Aberrantly Expressed MicroRNAs in Cancer-Associated Fibroblasts and Their Target Oncogenic Signatures in Hepatocellular Carcinoma.

Cancer-associated fibroblasts (CAFs) contribute to tumor progression, and microRNAs (miRs) play an important role in regulating the tumor-promoting properties of CAFs. The objectives of this study were to clarify the specific miR expression profile in CAFs of hepatocellular carcinoma (HCC) and identify its target gene signatures. Small-RNA-sequencing data were generated from nine pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues, respectively. Bioinformatic analyses were performed to identify the HCC-CAF-specific miR expression profile and the target gene signatures of the deregulated miRs in CAFs. Clinical and immunological implications of the target gene signatures were evaluated in The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA_LIHC) database using Cox regression and TIMER analysis. The expressions of hsa-miR-101-3p and hsa-miR-490-3p were significantly downregulated in HCC-CAFs. Their expression in HCC tissue gradually decreased as HCC stage progressed in the clinical staging analysis. Bioinformatic network analysis using miRWalks, miRDB, and miRTarBase databases pointed to TGFBR1 as a common target gene of hsa-miR-101-3p and hsa-miR-490-3p. TGFBR1 expression was negatively correlated with miR-101-3p and miR-490-3p expression in HCC tissues and was also decreased by ectopic miR-101-3p and miR-490-3p expression. HCC patients with TGFBR1 overexpression and downregulated hsa-miR-101-3p and hsa-miR-490-3p demonstrated a significantly poorer prognosis in TCGA_LIHC. TGFBR1 expression was positively correlated with the infiltration of myeloid-derived suppressor cells, regulatory T cells, and M2 macrophages in a TIMER analysis. In conclusion, hsa-miR-101-3p and hsa-miR-490-3p were substantially downregulated miRs in CAFs of HCC, and their common target gene was TGFBR1. The downregulation of hsa-miR-101-3p and hsa-miR-490-3p, as well as high TGFBR1 expression, was associated with poor clinical outcome in HCC patients. In addition, TGFBR1 expression was correlated with the infiltration of immunosuppressive immune cells.

Liver stiffness in magnetic resonance elastography is prognostic for sorafenib-treated advanced hepatocellular carcinoma.

OBJECTIVE: We investigated whether liver stiffness (LS) quantified using magnetic resonance elastography (MRE) could predict the prognosis of advanced hepatocellular carcinoma (HCC) patients treated with sorafenib. METHODS: We selected 50 sorafenib-treated advanced HCC patients who underwent MRE within 3 months before drug administration from a prospectively maintained cohort of chronic liver disease patients, according to the inclusion and exclusion criteria. Univariate and multivariate analyses were performed to evaluate the prognostic role of laboratory data, tumor characteristics, and MRE-assessed LS for overall survival (OS), progression-free survival (PFS), and significant liver injury (grade ≥ 3) after sorafenib administration. RESULTS: High MRE-assessed LS either as continuous (per kPa, hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.23-1.92, p < 0.001) or categorical (> 7.5 kPa, HR 4.06, 95% CI 1.40-11.79, p < 0.01) variable was significantly associated with poor OS along with higher serum alpha-fetoprotein (AFP, ≥ 400 ng/mL) and advanced tumor stage (modified Union for International Cancer Control (mUICC) IVb). Higher MRE-assessed LS was also significantly associated with the development of significant liver injury after sorafenib administration (per kPa, HR 1.62, 95% CI 1.21-2.17, p = 0.001; > 7.5 kPa, HR 10.11, 95% CI 2.41-42.46, p = 0.002). PFS analysis identified higher serum AFP (≥ 400 ng/mL) and advanced tumor stage (mUICC IVb) as significant risk factors for early disease progression, whereas LS was not associated with PFS CONCLUSION: Higher MRE-assessed LS is a potential biomarker for predicting poor OS and significant liver injury in advanced HCC patients treated with sorafenib. KEY POINTS: • Higher pretreatment LS by MRE (> 7.5 kPa), higher AFP (≥ 400 ng/mL), and advanced tumor stage (mUICC IVb) were associated with poor OS in advanced HCC patients treated with sorafenib. • Higher pretreatment LS by MRE was associated with developing significant (grade ≥ 3) liver injury during sorafenib treatment, which required termination of the therapy. • Patients with high pretreatment LS by MRE should be monitored carefully for potential liver injury during sorafenib treatment.

