Development and evaluation of two rapid lateral flow assays for on-site detection of African swine fever virus.

Introduction: African swine fever (ASF) is a lethal and highly contagious transboundary animal disease with the potential for rapid international spread. In the absence of a widely available and definitively proven vaccine, rapid and early detection is critical for ASF control. The quick and user-friendly lateral flow assay (LFA) can easily be performed by following simple instructions and is ideal for on-site use. This study describes the development and validation of two LFAs for the rapid detection of ASF virus (ASFV) in pig serum. Methods: The highly immunogenic antigens (p30 and p72) of ASFV Georgia 2007/1 (genotype II) were expressed in plants (Nicotiana benthamiana) and were used to immunize BALB/c mice to generate specific monoclonal antibodies (mAbs) against the p30 and p72 proteins. mAbs with the strongest binding ability to each protein were used to develop p30_LFA and p72_LFA for detecting the respective ASFV antigens. The assays were first evaluated using a spike-in test by adding the purified p30 or p72 protein to a serum sample from a healthy donor pig. Further validation of the tests was carried out using serum samples derived from experimentally infected domestic pigs, field domestic pigs, and feral pigs, and the results were compared with those of ASFV real-time PCR. Results: p30_LFA and p72_LFA showed no cross-reaction with common swine viruses and delivered visual results in 15 min. When testing with serially diluted proteins in swine serum samples, analytical sensitivity reached 10 ng/test for p30_LFA and 20 ng/test for p72_LFA. Using real-time PCR as a reference, both assays demonstrated high sensitivity (84.21% for p30_LFA and 100% for p72_LFA) with experimentally ASFV-infected pig sera. Specificity was 100% for both LFAs using a panel of PBS-inoculated domestic pig sera. Excellent specificity was also shown for field domestic pig sera (100% for p30_LFA and 93% for p72_LFA) and feral pig sera (100% for both LFAs). Conclusion: The results obtained in this study suggest that p30_LFA and p72_LFA hold promise as rapid, sensitive, user-friendly, and field-deployable tools for ASF control, particularly in settings with limited laboratory resources.

PAGE-B incorporating moderate HBV DNA levels predicts risk of HCC among patients entering into HBeAg-positive chronic hepatitis B.

BACKGROUND & AIMS: Recent studies reported that moderate HBV DNA levels are significantly associated with hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-positive, non-cirrhotic patients with chronic hepatitis B (CHB). We aimed to develop and validate a new risk score to predict HCC development using baseline moderate HBV DNA levels in patients entering into HBeAg-positive CHB from chronic infection. METHODS: This multicenter cohort study recruited 3,585 HBeAg-positive, non-cirrhotic patients who started antiviral treatment with entecavir or tenofovir disoproxil fumarate at phase change into CHB from chronic infection in 23 tertiary university-affiliated hospitals of South Korea (2012-2020). A new HCC risk score (PAGED-B) was developed (training cohort, n = 2,367) based on multivariable Cox models. Internal validation using bootstrap sampling and external validation (validation cohort, n = 1,218) were performed. RESULTS: Sixty (1.7%) patients developed HCC (median follow-up, 5.4 years). In the training cohort, age, gender, platelets, diabetes and moderate HBV DNA levels (5.00-7.99 log10 IU/ml) were independently associated with HCC development; the PAGED-B score (based on these five predictors) showed a time-dependent AUROC of 0.81 for the prediction of HCC development at 5 years. In the validation cohort, the AUROC of PAGED-B was 0.85, significantly higher than for other risk scores (PAGE-B, mPAGE-B, CAMD, and REAL-B). When stratified by the PAGED-B score, the HCC risk was significantly higher in high-risk patients than in low-risk patients (sub-distribution hazard ratio = 8.43 in the training and 11.59 in the validation cohorts, all p <0.001). CONCLUSIONS: The newly established PAGED-B score may enable risk stratification for HCC at the time of transition into HBeAg-positive CHB. IMPACT AND IMPLICATIONS: In this study, we developed and validated a new risk score to predict hepatocellular carcinoma (HCC) development in patients entering into hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) from chronic infection. The newly established PAGED-B score, which included baseline moderate HBV DNA levels (5-8 log10 IU/ml), improved on the predictive performance of prior risk scores. Based on a patient's age, gender, diabetic status, platelet count, and moderate DNA levels (5-8 log10 IU/ml) at the phase change into CHB from chronic infection, the PAGED-B score represents a reliable and easily available risk score to predict HCC development during the first 5 years of antiviral treatment in HBeAg-positive patients entering into CHB. With a scoring range from 0 to 12 points, the PAGED-B score significantly differentiated the 5-year HCC risk: low <7 points and high ≥7 points.

