CAGE-B and SAGE-B models better predict the hepatitis B virus-related hepatocellular carcinoma after 5-year entecavir treatment than PAGE-B.

OBJECTIVES: The PAGE-B model consists of variables at the initiation of antiviral therapy (AVT), whereas the SAGE-B and CAGE-B models consist of variables after 5 years of AVT. We aimed to compare the predictive accuracy of three risk prediction models for hepatocellular carcinoma (HCC) development after 5 years of AVT in patients with chronic hepatitis B (CHB). METHODS: A total of 1335 patients who initiated entecavir (ETV) treatment between 2006 and 2011 and were followed up for more than 5 years were enrolled in the study. RESULTS: At ETV initiation, the median age was 49 years and the median score of the PAGE-B model was 14. After 5 years of ETV treatment, the median SAGE-B and CAGE-B scores were 6 and 6. During the study period, 93 (7.0%) patients developed HCC after 5-year treatment. In multivariate analysis, PAGE-B (hazard ratio [HR] 1.151, 95% confidence interval [CI] 1.087-1.219), SAGE-B (HR 1.340, 95% CI 1.228-1.463), and CAGE-B (HR 1.327, 95% CI 1.223-1.440) models independently predicted HCC development after 5 years of treatment (all P < 0.001). The high-risk groups of the three risk prediction models showed a significantly higher risk of HCC development compared to the medium- and low-risk groups (both P < 0.05). The AUROC of the SAGE-B (0.772-0.844) and CAGE-B (0.785-0.838) models was significantly higher than those of the PAGE-B model (0.696-0.745) in predicting HCC development after 5 years of treatment (both P < 0.05). CONCLUSION: The SAGE-B and CAGE-B models might be better than the PAGE-B model in predicting HCC development after 5 years of ETV treatment.

Effect of Laparoscopic Proximal Gastrectomy With Double-Tract Reconstruction vs Total Gastrectomy on Hemoglobin Level and Vitamin B12 Supplementation in Upper-Third Early Gastric Cancer: A Randomized Clinical Trial.

Importance: Patients undergoing proximal gastrectomy (PG) with double-tract reconstruction (DTR) have been reported to have an incidence of reflux esophagitis that is as low as that observed after total gastrectomy (TG). It is unclear whether PG has an advantage over TG for the treatment of patients with upper early gastric cancer (GC). Objective: To evaluate the effect of laparoscopic PG with DTR (LPG-DTR) vs laparoscopic TG (LTG) on levels of hemoglobin and vitamin B12 supplementation required among patients with clinically early GC in the upper third of the stomach (upper-third early GC). Design, Setting, and Participants: This multicenter open-label superiority randomized clinical trial was conducted at 10 institutions in Korea. A total of 138 patients with upper-third cT1N0M0 GC were enrolled between October 27, 2016, and September 9, 2018. Follow-up ended on December 3, 2020. Interventions: Patients were randomized to undergo either LPG-DTR or LTG. Main Outcomes and Measures: The primary co-end points were change in hemoglobin level and cumulative amount of vitamin B12 supplementation at 2 years after LPG-DTR or LTG. The secondary end points included morbidity, postoperative reflux esophagitis, quality of life, overall survival, and disease-free survival. Quality of life outcomes were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) 30-item core questionnaire (C30) and the EORTC QLQ stomach cancer-specific questionnaire at 3 months, 12 months, and 24 months. Results: Among 138 patients (mean [SD] age, 60.0 [10.9] years; 87 men [63.0%]; all of Asian race and Korean ethnicity), 68 (mean [SD] age, 56.7 [10.4] years; 39 men [57.4%]) were randomized to receive LPG-DTR and 69 (mean [SD] age, 61.3 [11.3] years; 48 men [69.6%]) were randomized to receive LTG. The mean (SD) changes in hemoglobin levels from baseline to month 24 were -5.6% (7.4%) in the LPG-DTR group and -6.9% (8.3%) in the LTG group, for an estimated difference of -1.3% (95% CI, -4.0% to 1.4%; P = .35). The mean (SD) cumulative amount of vitamin B12 supplementation was 0.4 (1.3) mg in the LPG-DTR group and 2.5 (3.0) mg in the LTG group, for an estimated difference of 2.1 mg (95% CI, 1.3-2.9 mg; P < .001). The late complication rates in the LPG-DTR and LTG groups were 17.6% and 10.1%, respectively (P = .31). The incidence of reflux esophagitis was not different between the LPG-DTR and LTG groups (2.9% vs 2.9%; P = .99). Compared with the LTG group, the LPG-DTR group had better physical functioning scores (85.2 [15.6] vs 79.9 [19.3]; P = .03) and social functioning scores (89.5 [17.9] vs 82.4 [19.4]; P = .03) on the EORTC QLQ-C30. Two-year overall survival (98.5% vs 100%; P = .33) and disease-free survival (98.5% vs 97.1%; P = .54) did not significantly differ between the LPG-DTR vs LTG groups. Conclusions and Relevance: In this study, patients with upper-third early GC who received LPG-DTR required less vitamin B12 supplementation than those who received LTG, with no increase in complication rates and no difference in overall and disease-free survival rates. There was no difference in change in hemoglobin level between groups. In addition, the LPG-DTR group had better physical and social functioning than the LTG group. These findings suggest that LPG-DTR may be as safe as LTG and may be a function-preserving procedure for the treatment of patients with upper-third early GC. Trial Registration: ClinicalTrials.gov Identifier: NCT02892643.

