, 471 patients underwent hepatic resection for HCC. Among them, 50 patients (10.6%) had a CCI ≥26.2. Age, model for end-stage liver disease (MELD) score and LSM values, together with serum albumin, were independent predictors of high CCI. The nomogram built on these variables was internally validated and showed good performance (optimism-corrected c-statistic = 0.751). A regression equation to predict the CCI was also established by multiple linear regression analysis: [LSM (kPa) × 0.254] + [age (years) × 0.118] + [MELD score (pt.) × 1.050] - [albumin (g/dl) × 2.395] - 3.639. CONCLUSION: A novel nomogram, combining LSM values, age and liver function tests provided an excellent preoperative prediction of high CCI in patients with resectable HCC. This predictive model could be used as a reference for clinicians and surgeons to help them in clinical decision-making. LAY SUMMARY: Liver stiffness measurement is increasingly being used to assess the degree of liver fibrosis in patients with cirrhosis and/or chronic hepatitis. Using Fibroscan, we developed a novel nomogram to predict severe complications following liver resection for hepatocellular carcinoma, according to the new comprehensive complication index. This tool could be used as a reference for clinicians and surgeons to help them in clinical decision-making.

Validation of the CAMD Score in Patients With Chronic Hepatitis B Virus Infection Receiving Antiviral Therapy.

BACKGROUND & AIMS: Researchers previously developed a scoring system to determine the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection, based on the presence of cirrhosis, patient age, male sex, and diabetes (called the CAMD scoring system). We validated the CAMD scoring system and compared its performance with that of other risk assessment models in an independent cohort. METHODS: We followed up 3277 patients with chronic HBV infection (mean age, 48.7 y; 62.6% male; 32.4% with cirrhosis) who were treated with entecavir (n = 1725) or tenofovir (n = 1552) as the first-line antiviral agent in 4 academic teaching hospitals in the Republic of Korea. The primary outcome was development of HCC. We evaluated the ability of the CAMD, PAGE-B, and mPAGE-B scoring systems to identify patients who would develop HCC using integrated area under the curve (iAUC) analysis. RESULTS: Over a median follow-up period of 58.2 months, 8.9% of the patients developed HCC. Patients who developed HCC were older, more likely to be male, and had higher proportions of cirrhosis and diabetes than patients who did not develop HCC (all P < .05). CAMD scores identified patients who developed HCC with an iAUC of 0.790, mPAGE-B scores with an iAUC of 0.769, and PAGE-B scores with an iAUC of 0.760. The 5-year cumulative risks of HCC were 1.3% in patients with low CAMD scores (<8), 8.0% in patients with intermediate CAMD scores (8-13), and 24.3% in patients with high CAMD scores (>13) (P < .001 for comparison of low- vs intermediate-score groups and between intermediate- vs high-score groups). The predicted and observed probabilities of HCC had excellent agreement. CONCLUSIONS: We validated the CAMD scoring system in determining the risk of HCC in patients with chronic HBV treatment receiving entecavir or tenofovir treatment. Validation was performed in a cohort of patients in the Republic of Korea, where most patients have genotype C2 HBV infection.

Outcomes of Long-term Treatment of Chronic HBV Infection With Entecavir or Other Agents From a Randomized Trial in 24 Countries.

BACKGROUND & AIMS: Treatment of chronic hepatitis B virus (HBV) infection with entecavir suppresses virus replication and reduces disease progression, but could require life-long therapy. To investigate clinical outcome events and safety associated with long-term treatment with entecavir, we followed up patients treated with entecavir or another standard-of-care HBV nucleos(t)ide analogue for up to 10 years. We assessed long-term outcomes and relationships with virologic response. METHODS: Patients with chronic HBV infection at 299 centers in Asia, Europe, and North and South America were assigned randomly to groups that received entecavir (n = 6216) or an investigator-selected nonentecavir HBV nucleos(t)ide analogue (n = 6162). Study participants were followed up for up to 10 years in hospital-based or community clinics. Key end points were time to adjudicated clinical outcome events and serious adverse events. In a substudy, we examined relationships between these events and virologic response. RESULTS: There were no significant differences between groups in time to event assessments for primary end points including malignant neoplasms, liver-related HBV disease progression, and death. There were no differences between groups in the secondary end points of nonhepatocellular carcinoma malignant neoplasms and hepatocellular carcinoma. In a substudy of 5305 patients in China, virologic response, regardless of treatment group, was associated with a reduced risk of liver-related HBV disease progression (hazard ratio, 0.09; 95% CI, 0.038-0.221) and hepatocellular carcinoma (hazard ratio, 0.03; 95% CI, 0.009-0.113). Twelve patients given entecavir (0.2%) and 50 patients given nonentecavir drugs (0.8%) reported treatment-related serious adverse events. CONCLUSIONS: In a randomized controlled trial of patients with chronic HBV infection, we associated entecavir therapy with a low rate of adverse events over 10 years of follow-up evaluation. Patients receiving entecavir vs another nucleos(t)ide analogue had comparable rates of liver- and non-liver-related clinical outcome events. Participants in a China cohort who maintained a virologic response, regardless of treatment group, had a reduced risk of HBV-related outcome events including hepatocellular carcinoma. ClinicalTrials.gov identifier no: NCT00388674.