Identification of patients with favorable prognosis after resection in intermediate-stage-hepatocellular carcinoma.

BACKGROUNDS: It is unclear which patients benefit from resection in intermediate-stage-hepatocellular carcinoma (HCC). The authors aimed to identify high-risk patients for early recurrence among patients with resectable intermediate-stage HCC. METHODS: This multicenter retrospective study included patients who underwent resection or trans-arterial chemoembolization (TACE) for intermediate-stage HCC (2008-2019). Multivariable Cox proportional analysis was performed to identify high-risk patients when treated with resection. A prediction score for 2-year recurrence-free survival (RFS) was developed using the training cohort and validated. The 2-year RFS in each risk group was compared with that in TACE group, after propensity score matching (PSM). RESULTS: A total of 1686 patients were included (480 and 1206 patients in the resection and TACE groups). During a median follow-up of 31.4 months, the 2-year RFS was significantly higher in the resection (47.7%) than in the TACE group (19.8%) [adjusted hazard ratio (aHR)=1.471, 95% CI: 1.199-1.803, P <0.001). On multivariate analysis, alpha-fetoprotein ≥5.0 ng/ml (aHR=0.202), ALBI grade ≥2 (aHR=0.709), tumor number ≥3 (aHR=0.404), and maximal tumor size ≥5 cm (aHR=0.323) were significantly associated with the lower risk of 2-year RFS in the resection group. The newly developed Surgery Risk score in BCLC-B (SR-B score) with four significant risk factors showed an area under the curve of 0.801 for the 2-year RFS and was validated. Based on the SR-B score, low-risk patients had a significantly higher 2-year RFS (training: aHR=5.834; validation: aHR=5.675) than high-risk patients (all P <0.001) did. In a PSM cohort, a low-risk resection group had a significantly higher (aHR=3.891); a high-risk resection group had a comparable 2-year RFS to those treated with TACE (aHR=0.816). CONCLUSIONS: Resection may be beneficial for resectable intermediate-stage HCC based on the SR-B score.

Bioreducible exosomes encapsulating glycolysis inhibitors potentiate mitochondria-targeted sonodynamic cancer therapy via cancer-targeted drug release and cellular energy depletion.

Nanocarrier-assisted sonodynamic therapy (SDT) has shown great potential for the effective and targeted treatment of deep-seated tumors by overcoming the critical limitations of sonosensitizers. However, in vivo SDT using nanocarriers is still constrained by their intrinsic toxicity and nonspecific cargo release. In this study, we developed bioreducible exosomes for the safe and tumor-specific delivery of mitochondria-targeting sonosensitizers [triphenylphosphonium-conjugated chlorin e6 (T-Ce6)] and glycolysis inhibitors (FX11). Redox-cleavable diselenide linker-bearing lipids were embedded into exosomes to trigger drug release in response to overexpressed glutathione in the tumor microenvironment. Bioreducible exosomes facilitate the cytoplasmic release of their payload in the reducing environment of tumor cells. They significantly enhance drug release and sonodynamic effects when irradiated with ultrasound (US). The mitochondria-targeted accumulation of T-Ce6 efficiently damaged the mitochondria of the cells under US irradiation, accelerating apoptotic cell death. FX11 substantially inhibited cellular energy metabolism, potentiating the antitumor efficacy of mitochondria-targeted SDT. Bioreducible exosomes effectively suppressed tumor growth in mice without significant systemic toxicity, via a combination of mitochondria-targeted SDT and energy metabolism-targeted therapy. This study offers new insights into the use of dual stimuli-responsive exosomes encapsulating sonosensitizers for safe and targeted sonodynamic cancer therapy.

Piezocatalytic 2D WS2 Nanosheets for Ultrasound-Triggered and Mitochondria-Targeted Piezodynamic Cancer Therapy Synergized with Energy Metabolism-Targeted Chemotherapy.