Sorafenib versus nivolumab after lenvatinib treatment failure in patients with advanced hepatocellular carcinoma.

BACKGROUND AND AIM: An optimal sequential anti-hepatocellular carcinoma (HCC) agent that can be used after failed lenvatinib treatment has not been established. Here, we compared the outcomes of sorafenib and nivolumab as second-line agents after failed lenvatinib treatment in patients with advanced HCC. METHODS: Patients with advanced HCC who had received sorafenib or nivolumab as second-line agents after failed lenvatinib treatment were recruited from two Korean tertiary institutions between November 2018 and June 2020. RESULTS: The median age of the 60 participants (52 treated with sorafenib and eight treated with nivolumab) at baseline was 56.8 years. The demographic, laboratory and tumor variables, as well as lenvatinib treatment duration, were similar between the two groups. The median durations of sorafenib and nivolumab treatment were 1.2 and 2.6 months, respectively ( P = 0.164). Twenty-four (40.0%) patients died during the follow-up period (median, 15.8 months). The median overall survival (OS) of the study population was 5.8 months. The median OS of patients treated with sorafenib was significantly longer than the median OS of patients treated with nivolumab (8.7 vs. 3.0 months; P = 0.046). Sorafenib treatment (vs. nivolumab) was independently associated with a lower risk of mortality (hazard ratio = 0.194; 95% confidence interval, 0.053-0.708; P = 0.013). Worse Eastern Cooperative Oncology Group performance status, larger maximal tumor size, lymph node metastases and higher total bilirubin levels were independently associated with increased mortality risk (all P < 0.05). CONCLUSIONS: Lenvatinib-sorafenib sequential treatment resulted in significantly better survival did than lenvatinib-nivolumab sequential treatment in patients with advanced HCC. Larger studies are needed to validate our results.

New Evidence of Oral Branched-Chain Amino Acid Supplementation on the Prognosis of Patients With Advanced Liver Disease.

INTRODUCTION: Oral branched-chain amino acids (BCAAs) might benefit patients with advanced liver disease. We assess its effects on prognosis compared with control from the meta-analysis. METHODS: Study end points were development of hepatic encephalopathy (HE), hepatocellular carcinoma (HCC), mortality, and overall liver-related events (LREs). Risk ratios (RRs) and hazard ratios (HRs) were calculated using random effects model and heterogeneity using I 2 statistic. RESULTS: Twenty-eight studies were included in this meta-analysis; 1,578 and 1,727 patients in oral BCAAs and control groups, respectively. From studies using RRs as outcome measures, oral BCAAs were better in preventing HE and LRE than controls, with RRs 0.684 (95% confidence interval [CI] 0.497-0.941; P = 0.019) and 0.788 (95% CI 0.585-0.810; P < 0.001), respectively. Oral BCAAs had marginal effect on preventing HCC compared with control, with RR 0.791 (95% CI 0.619-1.011; P = 0.061); no significant difference in mortality was detected. From studies using HRs as outcome measures, oral BCAAs were superior to control in preventing LRE with adjusted HR 0.497 (95% CI 0.321-0.770; P = 0.002). In subgroups undergoing HCC resection, oral BCAAs had beneficial effect in preventing HE (RR 0.716, 95% CI 0.514-0.996; P = 0.047) and LRE (RR 0.716, 95% CI 0.595-0.860; P < 0.001). DISCUSSION: Oral BCAAs could afford clinical benefits in reducing HE and LRE risks, especially among patients undergoing HCC resection.

