Subclinical diabetes confirmed by 75-g OGTT influence on the prognosis of decompensated cirrhosis.

BACKGROUND AND AIM: Disorders of glucose metabolism, such as impaired glucose tolerance (IGT) and diabetes mellitus (DM), frequently occur in cirrhosis. We aimed to evaluate who needs to be undertaken a 75-g oral glucose tolerance test (OGTT) to find underlying subclinical diabetes. METHODS: This prospective study included 713 patients with either compensated (Child-Turcotte-Pugh [CTP] class A) or decompensated cirrhosis (CTP class B/C) without previous DM history. All patients underwent a 75-g OGTT. The patients were divided into three groups: normal glucose tolerance (NGT), IGT, and newly diagnosed DM (subclinical DM). RESULTS: Among 713 patients, NGT was diagnosed in 139 (19.5%), IGT in 252 (35.3%), and subclinical DM in 322 (45.2%) patients, respectively. During a median follow-up period of 42.0 months, the cumulative survival rates of patients were as follows: NGT, 75.6%; IGT, 57.6%; and subclinical DM, 54.8%. Overall, IGT (adjusted hazard ratio [aHR], 1.605; 95% confidence interval [CI] = 1.009-2.553; P = 0.046) and subclinical DM (aHR, 1.840; 95% CI = 1.183-2.861; P = 0.001) were identified as independent predictors of mortality. In patients with compensated cirrhosis (n = 415), neither IGT nor subclinical DM conferred a higher mortality risk. However, among patients with decompensated cirrhosis (n = 298), those with IGT (aHR, 2.394; P = 0.015) and subclinical DM (aHR, 2.211; P = 0.022) showed a survival rate worse than those with NGT. In addition, subclinical DM was identified as an independent risk factor for infection (aHR, 2.508; P = 0.007). CONCLUSIONS: IGT and subclinical diabetes by OGTT are associated with an unfavorable prognosis in cirrhosis, and the effect is pronounced in the decompensated state. CLINICALTRIALS: gov, Number NCT04828512 (https://clinicaltrials.gov/ct2/show/NCT04828512).

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

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

Anti-cancer effects of plant-derived Micromonospora sp. M2 against A549 and MCF-7 cell lines.

The huge diversity of secondary bioactive metabolites, such as antibiotic and anticancer compounds produced by Micromonospora sp., makes it an attractive target for study. Here, we explored the anti-proliferative activities of Micromonospora sp. M2 extract (MBE) in relation to its pro-oxidative activities in A549 and MCF7 cell lines. Anti-proliferative effects were assessed by treating cells with MBE. We found that treatment with MBE decreased cell proliferation and increased intracellular reactive oxygen species, and that these observations were facilitated by the suppression of the PI3K-AKT pathway, alterations to the Bcl/Bad ratio, and increased caspase activity. These observations also demonstrated that MBE induced apoptotic cell death in cell lines. In addition, the phosphorylation of P38 and c-Jun N-terminal kinase (JNK) were upregulated following MBE treatment in both cell lines. Collectively, these results indicate that MBE acts as an anticancer agent via oxidative stress and JNK/mitogen-activated protein kinase pathway activation, enhancing apoptotic cell death in cell lines.

IFN-ß Overexpressing Adipose-Derived Mesenchymal Stem Cells Mitigate Alcohol-Induced Liver Damage and Gut Permeability.