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.

Assessment of medical students' clinical performance using high-fidelity simulation: comparison of peer and instructor assessment.

BACKGROUND: High-fidelity simulators are highly useful in assessing clinical competency; they enable reliable and valid evaluation. Recently, the importance of peer assessment has been highlighted in healthcare education, and studies using peer assessment in healthcare, such as medicine, nursing, dentistry, and pharmacy, have examined the value of peer assessment. This study aimed to analyze inter-rater reliability between peers and instructors and examine differences in scores between peers and instructors in the assessment of high-fidelity-simulation-based clinical performance by medical students. METHODS: This study analyzed the results of two clinical performance assessments of 34 groups of fifth-year students at Ajou University School of Medicine in 2020. This study utilized a modified Queen's Simulation Assessment Tool to measure four categories: primary assessment, diagnostic actions, therapeutic actions, and communication. In order to estimate inter-rater reliability, this study calculated the intraclass correlation coefficient and used the Bland and Altman method to analyze agreement between raters. A t-test was conducted to analyze the differences in evaluation scores between colleagues and faculty members. Group differences in assessment scores between peers and instructors were analyzed using the independent t-test. RESULTS: Overall inter-rater reliability of clinical performance assessments was high. In addition, there were no significant differences in overall assessment scores between peers and instructors in the areas of primary assessment, diagnostic actions, therapeutic actions, and communication. CONCLUSIONS: The results indicated that peer assessment can be used as a reliable assessment method compared to instructor assessment when evaluating clinical competency using high-fidelity simulators. Efforts should be made to enable medical students to actively participate in the evaluation process as fellow assessors in high-fidelity-simulation-based assessment of clinical performance in situations similar to real clinical settings.

Predictive score for hepatocellular carcinoma after hepatitis B e antigen loss in patients treated with entecavir or tenofovir.

The risk of developing hepatocellular carcinoma (HCC) after hepatitis B e antigen seroclearance (ESC) remains unclear. We established and validated a new risk prediction model for HCC development after ESC in patients with chronic hepatitis B (CHB) receiving antiviral therapy (AVT). Between 2006 and 2016, 769 patients (training cohort) and 1,061 patients (validation cohort) with CHB who experienced ESC during AVT using entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were recruited. In the multivariate analysis, male sex (hazard ratio [HR] = 2.092; 95% confidence interval [CI] = 1.152-3.800), cirrhosis (HR = 5.141; 95% CI = 2.367-11.167) and fibrosis-4 index (FIB-4) of >3.25 (HR = 2.070; 95% CI = 1.184-3.620) were the independent risk factors for HCC development (all P < .05). Accordingly, a novel HCC-ESCAVT model was developed (1x[sex: male = 1, female = 0] + 3x(cirrhosis = 1, noncirrhosis = 0) + 1x(FIB-4: >3.25 = 1, ≤3.25 = 0). The cumulative risk for HCC development was significantly different among the risk groups based on the HCC-ESCAVT category (0-1, 2-4 and 5 for the low-, intermediate- and high-risk groups, respectively) (overall P < .001, log-rank test). The area under the receiver operating characteristic curve (AUC) for predicting HCC development 3, 5 and 10 years after ESC was 0.791, 0.771 and 0.790, respectively (all P < .05). The predictive value of the HCC-ESCAVT model was similar in the validation cohort (AUC = 0.802, 0.774 and 0.776 at 3, 5 and 10 years, respectively; all P < .05). Hence, we have developed and validated a new HCC-ESCAVT model for HCC development, which includes male sex, cirrhosis and FIB-4 of >3.25 as constituent variables.

Liver stiffness measured by MR elastography is a predictor of early HCC recurrence after treatment.