Co-administration of ursodeoxycholic acid with rosuvastatin/ezetimibe in a non-alcoholic fatty liver disease model.

Background: Ursodeoxycholic acid (UDCA), statins, and ezetimibe (EZE) have demonstrated beneficial effects against non-alcoholic fatty liver disease (NAFLD). We investigated the efficacy of the combination of UDCA and the mix of rosuvastatin (RSV)/EZE in the treatment of NAFLD. Methods: NAFLD mouse models were developed by injecting thioacetamide, fasting, and high-carbohydrate refeeding, high-fat diet, and choline-deficient L-amino acid-defined high-fat diet (CDAHFD). Low-dose UDCA (L-UDCA; 15 mg/kg) or high-dose UDCA (H-UDCA; 30 mg/kg) was administered with RSV/EZE. We also employed an in vitro model of NAFLD developed using palmitic acid-treated Hepa1c1c7 cells. Results: Co-administration of RSV/EZE with UDCA significantly decreased the collagen accumulation, serum alanine aminotransferase (ALT) levels, and mRNA levels of fibrosis-related markers than those observed in the vehicle group in thioacetamide-treated mice (all P < 0.01). In addition, in the group fasted and refed with a high-carbohydrate diet, UDCA/RSV/EZE treatment decreased the number of apoptotic cells and serum ALT levels compared with those observed in the vehicle group (all P < 0.05). Subsequently, H-UDCA/RSV/EZE treatment decreased the number of ballooned hepatocytes and stearoyl-CoA desaturase 1 (SCD-1) mRNA levels (P = 0.027) in the liver of high-fat diet-fed mice compared with those observed in the vehicle group. In the CDAHFD-fed mouse model, UDCA/RSV/EZE significantly attenuated collagen accumulation and fibrosis-related markers compared to those observed in the vehicle group (all P < 0.05). In addition, UDCA/RSV/EZE treatment significantly restored cell survival and decreased the protein levels of apoptosis-related markers compared to RSV/EZE treatment in palmitic acid-treated Hepa1c1c7 cells (all P < 0.05). Conclusion: Combination therapy involving UDCA and RSV/EZE may be a novel strategy for potent inhibition of NAFLD progression.

Predictive Performance of CAGE-B and SAGE-B Models in Asian Treatment-Naive Patients Who Started Entecavir for Chronic Hepatitis B.

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

Development and initial validation of the nonalcoholic fatty liver disease self-management questionnaire.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing, and self-management is essential to improve health outcomes in this population. Despite the importance of self-management, there is no instrument to assess it in patients with NAFLD. The purpose of this study was to develop and validate an initial version of a self-management questionnaire for patients with NAFLD. This was a methodological and psychometric study conducted between April and November 2019. The NAFLD self-management questionnaire was developed after a theoretical and literature review and focus group interviews in three phases: (1) item generation, (2) item evaluation, and (3) psychometric evaluation. Participants (N = 155) were recruited from a hospital in Seoul, South Korea. Items were generated based on clinical NAFLD guidelines and the individual and family self-management theory. Construct validity was assessed using exploratory factor analysis. Six-factors were extracted from 22 items: lifestyle management, medical treatment compliance, management of medication and dietary supplements, alcohol consumption management, sleep management, and family support. These factors accounted for 67.4% of the total variance; each factor had an eigenvalue greater than 1, and Cronbach's alpha for the scale was 0.87. The NAFLD self-management questionnaire showed acceptable initial validity and reliability. The instrument can prove useful in the formulation of tailored interventions based on individual patients' care needs. Furthermore, it may be used as an indicator of health outcomes in this population.

Treatment efficacy by hepatic arterial infusion chemotherapy vs. sorafenib after liver-directed concurrent chemoradiotherapy for advanced hepatocellular carcinoma.