Alcoholic liver disease (ALD) is a form of hepatic inflammation. ALD is mediated by gut leakiness. This study evaluates the anti-inflammatory effects of ASCs overexpressing interferon-beta (ASC-IFN-ß) on binge alcohol-induced liver injury and intestinal permeability. In vitro, ASCs were transfected with a non-viral vector carrying the human IFN-ß gene, which promoted hepatocyte growth factor (HGF) secretion in the cells. To assess the potential effects of ASC-IFN-ß, C57BL/6 mice were treated with three oral doses of binge alcohol and were administered intraperitoneal injections of ASC-IFN-ß. Mice treated with binge alcohol and administered ASC-IFN-ß showed reduced liver injury and inflammation compared to those administered a control ASC. Analysis of intestinal tissue from ethanol-treated mice administered ASC-IFN-ß also indicated decreased inflammation. Additionally, fecal albumin, blood endotoxin, and bacterial colony levels were reduced, indicating less gut leakiness in the binge alcohol-exposed mice. Treatment with HGF, but not IFN-ß or TRAIL, mitigated the ethanol-induced down-regulation of cell death and permeability in Caco-2 cells. These results demonstrate that ASCs transfected with a non-viral vector to induce IFN-ß overexpression have protective effects against binge alcohol-mediated liver injury and gut leakiness via HGF.

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

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

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

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

Prognosis of Patients with Chronic Hepatitis C Genotype 1b Infection Treated Using Daclatasvir/Asunaprevir after Sustained Virologic Response: A 6-Year Multicenter Prospective Observational Study.

Aim and Objectives: Direct-acting antiviral (DAA) therapy can cure chronic hepatitis C (CHC), and daclatasvir (DCV)/asunaprevir (ASV) was the first interferon-free DAA therapy introduced in Korea. Patients who achieve sustained virologic response (SVR) after DAA treatment are expected to have good prognoses. Therefore, in this study, we aimed to investigate the prognosis of these patients. Materials and Methods: This multicenter prospective observational study included patients with CHC who achieved SVR after DCV/ASV treatment. The primary endpoint was hepatocellular carcinoma (HCC) occurrence, which was reviewed annually. Results: We included 302 patients (median follow-up duration: 38 [16.5-60.0] months; median age: 58 [49-67] years) in the study. Cirrhosis was observed in 103 patients (34.1%), and the median Child-Pugh score was 5.0. HCC occurred in 16 patients (5.3%) within six years post-SVR; these patients were older and had higher cirrhosis prevalence, alpha-fetoprotein levels, and fibrosis-4 index scores than did those without HCC development. Cox proportional hazards analysis revealed that age > 71 years (p = 0.005) and cirrhosis (p = 0.035) were significant risk factors for HCC occurrence. Conclusions: Although the prognoses of patients who achieved SVR with DCV/ASV therapy were generally good, the risk for HCC was present, especially in older patients and in those with cirrhosis. Hence, early treatment at younger ages and regular follow-up surveillance after achieving SVR are warranted.

Switching from Tenofovir-Based Combination Therapy to Tenofovir Monotherapy in Multidrug-Experienced Chronic Hepatitis B Patients: a 5-Year Experience at Two Centers.

Patients with chronic hepatitis B (CHB) who were administered tenofovir disoproxil fumarate (TDF)-based combination therapy after receiving multiple drugs are frequently switched to TDF monotherapy in South Korea. We evaluated the efficacy and safety of switching to TDF monotherapy from TDF-based combination therapy over 5 years. This was a retrospective study of multidrug-experienced CHB patients who switched from TDF-based combination therapy to TDF monotherapy after achieving a virologic response (VR; <20 IU/mL) at Konkuk University Hospital and Sanggye Paik Hospital. The biochemical response was defined as a normalized serum ALT level during follow-up. Each patient was assessed from the date of switching to TDF monotherapy to the date of the last follow-up over 5 years. A total of 39 patients who received at least one antiviral therapy before TDF-based combination therapy were analyzed. The median duration of VR before switching to TDF monotherapy was 18 months and the median duration of TDF monotherapy was 55 months. In this study, except for one patient who had poor compliance, all patients maintained a VR. Three patients had a temporarily increased HBV DNA level and 91.2% of the patients showed a biochemical response. Switching multidrug-experienced patients to TDF monotherapy is generally safe and effective.

Skeletal muscle satellite cell-derived mesenchymal stem cells ameliorate acute alcohol-induced liver injury.