OBJECTIVES: Magnetic resonance elastography (MRE) is a non-invasive tool for measuring liver stiffness (LS) with high diagnostic accuracy. This study investigated whether quantified LS by MRE could predict early recurrence of patients with hepatocellular carcinoma (HCC) within the Milan criteria. METHODS: A prospectively collected cohort, which included the HCC patients who underwent MRE before treatment (an HCC-MRE cohort), was analyzed. In the HCC-MRE cohort, only patients under the Milan criteria, who underwent hepatic resection, radiofrequency ablation (RFA), or transarterial chemoembolization (TACE), were reviewed. We investigated whether LS assessed by MRE was an independent predictor of early recurrence using Cox regressions and Kaplan-Meier analyses. RESULTS: A total of 192 HCC patients under the Milan criteria who underwent hepatic resection (n = 96), RFA (n = 23), or TACE (n = 73) were included. Higher LS ratings (kPa; hazard ratio [HR] = 1.12; 95% confidence interval [CI] = 1.01-1.25; p = 0.040) emerged as an independent risk factor for early tumor recurrence. In the subgroup analysis, higher LS ratings were associated with higher risks of early HCC recurrence in both the resection/RFA group (> 4.5 kPa; HR = 2.95; 95% CI = 1.26-6.94; p = 0.013) and the TACE group (> 6 kPa; HR = 2.94; 95% CI = 1.27-6.83; p = 0.012). CONCLUSION: LS assessed by MRE was an independent predictor of early recurrence among HCC patients under the Milan criteria after achieving a complete response. KEY POINTS: • Liver parenchymal stiffness measured by MRE predicts early recurrence of treated HCC under Milan criteria. • A liver stiffness > 5.5 kPa was associated with worse recurrence-free survival. • Patients with high pre-treatment LS may benefit from stringent follow-up.

Treatment and prognosis of hepatic epithelioid hemangioendothelioma based on SEER data analysis from 1973 to 2014.

BACKGROUND: Hepatic epithelioid hemangioendothelioma (HEH) is a rare tumor of vascular origin with an unknown etiology, a low incidence, and a variable natural course. We evaluated the management and prognosis of HEH from the Surveillance, Epidemiology and End Results (SEER) program and changes in treatment modalities of HEH over 30 years. METHODS: From 1973 to 2014 in the SEER database, we selected patients diagnosed with HEH. We analyzed the clinical characteristics, patterns of management, and clinical outcomes of patients with HEH. RESULTS: We identified 79 patients with HEH (median age: 54.0 years; male to female ratio: 1:2.6). The initial extent of disease was local in 22 (27.8%) patients, regional metastasis in 22 (27.8%), distant metastasis in 31 (39.2%) and unknown in 4 (5.1%). The median size of primary tumor was 3.85 cm (interquartile range, 2.50-7.93 cm). Among 74 patients with available management data, the most common management was no treatment (29/74, 39.2%), followed by chemotherapy only (22/74, 29.7%), liver resection-based (13/74, 17.6%), and transplantation-based therapy (6/74, 8.1%). The 5-year cancer-specific survival rate was 57.8%. Patients who underwent surgical treatment had significantly higher survival than those who underwent non-surgical treatment (5-year survival; 88% vs. 49%, P = 0.019). Multivariate analysis revealed that surgical therapy was the only independent prognostic factor for survival (hazard ratio: 0.20, P = 0.040). CONCLUSIONS: Resection or liver transplantation is worth considering for treatment of patients with HEH.

Comparisons of the Mucosal Healing Process between Flat and Protruded Type after Endoscopic Submucosal Dissection for Gastric Neoplasms.

BACKGROUND/AIMS: The mucosal healing process after endoscopic submucosal dissection (ESD) is mostly scarring change (flat type), but a protruded lesion is occasionally found. We investigated the factors influencing the mucosal healing process, such as the flat and protruded types. METHODS: A total of 2,096 ESD cases were performed from February 2005 to December 2013, and 1,757 underwent follow-up endoscopy after 3 months to check the healing type of the ulceration. We retrospectively reviewed the medical charts to analyze demographic, endoscopic, and pathological findings between the 2 groups. RESULTS: Forty-eight cases were of the protruded type and 1,709 were of the flat type. In univariate analysis, the protruded type was found more in the antrum, anterior wall, and greater curvature (p < 0.001). In protruded types, the Helicobacter pylori (H. pylori) infection rate was lower (p < 0.017), the mean length of ESD specimen was shorter (p < 0.012), the fibrosis rate was lower (p < 0.033), and the mean number of hot biopsy and clips during ESD were less (p < 0.008 and p < 0.001 respectively). CONCLUSIONS: The healing type of mucosal ulceration after ESD seemed to be influenced by location, specimen size, and the presence of an H. pylori infection.

