Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patient with chronic hepatitis B.

BACKGROUND AND AIM: Our study evaluated the outcomes of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in patients with chronic hepatitis B (CHB). We assessed viral and biochemical responses as well as changes in the estimated glomerular filtration rate (eGFR) and bone mineral density (BMD). METHODS: This retrospective multicenter study included CHB patients who achieved virologic response (VR) (HBV DNA < 20 IU/mL) while on TDF and were subsequently switched to TAF between April 2018 and October 2021. RESULTS: This study included 309 patients with a median age of 59 years, and 42.1% were male. The mean duration of TDF and TAF administration were 54.0 and 37.5 months, respectively. All patients maintained VR after switching to TAF. Alanine aminotransferase (ALT) normalization rate significantly increased 6 months after switching (74.8%-83.5%; P = 0.008). Adjusted eGFR significantly improved at 6 months (+5.55 ± 10.52 mL/min/1.73 m2; P < 0.001) and 12 months (+6.02 ± 10.70 mL/min/1.73 m2; P < 0.001) after switching. In the subgroup of patients with renal impairment (eGFR < 60 mL/min/1.73 m2), significant improvement in renal function was observed at 6 months (+0.6 ± 10.5 mL/min/1.73 m2; P < 0.001) and 12 months (+1.0 ± 10.7 mL/min/1.73 m2; P < 0.001) after switching to TAF. In patients with osteoporosis (n = 182), switching to TAF resulted in significant improvement in spine and hip BMD at 12 months, with increases of 9.7% (95% CI: 7.0-12.5) and 9.4% (95% CI: 7.0-11.8), respectively. CONCLUSION: In this real-world study, switching to TAF was effective and safe in patients, with notable improvements in ALT levels, renal function, and BMD.

Reduced Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Receiving Long-Term Besifovir Therapy.

No information is available regarding the influence of besifovir (BSV), a new nucleotide analogue, on the occurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study evaluated the reduced risk of HCC in patients undergoing BSV treatment. A total of 188 patients with CHB were treated with BSV for up to 8 years. We prospectively assessed the incidence of HCC compared with the risk from prediction models. During the follow-up, 5 patients developed HCC: 1 of 139 patients with non-cirrhotic CHB, and 4 of 49 patients with liver cirrhosis. We compared the HCC incidence in non-cirrhotic and cirrhotic patients with the predicted number derived from the REACH-B (risk estimation for HCC in CHB) model and GAG-HCC (guide with age, gender, HBV DNA, core promotor mutation, and cirrhosis) model, respectively. The standardized incidence ratio (SIR) was 0.128 (p = 0.039) at 7 years in non-cirrhotic CHB patients, and the SIR was 0.371 (p = 0.047) at 7.5 years in cirrhotic patients, suggesting a significantly decreased HCC incidence in both groups. HCC prediction was available for BSV-treated patients using existing models. In conclusion, BSV decreased the risk of HCC in patients with CHB, and prediction models were applicable. Clinical trial registry website and trial number: ClinicalTrials.gov no: NCT01937806.

A Real-World Comparative Analysis of Atezolizumab Plus Bevacizumab and Transarterial Chemoembolization Plus Radiotherapy in Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombosis.

This study aimed to compare the treatment outcomes of atezolizumab-plus-bevacizumab (Ate/Bev) therapy with those of transarterial chemoembolization plus radiotherapy (TACE + RT) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) and without metastasis. Between June 2016 and October 2022, we consecutively enrolled 855 HCC patients with PVTT. After excluding 758 patients, 97 patients (n = 37 in the Ate/Bev group; n = 60 in the TACE + RT group) were analyzed. The two groups showed no significant differences in baseline characteristics and had similar objective response and disease control rates. However, the Ate/Bev group showed a significantly higher one-year survival rate (p = 0.041) compared to the TACE + RT group, which was constantly displayed in patients with extensive HCC burden. Meanwhile, the clinical outcomes were comparable between the two groups in patients with unilobar intrahepatic HCC. In Cox-regression analysis, Ate/Bev treatment emerged as a significant factor for better one-year survival (p = 0.049). Finally, in propensity-score matching, the Ate/Bev group demonstrated a better one-year survival (p = 0.02) and PFS (p = 0.01) than the TACE + RT group. In conclusion, Ate/Bev treatment demonstrated superior clinical outcomes compared to TACE + RT treatment in HCC patients with PVTT. Meanwhile, in patients with unilobar intrahepatic HCC, TACE + RT could also be considered as an alternative treatment option alongside Ate/Bev therapy.