BACKGROUND: We compared the clinical efficacies of hepatic arterial infusion chemotherapy (HAIC) vs. sorafenib as sequential maintenance therapy following liver-directed concurrent chemoradiotherapy (LD-CCRT) for locally advanced-stage hepatocellular carcinoma (HCC). METHODS: Patients undergoing HAIC with 5-fluorouracil and cisplatin (HAIC-maintain group, n = 151) or sorafenib (Sorafenib-maintain group, n = 37) after LD-CCRT were consecutively enrolled. The study endpoints were overall survival (OS), progression-free survival (PFS), and treatment response rates. RESULTS: The median OS among HAIC-maintain and Sorafenib-maintain groups were 15.9 and 24.3 months (p = 0.287), whereas the median PFS were 8.1 and 9.1 months (p = 0.651), respectively. During the planned treatments, the radiological objective response rate (54.3% vs. 64.9%; p = 0.246), and conversion rate to surgical resection or liver transplantation after successful down-staging (15.9% vs. 18.9%; p = 0.657) were comparable between the HAIC-maintain and Sorafenib-maintain groups. Similar results were found after the inverse probability of treatment weighting and propensity score-matching analyses. Regarding treatment-related adverse events, the HAIC-maintain group showed worse profiles in terms of leukopenia (all grades [p = 0.001] and grades 3 or 4 [p = 0.041]) and hypoalbuminemia (p = 0.001) than the Sorafenib-maintain group. CONCLUSIONS: The overall clinical efficacies between the sequential treatment of HAIC vs. sorafenib after LD-CCRT were comparable for locally advanced HCC.

Lenvatinib is independently associated with the reduced risk of progressive disease when compared with sorafenib in patients with advanced hepatocellular carcinoma.

BACKGROUND AND AIMS: Recently, lenvatinib demonstrated non-inferiority to sorafenib in terms of overall survival (OS) in a randomized phase III study that was conducted at 154 sites in 20 countries. Here, we investigated treatment outcomes and safety of lenvatinib compared with sorafenib and identified independent predictors of poor outcomes, including shorter progression-free survival (PFS) and OS in Korean patients with unresectable hepatocellular carcinoma (HCC). METHODS: Patients with advanced HCC treated with lenvatinib or sorafenib at Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine between October 2018 to October 2019 were considered eligible. Response evaluation was performed according to the modified Response Evaluation Criteria in Solid Tumors. RESULTS: The lenvatinib arm had a significantly lower proportion of patients who received prior anti-HCC treatments (47.7% vs 78.7%; P < 0.001) than those in the sorafenib arm. Univariate analysis showed that ECOG 1 (vs 0), serum albumin, alpha-fetoprotein (AFP), previous anti-HCC treatments, and lenvatinib (vs sorafenib) were significant predictors of progressive disease (all P < 0.05). In the subsequent multivariate analysis, ECOG 1 (vs 0) (hazard ratio [HR] = 4.721, 95% confidence interval [CI] 1.371-16.259; P = 0.014), higher AFP level (HR = 1.000, 95% CI 1.000-1.000; P = 0.015), and lenvatinib treatment (vs sorafenib) (HR = 0.461, 95% CI 0.264-0.804; P = 0.006) independently predicted a higher probability of progressive disease. CONCLUSIONS: Patients treated with lenvatinib demonstrated significantly longer PFS than those treated with sorafenib. Furthermore, no significant differences were observed in mortality rates between the two groups, which indicated that lenvatinib is non-inferior to sorafenib in terms of OS.

Efficacy and Safety of Liver-Directed Concurrent Chemoradiotherapy and Sequential Sorafenib for Advanced Hepatocellular Carcinoma: A Prospective Phase 2 Trial.

PURPOSE: Although sorafenib as a standard of care for advanced hepatocellular carcinoma (HCC) prolongs overall survival (OS), its efficacy is limited owing to its unsatisfactory objective response and marginal survival benefit. To counter these limitations, we designed a single-arm, phase II trial with liver-directed concurrent chemoradiotherapy (LD-CCRT) and sequential sorafenib treatment in patients with advanced HCC. METHODS AND MATERIALS: We enrolled advanced HCC patients diagnosed between 2014 and 2017 who were ineligible for curative treatment. During the first and last 5 days of 5-week radiation therapy, concurrent hepatic arterial infusion with 5-fluorouracil (500 mg/d) and leucovorin (50 mg/d) through an implanted port was administered 4 weeks after initiation of LD-CCRT and sequential sorafenib treatment (400 mg, twice daily). The primary endpoint was OS. This trial has been registered at clinicaltrials.gov. RESULTS: Among the enrolled patients (n = 47), objective response rates 4 weeks after LD-CCRT and during/up to sorafenib maintenance were 44.7% and 53.2%, respectively. Overall, 9 patients (19.1%) underwent curative resection or transplantation after down staging. The median radiation dose was 60 Gy. The median OS was 24.6 months for the entire cohort and 13.0 months for the subgroup with tumor invasion into the main portal trunk or its first branch, whereas the median progression-free survival for the cohort and subgroup was 6.8 and 5.6 months, respectively. The most frequent treatment-related adverse events were diarrhea (36.2%) and hand-foot skin reaction (34%), which were manageable with conservative treatment. CONCLUSIONS: LD-CCRT and sequential sorafenib treatment provided favorable OS and progression-free survival with good tolerability. Tumor reduction using an initial LD-CCRT enabled down staging, subsequent curative treatment, and long-term survival in about 20% of the patients with advanced HCC. However, further randomized trials are required to confirm these results.

