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Whether entecavir (ETV) or tenofovir alafenamide (TAF) is better at preventing hepatocellular carcinoma (HCC) development among patients with chronic hepatitis B (CHB) remains unclear. The present study was conducted to explore the ability of these two antivirals to prevent HCC. From 2012 to 2019, treatment-naive CHB patients undergoing ETV or TAF therapy were recruited at three academic teaching hospitals. The TAF group comprised patients starting TAF as first-line antiviral and those switching antivirals from tenofovir disoproxil fumarate to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded from the analysis. Cumulative probabilities of HCC were assessed using the Kaplan–Meier method. In total, 1810 patients (1525 and 285 in ETV and TAF groups, respectively) were recruited. The annual HCC incidence was statistically not different between the ETV and TAF groups (1.67 vs. 1.19 per 100 person-years, respectively) with an adjusted hazard ratio (HR) of 0.681 (p = 0.255), as determined by multivariate analysis. Male, hypertension, liver cirrhosis, FIB-4 index, and albumin were independent prognostic factors for HCC development. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results, with non-statistically different HCC incidence between the ETV and TAF groups (1.07 vs. 1.19 per 100 person-years (HR = 0.973; p = 0.953) and 1.67 vs. 1.89 per 100 person-years, respectively (HR = 0.949; p = 0.743). These findings suggest that ETV- and TAF-treated CHB patients have similar risk of developing HCC. Further studies with the larger sample size and longer follow-up are needed to validate these results.

HBeAg seroconversion is an important treatment endpoint. We aimed to identify predictors of seroconversion using serum HBsAg and hepatitis B core-related antigen (HBcrAg) in HBeAg-positive patients treated with nucleos(t)ide analogs (NAs). Data and samples from 70 HBeAg-positive patients treated with entecavir or tenofovir between January 2007 and December 2017 were retrospectively analysed. The mean follow-up period was 11 years. The predictive power for HBeAg seroconversion of HBcrAg levels at baseline and 2 years after antiviral therapy was determined using receiver operating curve analysis. Twenty-one patients (30%) achieved HBeAg seroconversion at a mean of 28 (range, 12-84) months after antiviral treatment. The median baseline HBcrAg and HBsAg levels were 6.9(5.7-7.0) vs. 5.8(5.5-6.5) log

Background/Aims: This study was performed to evaluate the efficacy of direct-acting antivirals (DAAs) in Korean patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) and to investigate the risk factors associated with HCC recurrence. Methods: A total of 100 patients with HCV-related HCC, who were treated with DAAs between May 2015 and December 2016, were recruited from seven university hospitals in Korea. Claim data of 526 patients with HCC obtained from the Health Insurance Review and Assessment Service in South Korea were used for external validation of the results. Results: Among the 100 patients, 88% achieved a sustained virological response (SVR) 12 weeks after the end of DAA therapy (SVR12), and 37% experienced HCC recurrence after DAA therapy. Short last HCC treatment durability (

Background Multiparametric US examination may have potential in the comprehensive evaluation of nonalcoholic fatty liver disease (NAFLD), but multicenter studies are lacking. Purpose To evaluate the diagnostic performance of multiparametric US with the attenuation coefficient (AC) from attenuation imaging (ATI) and liver stiffness (LS) and dispersion slope (DS) from two-dimensional (2D) shear-wave elastography (SWE) in a multicenter study of patients with NAFLD. Materials and Methods This prospective study enrolled consecutive participants between December 2019 and June 2021 with suspected nonalcoholic steatohepatitis (NASH) who were scheduled to undergo liver biopsy in five tertiary hospitals. Before the procedure, all participants underwent US with ATI and 2D SWE according to the study protocol. Multivariable linear regression analyses were performed to determine the significant determinant factors for AC, LS, and DS. Diagnostic performance was decided based on the areas under the receiver operating characteristic curve (AUCs). Results A total of 132 participants (median age, 38 years; IQR, 27-54 years; 69 women) were evaluated. Among the participant characteristics, including pathologic findings, demographic characteristics, body mass index, and serum markers, hepatic steatosis for AC (