Cultured human skeletal-muscle satellite cells have properties of mesenchymal stem cells (skeletal muscle satellite cell-derived mesenchymal stem cells, SkMSCs) and play anti-inflammatory roles by secreting prostaglandin E2 and hepatocyte growth factor (HGF). To evaluate the utility of SkMSCs in treating liver diseases, we determined whether SkMSCs could ameliorate acute liver and gut inflammation induced by binge ethanol administration. Binge drinking of ethanol led to weight loss in the body and spleen, liver inflammation and steatosis, and increased serum ALT and AST levels (markers of liver injury), along with increased IL-1ß, TNF-α, and iNOS expression levels in mice. However, levels of these binge-drinking-induced indicators were reduced by a single intraperitoneal treatment of SkMSCs. Furthermore, levels of bacteria-derived lipopolysaccharide decreased in the livers and sera of ethanol-exposed mice after SkMSC administration. SkMSCs decreased the extent of tissue inflammation and reduced villus and crypt lengths in the small intestine after alcohol binge drinking. SkMSCs also reduced the leakage of blood albumin, an indicator of leaky gut, in the stool of ethanol-exposed mice. Alcohol-induced damage to human colonic Caco-2/tc7 cells was also alleviated by HGF. Therefore, a single treatment with SkMSCs can attenuate alcoholic liver damage by reducing inflammatory responses in the liver and gut, suggesting that SkMSCs could be used in cell therapy to treat alcoholic liver diseases.

Autoimmune Hepatitis Following Vaccination for SARS-CoV-2 in Korea: Coincidence or Autoimmunity?

Autoimmune hepatitis (AIH) is a chronic, autoimmune disease of the liver that occurs when the body's immune system attacks liver cells, causing the liver to be inflamed. AIH is one of the manifestations of a coronavirus disease 2019 (COVID-19), as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Few cases of AIH have been described after vaccination with two messenger RNA (mRNA)-based vaccines-BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)-against SARS-CoV-2. Herein, we report a case of AIH occurring after Pfizer-BioNTech COVID-19 vaccine. A 27-year-old female presented with jaundice and hepatomegaly, appearing 14 days after receiving the second dose of Pfizer-BioNTech vaccine. Her laboratory results showed abnormal liver function with high total immunoglobulin G level. She was diagnosed with AIH with histologic finding and successfully treated with oral prednisolone. We report an AIH case after COVID-19 vaccination in Korea.

Empirical Treatment With Carbapenem vs Third-generation Cephalosporin for Treatment of Spontaneous Bacterial Peritonitis.

BACKGROUND & AIMS: Third-generation cephalosporins (TGCs) are recommended as first-line antibiotics for treatment of spontaneous bacterial peritonitis (SBP). However, antibiotics against multidrug-resistant organisms (such as carbapenems) might be necessary. We aimed to evaluate whether carbapenems are superior to TGC for treatment of SBP. METHODS: We performed a retrospective study of 865 consecutive patients with a first presentation of SBP (275 culture positive; 103 with TGC-resistant bacterial infections) treated at 7 referral centers in Korea, from September 2013 through January 2018. The primary outcome was in-hospital mortality. We made all comparisons using data from patients whose baseline characteristics were balanced by inverse probability of treatment weighting. RESULTS: Of patients who initially received empirical treatment with antibiotics, 95 (11.0%) received carbapenems and 655 (75.7%) received TGCs. Among the entire study cohort, there was no significant difference in in-hospital mortality between the carbapenem (25.8%) and TGC (25.3%) groups (adjusted odds ratio [aOR], 0.97; 95% CI, 0.85-1.11; P = .66). In the subgroup of patients with high chronic liver failure-sequential organ failure assessment (CLIF-SOFA) scores (score of 7 or greater, n = 314), carbapenem treatment was associated with lower in-hospital mortality (23.1%) than in the TGC group (38.8%) (aOR, 0.84; 95% CI, 0.75-0.94; P=.002). In contrast, among patients with lower CLIF-SOFA scores (n = 436), in-hospital mortality did not differ significantly between the carbapenem group (24.7%) and the TGC group (16.0%) (aOR, 1.06; 95% CI, 0.85-1.32; P = .58). CONCLUSIONS: For patients with a first presentation of SBP, empirical treatment with carbapenem does not reduce in-hospital mortality compared to treatment with TGCs. However, among critically ill patients (CLIF-SOFA scores ≥7), empirical carbapenem treatment was significantly associated with lower in-hospital mortality than TGCs.