Association between serum tumor necrosis factor-α and sarcopenia in liver cirrhosis.

BACKGROUND/AIMS: Sarcopenia is an independent prognostic factor of liver cirrhosis (LC). However, the association between LC-related systemic inflammation and sarcopenia is unclear. METHODS: Sprague-Dawley rats were treated with thioacetamide (TAA) or saline as a control. Rifaximin was administered to TAA-induced LC rats. Enzyme-linked immunosorbent assay was performed to measure inflammatory mediators in rat serum. RT-PCR was performed to measure the molecular expression in tissues. Hematoxylin and eosin (H&E) staining and immunohistochemistry were performed to investigate tissue pathology. Serum tumor necrosis factor-α levels, liver stiffness (LS), and the L3 skeletal muscle index (L3SMI) were measured in 60 patients with chronic liver disease. RESULTS: LC and sarcopenia were successfully induced by TAA. Serum TNF-α levels were increased in LC rats and correlated with myostatin expression, muscle weight, and myofiber diameter. The expression of intestinal occludin and zona occludens-1 was reduced in LC rats and associated with serum TNF-α levels and sarcopenia. In patients with LS ≥7 kPa or sarcopenia, serum TNF-α levels were significantly increased, which was also confirmed when we raised the LS cutoff to 10 kPa. The L3SMI was inversely correlated with serum TNF-α levels in patients with LS ≥7 kPa. TNF-α was reduced by rifaximin, which might have resulted in reduced expression of muscular MuRF1 and myostatin and improvements in myofiber diameters within muscle tissues. CONCLUSION: These results suggest that serum TNF-α is associated with LC-related sarcopenia. Rifaximin might be effective in reducing serum TNF-α levels and improving sarcopenia in LC, but these results need to be validated in future studies.

Prediction of Hepatocellular Carcinoma by On-Therapy Response of Noninvasive Fibrosis Markers in Chronic Hepatitis B.

INTRODUCTION: Antiviral therapy improves hepatic fibrosis and reduces hepatocellular carcinoma (HCC) incidence. This study aimed to evaluate whether on-therapy changes in scores for fibrosis index based on 4 factors and aspartate aminotransferase-to-platelet ratio index are associated with HCC development and establish an HCC risk score model incorporating noninvasive fibrosis marker (NFM) response. METHODS: This multicenter study recruited 5,147 patients with chronic hepatitis B (4,028 for derivation cohort and 1,119 for validation cohort) who were given entecavir/tenofovir for >12 months between 2007 and 2018. A risk prediction model for HCC was developed using predictors based on multivariable Cox models, and bootstrapping was performed for validation. RESULTS: The 10-year cumulative HCC incidence rates were 12.6% and 13.7% in the derivation and validation cohorts, respectively. The risk of HCC significantly differed with early NFM response, with a marked reduction in HCC risk in patients achieving a significant decrease in NFM by 12 months (P < 0.001). NFM response, sex, age, and cirrhosis were independently predictive of HCC. We developed the Fibrosis marker response, Sex, Age, and Cirrhosis (FSAC) score based on regression coefficients of each variable. For the 10-year prediction of HCC, FSAC showed higher C-index values than PAGE-B, modified PAGE-B, CU-HCC, and REACH-B (0.84 vs 0.77, 0.80, 0.77, and 0.67, respectively; all P < 0.005). The predictive performance of FSAC was corroborated in the validation cohort, with higher C-index than other models (all P < 0.050). DISCUSSION: On-therapy changes in NFM are an independent indicator of HCC risk. FSAC incorporating NFM response is a reliable risk score for risk estimation for HCC with better performance than other models.

Acute gastric injury after ingestion of substrate with hyperosmolar glucose and benzoate inversely related with small intestinal bacterial overgrowth.