Piezoelectric nanomaterials that can generate reactive oxygen species (ROS) by piezoelectric polarization under an external mechanical force have emerged as an effective platform for cancer therapy. In this study, piezoelectric 2D WS2 nanosheets are functionalized with mitochondria-targeting triphenylphosphonium (TPP) for ultrasound (US)-triggered, mitochondria-targeted piezodynamic cancer therapy. In addition, a glycolysis inhibitor (FX11) that can inhibit cellular energy metabolism is loaded into TPP- and poly(ethylene glycol) (PEG)-conjugated WS2 nanosheet (TPEG-WS2 ) to potentiate its therapeutic efficacy. Upon US irradiation, the sono-excited electrons and holes generated in the WS2 are efficiently separated by piezoelectric polarization, which subsequently promotes the production of ROS. FX11-loaded TPEG-WS2 (FX11@TPEG-WS2 ) selectively accumulates in the mitochondria of human breast cancer cells. In addition, FX11@TPEG-WS2 effectively inhibits the production of adenosine triphosphate . Thus, FX11@TPEG-WS2 exhibits outstanding anticancer effects under US irradiation. An in vivo study using tumor-xenograft mice demonstrates that FX11@TPEG-WS2 effectively accumulated in the tumors. Its tumor accumulation is visualized using in vivo computed tomography . Notably, FX11@TPEG-WS2 with US irradiation remarkably suppresses the tumor growth of mice without systemic toxicity. This study demonstrates that the combination of piezodynamic therapy and energy metabolism-targeted chemotherapy using mitochondria-targeting 2D WS2 is a novel strategy for the selective and effective treatment of tumors.

Outcome of Intermittent Thoracentesis versus Pigtail Catheter Drainage for Hepatic Hydrothorax.

Background/Aims: The management of hepatic hydrothorax (HH) remains a challenging clinical scenario with suboptimal options. We investigated the effect and safety of pigtail catheter drainage compared to intermittent thoracentesis. Methods: This multicenter, retrospective study included 164 cirrhotic patients with recurrent pleural effusion from March 2012 to June 2017. Patients with neoplasms, cardiopulmonary disease, and infectious conditions were excluded. We compared the clinical outcomes of pigtail catheter drainage versus thoracentesis for variables including complications related to procedures, overall survival, and re-admission rates. Results: A total of 164 patients were divided into pigtail catheter (n = 115) and thoracentesis (n = 49) groups. During the follow-up period of 6.93 months after discharge, 98 patients died (pigtail; n = 47 vs. thoracentesis; n = 51). The overall survival (p = 0.61) and 30-day mortality (p = 0.77) rates were similar between the pigtail catheter and thoracentesis groups. Only MELD scores were associated with overall survival (adjusted HR, 1.08; p < 0.01) in patients with HH. Spontaneous pleurodesis occurred in 59 patients (51.3%) in the pigtail catheter group. Re-admission rates did not differ between the pigtail catheter and thoracentesis groups (13.2% vs 19.6% p = 0.7). A total of five complications occurred, including four total cases of bleeding (one patient in the pigtail catheter group and three in the thoracentesis group) and one case of empyema in the pigtail catheter group. Conclusions: Pigtail catheter drainage is not inferior to that of intermittent thoracentesis for the management of HH, proving it may be an effective and safe clinical option.

De novo selected hACE2 mimics that integrate hotspot peptides with aptameric scaffolds for binding tolerance of SARS-CoV-2 variants.

The frequent occurrence of viral variants is a critical problem in developing antiviral prophylaxis and therapy; along with stronger recognition of host cell receptors, the variants evade the immune system-based vaccines and neutralizing agents more easily. In this work, we focus on enhanced receptor binding of viral variants and demonstrate generation of receptor-mimicking synthetic reagents, capable of strongly interacting with viruses and their variants. The hotspot interaction of viruses with receptor-derived short peptides is maximized by aptamer-like scaffolds, the compact and stable architectures of which can be in vitro selected from a myriad of the hotspot peptide-coupled random nucleic acids. We successfully created the human angiotensin-converting enzyme 2 (hACE2) receptor-mimicking hybrid ligand that recruits the hACE2-derived receptor binding domain-interacting peptide to directly interact with a binding hotspot of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Experiencing affinity boosting by ~500% to Omicron, the de novo selected hACE2 mimic exhibited a great binding tolerance to all SARS-CoV-2 variants of concern.