Centipedegrass extract enhances radiosensitivity in melanoma cells by inducing G2/M cell cycle phase arrest.

Melanoma is aggressive, highly metastatic, and potentially fatal. In the case of patients with advanced melanoma, it is difficult to expect a good prognosis, since this cancer has low sensitivity to chemotherapy and radiation therapy. The use of natural ingredients may enhance existing therapies. Centipedegrass extract (CGE) which contains phenolic structures and C-glycosyl flavones, has been shown to have anti-inflammatory effects and anti-cancer effects. The purpose of this study was to evaluate the radio sensitizing effects of CGE in combination with ionizing radiation (IR). Two melanoma cell lines were exposed to IR after treatment with CGE at concentrations that were not toxic alone. The effects of CGE + IR on cell survival, cell cycle, and apoptotic cell death were examined using MTT and Muse® Cell Analyzer, and fluorescence microscopy. Molecular signaling mechanisms were explored by western blots. Our findings showed that co-treatment of CGE + IR reduced the survival of melanoma cells more than IR alone. Also, cell cycle arrest in CGE-treated cells was enhanced and these cells became more radiosensitive. CGE + IR increased apoptotic cell death more than IR alone. Western blot results showed that the effect of CGE + IR involved MAPKs (ERK1/2, p38, and JNK) pathway. Our study suggests that CGE + IR treatment enhanced radio-sensitization and cell death of melanoma cells via cell cycle arrest and the MAPKs pathway.

Spermidine promotes melanin production through an MITF signalling pathway.

Melanin plays an important role in determining skin colour. Apoptosis of melanocytes and defect in melanin production cause vitiligo. Various studies have been conducted to treat the disease, but its treatment is still difficult. Therefore, this study aimed to investigate the effect of spermidine, which is known as an inhibitor of ageing-related oxidized proteins, on melanogenesis. Even though spermidine above 50 µM had no effect on antioxidant activity and DOPA oxidation, it displayed tyrosinase activity. However, spermidine at 2000 µM was cytotoxic in B16F1 cells using MTT assay. Spermidine above 125 µM decreased the amount of intracellular hydrogen peroxide in a concentration-dependent manner in DCFH-DA analysis. It was also found that spermidine above 2000 µM increased melanin synthesis in living cells. However, spermidine above 1000 µM increased melanin synthesis in a concentration-dependent manner in H2 O2 -treated B16F1 cells. Furthermore, spermidine enhanced the expression of tyrosine hydroxylase via MITF transcription factor involved in melanogenesis in H2 O2 -treated B16F1 cells. Therefore, these results suggest that spermidine could be applied as a potential stimulator of melanin synthesis for the prevention of hair greying.

Changing Trends in Liver Cirrhosis Etiology and Severity in Korea: the Increasing Impact of Alcohol.