BACKGROUND/AIMS: The occurrence of gastrointestinal symptoms and the presence of small intestinal bacterial overgrowth (SIBO) could be determined after ingestion of substrate with highly concentrated glucose for glucose breath test (GBT), after which endoscopic images for acute gastric injury have not been clarified. The aims of this study were to investigate the prevalence and relationship of acute gastric injury with SIBO after GBT. MATERIALS AND METHODS: A cohort of 235 patients with functional gastrointestinal symptoms undergoing breath test with 50 g glucose solution, immediately followed by upper endoscopy were surveyed. The acute gastric injury in endoscopic images and the GBT for hydrogen (H2) or methane (CH4) were assessed. RESULTS: The prevalence of acute gastric injury was 28.1% (66/235) after GBT. There were significant differences in GBT positivity (+) with and without gastric injury (25.8% vs 40.8%, p=0.03). In subtypes, GBT (H2) + was significantly lower in group with gastric injury than in the group without. No differences were seen in GBT (CH4) + between two groups. On multivariate analysis, the subtype of GBT (H2) + (Odds ratio (OR)=0.42; 95% Confidence interval (CI)=0.20-0.90; p=0.03) inversely and female (OR=2.11; 95% CI=1.11-4.00; p=0.02) were significantly related with gastric injury. Whereas gastric injury was the only independent related factor for GBT + inversely (OR=0.51; 95% CI=0.27-0.97; p=0.04). CONCLUSION: Highly concentrated glucose might provoke acute gastric injury, which could predict the absence of SIBO.

Effectiveness of sorafenib dose modifications on treatment outcome of hepatocellular carcinoma: Analysis in real-life settings.

Controlling adverse events (AEs) through dose reduction can enhance drug adherence and treatment response. Currently, there is no guide for sorafenib dosing. The aim of this study was to evaluate whether sorafenib dosing could affect treatment outcomes. A total of 782 hepatocellular carcinoma (HCC) patients treated with sorafenib were evaluated for sorafenib dosing and its modifications via medical records at baseline and regular follow-up. Study outcomes included progression-free survival (PFS), overall survival (OS), sorafenib duration, cumulative dose, AEs and drug discontinuation. The median patient survival was 7.7 months. Overall, 242 (30.9%) patients underwent dose reduction and 121 (17.5%) discontinued sorafenib due to AEs. In multivariate analysis, dose reduction was identified to be independently predictive of PFS and OS. The 800-to-400 mg/day group provided significantly better PFS than the 800 mg/day-maintained group or the 800-to-600 mg/day group. Likewise, the 800-to-400 mg/day group resulted in a significantly better OS than other dosing. However, dose reduction to 200 mg/day led to significantly worse PFS and OS. Hand-foot skin reaction and drug discontinuation due to AEs were higher in the 800-to-600 mg/day group than the 800-to-400 mg/day group. The 800-to-400 mg/day group had significantly longer treatment duration and higher cumulative dose than the 800 mg/day-maintained group. Sorafenib dose reduction can improve HCC survival and increase patient tolerance and adherence coupled with longer duration and higher cumulative dose. Dose reduction from 800 to 400 mg/day than to 600 mg/day is recommended when clinically warranted. However, dose reduction to 200 mg/day is not recommendable.

Efficacy and Safety of Tenofovir Disoproxil Fumarate in Treatment-Naïve Patients with Chronic Hepatitis B in Korea.

AIMS: To evaluate the efficacy and safety of 144-week tenofovir disoproxil fumarate (TDF) therapy in treatment-naïve chronic hepatitis B (CHB) patients in Korean. METHODS: In total, 579 treatment-naïve CHB patients at 11 medical centers were enrolled retrospective and prospective from September 2015 to January 2016 by design (NCT02533544). We evaluated the complete virologic response (CVR) rate and the renal safety of TDF. RESULTS: The overall CVR rate was 69.4%, 87.0%, and 89.7% at weeks 48, 96, and 144, respectively. In the HBeAg-positive CHB patients, the CVR rate at weeks 48, 96, and 144 was 61.4%, 83.1%, and 89.6%, respectively. The rates of HBeAg loss and seroconversion at weeks 48, 96, and 144 were 16.6%, 23.5%, 34.1%, and 7.6%, 8.9%, 13.3%, respectively. In HBeAg-negative CHB patients, the CVR rate at weeks 48, 96, and 144 was 82.5%, 93.2%, and 90.0%, respectively. The rate of alanine aminotransferase normalization was 36.9%, 45.4%, and 46.8% at weeks 48, 96, and 144, respectively. Of the CHB patients, 0.9% showed an elevated creatinine (> 0.5 mg/dL from baseline). Age (≥ 60 years) was significantly associated with a decline in renal function at week 144 (P < 0.0001). Comorbidities (diabetes or hypertension) showed the tendency to reduce renal function (P = 0.0624). Hepatocellular carcinoma developed in 10 (1.7%) patients and was related to cirrhosis. CONCLUSIONS: TDF therapy induced sustained viral suppression and had a favorable safety profile over a 3-year period. However, close monitoring of renal function should be mandatory in treating CHB patients receiving TDF, particularly older patients.