To determine the technical success rates of MR elastography (MRE) according to established gradient-recalled echo (GRE) and spin-echo echo-planar imaging (SE-EPI) sequences and to compare liver stiffness (LS) values between the sequences during expiratory and inspiratory phases in patients with chronic liver disease or liver cirrhosis.One hundred and eight patients who underwent MRE were included in this retrospective study. MRE was performed at 3 T based on both sequences during expiration as well as inspiration. Technical failure of MRE was determined if there was no pixel value with a confidence index higher than 95% and/or no apparent shear waves imaged. LS measurements were performed using free-drawing region of interest. To evaluate clinical factors related to the technical success rate of MRE, we assessed etiology of liver disease, ascites, body habitus, iron deposition, and liver morphology of patients. Statistical analysis was performed with the Wilcoxon test, Bland-Altman plot, independent t test, Mann-Whitney test, and McNemar test.The technical success rate of MRE in SE-EPI was significantly higher than that of GRE (98.1% vs. 80.7%, p0.0001). On the basis of univariate analysis, height, weight, and BMI were significantly associated with failure of MRE (p0.05). There was no significant difference in LS values between GRE and SE-EPI (2.82 kPa vs. 2.92 kPa (p0.05)). However, the LS values were significantly higher during inspiration than expiration with both GRE and SE-EPI (p0.0001).MRE in SE-EPI during expiratory breath-hold can be used as a reliable examination to evaluate liver fibrosis.• The technical success rate of MR elastography in spin-echo echo-planar imaging (SE-EPI) was significantly higher than that in gradient-recalled echo (GRE) during both the inspiratory and expiratory phases. • Liver stiffness values were significantly higher during inspiration than during expiration in both GRE and SE-EPI. • MR elastography in SE-EPI during expiratory breath-hold can be used as a reliable examination in patients with liver fibrosis.

It is unclear whether tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) is more effective for preventing hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB). In this study, we compared the effectiveness of these two antiviral agents for preventing HCC. We included treatment-naive CHB patients undergoing antiviral therapy with TDF only (TDF group) or a TAF-based regimen (TAF group) at three academic teaching hospitals from 2012 to 2019. The TAF group included patients receiving TAF as first-line treatment and patients switching from TDF to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded. Cumulative probabilities of HCC were assessed using Kaplan-Meier methodology. In total, 2,117 patients were included: 1,832 in the TDF group and 285 in the TAF group. The annual HCC incidence was not significantly different between TDF and TAF groups: 1.66 vs. 1.19 per 100 person-years [PY], respectively (multivariate analysis: adjusted hazard ratio [HR] 0.774 [reference: TDF group]; p = .438). Male, liver cirrhosis, hepatitis B e antigen negativity, Fibrosis-4 index>3.25 and low albumin were independently associated with a higher risk of HCC. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results: 1.56 vs. 1.19 per 100 PY, respectively (HR 1.175; p = .708) and 1.66 vs. 1.29 per 100 PY, respectively (HR 0.888; p = .446). The risk of HCC development was not significantly different between TDF and TAF groups of CHB patients. Further studies with a larger sample size and longer follow-up are required to validate our results.