BACKGROUND: Chronic hepatitis B is the most common cause of liver cirrhosis in South Korea. However, alcoholic liver disease has shown an increasing trend. Although the clinical implications surrounding liver cirrhosis have been changing over the years, few studies have recently examined cirrhosis epidemiology. Therefore, we aimed to investigate changes in liver cirrhosis etiology and severity in Korea. METHODS: We retrospectively reviewed 16,888 records of cirrhotic patients from six tertiary hospitals in Korea from 2008 to 2017. Continuous and non-continuous variables were processed via linear and Poisson regression, expressed as beta (B) coefficients and as exponentiated values of coefficients (Exp[B]), respectively. RESULTS: Chronic hepatitis B showed a decreasing trend (Exp[B] = 0.975, P < 0.001), whereas alcohol showed an increasing trend (Exp[B] = 1.013, P = 0.003), occupying the most common etiology in 2017. The Child-Turcotte-Pugh (CTP) score and decompensated liver cirrhosis prevalence did not change over the 10-year period. The incidence of variceal bleeding, severe ascites, hepatic encephalopathy, and spontaneous bacterial peritonitis significantly decreased from 12.3% to 7.7%, 7.8% to 4.1%, 1.0% to 0.5%, and 1.9% to 1.1%, respectively (P < 0.05 for all). In the subgroup analysis, the chronic hepatitis B group showed improving CTP scores (B = -0.025, P < 0.001) and decreasing decompensated liver cirrhosis rates (Exp[B] = 0.977, P = 0.016), whereas the alcohol group demonstrated increasing CTP class C (Exp[B] = 1.031, P = 0.005) and model for end-stage liver disease scores (B = 0.081, P = 0.005) over 10 years. CONCLUSION: The chronic hepatitis B group exhibited improved results, whereas the alcohol group still presented poor liver functions and outcomes. Future national policies and systematic approaches addressing the incidence, prevention, and treatment of alcoholic liver cirrhosis are indispensable.

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

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

Interaction between the tumor microenvironment and resection margin in different gross types of hepatocellular carcinoma.

BACKGROUND AND AIM: There is no consensus regarding the safe resection margin in hepatocellular carcinoma (HCC). Several studies reported that different gross types require different resection margins. We investigated the changes in the tumor microenvironment (TME) in different gross types of HCC. METHODS: We selected tumor tissue and normal tissue 1 and 2 cm away from the HCC. We analyzed the expression status of TME genes and the correlation between TME genes and the effective resection margin. We further divided the patients into two groups: group 1 included expanding and vaguely nodular types, whereas group 2 included nodular with perinodular extension, multinodular confluent, and infiltrative types. RESULTS: Group 2 showed 27% and 45% 5-year disease-free survival (DFS) and overall survival (OS) rates, respectively. Group 2 was a significant prognostic factor for DFS and OS. In cases with a resection margin of less than 1 cm or more than 2 cm, there were no differences in recurrence and survival rate between the two groups. Group 1 patients who had a resection margin that ranged from 1 to 2 cm showed significantly better DFS and OS rates. ß-Catenin and matrix metalloproteinase 9 expression was significantly decreased and that of E-cadherin was significantly increased according to the resection margin in group 1. CONCLUSIONS: Patients with expanding and vaguely nodular HCC may safely undergo surgical resection with a narrow resection margin, and patients with the other gross types must undergo surgical resection with more than a 2-cm resection margin because of their TME conditions.

Improved detection of hepatocellular carcinoma by dynamic computed tomography in cirrhotic patients with chronic hepatitis B: A multicenter study.

BACKGROUND AND AIMS: Current guidelines for chronic hepatitis B (CHB) patients are to undergo surveillance for hepatocellular carcinoma (HCC) with 6-monthly ultrasonography (US). However, sensitivities of US to detect early-stage HCC in cirrhotic patients are suboptimal. We aimed to compare overall survival and detection rates of very-early-stage HCC in two groups: group A, undergoing 6-monthly US versus group B, undergoing 6-monthly US alternating with dynamic computed tomography (CT). METHODS: This retrospective multicenter study assessed 1235 cirrhotic patients with CHB under entecavir/tenofovir therapy from 2007 to 2016. The primary endpoint was overall survival rates between the two groups. The Cox proportional hazards model and propensity score matching analyses were used to assess the effect of surveillance modalities on overall survival and detection of Barcelona Clinic Liver Cancer stage 0 HCC after balancing. RESULTS: During a median follow-up of 4.5 years, 10-year cumulative HCC incidence rates of 16.3% were significantly higher in group B (n = 576) than 13.7% in group A (n = 659; P < 0.001). However, in patients with HCC, 10-year overall survival rates of 85.1% were significantly higher in group B than 65.6% in group A (P = 0.001 by log-rank test). CT exam alternating with US was independently associated with reduced overall mortality (hazard ratio 0.47, P = 0.02). Cumulative incidence of Barcelona Clinic Liver Cancer stage 0 HCC was significantly higher in group B than in group A (hazard ratio 2.82, P < 0.001). CONCLUSION: In cirrhotic patients with CHB, dynamic CT exam alternating with US led to higher detection rates of very-early-stage HCC and benefit of overall survival than did US exams.