Clinical outcomes after the introduction of direct antiviral agents for patients infected with genotype 1b hepatitis C virus depending on the regimens: A multicenter study in Korea.

BACKGROUND: A real-life study is essential outside clinical trials. The aim is to evaluate the clinical outcomes of direct acting agents (DAA) for patients with chronic hepatitis C (CHC) in real practice. METHODS: We analyzed 590 consecutively enrolled patients with CHC-1b who received DAAs since 2015, when DAAs were introduced in Korea. The patients were checked for resistance-associated variants (RAV) against nonstructural protein 5A inhibitors and then daclatasvir/asunaprevir or sofosbuvir based regimens were chosen. RESULTS: The frequency of patients with cirrhosis and prior hepatocellular carcinoma (HCC) was 29.2% and 4.7%, respectively. For the RAV test, 10% were positive and in 3.6% the result was "indeterminate." Overall, 518 patients were treated with a 24-week regimen of daclatasvir/asunaprevir, 72 patients (RAV positive 75%) were treated with 12 weeks regimen of ledipasvir/sofosbuvir or daclatasvir/sofosbuvir. The SVR12 was 94.0% in the daclatasvir/asunaprevir, 98.2% in the ledipasvir/sofosbuvir, and 100% in the daclatasvir/sofosbuvir group. A total of 93.3% of SVR12 in the RAV-"indeterminate" patients was not difference 95.0% in the RAV-negative patients. Up to 1 year, de novo HCC occurrence and recurrence developed in 2.6% and 17.8%, respectively. HCC was more frequent in cirrhotic patients than in noncirrhotic patients (P = 0.000). α Fetoprotein (AFP) level at the end of treatment was a predicting factor for de novo HCC. CONCLUSIONS: Optimizing the choice of DAAs according to RAV test resulted in high SVR among CHC-1b Korean patients. This real practice multicenter cohort study suggests the importance of AFP and HCC surveillance in cirrhotic patients even after successful HCV therapy.

Positive Glucose Breath Tests in Patients with Hysterectomy, Gastrectomy, and Cholecystectomy.

BACKGROUND/AIMS: This study aimed to investigate the prevalence and characteristics of small intestinal bacterial overgrowth (SIBO) in patients undergoing abdominal surgeries, such as gastrectomy, cholecystectomy, and hysterectomy. METHODS: One hundred seventy-one patients with surgery (50 hysterectomy, 14 gastrectomy, and 107 cholecystectomy), 665 patients with functional gastrointestinal disease (FGID) and 30 healthy controls undergoing a hydrogen (H2)-methane (CH4) glucose breath test (GBT) were reviewed. RESULTS: GBT positivity (+) was significantly different among the surgical patients (43.9%), FGID patients (31.9%), and controls (13.3%) (p<0.01). With respect to the patients, 65 (38.0%), four (2.3%), and six (3.5%) surgical patients and 150 (22.6%), 30 (4.5%), and 32 (4.8%) FGID patients were in the GBT (H2)+, (CH4)+ and (mixed)+ groups, respectively (p<0.01). The gastrectomy group had a significantly increased preference in GBT+ (71.4% vs 42.0% or 41.1%, respectively) and GBT (H2)+ (64.3% vs 32.0% or 37.4%, respectively) compared with the hysterectomy or cholecystectomy groups (p<0.01). During GBT, the total H2 was significantly increased in the gastrectomy group compared with the other groups. CONCLUSIONS: SIBO producing H2 is common in abdominal surgical patients. Different features for GBT+ may be a result of the types of abdominal surgery.

