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The capsid protein of porcine circovirus type 2 (PCV2) encoded by open reading frame 2 (ORF2) is important for neutralizing activity against PCV2 infection. This study investigated the heterogeneity of the ORF2 gene of PCV2 isolated in Korea during 2016–2017. The results revealed that PCV2d is currently the predominant genotype. Moreover, comparison of ORF2 from 17 PCV2 isolates revealed 88.3–100% homology at the nucleotide (deduced amino acid 86.3–100%) level. Interestingly, 61.5% (8/13) of the PCV2d isolates had glycine at position 210. These data provide a useful information for PCV2 epidemiology in Korea. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the pattern of serial HBV DNA levels in known cirrhosis patients and its impact on the development of hepatocellular carcinoma (HCC). Methods: We analyzed a retrospective case/control study based on 352 HCC patients associated with HBV between 2005 and 2007. Prior to HCC development, 49 cirrhosis patients were tested for HBV DNA levels more than once a year (median 4 times) during the follow-up period. Ninety-eight consecutive cirrhosis patients without HCC, matched for age, sex and HBe Ag status were included as controls. Eighty-three patients in both groups had undergone antiviral therapy. Results: In cirrhosis, the most common HBV DNA pattern was fluctuating (33.3%), followed by persistently high (≥104 copies/ml, 23.8%). Compared to a persistently low pattern (<104 copies/ml), the relative risks of HCC in patients with persistently high and fluctuating patterns were 2.650 and 1.475. At multivariate analysis, a persistently high pattern was an independent risk factor for HCC (hazard ratio 3.135). Patients with sustained HBV DNA suppression during antiviral therapy were less likely to develop HCC than those with viral breakthrough/nonresponse. Conclusions: This study showed that persistent suppression of HBV DNA is also important to prevent the development of HCC in known cirrhosis patients. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article focuses on a study on the impact of hepatitis B viral (HBV) load on recurrence after complete necrosis in patients with hepatocellular carcinoma (HCC) who receive transarterial chemolipiodolization. The study involved several patients who had HBV-related HCC. Risk factors including viral load for posttreatment recurrence were analyzed. The study found that most of the patients developed a recurrence during the study period. Additionally, high HBV viral load was among the most important risk factors for posttreatment recurrence.

Choi JY, Bae SH, Yoon SK, Cho SH, Yang JM, Han JY, Ahn BM, Chung KW, Sun HS, Kim DG. Preconditioning by extracorporeal liver support (MARS) of patients with cirrhosis and severe liver failure evaluated for living donor liver transplantation – a pilot study. Liver International 2005: 25: 740–745. © Blackwell Munksgaard 2005 The aim of this prospective study was to evaluate the effectiveness of preconditioning molecular adsorbent recirculating system (MARS) treatment on patients with acute-on-chronic liver failure (AoCLF), who were awaiting living donor liver transplantation (LDLT). Between January and December 2001, 10 consecutive AoCLF patients (with progressive hyperbilirubinemia (>20 mg/dl) and hepatic encephalopathy grade ≥2) were studied. MARS was used in eight of these patients who were evaluated for LDLT during 2001. Three AoCLF patients who received LDLT before clinical use of MARS were used as historical controls. Because of a shortage of donors, only five out of 10 patients considered for LDLT could receive transplants. Three patients were treated with MARS for 8 h the day before receiving LDLT, and all three survived. The remaining two patients who received transplants, and who were not pretreated with MARS, died from sepsis and multi-organ failure within 2 weeks. Four of the patients who did not receive transplants because of donor shortage died despite 1 or 3 MARS treatments, however bilirubin levels and grade of encephalopathy were significantly reduced in these patients. Results of this small pilot study suggest that MARS, by reducing the severity of jaundice and encephalopathy, might be effective as a bridging option in AoCLF patients awaiting LDLT. [ABSTRACT FROM AUTHOR]