Application of Baveno Criteria and Modified Baveno Criteria with Shear-wave Elastography in Compensated Advanced Chronic Liver Disease.

BACKGROUND: We aimed to validate Baveno VI and expanded Baveno VI criteria using two dimensional shear-wave elastography (2D-SWE) in compensated advanced chronic liver disease (cACLD) patients with alcohol as the main etiology. METHODS: Clinical data from 305 patients with cACLD who underwent a liver stiffness measurement (LSM) with 2D-SWE and endoscopy were consecutively collected. RESULTS: Among 305 patients, high-risk varix (HRV) was identified in 21.3% (n = 65). The main etiology was alcoholic liver disease (51.8%), followed by hepatitis B virus (29.8%) and hepatitis C virus (9.1%). Baveno VI criteria spared endoscopy in 118 of the 305 (38.7%) patients, and 7 (5.9%) were missed with HRV. Expanded Baveno VI criteria spared more endoscopies (60.0%), but missed more HRV (9.8%) compared with Baveno VI criteria. The other classification described as the modified Baveno VI criteria were LSM < 25 kPa and PLT ≥ 150 × 10³/mm³. In total, 131 of the 305 (43.0%) patients were within the modified Baveno VI criteria, of whom seven (5.3%) had missed HRV. After adding spleen diameter < 12 cm to the modified Baveno VI criteria, the number of spared endoscopies increased by 106/305 (34.8%), with three (2.8%) presenting with HRV, indicating a risk of missing HRV. CONCLUSION: Baveno VI and expanded Baveno VI criteria with 2D-SWE were insufficient with an HRV miss rate of over 5%. The modified Baveno VI criteria with spleen diameters < 12 cm with 2D-SWE spared more endoscopies with a minimal risk of missing HRV in cACLD patients with alcohol as the main etiology.

Delphinidin enhances radio-therapeutic effects via autophagy induction and JNK/MAPK pathway activation in non-small cell lung cancer.

Delphinidin is a major anthocyanidin compound found in various vegetables and fruits. It has anti-oxidant, anti-inflammatory, and various other biological activities. In this study we demonstrated the anti-cancer activity of delphinidin, which was related to autophagy, in radiation-exposed non-small cell lung cancer (NSCLC). Radiosensitising effects were assessed in vitro by treating cells with a subcytotoxic dose of delphinidin (5 µM) before exposure to γ-ionising radiation (IR). We found that treatment with delphinidin or IR induced NSCLC cell death in vitro; however the combination of delphinidin pre-treatment and IR was more effective than either agent alone, yielding a radiation enhancement ratio of 1.54 at the 50% lethal dose. Moreover, combined treatment with delphinidin and IR, enhanced apoptotic cell death, suppressed the mTOR pathway, and activated the JNK/MAPK pathway. Delphinidin inhibited the phosphorylation of PI3K, AKT, and mTOR, and increased the expression of autophagy-induced cell death associated-protein in radiation-exposed NSCLC cells. In addition, JNK phosphorylation was upregulated by delphinidin pre-treatment in radiation-exposed NSCLC cells. Collectively, these results show that delphinidin acts as a radiation-sensitizing agent through autophagy induction and JNK/MAPK pathway activation, thus enhancing apoptotic cell death in NSCLC cells.

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

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