A survey on transarterial chemoembolization refractoriness and a real-world treatment pattern for hepatocellular carcinoma in Korea.

BACKGROUND/AIMS: Transarterial chemoembolization (TACE) is a standard treatment for intermediate-stage hepatocellular carcinoma (HCC), but there is much controversy about TACE refractoriness. The aim of this study was to identify trends in the actual clinical application of TACE and recognition of TACE refractoriness by Korean experts. METHODS: In total, 17 questionnaires on TACE refractoriness were administered to 161 clinicians via an online survey. Multiple answers were allowed for some questions. RESULTS: Most clinicians agreed that there is a need for standardization of TACE application through specific scoring systems (n=124, 77.0%). TACE refractoriness was predominantly expected by participants when recurrences were detected within 1 month (n=70, 43.5%), there were 4 to 6 tumors (n=77, 47.8%), the maximal tumor size was 3-5 cm (n=49, 30.4%), and when there was insufficient tumor necrosis despite TACE being repeated more than three times (n=78, 48.4%). Overall, sorafenib therapy (n=137) and radiotherapy (n=114) were preferred when repeated TACE was considered ineffective. CONCLUSION: Treatment of HCC is often based on the clinical judgment of clinicians because of the heterogeneity among individuals. Experts need to continue discussions on the standardization and sub-classification of HCC treatment guidelines in Korea.

Transarterial Chemoembolization in Treatment-Naïve and Recurrent Hepatocellular Carcinoma: A Propensity-Matched Outcome Analysis.

OBJECTIVES: Transarterial chemoembolization (TACE) improves the survival of patients with hepatocellular carcinoma (HCC); however, TACE treatment outcomes of patients with treatment-naïve HCC (TN-HCC) and those with recurrent HCC after curative resection (R-HCC) have not yet been compared. METHODS: We recruited 448 patients with TN-HCC, and 275 patients with R-HCC treated with TACE as first-line anti-cancer treatment. RESULTS: At first TACE, patients with TN-HCC showed a significantly lower proportion of male gender (74.9% vs. 84.3%), higher proportion of liver cirrhosis (61.9% vs. 49.3%), higher aspartate aminotransferase (median 48 vs. 31 IU/L), alanine aminotransferase (median 38 vs. 26 IU/L), alpha-fetoprotein (AFP) (median 96.6 vs. 7.7 ng/mL), and total bilirubin (mean 1.0 vs. 0.8 mg/dL) levels, longer prothrombin time (median 1.05 vs. 1.01 international normalized ratio), higher tumor number (mean 2.1 vs. 1.7), larger tumor size (median 3.1 vs. 1.6 cm), and lower proportion of Barcelona Clinic Liver Cancer stage 0-A (55.6% vs. 71.9%) than patients with R-HCC (all P < 0.05). Multivariate analysis showed that TACE for TN-HCC (vs. R-HCC) was an independent predictor of mortality (hazard ratio, 1.328; P = 0.024) with AFP level and tumor number (all P < 0.05). However, treatment outcomes between TN-HCC and R-HCC became statistically similar after propensity score-matched (PSM) analysis using liver cirrhosis, tumor size, and multiple tumors (P < 0.05). CONCLUSIONS: Based on the similar TACE treatment outcomes observed with the PSM analysis, the current TACE treatment guideline for patients with TN-HCC might similarly be applied for patients with R-HCC.

Reproducibility of European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in patients treated with sorafenib.