Background/Aims: Bile duct invasion (BDI) is rarely observed in patients with advanced hepatocellular carcinoma (HCC), leading to hyperbilirubinemia. However, the efficacy of pretreatment biliary drainage for HCC patients with BDI and obstructive jaundice is currently unclear. Thus, the aim of this study was to assess the effect of biliary drainage on the prognosis of these patients. Methods: We retrospectively enrolled a total of 200 HCC patients with BDI from multicenter cohorts. Patients without obstructive jaundice (n=99) and those who did not undergo HCC treatment (n=37) were excluded from further analysis. Finally, 64 patients with obstructive jaundice (43 subjected to drainage and 21 not subjected to drainage) were included. Propensity score matching was then conducted. Results: The biliary drainage group showed longer overall survival (median 10.13 months vs 4.43 months, p=0.004) and progression-free survival durations (median 7.00 months vs 1.97 months, p<0.001) than the non-drainage group. Multivariate analysis showed that biliary drainage was a significantly favorable prognostic factor for overall survival (hazard ratio, 0.42; p=0.006) and progression-free survival (hazard ratio, 0.30; p<0.001). Furthermore, in the evaluation of first response after HCC treatment, biliary drainage was beneficial (p=0.005). Remarkably, the durations of overall survival (p=0.032) and progression-free survival (p=0.004) were similar after propensity score matching. Conclusions: Biliary drainage is an independent favorable prognostic factor for HCC patients with BDI and obstructive jaundice. Therefore, biliary drainage should be contemplated in the treatment of advanced HCC with BDI to improve survival outcomes [ABSTRACT FROM AUTHOR]

Local ablation for hepatocellular carcinoma, a non-surgical option that directly targets and destroys tumor cells, has advanced significantly since the 1990s. Therapies with different energy sources, such as radiofrequency ablation, microwave ablation, and cryoablation, employ different mechanisms to induce tumor necrosis. The precision, safety, and effectiveness of these therapies have increased with advances in guiding technologies and device improvements. Consequently, local ablation has become the first-line treatment for early-stage hepatocellular carcinoma. The lack of organized evidence and expert opinions regarding patient selection, pre-procedure preparation, procedural methods, swift post-treatment evaluation, and follow-up has resulted in clinicians following varied practices. Therefore, an expert consensus-based practical recommendation for local ablation was developed by a group of experts in radiology and hepatology from the Research Committee of the Korean Liver Cancer Association in collaboration with the Korean Society of Image-Guided Tumor Ablation to provide useful information and guidance for performing local ablation and for the pre- and post-treatment management of patients. [ABSTRACT FROM AUTHOR]

Background/Aims Growth differentiation factor (GDF15) is one of the transforming growth factor β superfamily and increased in several cancers including hepatocellular carcinoma (HCC). However, the level of GDF15 according to the characteristics of HCC has not been investigated. We examined the serum level of GDF15 in HCC patients and correlated with the clinical tumor characteristics. Methods A total of 80 patients diagnosed with HCC between 2013 and 2017 were analyzed in our study. In 80 enrolled patients, 20 patients for each modified UICC stage (I-IV) were included. The 15 healthy patients were also included as control group. The serum level of GDF15 and programmed death-1 ligand 1 (PD-L1) were checked by enzyme-linked immunosorbent assay at the time of initial diagnosis of HCC. The level of GDF15 were analyzed with tumor characteristics including tumor stage, size, presence of portal vein thrombosis (PVT) and metastasis. Results The mean age of whole patients were 59.9 years and 54 patients (67.5%) were HBV-related HCC. The median level of GDF15 and PD-L1 were 782.7 pg/mL (range, 624.1 to 909.1 pg/mL) and 35.4 pg/mL (range, 15.7 to 63.4 pg/mL), respectively. The serum level of GDF15 were significantly higher in HCC patients than healthy control (p<0.001). However, PD-DL1 level were significantly lower in HCC patients (p=0.001). Moreover, advanced stage (III-IV) had higher level of GDF15 than stage I-II (p<0.05) and PD-L1 level were not differ between tumor stage. The size of tumor had a significantly positive correlation with the level of GDF15 (r=0.50, p<0.001). The patients with metastasis or PVT had higher GDF15 level with significance (p<0.003, p=0.001, respectively). Conclusions The serum level of GDF15 is high in HCC patients and higher level represent the aggressiveness of HCC including tumor size, PVT and metastasis. [ABSTRACT FROM AUTHOR]