Evaluation of risk factors for recurrent primary common bile duct stone in patients with cholecystectomy.

OBJECTIVES: Recurrence of primary common bile duct (CBD) stone commonly occurs after complete removal of CBD stones in patients with cholecystectomy. This study aimed to investigate potential risk factors for the recurrence of primary CBD stones after endoscopic treatment. MATERIALS AND METHODS: Between January 2005 and December 2015, the endoscopic retrograde cholangiopancreatography (ERCP) database of our medical center was retrospectively reviewed; information regarding eligible patients who had recurrent CBD stones with a history of previous cholecystectomy was collected. The characteristics of the patients, CBD stone, CBD and ERCP-related factors were analyzed. RESULTS: The recurrence rate of CBD stone was 18.5% (115/622) after endoscopic treatment in patients with cholecystectomy. In univariate analysis, the number of CBD stones (≥2), CBD stone diameter (≥10 mm), stone composition, stone consistency, CBD diameter (≥15 mm), bile duct dilatation pattern, sharp bile duct angulation (<145°), balloon dilatation, large balloon (>12 mm) dilatation, endoscopic mechanical lithotripsy, endoscopic sphincterotomy, and endoscopic papillary balloon dilatation alone method were significant between the non-recurrence and recurrence groups. However, in multivariate analysis (based on the binary logistic regression method), the number of CBD stones (≥2) (adjusted odds ratio [AOR] 3.232; 95% confidence interval [CI] 1.344-7.773; p = .009), cholesterol stone (AOR 2.824; 95% CI 1.175-6.786; p =.02) and sharp bile duct angulation (<145°) (AOR 2.462; 95% CI 1.062-5.711; p = .036) were independent risk factors of CBD stone recurrence after cholecystectomy. CONCLUSIONS: CBD stone number (≥2), cholesterol stone and sharp bile duct angulation (<145°) are associated with recurrent common bile duct stones after cholecystectomy.

A prospective randomized study of loop-tip versus straight-tip guidewire in wire-guided biliary cannulation.

BACKGROUND: Wire-guided cannulation has been widely accepted as a useful technique for achieving selective biliary access because it has significantly increased the success rate of biliary cannulation compared with conventional contrast-assisted cannulation. Unlike conventional guidewires with a straight tip, a loop-tip guidewire (LGW) has a closed distal loop that may facilitate less traumatic access through the epithelial folds of the intra-duodenal biliary segments. The aim of this study was to compare the performance of a LGW with a straight-tip guidewire (SGW) in achieving successful selective biliary cannulation. METHODS: From December 2014 to December 2015, we performed 192 wire-guided biliary cannulations for a naïve papilla in a randomized controlled trial. Patients were randomly assigned to the LGW group (n = 96) or the SGW group (n = 96). Our study protocol did not include crossover to the other guidewire arm if randomized wire-guided cannulation proved unsuccessful within the first 10 min. RESULTS: There was no significant difference in primary successful biliary cannulation between the two groups (LGW group: 86.5%; SGW group: 77.1%; p = 0.134). The rate and the mean number of unintentional pancreatic duct cannulations during wire-guided biliary cannulation were significantly lower in the LGW group than in the SGW group (LGW group: 14.6%; SGW group: 28.1%; p = 0.034; LGW group: 0.2 ± 0.5; SGW group: 0.6 ± 1.3; p = 0.007). Post-ERCP pancreatitis developed in 5.2% of patients in the LGW group and 8.3% of patients in the SGW group (p = 0.567). CONCLUSIONS: The biliary cannulation rate of the LGW was not significantly different from those of conventional guidewires. Use of the LGW was associated with a lower rate of unintentional pancreatic duct cannulation during wire-guided biliary cannulation than use of the SGW.

Cyclic Change of Sphincter of Oddi Motility and Its Relationship with Small Bowel Migrating Motor Complex in Humans.