Nonalcoholic Fatty Liver Disease and Sarcopenia Are Independently Associated With Cardiovascular Risk.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) and sarcopenia have a close association with an increased risk of atherosclerotic cardiovascular disease (ASCVD). This study investigated the influence of NAFLD and sarcopenia on ASCVD risk. METHODS: Data from the 2008-2011 Korean National Health and Nutrition Examination Surveys database were analyzed (n = 7,191). The sarcopenia index was calculated using dual-energy x-ray absorptiometry. Sarcopenia was defined as the lowest quintile sarcopenia index value (cutoffs = 0.882 for men and 0.582 for women). NAFLD was defined as a comprehensive NAFLD score ≥40. Liver fibrosis was assessed using the fibrosis-4 (FIB-4) index. ASCVD risk was evaluated using American College of Cardiology/American Heart Association guidelines. High probability of ASCVD was defined as ASCVD risk >10%. RESULTS: The prevalence rates of NAFLD and sarcopenia were 31.2% (n = 2,241) and 19.5% (n = 1,400), respectively. The quartile-stratified ASCVD risk scores were positively associated with NAFLD and sarcopenia (all P for trend < 0.001). Subjects with both NAFLD and sarcopenia had a higher risk for high probability of ASCVD (odds ratio = 1.83, P = 0.014) compared with controls without NAFLD and sarcopenia. Among subjects with NAFLD, FIB-4-defined significant liver fibrosis and sarcopenia additively raised the risk for high probability of ASCVD (odds ratio = 3.56, P < 0.001) compared with controls without FIB-4-defined significant liver fibrosis or sarcopenia. DISCUSSION: NAFLD and sarcopenia were significantly associated with an increased risk of ASCVD in the general population. In addition, NAFLD with significant liver fibrosis and sarcopenia were significantly associated with an increased risk of ASCVD in subjects with NAFLD.

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.

An observational study on long-term renal outcome in patients with chronic hepatitis B treated with tenofovir disoproxil fumarate.

In patients with chronic hepatitis B (CHB), long-term effects of tenofovir disoproxil fumarate (TDF) on renal function have been controversial. This study aimed to analyse the real-world long-term effects of TDF on renal function in Korean patients with CHB. We analysed a cohort of 640 treatment-naïve patients with CHB who were treated with TDF between May 2012 and December 2015 at Severance Hospital, Seoul, Republic of Korea. The mean age was 48.3 years old, and 59.5% were male. The proportions of hypertension and diabetes mellitus (DM) were 11.6% and 14.2%, respectively, and that of liver cirrhosis was 20.8%. During the 5-year follow-up, using a linear mixed model, serum creatinine increased from 0.77 ± 0.01 mg/dL to 0.85 ± 0.02 mg/dL (P < .001), and eGFR decreased from 102.6 ± 0.6 mL/min/1.73 m2 to 93.4 ± 1.4 mL/min/1.73 m2 (P < .001). In subgroup analysis, eGFR was statistically more decreased in patients with age > 60 than ≦60 years old (P = .027), and in patients with diuretic use than without diuretic use (P = .008). In multivariate analysis, the independent risk factors for eGFR decrease > 20% were baseline eGFR < 60mL/min/1.73 m2 (P = .034) and the use of diuretics (P < .001). CHB patients on TDF experienced greater reduction in renal function with age > 60 and with diuretic use compared to those without these characteristics. Baseline eGFR < 60 mL/min/1.73 m2 and use of diuretics were independent risk factors of eGFR decline of more than 20% on TDF therapy.

Entecavir and tenofovir on renal function in patients with hepatitis B virus-related hepatocellular carcinoma.