BACKGROUND & AIMS: The European Association for the Study of the Liver criteria and the modified Response Evaluation Criteria in Solid Tumors are used for assessing the treatment outcomes of hepatocellular carcinoma. We investigated the inter- and intra-observer reproducibility of the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in patients with advanced hepatocellular carcinoma treated with sorafenib. METHODS: A total of 99 patients with treatment-naive advanced hepatocellular carcinoma receiving sorafenib were included. The κ-values for the inter- and intra-observer agreement of the treatment response were calculated. RESULTS: Inter-observer agreement for baseline tumour number was excellent, as reflected by the high κ-value. The κ-statistics showed "excellent" concordance between the 2 sets of measurements by observer A regarding the overall responses using the European Association for the Study of the Liver criteria (κ = .948, agreement rate = 84.8%) and modified Response Evaluation Criteria in Solid Tumors (κ = .944, agreement rate = 83.8%; all P < .001). In addition, high κ-values indicated concordance between the first sets of measurements by observers A and B (κ = .991 by the European Association for the Study of the Liver criteria and .988 by modified Response Evaluation Criteria in Solid Tumors, all P < .001). When agreements in radiological overall responses between the 2 sets of measurements by observer B and between the second sets of measurements by observers A and B were calculated, similar results regarding high κ-values (>.8) were obtained. CONCLUSIONS: The reproducibility of the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in assessing treatment outcomes was high in patients with advanced hepatocellular carcinoma treated with sorafenib.

Laparoscopic proximal gastrectomy with double tract reconstruction is superior to laparoscopic total gastrectomy for proximal early gastric cancer.

BACKGROUND: Laparoscopic proximal gastrectomy (LPG) with double tract reconstruction (DTR) is known to reduce reflux symptoms, which is a major concern after proximal gastrectomy. The aim of this study is to compare retrospectively the clinical outcomes of patients undergoing LPG with DTR with those treated by laparoscopic total gastrectomy (LTG). METHODS: Ninety-two and 156 patients undergoing LPG with DTR and LTG for proximal stage I gastric cancer were retrospectively analyzed for short- and long-term clinical outcomes. RESULTS: There were no significant differences in the demographics, T-stage, N-stage, and complications between the groups. The LPG with DTR group had a shorter operative time and lower estimated blood loss than the LTG group (198.3 vs. 225.4 min, p < 0.001; and 84.7 vs. 128.3 mL p = 0.001). The incidence of reflux symptoms ≥ Visick grade II did not significantly differ between the groups during a mean follow-up period of 37.2 months (1.1 vs. 1.9%, p = 0.999). The hemoglobin change was significantly lower in the LPG with DTR group compared to in the LTG group in the first and second postoperative years (5.03 vs. 9.18% p = 0.004; and 3.45 vs. 8.30%, p = 0.002, respectively), as was the mean amount of vitamin B12 supplements 2 years after operation (0.1 vs. 3.1 mg, p < 0.001). The overall survival rate was similar between the groups. CONCLUSIONS: LPG with DTR maintained comparable oncological safety and anastomosis-related late complications compared to LTG and is preferred over LTG in terms of preventing postoperative anemia and vitamin B12 deficiency.

Prognostic factors of sorafenib therapy in hepatocellular carcinoma patients with failure of transarterial chemoembolization.

BACKGROUND: There is no approved therapy for patients with failed transarterial chemoembolization (TACE) and progression of hepatocellular carcinoma. We aimed to investigate the efficacy and prognostic factors in patients with TACE failure who received sorafenib rescue therapy. METHODS: We investigated 54 patients who met the criteria of TACE failure as defined by the international guidelines of Europe and Japan. Sorafenib was used as a rescue therapy. Overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier methods, and multivariate analysis was performed to find prognostic factors. RESULTS: The patients were followed for a median 5.5 months, and the median duration of sorafenib administration was 3.3 months. The presence of main (or lobar) portal vein invasion (PVI) (3.7 versus 8.4 months, p = 0.004), dose reduction of sorafenib (4.0 versus 8.8 months, p = 0.002) and Child-Pugh class B (5.3 versus 8.9 months, p = 0.004) were associated with shorter OS compared to the presence of segmental PVI (or absence of macroscopic vascular invasion, MVI), full dosage of sorafenib and Child-Pugh class A, respectively. The presence of main (or lobar) PVI was associated with poorer PFS compared to the presence of segmental PVI (or absence of MVI) (2.1 versus 3.8 months p = 0.010). CONCLUSIONS: Sorafenib is a potential rescue therapy in patients with TACE failure. However, the clinical benefits need to be further evaluated for patients with main (or lobar) PVI or those treated with reduced doses of sorafenib.