Sung Won Chung,1,* Min Kyung Park,1,* Young Youn Cho,1,2,* Youngsu Park,1 Cheol-Hyung Lee,1 Hyunwoo Oh,1 Heejoon Jang,1 Minseok Albert Kim,1 Sun Woong Kim,1 Joon Yeul Nam,1 Yun Bin Lee,1 Eun Ju Cho,1 Su Jong Yu,1 Hyo-Cheol Kim,3 Yoon Jun Kim,1 Jin Wook Chung,3 Jung-Hwan Yoon,1 Jeong-Hoon Lee1 1Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea; 2Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Korea; 3Department of Radiology, Seoul National University College of Medicine, Seoul, Korea*These authors contributed equally to this workCorrespondence: Jeong-Hoon LeeDepartment of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, KoreaTel +82-2-2072-2228Fax +82-2-743-6701Email pindra@empal.comBackground: Still in real-world practice, advanced hepatocellular carcinoma (HCC) patients are treated with transarterial chemoembolization (TACE). This study compared the therapeutic effectiveness of initial TACE treatment and initial sorafenib treatment in advanced HCC patients.Patient and Methods: Advanced HCC patients initially treated with sorafenib or TACE were included in this study. Treatment crossover due to an unfavorable response to initial treatment was allowed. Propensity score (PS) matching was applied for balancing baseline characteristics. The primary outcome was overall survival (OS) and the secondary outcomes included tumor response.Results: A total of 554 patients were included in this study: 85 were initially treated with sorafenib (the sorafenib-first group) and 469 with TACE (the TACE-first group). In the entire cohort, the TACE-first group was associated with lower risk of death [adjusted hazard ratio (HR)=0.75, P=0.04]. In the PS-matched cohort (85 patients per group), the TACE-first group showed longer OS than the sorafenib-first group in both univariable (HR=0.68, P=0.02) and multivariable analyses (adjusted HR=0.58, P=0.002). Specifically, within both the entire and the PS-matched cohorts, the TACE-first group showed longer OS in subgroups with major portal vein tumor thrombosis (HR=0.72, P=0.048; HR=0.52, P=0.003) or infiltrative HCC (HR=0.42, P< 0.001; HR=0.30, P=0.004, respectively). The objective response rate was higher in the TACE-first group (29.3% vs 14.7%, P=0.03) within the PS-matched cohort.Conclusion: For advanced HCC, initial TACE leads to longer OS with a more favorable tumor response than initial sorafenib treatment. Intrahepatic tumor control with initial locoregional therapy may be a potent strategy for advanced HCC.Keywords: liver cancer, transarterial therapy, locoregional therapy, tyrosine kinase inhibitor

Background/Aims: Tenofovir disoproxil fumarate (TDF) is potentially nephrotoxic in chronic hepatitis B patients. Hepatocellular carcinoma (HCC) patients treated using transarterial chemoembolization (TACE) are at an increased risk of renal injury. The aim of this study was to determine whether TDF is associated with more renal adverse events than entecavir (ETV) in HCC patients treated with TACE. Methods: In this retrospective single-center study, we selected 53 HCC patients who were treated with TDF from January 2012 to July 2013 and had their first TACE procedure in the same period. These patients were matched by age and sex to patients treated with ETV. Results: There were no significant differences in baseline characteristics, including HCC factors, and nephrotoxic drug use, between the two groups. The median follow-up period was 17.0 and 20.0 months for the TDF and ETV groups, respectively. There was no difference during the follow-up period between the TDF and ETV groups in the increase in creatinine over 0.5 mg/dL (17.0% and 17.0%, P=1.00, respectively) and the decrease in eGFR over 25% (43.4% and 41.5%, P=0.84, respectively). Multivariate analysis revealed that Child-Pugh class over B (hazard ratio [HR], 7.30; 95% confidence interval [CI] 2.79-19.10; P

BACKGROUND AND GOALS Although nonalcoholic fatty liver disease (NAFLD) is a risk factor of hepatocellular carcinoma (HCC), it is unclear whether NAFLD additionally increases the risk of HCC among chronic hepatitis B (CHB) patients. This study evaluated the association between NAFLD and the risk of HCC in patients whose hepatitis B virus (HBV) was well controlled. STUDY This study included consecutive CHB patients whose serum HBV DNA levels were continuously suppressed

Hepatitis B virus X protein (HBx) functions in a variety of cellular events during the HBV life cycle. In a previous study, we reported that the HBx protein is sufficient to induce mitochondrial membrane permeabilization; however, the exact mechanism of HBx-induced mitochondrial membrane permeabilization has been not proposed. In this study, we report that HBx specifically targets cardiolipin (CL) and induces membrane permeabilization depending on CL concentration in mitochondrial outer membrane–mimic artificial liposomes. Interestingly, HBx-induced membrane permeabilization was enhanced by liposomes containing phosphatidylethanolamine, which plays a crucial role in forming a negative curvature on the membrane. We also show that the 68-117 region of HBx, which interacts with mitochondria, is necessary for membrane permeabilization. We examined the size of the pores formed by HBx and found that HBx permeates fluorescent dyes depending on the hydrodynamic diameter with a pore size of approximately 10 nm. The results of this study suggest that CL is necessary for HBx-induced membrane permeabilization and provide important information that suggests a new strategy for anti-HBV therapy.