Exercise reduces the risk of chronic kidney disease in individuals with nonalcoholic fatty liver disease: A nationwide cohort study.

AIMS: Recent studies of individuals with nonalcoholic fatty liver disease (NAFLD) have indicated benefits of exercise in improving outcomes. We investigated whether exercise reduces the risk of chronic kidney disease (CKD) in individuals with NAFLD. METHODS: A total of 7275 participants from the Korea National Health and Nutrition Examination Survey (KNHANES) cohort, and 40,418 participants with NAFLD from the National Health Insurance Service (NHIS) cohort were included for the cross-sectional and longitudinal analyses, respectively. For the cross-sectional analysis, the primary outcome was prevalent CKD, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. For the longitudinal analysis, the primary outcome was incident CKD, defined as the occurrence of eGFR <60 mL/min/1.73m2 or proteinuria (≥ trace) on two consecutive measurements during follow-up. RESULTS: In the KNHANES cohort, prevalent CKD was observed in 229 (6.1%), 48 (2.6%), and 36 (2.1%) participants in the 0, 1-2, and ≥ 3 exercise sessions/week groups, respectively. The likelihood of prevalent CKD was lowest in participants allocated to the ≥ 3 sessions/week group (adjusted OR 0.49; 95% CI, 0.33-0.71; P < 0.001). During a median follow-up of 5.0 years in the NHIS cohort, incident CKD occurred in 1,047 (9.7/1,000 person-years), 188 (7.3/1,000 person-years), and 478 (7.4/1,000 person-years) participants in the 0, 1-2, and ≥ 3 sessions/week groups, respectively. The risk of incident CKD was lowest in participants allocated to the ≥ 3 sessions/week group (adjusted HR 0.85; 95% CI, 0.76-0.95; P = 0.004). CONCLUSIONS: Exercise was significantly associated with a reduced risk of both prevalent and incident CKD in individuals with NAFLD.

Toward a complete cure for chronic hepatitis B: Novel therapeutic targets for hepatitis B virus.

Hepatitis B virus (HBV) affects approximately 250 million patients worldwide, resulting in the progression to cirrhosis and hepatocellular carcinoma, which are serious public health problems. Although universal vaccination programs exist, they are only prophylactic and not curative. In the HBV life cycle, HBV forms covalently closed circular DNA (cccDNA), which is the viral minichromosome, in the nuclei of human hepatocytes and makes it difficult to achieve a complete cure with the current nucleos(t)ide analogs and interferon therapies. Current antiviral therapies rarely eliminate cccDNA; therefore, lifelong antiviral treatment is necessary. Recent trials for antiviral treatment of chronic hepatitis B have been focused on establishing a functional cure, defined by either the loss of hepatitis B surface antigen, undetectable serum HBV DNA levels, and/or seroconversion to hepatitis B surface antibody. Novel therapeutic targets and molecules are in the pipeline for early clinical trials aiming to cure HBV infection. The ideal strategy for achieving a long-lasting functional or complete cure might be using combination therapies targeting different steps of the HBV life cycle and immunomodulators. This review summarizes the current knowledge about novel treatments and combination treatments for a complete HBV cure.

Metformin and Dichloroacetate Suppress Proliferation of Liver Cancer Cells by Inhibiting mTOR Complex 1.