BACKGROUND: Several animal and human studies have reported that sphincter of Oddi (SO) motility shows cyclical changes during the fasting state. However, to date, the relationship between the SO motility and the migrating motor complex (MMC) of the small bowel (SB) remains unclear in humans. AIMS: We observed SO motility over a long study period and evaluated its relationship with the MMC of the SB in humans using percutaneous long-term manometry. METHODS: Our study included patients with hepatolithiasis who required percutaneous transhepatic catheter placement and subsequently underwent choledochoscopy and stone removal. Long-term percutaneous transhepatic SO manometry was performed after complete stone removal. SO and SB motility were simultaneously recorded. RESULTS: SO motility showed cyclical phasic changes with periodic high-frequency contractions similar to the MMC contractions of the SB. All high-frequency contractions of the SO coincided with phase III contractions of the MMC of the SB. The proportions of phase III contractions of SO and SB were similar, but the proportions of phase I (P = 0.001) and phase II (P = 0.002) contractions were significantly different. The mean basal SO pressure was observed to significantly increase in phase III compared to phase I (P = 0.001) and phase II (P = 0.001) contractions. CONCLUSIONS: SO motility in humans showed cyclical phasic changes closely coordinated with the MMC of the SB in a fasting state; however, the proportion of phases differed between the SO and the SB. The basal pressure significantly increased during physiological high-frequency phase III contractions of the SO.

Plasma MicroRNA-21, 26a, and 29a-3p as Predictive Markers for Treatment Response Following Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma.

BACKGROUND: We investigated an association between the levels of plasma microRNA (miRNA)-21, -26a, and -29a-3p and treatment outcomes following transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). METHODS: A total of 198 patients with TACE-treated HCC were followed up for TACE refractoriness and liver transplantation (LT)-free survival. Pretreatment plasma miRNA-21, -26a, and -29a-3p levels were measured using quantitative real-time polymerase chain reaction. RESULTS: During the mean follow-up of 22.3 (range, 0.7-79) months, 118 (59.6%) patients exhibited TACE refractoriness. Multivariate analyses showed that expression of a specific combination of miRNAs (miRNA-21 ≥ 2.5, miRNA-26a ≥ 1.5, and miRNA-29a-3p < 0.4) was associated with early TACE refractoriness (within 1 year; hazard ratio [HR], 2.32; 95% confidence interval [CI], 1.08-4.99; P = 0.031) together with tumor size (HR, 4.62; 95% CI, 1.50-14.21; P = 0.008), and macrovascular invasion (HR, 3.80; 95% CI, 1.19-12.20; P = 0.025). However, miRNA-21, -26a, and -29a-3p levels were not significantly associated with overall TACE refractoriness or LT-free survival. Additionally, large tumor size and macrovascular invasion were common predictive factor of overall TACE refractoriness and survival. CONCLUSION: Combination of plasma miRNA-21, -26a, and -29a-3p expression could predict early TACE refractoriness in patients with TACE-treated HCC.

Development of Risk Prediction Model for Hepatocellular Carcinoma Progression of Indeterminate Nodules in Hepatitis B Virus-Related Cirrhotic Liver.

OBJECTIVES: This study was performed to evaluate long-term outcome of indeterminate nodules detected on cirrhotic liver and to develop risk prediction model for hepatocellular carcinoma (HCC) progression of indeterminate nodules on hepatitis B virus (HBV)-related cirrhotic liver. METHODS: Indeterminate nodules up to 2 cm with uncertain malignant potential detected on computed tomography of cirrhotic liver during HCC surveillance were analyzed retrospectively. HCC risk prediction model of indeterminate nodules in HBV-related cirrhotic liver was deduced based on result of Cox regression analysis. RESULTS: A total of 494 indeterminate nodules were included. Independent risk factors of HCC progression were old age, arterial enhancement, large nodule size, low serum albumin level, high serum α-fetoprotein (AFP) level, and prior HCC history in all included subjects. In subjects with chronic hepatitis B, old age (year; hazard ratio (HR)=1.06; P<0.001), arterial enhancement (HR=2.62; P=0.005), large nodule size (>1 cm; HR=7.34; P<0.001), low serum albumin level (≤3.5 g/dl; HR=3.57; P=0.001), high serum AFP level (≥100 ng/ml; HR=6.04; P=0.006), prior HCC history (HR=4.24; P=0.001), and baseline hepatitis B e antigen positivity (HR=2.31; P=0.007) were associated with HCC progression. We developed a simple risk prediction model using these risk factors and identified patients at low, intermediate, and high risk for HCC; 5-year cumulative incidences were 1%, 14.5%, and 63.1%, respectively. The developed risk score model showed good performance with area under the curve at 0.886 at 3 years, and 0.920 at 5 years in leave-one-out cross-validation. CONCLUSIONS: We developed a useful and accurate risk score model for predicting HCC progression of indeterminate nodules detected on HBV-related cirrhotic liver.