Hypoxic conditions, which large or infiltrative hypovascular tumors may encounter, also produce acidic environments. Carbonic anhydrase-IX (CA-IX), an enzyme involved in lowering pH, is overexpressed in hepatocellular carcinoma (HCC). In the present study, whether inhibition of CA-IX enhances the efficacy of a hexokinase II inhibitor in an in vivo murine model was examined and its prognostic implication in HCC patients was investigated. CA-IX expression was evaluated using quantitative real-time PCR and western blot analysis using human HCC cell lines. 3-bromopyruvate (3-BP), a hexokinase II inhibitor, and acetazolamide, a carbonic anhydrase inhibitor, were used to target hexokinase II and CA-IX in vitro and in vivo, respectively. A human HCC cell line (Huh-7) was tested as a subcutaneous tumor model in BALB/c nu/nu mice. The prognostic role of CA-IX was evaluated in the TCGA database. Quantitative real-time PCR and western blot analysis revealed that CA-IX expression was activated in the presence of 3-BP. Further analysis showed that introducing an additional stress by treating the orally active CA-IX inhibitor (acetazolamide) can synergistically increase the efficacy of 3-BP in vivo, which was confirmed using a mouse model. We also found that HCC patients with high CA-IX expression show poor overall survival in TCGA database. These results indicate CA-IX is a promising therapeutic target for enhancing the efficacy of 3-BP and can be a prognostic factor for HCC.

Background & aims: Whether entecavir (ETV) or tenofovir alafenamide (TAF) is better at preventing hepatocellular carcinoma (HCC) development among patients with chronic hepatitis B (CHB) remains unclear. The present study was conducted to explore the ability of these two antivirals to prevent HCC.Methods: From 2012 to 2019, treatment-naïve CHB patients undergoing ETV or TAF therapy were recruited at three academic teaching hospitals. The TAF group comprised patients starting TAF as first-line antiviral and those switching antivirals from tenofovir disoproxil fumarate to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded from the analysis. Cumulative probabilities of HCC were assessed using the Kaplan-Meier method.Results: In total, 1,810 patients (1,525 and 286 in ETV and TAF groups, respectively) were recruited. The annual HCC incidence was statistically not different between the ETV and TAF groups (1.67 vs. 1.19 per 100 person-years, respectively) with an adjusted hazard ratio (HR) of 0.681 (p=0.255), as determined by multivariate analysis. Male, hypertension, liver cirrhosis, FIB-4 index, and albumin were independent prognostic factors for HCC development. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results, with non-statistically different HCC incidence between the ETV and TAF groups (1.07 vs. 1.19 per 100 person-years (HR=0.973; p=0.953) and 1.67 vs. 1.89 per 100 person-years, respectively (HR=0.949; p=0.743).Conclusions: These findings suggest that ETV- and TAF-treated CHB patients have similar risk of developing HCC. Further studies with the larger sample size and longer follow-up are needed to validate these results.

