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Irreversible electroporation (IRE) is a newly developed non-thermal ablative therapy. During the IRE procedure, the permeability of the cell membrane is irreversibly changed by application of high-energy pulses across the tissue. This induces the breakdown of cell homeostasis, and thereby cell death. Here, we present an in vivo study to demonstrate IRE ablation of gastric tissue and characterize the changes that occur with time therein. No significant complications were observed in the test rats during the experiment. The electroporated tissues exhibited apoptosis at 10, 24 and 48 h after IRE ablation. The apoptosis peaked at 10 h after IRE and then declined, suggesting that the ablated tissue rapidly recovered owing to intense metabolic activity. In addition, the electroporated tissues exhibited morphological changes such as pyknosis and karyorrhexis, while histological analysis showed that the blood vessels were preserved. Interestingly, electroporation greatly affected the mucosa and muscularis propria, but not the submucosa and serosa. This study suggests that IRE could potentially be used as a minimally invasive treatment for early gastric cancer that does not exhibit lymph node metastasis or dysplasia.

Non-alcoholic fatty liver disease (NAFLD) is a dominant cause of chronic liver disease, but the exact mechanism of progression from simple steatosis to nonalcoholic steatohepatitis (NASH) remains unknown. Here, we investigated the role of exosomes in NAFLD progression. Exosomes were isolated from a human hepatoma cell line treated with palmitic acid (PA) and their miRNA profiles examined by microarray. The human hepatic stellate cell (HSC) line (LX-2) was then treated with exosome isolated from hepatocytes. Compared with controls, PA-treated hepatocytes displayed significantly increased CD36 and exosome production. The microarray analysis showed there to be distinctive miRNA expression patterns between exosomes from vehicle- and PA-treated hepatocytes. When LX-2 cells were cultured with exosomes from PA-treated hepatocytes, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with exosomes from vehicle-treated hepatocytes. In conclusion, PA treatment enhanced the production of exosomes in these hepatocytes and changed their exosomal miRNA profile. Moreover, exosomes derived from PA-treated hepatocytes caused an increase in the expression levels of fibrotic genes in HSCs. Therefore, exosomes may have important roles in the crosstalk between hepatocytes and HSCs in the progression from simple steatosis to NASH.

Long-term data on antiviral therapy in Korean patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) are limited. This study evaluated the efficacy and safety of entecavir (ETV) and lamivudine (LAM) over 240 weeks. Treatment-naive patients with HBeAg-negative CHB were randomized to receive ETV 0.5 mg/day or LAM 100 mg/day during the 96 week double-blind phase, followed by open-label treatment through week 240. The primary endpoint was the proportion of patients with virologic response (VR; hepatitis B virus [HBV] DNA<300 copies/mL) at week 24. Secondary objectives included alanine aminotransferase (ALT) normalization and emergence of ETV resistance (week 96), VR and log reduction in HBV DNA levels (week 240), and safety evaluation. In total, 120 patients (>16 years old) were included (ETV, n=56; LAM, n=64). Baseline characteristics were comparable between the two groups. A significantly higher proportion of ETV-treated patients achieved VR compared to LAM at week 24 (92.9% vs. 67.2%, P=0.0006), week 96 (94.6% vs. 48.4%, P<0.0001), and week 240 (95.0% vs. 47.6%, P<0.0001). At week 96, ALT normalization was observed in 87.5% and 51.6% of ETV and LAM patients, respectively (P<0.0001). Virologic breakthrough occurred in one patient (1.8%) receiving ETV and 26 patients (42.6%) receiving LAM (P<0.0001) up to week 96. Emergence of resistance to ETV was not detected. The incidence of serious adverse events was low and unrelated to the study medications. Long-term ETV treatment was superior to LAM, with a significantly higher proportion of patients achieving VR. Both treatments were well tolerated.

Nonalcoholic steatohepatitis (NASH) is considered as a progressive form of nonalcoholic fatty liver disease (NAFLD). To distinguish NASH from nonalcoholic fatty liver (NAFL), we evaluated the diagnostic value of circulating miRNAs. Small RNA sequencing was performed on 12 NAFL patients and 12 NASH patients, and the miRNA expression was compared. After selecting miRNAs for the diagnosis of NASH, we analyzed the diagnostic accuracy of each miRNA and the combination of miRNAs. External validation was performed using quantitative reverse transcription PCR. Among the 2,588 miRNAs, 26 miRNAs significantly increased in the NASH group than in the NAFL group. Among the 26 elevated miRNAs in the NASH group, 8 miRNAs were selected, and in silico analysis was performed. Only four miRNAs (miR-21-5p, miR-151a-3p, miR-192-5p, and miR-4449) showed significant area under the receiver operating characteristic curve (AUC) values for NASH diagnosis. The combination of the four miRNAs showed satisfactory diagnostic accuracy for NASH (AUC 0.875; 95% CI 0.676–0.973). External validation revealed similar diagnostic accuracy for NASH (AUC 0.874; 95% CI 0.724–0.960). NASH represents significantly distinct miRNA expression profile compared with NAFL. The combination of serum circulating miRNAs can be used as a novel biomarker for the NASH diagnosis in NAFLD.