Background/Aims It has been 4 years since the FDA approved the immunotherapybased regimen atezolizumab-bevacizumab as the first-line treatment of hepatocellular carcinoma. Hence, accurate biomarkers predicting prognosis of the relatively new treatment has not been discovered. In 2022, Scheiner et al suggested a scoring system named CRAFITY score, including CRP and AFP, that accurately predicted prognosis of HCC patients who were treated with atezolizumab-bevacizumab combination therapy. There have also been multiple studies suggesting PIVKA-II as an additionally accurate biomarker and NLR(neutrophil-lymphocyte ratio) as an accurate predictive factor for HCC patients. Naturally, we experimented in including PIVKA-II and NLR into the CRAFITY score system. Methods We included 146 patients diagnosed with HCC who were treated with atezolizumab-bevacizumab. We assigned 1 point for having an AFP ≥100 ng/ml and 1 point for having a CRP ≥1 mg/dl. As we added the PIVKA-II and NLR as new factors included in the scoring system (mCRAFITY), we assigned 1 point for having a PIVKA-II ≥40 mAU/ml and an additional 1 point for having NLR >2.5. We used the AUROC(area under the receiver operating characteristic) to evaluate the performance of our scoring system. Results The AUROC curve showed that the mCRAFITY score had better performance at 6 months and 12 months but worse performance at 18 months in predicting the prognosis of HCC patients. When OS and PFS was calculated, patients with mCRAFITY scores of less than 3 had significantly better prognosis than those with scores more than or equal to 3. (p value=0.0015 and 0.0391 respectively) Conclusion In conclusion, the mCRAFITY score that includes PIVKA-II and NLR may be more accurate than the previously announced CRAFITY score. Patients with mCRAFITY scores less than 3 had significantly better prognosis than whom at scores more than or equal to 3. [ABSTRACT FROM AUTHOR]

Background/Aims: Data on the epidemiology of alcoholic cirrhosis, especially in Asian countries, are limited. We compared the temporal evolution of patterns of alcoholic and nonalcoholic cirrhosis over the last decade. Methods: We retrospectively examined the inpatient datasets of five referral centers during 2002 and 2011. The study included patients who were admitted due to specific complications of liver cirrhosis. We compared the causes of hospital admissions and in-hospital deaths between patients with alcoholic and nonalcoholic cirrhosis. Results: Among the included 2,799 hospitalizations (2,165 patients), 1,496 (1,143 patients) were from 2002, and 1,303 (1,022 patients) were from 2011. Over time, there was a reduction in the rate of hepatic encephalopathy (HE) as a cause of hospitalization and an increase in the rate of hepatocellular carcinoma. Deaths that were attributable to HE or spontaneous bacterial peritonitis (SBP) significantly decreased, whereas those due to hepatorenal syndrome (HRS) significantly increased over time in patients with alcoholic cirrhosis. However, in patients with nonalcoholic cirrhosis, hepatic failure and HRS remained the principal causes of in-hospital death during both time periods. Conclusions: The major causes of in-hospital deaths have evolved from acute cirrhotic complications, including HE or SBP to HRS in alcoholic cirrhosis, whereas those have remained unchanged in nonalcoholic cirrhosis during the last decade. [ABSTRACT FROM AUTHOR]

Background: Porcine reproductive and respiratory syndrome virus (PRRSV) causes a loss of approximately US$ 70 million every year to the South Korean pork industry. There are two distinct genotypes: European (type 1) and North American (type 2). In South Korea, type 1 and type 2 PRRSV are widely distributed and have evolved continuously since the infection was first described. Here, we present two field cases of type 1 PRRSV infection with unusually severe pathogenicity. Case presentation: The first case farm was a two-site production system comprising farrow-to-grower and grower-to-finish units and was historically free from PRRSV infections. The PRRSV vaccine had not been used in both units. In October 2014, pigs in the grower-to-finish unit experienced severe respiratory distress with the mortality rate reaching to 22 %. Despite antibiotic treatment, clinical signs were still noticed in most pigs. The second case farm was also a two-site production system, but had two separate farrow-to-grower units (unit A and unit B). Historically, type 1 PRRSV was continuously present in unit A, but unit B was free from PRRSV. Thus, all grower pigs of unit B were vaccinated before being moved to the grower-to-finish unit. In November 2014, severe respiratory distress was seen in pigs of the grower-to-finish unit. Significant respiratory distress was observed in only the grower herd moved from unit B, and the mortality of those pigs was ~50 %. However, no disease was shown in the grower pigs from unit A. Conclusions: To our knowledge, the present study is the first observation of the cases of infection by highly pathogenic type 1 PRRSV in South Korea. The Korean type 1 PRRSV strains have undergone unique evolutionary dynamics for the last decade in this country. Although there are known to be three clusters of Korean type 1 PRRSV, their pathogenicity could not be categorized owing to their high level of genetic diversity. Therefore, further studies are needed to demonstrate the novel classification of Korean type 1 PRRSV strains according to their virulence factors. [ABSTRACT FROM AUTHOR]