Cudrania tricuspidata Stem Extract Induces Apoptosis via the Extrinsic Pathway in SiHa Cervical Cancer Cells.

The focus of this study is the anti-cancer effects of Cudrania tricuspidata stem (CTS) extract on cervical cancer cells. The effect of CTS on cell viability was investigated in HPV-positive cervical cancer cells and HaCaT human normal keratinocytes. CTS showed significant dose-dependent cytotoxic effects in cervical cancer cells. However, there was no cytotoxic effect of CTS on HaCaT keratinocytes at concentrations of 0.125-0.5 mg/mL. Based on this cytotoxic effect, we demonstrated that CTS induced apoptosis by down-regulating the E6 and E7 viral oncogenes. Apoptosis was detected by DAPI staining, annexin V-FITC/PI staining, cell cycle analysis, western blotting, RT-PCR, and JC-1 staining in SiHa cervical cancer cells. The mRNA expression levels of extrinsic pathway molecules such as Fas, death receptor 5 (DR5), and TNF-related apoptosis-inducing ligand (TRAIL) were increased by CTS. Furthermore, CTS treatment activated caspase-3/caspase-8 and cleavage of poly (ADP-ribose) polymerase (PARP). However, the mitochondrial membrane potential and expression levels of intrinsic pathway molecules such as Bcl-2, Bcl-xL, Bax, and cytochrome C were not modulated by CTS. Taken together, these results indicate that CTS induced apoptosis by activating the extrinsic pathway, but not the intrinsic pathway, in SiHa cervical cancer cells. These results suggest that CTS can be used as a modulating agent in cervical cancer.

Summary scores captured changes in subjects' QoL as measured by the multiple scales of the EORTC QLQ-C30.

OBJECTIVES: To examine the performance of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status/quality of life (QoL) scale and two summary scores to detect changes in the QoL profile over time, according to changes in the individual scales. STUDY DESIGN AND SETTING: Data came from 167 clinical trial patients with unresectable (advanced) hepatocellular carcinoma. The global health status/QoL scale of the questionnaire contained two items: overall health and overall QoL. Nordin and Hinz proposed summary scores for the questionnaire. A mixed-effect model was fitted to estimate trends in scores over time. RESULTS: Predominantly the individual scale scores declined over time; however, the global health status/QoL score was stable [rate of change = -0.3 per month; 95% confidence interval (CI): -1.2, 0.6]. Nordin's summary score, which gave equal weight to the 15 questionnaire scales, and Hinz's summary score, which gave equal weight to the 30 questionnaire items, showed a statistically significant decline over time, 3.4 (95% CI: -4.5, -2.4) and 4.2 (95% CI: -5.3, -3.0) points per month, respectively. CONCLUSION: In contrast to the global health status/QoL scale, the summary scores proposed by Nordin and Hinz detected changes in subjects' QoL profile described by the EORTC QLQ-C30 individual scales.

A comparative study between sorafenib and hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis.

BACKGROUND: The aim of this study was to compare the efficacy of hepatic arterial infusion chemotherapy (HAIC) and sorafenib in advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). METHODS: A total of 110 patients were observed between February 2008 and May 2013 in seven Korean centers. Fifty patients were treated with HAIC, and 60 patients were treated with sorafenib. RESULTS: The disease control rate in the HAIC was significantly higher than that in the sorafenib group (p < 0.001), although there was no significant difference in the objective response rate (p = 0.214). The median overall survival (OS) was significantly longer in the HAIC group than in the sorafenib group (7.1 vs. 5.5 months, p = 0.011). The median time to-progression (TTP) was also significantly longer in the HAIC group than in the sorafenib group (3.3 vs. 2.1 months, p = 0.034). In the multivariate analysis, tumor diameter (≥ 10 cm) and the absence of combined loco-regional treatment were significant prognostic factors influencing OS (p = 0.002 and p = 0.010, respectively) and TTP (p = 0.017 and p = 0.006, respectively). The treatment modality tended to be a significant prognostic factor for survival (p = 0.052), but not for tumor progression (p = 0.121). CONCLUSIONS: HAIC is comparable with sorafenib in terms of OS and TTP in advanced HCC patients with PVTT. HAIC shows more favorable treatment responses compared with sorafenib. Therefore, HAIC might be an alternative treatment modality to sorafenib in advanced HCC patients with PVTT.