The Warburg effect is important for cancer cell proliferation. This phenomenon can be flexible by interaction between glycolysis and mitochondrial oxidation for energy production. We aimed to investigate the anticancer effects of the pyruvate dehydrogenase kinase inhibitor, dichloroacetate (DCA) and the mitochondrial respiratory complex I inhibitor metformin in liver cancer cells. The anticancer effect of DCA and/or metformin on HepG2, PLC/PRF5 human liver cancer cell lines, MH-134 murine hepatoma cell lines, and primary normal hepatocytes using MTT assay. Inhibition of lactate/ATP production and intracellular reactive oxygen species generation by DCA and metformin was investigated. Inhibition of PI3K/Akt/mTOR complex I was evaluated to see whether it occurred through AMPK signaling. Anticancer effects of a combination treatment of DCA and metformin were evaluated in HCC murine model. The results showed that metformin and DCA effectively induced apoptosis in liver cancer cells. A combination treatment of metformin and DCA did not affect viability of primary normal hepatocytes. Metformin upregulated glycolysis in liver cancer cells, thereby increasing sensitivity to the DCA treatment. Metformin and DCA inhibited mTOR complex I signaling through upregulated AMPK-independent REDD1. In addition, metformin and DCA increased reactive oxygen species levels in liver cancer cells, which induced apoptosis. A combination treatment of metformin and DCA significantly suppressed the tumor growth of liver cancer cells using in vivo xenograft model. Taken together, the combined treatment of metformin and DCA suppressed the growth of liver cancer cells. This strategy may be effective for patients with advanced liver cancer.

Association of Physical Activity with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B.

BACKGROUND AND AIMS: In the general population, previous studies reported that physical activity was associated with risk of hepatocellular carcinoma (HCC) development. However, it is unclear whether physical activity is associated with risk of HCC development in patients with chronic hepatitis B (CHB). We aimed to elucidate the association between physical activity and risk of HCC development in CHB patients. METHODS: This nationwide cohort study involved treatment-naive patients with CHB (n = 9727) who started treatment with entecavir or tenofovir and answered self-reported questionnaires between January 2012 and December 2017, using data from the Korean National Health Insurance Service database. The primary endpoint was development of HCC. Multivariable Cox regression and competing risk analyses were used. RESULTS: During a median follow-up of 3.1 years, cumulative HCC incidence rates were 8.3%. There was an inverse association between physical activity and the risk of HCC (p < 0.001). Patients with 1000-1500 metabolic equivalent task (MET)-min/week, compared to those without physical activity, showed a significantly lower risk of HCC in both patients without cirrhosis (adjusted hazard ratio [aHR] 0.66, p = 0.02) and patients with cirrhosis (aHR 0.61, p = 0.02). In patients who were younger (<60), male, without diabetes, and with high BMI, amounts of physical activity of 1000-1500 MET-min/week showed an inverse association with the risk of HCC (aHR 0.65, 0.63, 0.65, and 0.64, respectively, all p < 0.05). CONCLUSION: Physical activity was significantly associated with a low risk of HCC in CHB patients treated with entecavir or tenofovir.

The FIB-4 Index Is a Useful Predictor for the Development of Hepatocellular Carcinoma in Patients with Coexisting Nonalcoholic Fatty Liver Disease and Chronic Hepatitis B.

BACKGROUND: The FIB-4 index, a noninvasive tool (FIB-4 index = age × aspartate transaminase (AST)/(platelet count × âˆšalanine aminotransferase (ALT)), is a useful assessment for liver fibrosis. Patients with a high FIB-4 index were reported to have a high risk of developing hepatocellular carcinoma (HCC). This study analyzed the clinical association of the FIB-4 index with HCC development in patients with coexisting nonalcoholic fatty liver disease and chronic hepatitis B (NAFLD-CHB). METHODS: This retrospective study analyzed 237 consecutive patients with NAFLD-CHB between January 2006 and December 2010 at the National Police Hospital in Korea. Patients with HCC at baseline and those diagnosed with HCC within 6 months from baseline were excluded. Propensity score matching analysis (PSM) was adopted to balance the baseline characteristics between patients with low and high FIB-4 index values. The cumulative rates of HCC development were compared between the two groups using the Kaplan-Meier method in the matched population. RESULTS: The median follow-up duration was 13 years (interquartile range, 8.2-15.7). The optimal cutoff for the FIB-4 index of 1.77 was calculated based on the maximum Youden index value, with an AUC of 0.70. Among a total of 237 patients with NAFLD-CHB, HCC developed in 20 patients (8.4%) (14 of the 90 patients with a high FIB-4 index vs. 6 of the 147 patients (4.1%) with a low FIB-4 index; log-rank p = 0.003). Patients with a high FIB-4 index had a significantly and independently higher risk of HCC than those with a low FIB-4 index (adjusted hazard ratio, 4.35; 95%; confidence interval, 1.42-13.24; log-rank test, p = 0.006). CONCLUSION: A high FIB-4 index (≥1.77) might be a useful marker for predicting the development of HCC in patients with NAFLD-CHB.