Feasibility of hyperthermic pressurized intraperitoneal aerosol chemotherapy in a porcine model.

BACKGROUND: Peritoneal carcinomatosis is an unmet therapeutic need. Several types of intraperitoneal chemotherapy have been introduced. However, hyperthermic intraperitoneal chemotherapy has limited drug distribution and poor peritoneal penetration. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) does not have the benefits of hyperthermia. We developed a device to apply hyperthermic PIPAC (H-PAC) and evaluated its feasibility in a porcine model. METHODS: The device for H-PAC consisted of a laparoscopic aerosol spray and a heater to create hyperthermic capnoperitoneum. We operated on five pigs for the development of the new device and on another five pigs as a survival model. After a pilot experiment of the survival model (Pig A), a hyperthermic pressurized intraperitoneal aerosol of indocyanine green was administered after insertion of three trocars (Pig B) and laparoscopy-assisted distal gastrectomy (LADG) (Pig C) without chemotherapeutic agents. After that, H-PAC with cisplatin was administered after insertion of three trocars (Pig D) and LADG (Pig E). Autopsies were performed on postoperative day 7. RESULTS: Median operation time was 85 min (80-110 min). Intraperitoneal temperature was constant for 1 h of H-PAC (38.8-40.2 °C). All five pigs were healthy and survived for 7 days. Median weight loss was 0.2 kg. Autopsy tissues of stomach, peritoneum, and jejunum were intact in all five pigs. CONCLUSIONS: H-PAC was feasible and safe in a porcine model.

Substitution at rt269 in Hepatitis B Virus Polymerase Is a Compensatory Mutation Associated with Multi-Drug Resistance.

The emergence of compensatory mutations in the polymerase gene of drug resistant hepatitis B virus (HBV) is associated with treatment failure. We previously identified a multi-drug resistant HBV mutant, which displayed resistance towards lamivudine (LMV), clevudine (CLV), and entecavir (ETV), along with a strong replication capacity. The aim of this study was to identify the previously unknown compensatory mutations, and to determine the clinical relevance of this mutation during antiviral therapy. In vitro mutagenesis, drug susceptibility assay, and molecular modeling studies were performed. The rtL269I substitution conferred 2- to 7-fold higher replication capacity in the wild-type (WT) or YMDD mutation backbone, regardless of drug treatment. The rtL269I substitution alone did not confer resistance to LMV, ETV, adefovir (ADV), or tenofovir (TDF). However, upon combination with YMDD mutation, the replication capacity under LMV or ETV treatment was enhanced by several folds. Molecular modeling studies suggested that the rtL269I substitution affects template binding, which may eventually lead to the enhanced activity of rtI269-HBV polymerase in both WT virus and YMDD mutant. The clinical relevance of the rtL269I substitution was validated by its emergence in association with YMDD mutation in chronic hepatitis B (CHB) patients with sub-optimal response or treatment failure to LMV or CLV. Our study suggests that substitution at rt269 in HBV polymerase is associated with multi-drug resistance, which may serve as a novel compensatory mutation for replication-defective multi-drug resistant HBV.

Two-year treatment outcome of chronic hepatitis B infection treated with besifovir vs. entecavir: results from a multicentre study.

BACKGROUND & AIMS: We aimed to compare the viral suppression, safety and rate of drug resistance between besifovir (a new acyclic nucleotide analogue) and entecavir. METHODS: Treatment-naïve chronic hepatitis B patients receiving besifovir 90 mg (n=31), 150 mg (n=28) and entecavir 0.5 mg (n=30) were monitored for liver biochemistry, viral serology, HBV DNA levels, development of drug resistance mutations, and adverse events throughout 96 weeks of treatment. RESULTS: The mean decline of HBV DNA levels from baseline to week 96 were 5.29, 5.15, and 5.67 logs IU/ml for patients receiving besifovir 90 mg, 150 mg and entecavir 0.5 mg, respectively (p>0.05). Undetectable HBV DNA (<20 IU/ml) were achieved in 80.7%, 78.6%, and 80%; ALT normalization in 90.3%, 78.6%, and 93.3%; and loss of HBeAg in 20%, 21.4%, and 22.2% of patients respectively (all p>0.05). One patient receiving besifovir 90 mg had a virological breakthrough due to drug non-compliance. No patient developed drug resistance mutations. Ten patients had serious adverse events, which were not related to the study medications. The most common side effect related to besifovir was carnitine depletion. Carnitine supplements were prescribed to 83.9% and 100% of patients, who had low carnitine level for any one time during follow-up, receiving besifovir 90 mg and 150 mg respectively. No patient had increased creatinine>0.5 mg/dl from baseline. CONCLUSIONS: Besifovir had the same antiviral property as compared to entecavir over 96 weeks of treatment for chronic hepatitis B patients. Besifovir was well tolerated and also had a good clinical safety profile.