Higher serum interleukin-17A levels as a potential biomarker for predicting early disease progression in patients with hepatitis B virus-associated advanced hepatocellular carcinoma treated with sorafenib.

BACKGROUND: Although sorafenib is the only available drug with proven efficacy for patients with advanced hepatocellular carcinoma (HCC), the clinical efficacy of sorafenib is variable and unpredictable. The aim of the current study was to identify potential serum biomarkers predicting cancer progression and overall survival (OS) in patients with hepatitis B virus (HBV)-related advanced HCC treated with sorafenib. METHODS: Thirty-four patients with HBV-related advanced HCC (modified Union for International Cancer Control [UICC] stage IVa or IVb) treated with sorafenib for more than 4weeks were retrospectively enrolled. Using a Luminex 200 system, 11 cytokines including interleukin-17A (IL-17A) were measured in baseline serum samples prior to sorafenib administration. Several clinical factors and the serum concentrations of the 11 cytokines were analyzed using Cox regression analysis. RESULTS: In the analysis of progression-free survival (PFS), older age (year; hazard ratio [HR]=1.07; 95% confidence interval [CI]=1.00-1.15; P=0.046) and higher baseline serum IL-17A level (>1.94pg/mL; HR=19.96; 95% CI=3.32-119.86; P=0.001) were identified as significant risk factors for early progression with good predictive power (Harrell's C=0.817, standard error estimates (se)=0.085). In the analysis of OS, higher Child-Pugh score (>5; HR=2.35, 95% CI=1.09-5.10, P=0.030) and lower serum baseline fibroblast growth factor-2 level (≤20.57pg/mL; HR=3.24, 95% CI=1.22-8.60, P=0.018) were identified as negative predictive factors for OS, even though the model did not have significant predictive power (Harrell's C=0.634, se=0.062). CONCLUSION: A higher serum IL-17A level is a potential biomarker for predicting poor PFS in patients with HBV-related advanced HCC treated with sorafenib.

Plasma micoRNA-122 as a predictive marker for treatment response following transarterial chemoembolization in patients with hepatocellular carcinoma.

BACKGROUND AND AIM: Circulating microRNA (miR)-122 has recently been investigated as a potential biomarker of various hepatic diseases, such as chronic hepatitis and hepatocellular carcinoma (HCC). We investigated the association between plasma miR-122 levels and the treatment outcomes following transarterial chemoembolization (TACE) in HCC patients. METHODS: We included 177 HCC patients treated with TACE in the study; TACE refractoriness and liver transplantation-free survival were evaluated during follow up. Pretreatment plasma miR-122 levels were assessed using quantitative real-time polymerase chain reaction. Relative quantification of miR-122 expression (fold change) was determined using the 2(-ΔΔCt) method. MiR-16 was used as an internal control for the normalization of miRNA data. RESULTS: During the mean follow up of 22.4 (range, 1-79) months, 112 (69.5%) patients exhibited TACE refractoriness. Multivariate analyses showed that tumor number (hazard ratio [HR], 2.51; 95% confidence interval [CI], 1.43-4.41; P = 0.001) and tumor size (HR, 2.65; 95% CI, 1.62-4.32; P = 0.000) can independently predict overall TACE refractoriness. High miR-122 expression (> 100) was associated with early TACE refractoriness (within 1 year; HR, 2.77; 95% CI, 1.12-6.86; P = 0.028), together with tumor number (HR, 22.73; 95% CI, 2.74-188.66; P = 0.004) and tumor size (HR, 4.90; 95% CI, 1.99-12.06; P = 0.001). Univariate analyses showed that high miR-122 expression tends to be associated with poor liver transplantation-free survival (HR, 1.42; 95% CI, 0.95-2.11; P = 0.085). However, it was statistically insignificant in multivariate analysis. CONCLUSION: High expression levels of plasma miR-122 are associated with early TACE refractoriness in HCC patients treated with TACE.