Individualized surveillance of chronic hepatitis B patients according to hepatocellular carcinoma risk based on PAGE-B scores.

BACKGROUND AND AIMS: Current guidelines for chronic hepatitis B (CHB) patients are to undergo surveillance for hepatocellular carcinoma (HCC) with 6-month ultrasonography. We aimed to compare detection rates of very-early-stage HCC in two groups: group A, undergoing 6-month ultrasonography versus group B, undergoing 6-month ultrasonography alternating with dynamic computed tomography (CT). METHODS: This retrospective study assessed 2151 CHB patients under entecavir/tenofovir therapy from 2007 to 2016. Detection rates of very-early-stage HCC were compared between groups A/B at intermediate/high risk based on platelets, age, gender-hepatitis B scores. The primary endpoint was the proportion of patients in each group with very-early-stage HCC. Cox proportional hazards model was used to assess the effect of surveillance modalities to detect very-early-stage HCC. RESULTS: Five-year cumulative HCC incidence rates in group A were 15.0% not significantly different from 18.2% in group B at high risk (P = 0.17). Detection rates of very-early-stage HCC were significantly higher in group B than in group A (P < 0.001), and surveillance using CT alternating with ultrasonography was significantly associated with detection of very-early-stage HCC (hazard ratio 3.89, P < 0.001). Among intermediate-risk patients, difference between detection rates of very-early-stage HCC in groups A and B was not significant (P = 0.30), and surveillance using CT alternating with ultrasonography was not significantly associated with detection of very-early-stage HCC (hazard ratio 1.61, P = 0.23). CONCLUSION: In high-risk CHB patients, surveillance using CT alternating with ultrasonography led to higher detection rates of very-early-stage HCC compared to surveillance using ultrasonography.

Serum Myostatin Predicts the Risk of Hepatocellular Carcinoma in Patients with Alcoholic Cirrhosis: A Multicenter Study.

Background and Aim: Previous studies reported that serum myostatin is associated with sarcopenia. We aimed to elucidate the association between serum myostatin levels and hepatocellular carcinoma (HCC) development in patients with alcoholic liver cirrhosis (ALC). Methods: This retrospective, multicenter study assessed 1077 Asian ALC patients enrolled from 2007 to 2017. The primary endpoint was the development of HCC within 5 years. Cox proportional hazards model analyses were used to assess the association of serum myostatin levels and HCC development. The time-dependent areas under the receiver operating characteristic curve (AUROC) of serum myostatin for 5-year HCC development were calculated. Serum myostatin levels were measured using an enzyme-linked immunosorbent assay with samples collected on the index date. Results: During a median follow-up of 2.5 years, 5-year cumulative HCC incidence rates were 6.7% in the total population. The median level of serum myostatin was 3.3 ng/mL (interquartile, 2.1-5.2 ng/mL). The AUROC of serum myostatin for 5-year HCC development was 0.78 (95% confidence interval [CI], 0.76-0.81). In Cox proportional hazards model analyses, age, gender, platelet counts, and serum myostatin levels were independent risk factors for HCC development (adjusted hazard ratios [HRs] of age, male gender, platelet counts, and serum myostatin: 1.03, 2.79, 0.996, 1.18, respectively; all p < 0.05). Patients with high myostatin levels had a significantly higher risk of 5-year HCC development than those with low myostatin levels (HR 7.53, p < 0.001). Conclusion: Higher serum myostatin levels were significantly associated with a higher risk of developing HCC in ALC patients, which could identify high-risk patients who need stringent surveillance.

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.

Association between interstitial cells of Cajal and anti-vinculin antibody in human stomach.