Clinical outcomes and prognostic factors of patients with advanced hepatocellular carcinoma treated with sorafenib as first-line therapy: a Korean multicenter study.

BACKGROUND AND AIM: Sorafenib is recommended as a standard treatment for advanced hepatocellular carcinoma (HCC). The efficacy and safety of sorafenib as a first-line therapy in Korean patients with advanced HCC were investigated. METHODS: From 2007 to 2012, 86 patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) treated with sorafenib as a first-line therapy were enrolled from five tertiary hospitals. Predictors of overall survival (OS) and progression-free survival (PFS) were analyzed. RESULTS: The median age was 59.5 years, and 71 (82.6%) were males; 57 (66.3%) patients were in Child-Pugh class A. The median OS and PFS were 5.0 (range 4.0-5.9) and 3.2 (range 2.6-3.7) months, respectively. Regarding OS, Child-Pugh class A (6.0 vs 2.8 months), tumor diameter < 5 cm (6.0 vs 4.3 months), baseline α-fetoprotein < 200 ng/mL (5.8 vs 4.1 months), and the advent of hand-foot-skin reaction of ≥ grade 2 (5.9 vs 4.0 months) were independent favorable predictors (all P < 0.05). Similarly, regarding PFS, Child-Pugh class A (4.3 vs 2.1 months), tumor diameter < 5 cm (3.9 vs 2.8 months), baseline α-fetoprotein < 200 ng/mL (5.6 vs 2.8 months), and the advent of hand-foot-skin reaction of ≥ grade 2 (4.5 vs 2.6 months) were independent favorable predictors (all P < 0.05). All toxicities during sorafenib treatment were manageable. CONCLUSIONS: Because the efficacy of sorafenib seems marginal in Korean patients with treatment-naïve HCC, how to select candidates with favorable outcomes should be further investigated.

Phase IIb multicentred randomised trial of besifovir (LB80380) versus entecavir in Asian patients with chronic hepatitis B.

BACKGROUND: Besifovir (LB80380) is an acyclic nucleotide phosphonate effective in hepatitis B virus (HBV) DNA suppression for both treatment-naive and lamivudine-resistant chronic hepatitis B (CHB) patients in preliminary studies. DESIGN: We aimed to compare the safety and antiviral activity of two doses of besifovir (90 mg and 150 mg daily) with entecavir 0.5 mg daily in CHB patients. 114 patients were randomised to receive besifovir 90 mg daily (n=36), besifovir 150 mg daily (n=39) or entecavir 0.5 mg daily (n=39). HBV DNA and liver biochemistry, including serum L-carnitine levels, were monitored. RESULTS: At week 48, in the intention-to-treat population, the proportion of patients achieving undetectable HBV DNA (<20 IU/mL) were 63.6%, 62.9% and 58.3%, respectively (p>0.05). The serum mean log10 HBV DNA changes from baseline for the HBeAg-positive patients were -5.84, -5.91 and -6.18, respectively; and for the HBeAg-negative patients were -4.65, -4.55 and -4.67, respectively (p>0.05). There were no differences in the proportions of patients achieving normalisation of alanine aminotransferase (91.7%, 76.9%, 89.7%, respectively) and HBeAg seroconversion (11.11%, 15%, 9.52%, respectively) among all three groups. None of the patients had resistant mutations or increase in serum creatinine of >0.5 mg/dL from baseline. 64 (94.1%) patients on besifovir had lowering of serum L-carnitine (not tested in entecavir patients). L-carnitine levels returned to normal with carnitine supplement. CONCLUSIONS: At 48 weeks, 90 mg and 150 mg daily of besifovir were non-inferior to entecavir 0.5 mg daily in treatment-naive CHB patients. The only significant side effect of besifovir was L-carnitine depletion, requiring carnitine supplementation.