Young Youn Cho,1,2 Su Jong Yu,1 Hye Won Lee,3 Do Young Kim,3 Wonseok Kang,4 Yong-Han Paik,4 Pil Soo Sung,5 Si Hyun Bae,6 Su Cheol Park,7 Young Seok Doh,8,9 Kang Mo Kim,9 Eun Sun Jang,10 In Hee Kim,11 Won Kim,12 Yoon Jun Kim1 1Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea; 2Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Korea; 3Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; 4Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 5Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea; 6Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea; 7Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea; 8Department of Internal Medicine, Eulji University Hospital, Daejeon, Korea; 9Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 10Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea; 11Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Cheongju-si, Korea; 12Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, KoreaCorrespondence: Yoon Jun KimDepartment of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-no, Jongno-gu, Seoul, 03080 (110-744), KoreaTel +82-2-2072-3081Fax +82-2-743-6701Email yoonjun@snu.ac.krBackground/Aim: Sorafenib is the first systemic therapy for the treatment of advanced-stage hepatocellular carcinoma (HCC) and progressive HCC after locoregional therapy. The aim of this study was to evaluate the prognostic factors of long-term survivors after sorafenib treatment.Methods: This multicenter, retrospective, cohort study included 1,566 unresectable HCC patients who received sorafenib treatment between 2007 and 2014 in nine tertiary centers in Korea. The patients were classified into a long-term survivor group (survival more than two years, n = 257) or a control group (n = 1309). The primary outcomes were the prognostic factors affecting long-term survival. Secondary endpoints included time-to-progression and other safety profiles.Results: The patients were predominantly men (83.8%) with chronic hepatitis B (77.3%) and Barcelona clinic of liver cancer-stage C (BCLC-C) (78.3%). The median overall survival was 9.0 months. After treatment, eight patients (0.4%) achieved complete response and 139 patients (8.8%) achieved partial response according to the mRECIST criteria. The prognostic factors predicting long-term survival were metformin use (adjusted hazard ratio [aHR] = 3.464; P < 0.001), hand-foot skin reaction (aHR = 1.688; P = 0.003), and concomitant treatment with chemoembolization or radiotherapy (aHR = 2.766; P < 0.001). Poor prognostic factors of long-term survival were a Child-Pugh score of B (HR = 0.422; P < 0.001), the presence of extrahepatic metastasis (HR = 0.639; P = 0.005), main portal vein invasion (HR = 0.502; P = 0.001), and elevated alpha-fetoprotein (> 1,000 ng/mL; HR = 0.361; P < 0.001).Conclusion: This large, multicenter, retrospective study showed an objective response rate of 9.1% and a proportion of long-term survivors of 16.4% in Korean patients. The prognostic factors derived in our study can be used in clinical practice during sorafenib treatment.Keywords: sorafenib, hepatocellular carcinoma, prognosis, survival

Fibronectin, a matrix glycoprotein aberrantly expressed in various tumor cells, is a known candidate biomarker for the early diagnosis of hepatocellular carcinoma (HCC). In this study, we investigated whether serum fibronectin levels could predict tumor recurrence in patients with early-stage HCC after curative treatment. A total of 83 patients who showed complete response after initial curative treatment were included. The levels of serum fibronectin at baseline and 4–6 weeks after initial treatment were analyzed with regard to their associations with recurrence. Multivariate logistic regression analyses were performed to construct a prognostic nomogram. Baseline fibronectin levels were not significantly correlated with tumor size, number, stage, and serum α-fetoprotein levels. However, decrease in serum fibronectin levels after treatment was significantly associated with reduced HCC recurrence in multivariate logistic regression (odds ratio, 0.009; p

Nucleos(t)ide analogues (NAs) have been shown to decrease the risk of hepatocellular carcinoma (HCC) recurrence. This study evaluated whether high-potency NAs (entecavir and tenofovir disoproxil fumarate [TDF]) reduce the risk of tumour recurrence more potently than low-potency NAs after curative treatment of hepatitis B virus (HBV)-related HCC. This study included 607 consecutive HBV-related HCC patients treated with surgical resection or radiofrequency ablation. The patients were categorized into three groups according to antiviral treatment: group A (no antiviral; n = 261), group B (low-potency NA; n = 90) and group C (high-potency NA; n = 256). The primary end-point was recurrence-free survival (RFS). During the duration of follow-up, the median RFS was 29.4, 25.1, and 88.2 months in groups A, B and C, respectively (P < .001, log-rank test). The multivariate Cox analysis indicated that group C had a significantly longer RFS than both group A (adjusted hazard ratio [HR] = 0.39, P < .001) and group B (adjusted HR = 0.47, P < .001). When baseline characteristics were balanced using inverse probability weighting, group C still had a significantly longer RFS than group A (adjusted HR = 0.46, P < .001) and group B (adjusted HR = 0.59, P = .007). Group C had significantly lower risk of viral breakthrough than group B (HR = 0.19, P < .001). Viral breakthrough was an independent risk factor for shorter RFS among groups B and C (adjusted HR = 2.03, P = .007, time-dependent Cox analysis). Antiviral agents with high genetic barrier to resistance (entecavir and TDF) reduced the risk of HCC recurrence compared with other antivirals and no antiviral treatment, especially in patients with high baseline viral load.