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

High body mass index hinders fibrosis improvement in patients receiving long-term tenofovir therapy in hepatitis B virus-related cirrhosis.

Long-term suppression of hepatitis B virus with tenofovir (TDF) induces fibrosis regression, and repeated liver stiffness (LS) measurement can indicate the improvement of fibrosis. We aimed to investigate predictors for LS improvement assessed by changes in patients receiving long-term TDF therapy in chronic hepatitis B (CHB) with liver cirrhosis. CHB patients with histologically proven liver cirrhosis who received TDF as the first-line therapy from 2012 to 2015 were recruited. LS and controlled attenuation parameter (CAP) measurements were repeated at baseline and 3 years after therapy. Liver stiffness improvement was defined as a drop of LS value ≥30% from the baseline. A total of 131 patients were enrolled (mean age 51.4% and male 64.9%). After 3 years of TDF therapy, the mean LS value significantly improved (from 14.7 to 8.6 kPa, P < .001), and 96 (73.3%) patients have achieved LS improvement. Predictors associated with improvement of LS were low body mass index (BMI), HBeAg positivity, and low CAP value at baseline. In multivariate analysis, low BMI was a single factor independently associated with LS improvement (odds ratio 0.680, 95% CI 0.560-0.825, P < .001). Patients with BMI < 23.5, had a 1.96 times more chance of achieving LS improvement compared to those with BMI ≥ 23.5 (90.1% vs. 46.0%, P = .001). High BMI was a single significant factor hindering the fibrosis improvement in patients receiving long-term TDF therapy in CHB with liver cirrhosis. Life style modification and BMI reduction should be encouraged to enhance fibrosis improvement.

Dose escalation in radiotherapy for incomplete transarterial chemoembolization of hepatocellular carcinoma.

PURPOSE: To investigate the efficacy of radiation dose escalation in patients with hepatocellular carcinoma (HCC) after incomplete transarterial chemoembolization (TACE). METHODS: This study evaluated retrospective data of 323 HCC patients who received radiotherapy after incomplete TACE from 2001-2016. Radiation dose in biologically effective dose (BED) (α/ß = 10) was categorized as <72 Gy (261 patients) and ≥72 Gy (62 patients). Simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) was used significantly more frequently in the high-dose group (64.5% vs. 12.9%; P < 0.001). Local failure-free rate (LFFR), progression-free rate (PFR), and toxicities were compared between the two groups. Additionally, propensity score matching was performed. RESULTS: Median follow-up time for patients who were alive at the time of analysis was 47 months (range 18-189 months). Median overall survival after radiotherapy was 14 months. In multivariate analysis, BED ≥72 Gy was an independent predictor of favorable LFFR (hazard ratio [HR] 0.32; 95% confidence interval [CI] 0.14-0.72; P = 0.006) and PFR (HR 0.67; 95% CI 0.45-0.98; P = 0.04). In the propensity score-matched cohort (62 pairs), 1­year LFFR (94% vs. 81%; P = 0.002), and 1­year PFR (49% vs. 42%; P = 0.01) were significantly higher in the high-dose group. Treatment-related toxicities were comparable between the high-dose and low-dose groups (classic radiation-induced liver disease: 5.3% [3/57] vs. 13.8% [29/210], P = 0.08; grade 2-4 gastrointestinal bleeding: 3.2% [2/62] vs. 7.3% [19/261], P = 0.39). CONCLUSION: Radiation dose with BED ≥72 Gy improved LFFR and PFR without increasing toxicity. In radiotherapy for incomplete TACE of HCC, dose escalation using SIB-IMRT should be actively considered to improve oncologic outcome.

Advanced Liver Fibrosis Predicts Unfavorable Long-Term Prognosis in First-Ever Ischemic Stroke or Transient Ischemic Attack.