Interstitial cells of Cajal (ICC) are known as the pacemaker cells of gastrointestinal tract, and it has been reported that acute gastroenteritis induces intestinal dysmotility through antibody to vinculin, a cytoskeletal protein in gut, resulting in small intestinal bacterial overgrowth, so that anti-vinculin antibody can be used as a biomarker for irritable bowel syndrome. This study aimed to determine correlation between serum anti-vinculin antibody and ICC density in human stomach. Gastric specimens from 45 patients with gastric cancer who received gastric surgery at Kangwon National University Hospital from 2013 to 2017 were used. ICC in inner circular muscle, and myenteric plexus were counted. Corresponding patient's blood samples were used to determine the amount of anti-vinculin antibody by enzyme-linked immunosorbent assay. Analysis was done to determine correlation between anti-vinculin antibody and ICC numbers. Patients with elevated anti-vinculin antibody titer (above median value) had significantly lower number of ICC in inner circular muscle (71.0 vs. 240.5, p = 0.047), and myenteric plexus (12.0 vs. 68.5, p < 0.01) compared to patients with lower anti-vinculin antibody titer. Level of serum anti-vinculin antibody correlated significantly with density of ICC in myenteric plexus (r = -0.379, p = 0.01; Spearman correlation). Increased level of circulating anti-vinculin antibody was significantly correlated with decreased density of ICC in myenteric plexus of human stomach.

Aspirin and the risk of hepatocellular carcinoma development in patients with alcoholic cirrhosis.

Aspirin therapy has shown protective effects against hepatocellular carcinoma (HCC) in preclinical studies. However, it is unclear whether aspirin therapy lowers the risk of HCC in patients with alcoholic cirrhosis.A retrospective analysis of data from 949 consecutive patients with alcoholic cirrhosis who abstained from alcoholic drinking was performed. The primary and secondary outcomes were development of HCC and gastrointestinal bleeding events, respectively. Risk was compared between patients with aspirin treatment and patients who were not treated (non-aspirin group) using a time-varying Cox proportional hazards model for total population and propensity score-matching analysis.The aspirin group included 224 patients and the non-aspirin group had 725 patients. During the study period of median duration of 3.1 years, 133 patients (13.6%) developed HCC. In time-varying Cox proportional analyses, the aspirin group showed a significantly lower risk of HCC (adjusted hazard ratio [aHR]: 0.13; 95% confidence interval [CI]: 0.08-0.21; P < .001). In propensity score-matched pairs, aspirin therapy significantly reduced the risk of HCC (aHR: 0.14; 95% CI: 0.09-0.22; P < .001). In bleeding risk, treatment with aspirin alone was not significantly associated with a higher bleeding risk (aHR: 0.81; 95% CI: 0.45-1.44; P = .46).Aspirin therapy was associated with the lower risk of HCC in patients with alcoholic cirrhosis.

The Model to Estimate Survival in Ambulatory Hepatocellular Carcinoma Patients Aids in the Decision for TACE Retreatment.

BACKGROUND/AIMS: Transarterial chemoembolization (TACE) is a major therapeutic modality for patients with unresectable hepatocellular carcinoma, which needs repeated treatments. Model to Estimate Survival in Ambulatory Hepatocellular carcinoma patients (MESIAH) was recently developed as a model for predicting survival. We aimed to develop a novel index for TACE retreatment using MESIAH scores. PATIENTS AND METHODS: From 2005 to 2008, 783 patients with hepatocellular carcinoma who had undergone 1 previous TACE procedure were enrolled. We calculated their pre-TACE and post-TACE-MESIAH and calculated the MESIAH ratio by dividing the post-TACE by pre-TACE score. The discriminatory abilities of the MESIAH ratio and post-TACE-MESIAH were compared with ART and ABCR scores. RESULTS: Among 783 patients, 355 (45.3%) received a second TACE (test set), and 195 (24.9%) patients received a third TACE treatment (validation set). In the test set, patients with a MESIAH ratio <0.9 obtained longer overall survival than patients with a MESIAH ratio ≥0.9 [26.0 vs. 9.0 mo, respectively; hazard ratio 1.66 (1.29-2.14)], and patients with a post-TACE-MESIAH<4.5 showed longer overall survival than patients with a post-TACE-MESIAH≥4.5 [38.0 vs. 7.0 mo, respectively; hazard ratio, 3.17 (2.45-4.09)]. The post-TACE-MESIAH [C-index 0.663 (0.628-0.697)] was better than the ART [C-index 0.596 (0.554-0.638)] and ABCR scores [C-index 0.576 (0.536-0.617)] at estimating prognosis. Our results were confirmed by the validation set. CONCLUSIONS: A MESIAH score ≥4.5 after TACE identifies patients with a poor prognosis. Randomized studies are needed to establish whether additional TACE may affect survival.