Background/Aims: In patients with hepatocellular carcinoma (HCC) exceeding the Milan criteria, the recurrence rate after liver transplantation is over 50%. We investigated pretransplant factor(s) that could predict recurrence after living donor liver transplantation (LDLT) in patients with HCC exceeding the Milan criteria. Methods: Pre-operative imaging showed that, of the 111 HCC patients who underwent LDLT between June 1995 and January 2006, 37 exceeded the Milan criteria. Clinical factors before LDLT were evaluated. Results: The 1- and 3-year cumulative recurrence rates were 35 and 55% respectively. Pretransplant risk factors for HCC recurrence were large tumour size (>6 cm, P=0.001), tumour exposed to the liver surface ( P=0.014) and progressive disease after pretransplant treatment ( P=0.038). The 2-year HCC recurrence rates in patients with 0, 1, 2 and 3 factors were 0% (0/4), 9% (1/16), 80% (8/10) and 100% (7/7) respectively ( P<0.001). The 2-year survival rate was significantly higher in patients with 0 or 1 factor than in patients with two or more factors ( P=0.022). Conclusions: In patients with HCC exceeding the Milan criteria, the three pretransplant factors that may be useful for identifying those with high HCC recurrence potential after LDLT are tumour size >6 cm, progressive disease after pretransplant treatment and tumour exposed to the liver surface. [ABSTRACT FROM AUTHOR]

Purpose: Hepatocellular carcinoma (HCC) invading the portal vein is a medical challenge. We evaluated the therapeutic efficacy of a combination of transarterial and systemic chemo-infusion for large HCC with portal vein thrombosis (PVT) compared with conservative management. Patients and methods: This was a case-control cohort study of 103 consecutive patients with Child-Pugh class A who had a large (>10 cm) HCC with PVT. The patients were assigned to receive either combined transarterial epirubicin (50 mg/m2) plus cisplatin (60 mg/m2) chemo-lipiodolization and systemic 5-fluorouracil (200 mg/m2) chemo-infusion (ECF regimen) at monthly intervals ( n=80) or conservative management ( n=23). Results: The objective tumor response (21.3 vs. 0%, P=0.011) and overall survival (8.7 vs. 3.5 months, P<0.001) were significantly better in the treatment group than in the conservative group. The prognostic factors for survival were tumor type ( P=0.007), bilobar involvement ( P=0.001), distant metastasis ( P=0.009) and objective tumor response ( P<0.001) for the treatment group. Survival benefits with the treatment were also maintained in each subgroup after stratification of these variables. Conclusions: This study suggests that when the hepatic function is preserved, a therapeutic strategy could be more beneficial than conservative management for such a large extensive HCC. As a therapeutic option, a combination therapy using ECF regimen may provide a significantly better tumor response and survival benefit in patients with large HCC invading the portal vein. [ABSTRACT FROM AUTHOR]

Background and Aim: Studies from hepatitis B virus endemic areas have shown less durable lamivudine-induced responses and have raised issues about the management of a post-treatment relapse. Methods: From January 2000 to June 2004, all 51 patients (43 HBeAg-positive and eight HBeAg-negative) were retreated with lamivudine for at least 12 months. All had a post-treatment relapse after HBeAg responses (HBeAg loss/seroconversion) during the first therapy. Results: During retreatment, HBeAg seroconversion occurred more frequently in those patients with HBeAg seroconversion than in those with HBeAg loss alone during prior lamivudine therapy ( P = 0.001). On multivariate analysis, prior HBeAg seroconversion and early virological response (EVR) (≤ 2 months of retreatment) independently predicted HBeAg seroconversion ( P = 0.012 and P = 0.004, respectively). With regard to virological breakthrough, only the time to virological response (> 2 months of retreatment) remained significant ( P = 0.048). Among the HBeAg-negative patients, virological breakthrough occurred in only one patient with a late virological response. Conclusions: EVR is a major predictor in determining a favorable response to lamivudine retreatment. Our observations suggest that lamivudine retreatment will provide more therapeutic gains in those patients with a prior HBeAg seroconversion than in those with HBeAg loss alone. [ABSTRACT FROM AUTHOR]