Background Angiotensin blockade such as with an angiotensin II receptor blocker (ARB) or angiotensinconverting enzyme inhibitor (ACEI) has antifibrotic properties. The aim of this study was to evaluate and compare the antifibrotic effect between ARBs and ACEIs. Methods Common bile duct-ligated (BDL) adult Sprague-Dawley rats were allocated to five groups (each group, n = 8) as follows: G1, BDL without drug; G2, BDL + captopril 100 mg/kg per day; G3, BDL + ramipril 10 mg/kg per day; G4, BDL + losartan 10 mg/kg per day; G5, BDL + irbesartan 15 mg/kg per day. Four weeks post-BDL, hepatic fibrosis was analyzed histomorphologically using Batts and Ludwig scores. α-Smooth muscle actin (α-SMA) expression by immunohistochemical staining, hydroxyproline contents of liver tissue by spectrophotometry, and angiotensin receptor, collagen, procollagen, and transforming growth factor β (TGF-β) expressions were evaluated by real-time reverse transcriptase-polymerase chain reaction. Angiotensin receptor expression was also determined by Western blotting. Results Batts and Ludwig scores were 3.8, 2.6, 2.4, 1.8, and 1.6 in G1, G2, G3, G4, and G5, respectively. Histologically, ARB groups (G4, G5) showed significant suppression of hepatic fibrosis compared with ACEI groups or the control. Expressions of α-SMA (%) and the content of hydroxyproline (μg liver tissue) were significantly lower in ARB groups (G4, G5) than in ACEI groups (G2, G3) (P < 0.05). Also, ARB reduced the expression of angiotensin receptor, collagen, procollagen, and TGF-β1 compared with ACEI. Western blot analysis showed that the expression of angiotensin receptor was inhibited in both ARB and ACEI groups. Conclusions Both ARB and ACEI attenuate hepatic fibrosis through inhibiting hepatic stellate cell activation, and the inhibitory effect of ARBs on hepatic fibrosis is superior to that of ACEIs in the BDL rat model.

The most widely used method for diagnosing sarcopenia is the skeletal muscle index (SMI). Several studies have suggested that psoas muscle thickness per height (PMTH) is also effective for detecting sarcopenia and predicting prognosis in patients with cirrhosis. The aim of this study was to evaluate the optimal cutoff values of PMTH for detecting sarcopenia in cirrhotic patients. All cirrhotic patients who underwent abdominal computed tomography (CT) scan including L3 and umbilical levels for measuring SMI and transverse psoas muscle thickness, respectively, were included. Two definitions of sarcopenia were used: (1) sex-specific cutoffs of SMI (≤52.4 cm2 /m2 in men and ≤38.5 cm2 /m2 in women) for SMI-sarcopenia and (2) cutoff of PMTH (<16.8 mm/m) for PMTH-sarcopenia. Six hundred fifty-three patients were included. The average age was 53.6 ± 10.2 years, and 499 patients (76.4%) were men. PMTH correlated well with SMI in both men and women (P<0.001). Two hundred forty-one (36.9%) patients met the criteria for SMI-sarcopenia. The best PMTH cutoff values for predicting SMI-sarcopenia were 17.3 mm/m in men and 10.4 mm/m in women, and these were defined as sex-specific cutoffs of PMTH (SsPMTH). The previously published cutoff of PMTH was defined as sex-nonspecific cutoff of PMTH (SnPMTH). Two hundred thirty (35.2%) patients were diagnosed with SsPMTH-sarcopenia, and 280 (44.4%) patients were diagnosed with SnPMTH-sarcopenia. On a multivariate Cox regression analysis, SsPMTH-sarcopenia (hazard ratio [HR], 1.944; 95% confidence interval [CI], 1.144-3.304; P=0.014) was significantly associated with mortality, while SnPMTH-sarcopenia was not (HR, 1.446; 95% CI, 0.861-2.431; P=0.164). PMTH was well correlated with SMI in cirrhotic patients. SsPMTH-sarcopenia was an independent predictor of mortality in these patients and more accurately predicted mortality compared to SnPMTH-sarcopenia.