Prediction of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis Using 4-Hour Post-Endoscopic Retrograde Cholangiopancreatography Serum Amylase and Lipase Levels.

Early post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) prediction may allow safe same-day outpatients discharge after ERCP and earlier proper management. This study aimed to assess the usefulness of the 4-hour post-ERCP serum amylase and lipase levels for PEP early prediction and to investigate predictive cut-off values for 4-hour post-ERCP serum amylase and lipase levels for safe discharge and urgent initiation of resuscitation. The data of 516 consecutive patients with native papilla who underwent ERCP between January 2013 and August 2014 were retrospectively reviewed. Serum amylase and lipase levels were measured before, and 4 and 24 hours after ERCP. PEP occurred in 16 (3.1%) patients. The receiver-operator characteristic curve for 4-hour post-ERCP serum amylase and lipase levels showed that the areas under the curve were 0.919 and 0.933, respectively, demonstrating good test performances as predictors for PEP (both P values < 0.001). The amylase level > 1.5 × the upper limit of reference (ULR) was found useful for PEP exclusion with a sensitivity of 93.8%, while 4 × ULR was found useful to guide preventive therapy with the best specificity of 93.2%. Similarly, the lipase level 2 × ULR showed best sensitivity, while 8 × ULR had the best specificity. Logistic regression analysis showed that 4-hour post-ERCP amylase level > 4 × ULR, lipase level > 8 × ULR, precut sphincterotomy, and pancreatic sphincterotomy were significant predictors for PEP. In conclusion, 4-hour post-ERCP amylase and lipase levels are useful early predictors of PEP that can ensure safe discharge or prompt resuscitation after ERCP.

Clinical course of partial virological responders under prolonged entecavir monotherapy in patients with chronic hepatitis B.

Studies about long-term entecavir (ETV) therapy for partial virological response (PVR) are lacking. This study aimed to assess the clinical course of PVR patients receiving ETV therapy and analyze the efficacy of tenofovir (TDF). We retrospectively evaluated 130 patients who showed a PVR to ETV. Among these patients, 102 were nucleot(s)ide analogue (NUC)-naïve and 28 were lamivudine (LAM)-experienced. The cumulative rates of VR were 54.1%, 70.8%, and 83.7% for the NUC-naïve group and 37.0%, 42.8%, and 42.8% for the LAM-experienced group after 24, 36, and 48 months of ETV therapy, respectively (P = 0.008). Low HBV DNA level at 12 months (P < 0.001) and absence of a LAM treatment history (P = 0.031) were significant associated factors for VR. In VR prediction at 36 months of ETV therapy in NUC-naïve patients, HBV DNA level <95 IU/ml at 12 months showed a 92.9% sensitivity and a 78.3% specificity (AUROC, 0.909; P < 0.001). ETV resistance did not develop in NUC-naïve patients with HBV DNA levels <95 IU/ml at 12 months. The cumulative probability of VR in patients who switched to or additionally received TDF was 91.3% at 15 months. Prolonged ETV therapy induced a VR without the risk of ETV resistance in NUC-naïve patients with HBV DNA levels <95 IU/ml at 12 months. All patients with LAM-experienced or NUC-naïve with HBV DNA levels ≥95 IU/ml at 12 months should be switched to TDF rescue therapy.

Endoscopic naso-gallbladder drainage versus gallbladder stenting before cholecystectomy in patients with acute cholecystitis and a high suspicion of choledocholithiasis: a prospective randomised preliminary study.

OBJECTIVE: Endoscopic transpapillary gallbladder drainage using a nasocystic tube or plastic stent has been attempted as an alternative to percutaneous drainage for patients with acute cholecystitis who are not candidates for urgent cholecystectomy. We aimed to assess the efficacy of single-step endoscopic drainage of the common bile duct and gallbladder, and to evaluate which endoscopic transpapillary gallbladder drainage method is ideal as a bridge before elective cholecystectomy. MATERIALS AND METHODS: From July 2011 to December 2014, 35 patients with acute moderate-to-severe cholecystitis and a suspicion of choledocholithiasis were randomly assigned to the endoscopic naso-gallbladder drainage (ENGBD) (n = 17) or endoscopic gallbladder stenting (EGBS) (n = 18) group. RESULTS: Bile duct clearance was performed successfully in all cases. No significant differences were found between the ENGBD and EGBS groups in the technical success rates [82.4% (14/17) vs. 88.9% (16/18), p = 0.658] and clinical success rates [by intention-to-treat analysis: 70.6% (12/17) vs. 83.3% (15/18), p = 0.443; by per protocol analysis of technically feasible cases: 85.7% (12/14) vs. 93.8% (15/16), p = 0.586]. Three ENGBD patients and two EGBS patients experienced adverse events (p = 0.658). No significant differences were found in operation time or rate of conversion to open cholecystectomy. CONCLUSIONS: Single-step endoscopic transpapillary drainage of the common bile duct and gallbladder seems to be an acceptable therapeutic modality in patients with acute cholecystitis and a suspicion of choledocholithiasis. There were no significant differences in the technical and clinical outcomes between ENGBD and EGBS as a bridge before cholecystectomy.