INTRODUCTION: There are a limited number of studies investigating the relationship between the degree of liver fibrosis and the long-term prognosis, especially ischemic stroke (IS) recurrence, in first-ever IS or transient ischemic attack (TIA). OBJECTIVE: We investigated whether there are differences in the long-term all-cause and cardiovascular mortalities and IS recurrence based on the degree of liver fibrosis in first-ever IS or TIA. METHODS: This analysis included 2,504 patients with first-ever IS or TIA recruited from a prospective stroke cohort. Liver fibrosis was predicted using the fibrosis-4 (FIB-4) index, and advanced fibrosis was defined as an FIB-4 index of >3.25. Using Cox regression models, we compared the all-cause and cardiovascular mortalities and IS recurrence. As measures for the additive predictive value of the FIB-4 index for prediction of all-cause mortality, the integrated area under the receiver operating characteristic curve (iAUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used. RESULTS: There were 231 (9.2%) patients with advanced fibrosis. During a median follow-up of 1.2 years, the cumulative all-cause and cardiovascular mortalities were 6.4 and 1.9%, and IS recurrence was observed in 5.3%. The advanced fibrosis was associated with an increased risk of all-cause mortality (hazard ratio [HR] = 3.98, 95% confidence interval [CI] = 2.40-6.59), cardiovascular mortality (HR = 4.48, 95% CI = 1.59-12.65), and IS recurrence (HR = 1.95, 95% CI = 1.05-3.65). Adding the FIB-4 index to the model consisting of traditional cardiovascular risk factors improved the predictive accuracy for all-cause mortality as measured using the iAUC (from 0.7594 to 0.7729) and for all-cause mortality at 1 year as measured using the NRI (38.6%) and IDI (0.037). CONCLUSIONS: The burden of liver fibrosis is associated with unfavorable long-term prognosis, including recurrent IS, in first-ever IS or TIA.

Influence of Besifovir Dipivoxil Maleate Combined with L-Carnitine on Hepatic Steatosis in Patients with Chronic Hepatitis B.

BACKGROUND: Besifovir dipivoxil maleate (BSV) with L-carnitine is the first-line antiviral agent for chronic hepatitis B (CHB) infection. We investigated whether BSV combined with L-carnitine improves hepatic steatosis (HS). METHODS: Treatment-naïve patients with CHB who were initiated on antiviral therapy (AVT) were enrolled. The magnitude of HS was assessed using hepatic steatosis index (HSI), and HS improvement was defined as a ≥ 10% reduction in the HSI score from the baseline. RESULTS: The mean age of the study patients was 56 years with a male predominance (n = 178, 64.7%). The mean body mass index (BMI), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count were 23.5 kg/m², 49.6 IU/L, 49.0 IU/L, and 191.3 × 109/L, respectively. The mean HSI and fibrosis (FIB)-4 index were 32.6 and 0.5, respectively. After 6 months of AVT, platelet count (mean, 191.3→167.0 × 109/L), fasting glucose (mean, 113.1→105.9 mg/dL), AST (mean, 49.6→28.0 IU/L), ALT (mean, 49.0→33.9 IU/L), and total cholesterol (mean, 170.0→162.1 mg/dL) levels significantly decreased (all P < 0.05). In the BSV group, AST (mean, 95.2→30.2 IU/L) and ALT (mean, 81.1→31.1 IU/L) levels significantly reduced (all P < 0.05), whereas HSI and FIB-4 index were maintained (all P > 0.05). In the univariate analysis, age, BMI, diabetes, cirrhosis, fasting glucose level, and ALT were significantly associated with HS improvement (all P < 0.05). CONCLUSION: BSV with L-carnitine did not show any improvement of HS in patients with CHB. Further prospective randomized controlled studies are needed to validate the potential beneficial effects of BSV with L-carnitine in CHB infection.

Fibrosis-4 index at diagnosis can predict all-cause mortality in patients with rheumatoid arthritis: A retrospective monocentric study.

Objectives: Comorbidities and conventional risk factors influence the prognosis of patients with rheumatoid arthritis (RA). We investigated whether liver fibrosis burden is associated with all-cause mortality in patients with RA.Methods: A total of 2812 patients with RA were retrospectively selected and reviewed. Liver fibrosis was assessed using the fibrosis-4 index (FIB-4) [age (years)× aspartate aminotransferase level (IU/L)/platelet count (109/L)/√alanine aminotransferase (IU/L)].Results: The mean patient age was 51.5 years (482 men and 2330 women). The mean erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and FIB-4 were 43.5 mm/h, 9.0 mg/L, and 1.0, respectively. Methotrexate was used in 2524 (89.9%) patients, and biological or targeted synthetic disease-modifying antirheumatic drugs were used in 310 (11.0%) patients. During the follow-up period (mean 93.7 months), 89 (3.2%) patients died. Deceased patients had a significantly higher age (mean 64.4 vs. 51.1 years); frequency of male sex (31.5% vs. 16.7%), hypertension (HTN; 40.4 vs. 18.5%), and diabetes mellitus (DM; 25.8% vs. 7.7%); ESR (mean 57.1 vs. 43.0 mm/h); CRP (mean 16.9 vs. 8.7 mg/L); and FIB-4 (mean 1.5 vs. 1.0) (all p < .05) than the survivors. On multivariate analysis, higher FIB-4 was found to be independently associated with a higher rate of all-cause mortality (hazard ratio =1.130, p = .004), together with male sex, HTN, DM, ESR, and intensity of glucocorticoid exposure, whereas the use of methotrexate was independently protective (all p < .05).Conclusion: Besides conventional risk factors, fibrotic burden, assessed using FIB-4, might be useful for risk stratification of patients newly diagnosed as having RA.