Caspase-cleaved fragments of cytokeratin-18 as a marker of inflammatory activity in chronic hepatitis B virus infection.

BACKGROUND: The differential diagnosis between inactive carrier and active hepatitis is important in patients with chronic hepatitis B (CHB) virus infection. Serum cytokeratin (CK)-18 fragments (M30-antigen) are proposed as biomarkers of apoptosis. OBJECTIVES: We investigated whether serum M30-antigen levels might help to characterize the various phases of CHB and predict the state of significant inflammation in patients with CHB. STUDY DESIGN: A total of 339 CHB patients who underwent liver biopsy, were included. Serum M30-antigen levels were compared between inactive carriers (n=21), patients with HBeAg-negative hepatitis (n=95), HBeAg-positive hepatitis (n=141) and liver cirrhosis (n=82). RESULTS: Serum M30-antigen levels were correlated significantly not only with AST (r=0.544, p<0.001) and ALT (r=0.315, p<0.001) and but also inflammatory grading score on liver biopsy (r=0.240, p<0.001). Serum M30-antigen level in HBeAg-negative CHB was significantly higher than that of inactive HBV carrier (399.78 U/L vs 148.90 U/L, p<0.001). Multivariate analysis showed that AST (p<0.001), albumin (p=0.009) and M30-antigen (p=0.020) were the independent predictors of significant inflammation. Combined serum M30-antigen level (>344 U/L) and AST (>78 IU/L) measurement provided the most accurate identification of significant inflammation, showing 38.2% sensitivity, 96.1% specificity, 91.0% positive predictive value and 56.1% negative predictive value. CONCLUSIONS: Serum M30-antigen can be a predictive marker for distinguishing between inactive carrier and HBeAg-negative CHB. Serum M30 levels are associated with the presence of significant inflammation, especially in patients with normal or minimally elevated ALT in CHB patients.

Noninvasive predictors of nonalcoholic steatohepatitis in Korean patients with histologically proven nonalcoholic fatty liver disease.

BACKGROUND/AIMS: The aims of this study were (1) to identify the useful clinical parameters of noninvasive approach for distinguishing nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver disease (NAFLD), and (2) to determine whether the levels of the identified parameters are correlated with the severity of liver injury in patients with NASH. METHODS: One hundred and eight consecutive patients with biopsy-proven NAFLD (age, 39.8±13.5 years, mean±SD; males, 67.6%) were prospectively enrolled from 10 participating centers across Korea. RESULTS: According to the original criteria for NAFLD subtypes, 67 patients (62.0%) had NASH (defined as steatosis with hepatocellular ballooning and/or Mallory-Denk bodies or fibrosis ≥2). Among those with NAFLD subtype 3 or 4, none had an NAFLD histologic activity score (NAS) below 3 points, 40.3% had a score of 3 or 4 points, and 59.7% had a score >4 points. Fragmented cytokeratin-18 (CK-18) levels were positively correlated with NAS (r=0.401), as well as NAS components such as lobular inflammation (r=0.387) and ballooning (r=0.231). Fragmented CK-18 was also correlated with aspartate aminotransferase (r=0.609), alanine aminotransferase (r=0.588), serum ferritin (r=0.432), and the fibrosis stage (r=0.314). A fragmented CK-18 cutoff level of 235.5 U/L yielded sensitivity, specificity, and positive and negative predictive values of 69.0%, 64.9%, 75.5% (95% CI 62.4-85.1), and 57.1% (95% CI 42.2-70.9), respectively, for the diagnosis of NASH. CONCLUSIONS: Serum fragmented CK-18 levels can be used to distinguish between NASH and NAFL. Further evaluation is required to determine whether the combined measurement of serum CK-18 and ferritin levels improves the diagnostic performance of this distinction.

Effect of ex vivo culture conditions on immunosuppression by human mesenchymal stem cells.