Summary Hepatitis B virus X protein (HBx) acts as a multifunctional protein that regulates intracellular signalling pathways during HBV infection. It has mainly been studied in terms of its interaction with cellular proteins. Here, we show that HBx induces membrane permeabilization independently of the mitochondrial permeability transition pore complex. We generated mitochondrial outer membrane‐mimic liposomes to observe the direct effects of HBx on membranes. We found that HBx induced membrane permeabilization, and the region comprising the transmembrane domain and the mitochondrial‐targeting sequence was sufficient for this process. Membrane permeabilization was inhibited by nonselective channel blockers or by N‐(n‐nonyl)deoxynojirimycin (NN‐DNJ), a viroporin inhibitor. Moreover, NN‐DNJ inhibited HBx‐induced mitochondrial depolarization in Huh‐7 cells. Based on the results of this study, we can postulate that the HBx protein itself is sufficient to induce mitochondrial membrane permeabilization. Our finding provides important information for a strategy of HBx targeting during HBV treatment.

Antiplatelet therapy has shown protective effects against hepatocellular carcinoma (HCC) in preclinical studies. However, it is unclear whether antiplatelet therapy lowers the risk of HCC in patients with chronic hepatitis B (CHB). A retrospective analysis was conducted of data from 1,674 CHB patients, enrolled between January 2002 and May 2015, whose serum hepatitis B virus (HBV) DNA levels were suppressed by antivirals to

Sorafenib is the only standard treatment for unresectable hepatocellular carcinoma (HCC), but it provides modest survival benefits over placebo, necessitating predictive biomarkers of the response to sorafenib. Serum samples were obtained from 115 consecutive patients with HCC before sorafenib treatment and analyzed by multiple reaction monitoring-mass spectrometry (MRM-MS) and ELISA to quantify candidate biomarkers. We verified a triple-marker panel to be predictive of the response to sorafenib by MRM-MS, comprising CD5 antigen-like (CD5L), immunoglobulin J (IGJ), and galectin-3-binding protein (LGALS3BP), in HCC patients. This panel was a significant predictor (AUROC > 0.950) of the response to sorafenib treatment, having the best cut-off value (0.4) by multivariate analysis. In the training set, patients who exceeded this cut-off value had significantly better overall survival (median, 21.4 months) than those with lower values (median, 8.6 months; p = 0.001). Further, a value that was lower than this cutoff was an independent predictor of poor overall survival [hazard ratio (HR), 2.728; 95% confidence interval (CI), 1.312–5.672; p = 0.007] and remained an independent predictive factor of rapid progression (HR, 2.631; 95% CI, 1.448–4.780; p = 0.002). When applied to the independent validation set, levels of the cut-off value for triple-marker panel maintained their prognostic value for poor clinical outcomes. On the contrast, the triple-marker panel was not a prognostic factor for patients who were treated with transarterial chemoembolization (TACE). The discriminatory signature of a triple-marker panel provides new insights into targeted proteomic biomarkers for individualized sorafenib therapy.

This study was aimed to identify blood-based biomarkers to predict a sustained complete response (CR) after transarterial chemoembolization (TACE) using targeted proteomics. Consecutive patients with HCC who had undergone TACE were prospectively enrolled (training (n = 100) and validation set (n = 80)). Serum samples were obtained before and 6 months after TACE. Treatment responses were evaluated using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). In the training set, the MRM-MS assay identified five marker candidate proteins (LRG1, APCS, BCHE, C7, and FCN3). When this five-marker panel was combined with the best-performing clinical variables (tumor number, baseline PIVKA, and baseline AFP), the resulting ensemble model had the highest area under the receiver operating curve (AUROC) value in predicting a sustained CR after TACE in the training and validation sets (0.881 and 0.813, respectively). Furthermore, the ensemble model was an independent predictor of rapid progression (hazard ratio (HR), 2.889; 95% confidence interval (CI), 1.612-5.178; P value0.001) and overall an unfavorable survival rate (HR, 1.985; 95% CI, 1.024-3.848; P value = 0.042) in the entire population by multivariate analysis. Targeted proteomics-based ensemble model can predict clinical outcomes after TACE. Therefore, this model can aid in determining the best candidates for TACE and the need for adjuvant therapy.