Urine protein:creatinine ratio vs 24-hour urine protein for proteinuria management: analysis from the phase 3 REFLECT study of lenvatinib vs sorafenib in hepatocellular carcinoma.

BACKGROUND: Proteinuria monitoring is required in patients receiving lenvatinib, however, current methodology involves burdensome overnight urine collection. METHODS: To determine whether the simpler urine protein:creatinine ratio (UPCR) calculated from spot urine samples could be accurately used for proteinuria monitoring in patients receiving lenvatinib, we evaluated the correlation between UPCR and 24-hour urine protein results from the phase 3 REFLECT study. Paired data (323 tests, 154 patients) were analysed. RESULTS: Regression analysis showed a statistically significant correlation between UPCR and 24-hour urine protein (R2: 0.75; P < 2 × 10-16). A UPCR cut-off value of 2.4 had 96.9% sensitivity, 82.5% specificity for delineating between grade 2 and 3 proteinuria. Using this UPCR cut-off value to determine the need for further testing could reduce the need for 24-hour urine collection in ~74% of patients. CONCLUSION: Incorporation of UPCR into the current algorithm for proteinuria management can enable optimisation of lenvatinib treatment, while minimising patient inconvenience. CLINICAL TRIAL REGISTRATION: NCT01761266.

Correction: Urine protein:creatinine ratio vs 24-hour urine protein for proteinuria management: analysis from the phase 3 REFLECT study of lenvatinib vs sorafenib in hepatocellular carcinoma.

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A multicenter study of entecavir vs. tenofovir on prognosis of treatment-naïve chronic hepatitis B in South Korea.

BACKGROUND & AIMS: It is currently unclear which antiviral agent, entecavir (ETV) or tenofovir disoproxil fumarate (TDF), is superior for improving prognosis in patients with chronic hepatitis B (CHB). Here, we assessed the ability of these 2 antivirals to prevent liver-disease progression in treatment-naïve patients with CHB. METHODS: From 2012 to 2014, treatment-naïve patients with CHB who received ETV or TDF as a first-line antiviral agent were recruited from 4 academic teaching hospitals. Patients with decompensated cirrhosis or hepatocellular carcinoma (HCC) at enrollment were excluded. Cumulative probabilities of HCC and death or orthotopic liver transplant (OLT) were assessed. RESULTS: In total, 2,897 patients (1,484 and 1,413 in the ETV and TDF groups, respectively) were recruited. The annual HCC incidence was not statistically different between the ETV and TDF groups (1.92 vs. 1.69 per 100 person-years [PY], respectively; adjusted hazard ratio [HR] 0.975 [p = 0.852] by multivariate analysis). Propensity score (PS)-matched and inverse probability of treatment weighting (ITPW) analyses yielded similar patterns of results (HR 1.021 [p = 0.884] and 0.998 [p = 0.988], respectively). The annual incidence of death or OLT was not statistically different between the ETV and TDF groups (0.52 vs. 0.53 per 100 PY, respectively; adjusted HR 1.202 [p = 0.451]). PS-matched and ITPW analyses yielded similar patterns of results (HR 1.248 [p = 0.385] and 1.239 [p = 0.360], respectively). These findings were consistently reproduced in patients with compensated cirrhosis (all p >0.05). CONCLUSIONS: The overall prognosis in terms of HCC and death or OLT was not statistically different between the ETV and TDF groups. Further studies are needed to validate our results. LAY SUMMARY: It is currently unclear which antiviral agent, entecavir or tenofovir disoproxil fumarate, is superior for improving prognosis in patients with chronic hepatitis B virus infection. In this analysis we found that there was no difference in terms of overall prognosis, including risk of hepatocellular carcinoma, death, or the need for a liver transplant, in patients receiving either antiviral.