A microarray analysis was performed to investigate whether ex vivo culture conditions affect the characteristics of MSCs. Gene expression profiles were mainly influenced by the level of cell confluence rather than initial seeding density. The analysis showed that 276 genes were upregulated and 230 genes downregulated in MSCs harvested at ~90% versus ~50% confluence (P < 0.05, FC > 2). The genes that were highly expressed in MSCs largely corresponded to chemotaxis, inflammation, and immune responses, indicating direct or indirect involvement in immunomodulatory functions. Specifically, PTGES and ULBP1 were up-regulated in MSCs harvested at high density. Treatment of MSCs with PTGES or ULBP1 siRNA reversed their inhibition of T-cell proliferation in vitro. The culture conditions such as cell confluence at harvest seem to be important for gene expression profile of MSCs; therefore, the results of this study may provide useful guidelines for the harvest of MSCs that can appropriately suppress the immune response.

Fracture of Self-Expandable Metal Stent during Endoscopic Removal in Benign Biliary Stricture.

The endoscopic insertion of the self-expandable metal stent (SEMS) in benign biliary stricture has become an alternative to surgery. Fracture or migration of SEMS can occur rarely as complications. We report a case of fracture of SEMS during endoscopic retrieval in patients with chronic pancreatitis. In this case, broken stent was successfully removed with endoscopic ballooning of bile duct and with a snare device.

A practical scoring system for predicting cirrhosis in patients with chronic viral hepatitis.

BACKGROUND/AIMS: The purpose of the current study was to develop a simple model for predicting cirrhosis in chronic viral hepatitis patients and to evaluate the usefulness of decision tree algorithms. METHODOLOGY: Serum markers of fibrosis were compared with the stage of fibrosis in liver biopsy specimens prospectively obtained from 526 subjects with chronic HBV and HCV infections (estimation set, 367; validation set, 159). RESULTS: Univariate analysis revealed that age, bilirubin, platelet count, APRI, ALP, hyaluronic acid (HA), α2-macroglobulin, MMP-2, TIMP-1, and procollagen III N-terminal peptide (PIIINP) were significantly different between patients with (F4) and without cirrhosis (F0123). Multivariate logistic regression analysis identified platelet count, HA and PIIINP as independent predictors of cirrhosis. We categorized the individual variable into the most appropriate cut-off value by calculating the likelihood ratio for predicting cirrhosis and constructed a score system expressed by the following simple formula: PHP index = platelet score + HA score + PIIINP score. For predicting cirrhosis, the area under the receiver operating characteristic curve (AUROC) was 0.824 and 0.759 in the estimation and validation set, respectively. Using a cut-off score of 4, the presence of cirrhosis was predicted with high accuracy. The diagnostic performance of the PHP index was similar to decision tree algorithms (AUROC=0.819) for predicting liver cirrhosis, but more useful in clinical situations. CONCLUSIONS: Compared to a decision tree model, a simple score system using a categorized value based on a combination of platelet count, HA and PIIINP identified patients with liver cirrhosis with a higher clinical usability.

Establishment of a bioluminescent imaging-based in vivo leukemia model by intra-bone marrow injection.

In vivo leukemia mouse models are usually generated by intraperitoneal (IP) or intravenous (IV) injection of leukemia cells. However, the pattern of leukemia development observed can be inconsistent. This study investigated injection directly into bone marrow [intra-bone marrow transplantation (IBMT)], the natural microenvironment of leukemia. A bioluminescent imaging-based leukemia animal model has been established by direct injection of a bioluminescent leukemia cells (CCRF-CEM/fLuc) into NOD/SCID mouse tibia bone marrow and compared with models established by IP and IV routes. The comparison revealed that a bioluminescent in vivo leukemia model established via IBMT could recapitulate leukemia more faithfully and facilitate improved quantification of leukemia engraftment kinetics with a wider range of bioluminescent intensity than IP or IV. IBMT of bioluminescent leukemic cells allowed quantification of dose-dependent responses to anti-leukemic drugs, thus validating this model as a potential preclinical anti-leukemic drug screening system. IBMT-leukemia cells isolated from peripheral blood of the model mice and then injected into new recipients successfully established a second generation IBMT in vivo model and demonstrated the reproducibility of the model. Bioluminescent imaging-based analysis of this IBMT-leukemia model could provide a means for the comprehensive evaluation of treatment responses with enhanced sensitivity in preclinical studies.