Noninvasive techniques for evaluating the severity of nonalcoholic fatty liver disease (NAFLD) have shown limited diagnostic performance. MicroRNAs (miRNAs) are useful biomarkers for diagnosing and monitoring the progression and treatment response to several diseases. Here, we evaluated whether serum exosomal miRNAs could be used for the diagnosis and prognosis of NAFLD severity. Exosomal miRNAs were isolated from the sera of 41 patients with NAFLD (diagnosed using liver biopsy) for microarray profiling. The degree of NAFLD severity was determined using inflammation, steatosis, and ballooning scores and the NAFLD activity score (NAS). Correlations between miRNA expression, clinical and biochemical parameters, and mRNA expression were analyzed. Overall, 25, 11, 13, and 14 miRNAs correlated with the inflammation score, steatosis score, ballooning score, and NAS, respectively, with 33 significant correlations observed between 27 miRNAs and six clinical variables. Eight miRNAs (let-7b-5p, miR-378h, -1184, -3613-3p, -877-5p, -602, -133b, and 509-3p) showed anticorrelated patterns with the corresponding mRNA expression. In fibrosis, 52 and 30 interactions corresponding to high miRNA-low mRNA and low miRNA-high mRNA expression, respectively, were observed. The present results therefore suggest that serum exosomal miRNAs can be used to evaluate NAFLD severity and identify potential targets for NAFLD treatment.

BackgroundEndoscopic irreversible electroporation (IRE) can be performed using a flexible, thin, needle-shaped electrode for an endoscopic ultrasound (EUS)-guided procedure. This study aimed to evaluate the feasibility and efficacy of performing EUS-guided IRE with endoscopic needle-electrode in porcine pancreas.MethodsExperimental endoscopic IRE on the pancreas were performed by EUS-guided approach in three pigs and compared with surgical approach in three pigs. The animals were killed after 24 h and their pancreases collected.ResultsIRE ablation using endoscopic needle-electrode was successful technically in EUS-guided approaches for the pancreas. Immediately following IRE, the ablated pancreatic tissue showed no gross change except focal hemorrhage. H&E staining presented a well-demarcated ablation site measuring 1.0–1.5 cm in diameter in the pancreas. TUNEL immunohistochemistry showed diffuse cell death along the puncture site 24 h after IRE. No complication was observed in pigs after endoscopic IRE ablation.ConclusionEUS-guided IRE ablation was feasible and effective for pancreas using the newly developed device.

ObjectivesFor the prevention of spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites, norfloxacin 400 mg per day is recommended as a standard regimen. This study aims to investigate whether ciprofloxacin once weekly administration is not inferior to norfloxacin once daily administration for the prevention of SBP.MethodsThis is an investigator-initiated open-label randomized controlled trial conducted at seven tertiary hospitals in South Korea. Liver cirrhosis patients with ascites were screened, and enrolled in this randomized controlled trial if ascitic protein ≤1.5 g/dL or the presence of history of SBP. Ascitic polymorphonucleated cell count needed to be <250/mm3. Patients were randomly assigned into norfloxacin daily or ciprofloxacin weekly group, and followed-up for 12 months. Primary endpoint was the prevention of SBP.ResultsOne hundred twenty-four patients met enrollment criteria and were assigned into each group by 1:1 ratio (62:62). Seven patients in the norfloxacin group and five patients in the ciprofloxacin group were lost to follow-up. SBP developed in four patients (4/55) and in three patients (3/57) in each group, respectively (7.3% vs. 5.3%, P = 0.712). The transplant-free survival rates at 1 year were comparable between the groups (72.7% vs. 73.7%, P = 0.970). Incidence of infectious complication, hepatorenal syndrome, hepatic encephalopathy, and variceal bleeding rates were not significantly different (all P = ns). The factors related to survival were models representing underlying liver function.ConclusionOnce weekly ciprofloxacin was as effective as daily norfloxacin for the prevention of SBP in cirrhotic patients with ascites.

Transarterial radioembolization (TARE) has become widely used in the treatment of HCC, one of the most common causes of cancer mortality worldwide. Here we investigated the long-term clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with TARE in a multi-medical center in Korea. A total of 149 patients treated with TARE from 2008–2014 were recruited. The pre-treatment HCC stage was classified according to the BCLC stage, of which C and D were defined as advanced HCC. Advanced HCC stage and Child–Turcotte–Pugh (CTP) score A were identified in 62 (42%) and 134 (90%) patients, respectively. Portal vein thrombosis (PVT) was identified in 58 patients (38.9%). The median time to progression (TTP) was 14 months, and the median overall survival (OS) and progression-free survival (PFS) were 18.6 and 8.9 months, respectively. The overall tumor response was 47%, and the disease control rate was 78%. OS and PFS differed significantly according to the presence of liver cirrhosis, extrahepatic metastasis, tumor response and curative treatment after TARE (all, p < 0.05). Multiple tumors and major PVT were other independent factors related to OS, while the des-gamma carboxy protein level predicted PFS (all, p < 0.05). Tumor size was an independent predictor of tumor response. TTP, OS and PFS all differed among BCLC stages. The serious adverse effect after TARE was clinically not significant. Therefore, TARE is safe and effective in treating early to advanced HCCs.