Tenofovir-based rescue therapy in chronic hepatitis B patients with suboptimal responses to adefovir with prior lamivudine resistance.

We evaluated the efficacy of tenofovir (TDF)-based rescue therapy and compared the outcomes of TDF monotherapy and TDF-based nucleoside analog (NA) combination therapy in patients with suboptimal response (SOR) to adefovir (ADV) with or without NAs in lamivudine (LAM)-resistant chronic hepatitis B. All study subjects received ADV with or without NAs due to prior LAM resistance, and were then switched to TDF-based rescue therapy due to SOR (hepatitis B virus DNA >20 IU/ml after at least 6 months of therapy). A total of 125 patients were eligible. The overall cumulative proportion of complete virologic response (CVR) was 64 of 74 patients (86.5%) at 48 weeks of treatment. During the follow-up period of 48 weeks, there was no significant difference in CVR rate (P = 0.750) between the TDF monotherapy (n = 18) and the TDF with NA groups (n = 107). Patients with ADV genotypic mutations showed inferior antiviral responses to TDF compared with the patients without ADV genotypic mutations, but this was not statistically significant (P = 0.069). Partial virological response to prior ADV therapy showed higher CVR rates compared to patients with non-response at 12 weeks (P = 0.013), but there was no significant difference after 24 (P = 0.076) and 48 weeks (P = 0.198) of treatment. TDF monotherapy is as effective as TDF plus NA combination therapy in patients with SOR to ADV-based rescue therapy and LAM resistance. TDF, with or without NAs, was effective even in cases of ADV resistance.

Low serum interleukin-6 levels as a predictive marker of recurrence in patients with hepatitis B virus related hepatocellular carcinoma who underwent curative treatment.

BACKGROUND: We aimed to investigate the use of novel serum biomarkers for predicting the recurrence and survival of patients with hepatitis B virus (HBV)-related early hepatocellular carcinoma (HCC) after hepatic resection or radiofrequency ablation (RFA). METHODS: One hundred and five patients with HBV-related HCC, who fulfilled the Milan criteria without vascular invasion and underwent hepatic resection or RFA, were followed-up for a median duration of 52months. Pretreatment serum concentrations of 16 cytokines including interleukin-6 (IL-6) were measured by using a Luminex 200 system. The measured serum cytokines and several clinical factors were analyzed retrospectively. RESULTS: Univariate analysis showed that patients with lower pretreatment serum levels of IL-10, IL-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α had significantly shorter disease-free survival (DFS) than those with higher levels. Multivariate analysis revealed that a low serum IL-6 level (⩽33.00pg/mL; hazard ratio [HR]=5.39; 95% confidence interval [CI]=1.27-22.93; P=0.022), low platelet count (<100×10(9)/L; HR=2.23; 95% CI=1.28-3.89; P=0.005), and low serum albumin level (⩽3.5g/L; HR=2.26; 95% CI=1.28-3.97; P=0.005) had a negative prognostic impact on DFS. In the analysis for overall survival, a low serum platelet level (<100×10(9)/L; HR=2.80; 95% CI=1.31-5.99; P=0.008) and multiple tumor (⩾2; HR=4.05; 95% CI=1.56-10.48; P=0.004) showed a negative prognostic impact on the overall survival. CONCLUSION: A low serum IL-6 level is, in addition to low platelet count and low serum albumin level, an independent prognostic factor for DFS in patients with HBV-related early HCC who underwent hepatic resection or RFA with curative intention.