Background Discovering reliable protein biomarkers is one of the most important issues in biomedical research. The ELISA is a traditional technique for accurate quantitation of well-known proteins. Recently, the multiple reaction-monitoring (MRM) mass spectrometry has been proposed for quantifying newly discovered protein and has become a popular alternative to ELISA. For the MRM data analysis, linear mixed modeling (LMM) has been used to analyze MRM data. MSstats is one of the most widely used tools for MRM data analysis that is based on the LMMs. However, LMMs often provide various significance results, depending on model specification. Sometimes it would be difficult to specify a correct LMM method for the analysis of MRM data. Here, we propose a new logistic regression-based method for Significance Analysis of Multiple Reaction Monitoring (LR-SAM). Results Through simulation studies, we demonstrate that LMM methods may not preserve type I error, thus yielding high false- positive errors, depending on how random effects are specified. Our simulation study also shows that the LR-SAM approach performs similarly well as LMM approaches, in most cases. However, LR-SAM performs better than the LMMs, particularly when the effects sizes of peptides from the same protein are heterogeneous. Our proposed method was applied to MRM data for identification of proteins associated with clinical responses of treatment of 115 hepatocellular carcinoma (HCC) patients with the tyrosine kinase inhibitor sorafenib. Of 124 candidate proteins, LMM approaches provided 6 results varying in significance, while LR-SAM, by contrast, yielded 18 significant results that were quite reproducibly consistent. Conclusion As exemplified by an application to HCC data set, LR-SAM more effectively identified proteins associated with clinical responses of treatment than LMM did.

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

Objective The aim of this study was to prospectively evaluate whether liver stiffness (LS) assessments, obtained by two-dimensional (2D)-shear wave elastography (SWE) with a propagation map, can evaluate liver fibrosis stage using histopathology as the reference standard. Materials and Methods We prospectively enrolled 123 patients who had undergone percutaneous liver biopsy from two tertiary referral hospitals. All patients underwent 2D-SWE examination prior to biopsy, and LS values (kilopascal [kPa]) were obtained. On histopathologic examination, fibrosis stage (F0–F4) and necroinflammatory activity grade (A0–A4) were assessed. Multivariate linear regression analysis was performed to determine the significant factors affecting the LS value. The diagnostic performance of the LS value for staging fibrosis was assessed using receiver operating characteristic (ROC) analysis, and the optimal cut-off value was determined by the Youden index. Results Reliable measurements of LS values were obtained in 114 patients (92.7%, 114/123). LS values obtained from 2D-SWE with the propagation map positively correlated with the progression of liver fibrosis reported from histopathology (p < 0.001). According to the multivariate linear regression analysis, fibrosis stage was the only factor significantly associated with LS (p < 0.001). The area under the ROC curve of LS from 2D-SWE with the propagation map was 0.773, 0.865, 0.946, and 0.950 for detecting F ≥ 1, F ≥ 2, F ≥ 3, and F = 4, respectively. The optimal cut-off LS values were 5.4, 7.8, 9.4, and 12.2 kPa for F ≥ 1, F ≥ 2, F ≥ 3, and F = 4, respectively. The corresponding sensitivity and specificity of the LS value for detecting cirrhosis were 90.9% and 88.4%, respectively. Conclusion The LS value obtained from 2D-SWE with a propagation map provides excellent diagnostic performance in evaluating liver fibrosis stage, determined by histopathology.

Whether a sustained virological response (SVR) improves long-term outcomes in chronic hepatitis C patients with earlier-stage fibrosis has not been established. We investigated the differential effect of SVR on the risk of outcomes according to hepatic fibrosis grade. Fibrosis grade was categorised using FIB-4: vs. untreated: adjusted hazard ratio [aHR], 0.165; 95% confidence interval [CI], 0.077–0.350; P vs. untreated; aHR, 0.146; 95% CI, 0.050–0.424; P n = 492: aHR, 0.171; 95% CI, 0.051–0.578; P = 0.004) and high-probability (n = 446: aHR, 0.243; 95% CI, 0.107–0.551; P