Background: Few clinical trials have investigated the use of lamivudine (LAM) in patients with decompensated cirrhosis related to chronic hepatitis B. The aim of the present study was to evaluate the efficacy of extended LAM treatment and to determine the timing of LAM administration in patients with decompensated cirrhosis. Methods: A total of 17 patients were treated with LAM 100 mg/day. The mean duration of follow up was 28 ± 8.4 months (range: 14–42 months). All patients were evaluated for evidence of clinical, biochemical and serologic replication of hepatitis B virus (HBV) infection. There were 12 patients with Child class B and five with Child class C. Results: Ten of 17 patients (58.2%) responded to LAM treatment. Of the breakthrough patients, six (86%) had YMDD motif variants. Clinical improvement was observed in nine out of 10 responders (90%), six of the seven breakthrough patients (86%) and five of six patients with YMDD variant DNA. Mean time to achieve a 2-point reduction in Child–Pugh–Turcotte score was 14 months in patients with Child class C, compared with 5.9 months in those with Child class B ( P < 0.001). Mean time required to gain a 0.5 g/dL increment in albumin was 14 months in Child class C and 5.8 months in Child class B. Hepatitis B e antigen (HBeAg) seroconversion was achieved in five of 13 HBeAg-positive patients at the last follow up and during the follow-up period. Conclusion: Long-term administration of LAM for patients with decompensated cirrhosis is effective. Earlier LAM administration in Child class B patients led to improved clinical outcomes. © 2005 Blackwell Publishing Asia Pty Ltd [ABSTRACT FROM AUTHOR]

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). NFMresponse, sex, age, and cirrhosis were independently predictive of HCC. Wedeveloped 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. [ABSTRACT FROM AUTHOR]

Actinobacillus pleuropneumoniae (App) and Mycoplasma hyopneumoniae (Mhp) cause porcine pleuropneumonia and mycoplasmal pneumonia, respectively, and have serious impacts on the swine industry because they retard the growth of pigs. To protect pigs against these diseases, we have developed a multivalent vaccine consisting of App bacterins, APP RTX toxins (Apx toxins), and Mhp bacterin and adhesin protein. This vaccine induced the production of higher levels of antibodies against App and Mhp than the commercial vaccine (Nisseiken Swine APM Inactivated Vaccine). Furthermore, the vaccine efficiently protected pigs against virulent App challenge, showing promise as an efficient vaccine for the prevention of two important respiratory diseases, porcine pleuropneumonia and mycoplasmal pneumonia. [ABSTRACT FROM AUTHOR]

Photothermolysis technique via array of gold nanograils had been developed by illuminating near infrared laser light onto captured bacteria in metal nanostructure. The strong electromagnetic field enhancement at the sharp edges of the gold nanograils produced local heating that was sufficient to break the thick cell walls of the gram-positive Staphylococcus aureus cells within a short time. Individual cells in the nanograil array can be selectively lysed by adjusting the laser scanning area to the micrometer scale. [ABSTRACT FROM AUTHOR]

Background/Aims: According to the results of several studies, the outcome of hepatitis C virus (HCV) reactivation is not as severe as the outcome of hepatitis B virus reactivation. The aim of this study was to evaluate the effect of pharmacological immunosuppression on HCV reactivation. Methods: The medical records of patients who underwent systemic chemotherapy, corticosteroid therapy, or other immunosuppressive therapies between January 2008 and March 2015 were reviewed. Subsequently, 202 patients who were seropositive for the anti-HCV antibody were enrolled. Exclusion criteria were: unavailability of data on HCV RNA levels, a history of treatment for chronic hepatitis C, and the presence of liver diseases other than a chronic HCV infection. Results: Among the 120 patients enrolled in this study, hepatitis was present in 46 patients (38%). None of the patients were diagnosed with severe hepatitis. Enhanced replication of HCV was noted in nine (27%) of the 33 patients who had data available on both basal and follow-up HCV RNA loads. Reappearance of the HCV RNA from an undetectable state did not occur after treatment. The cumulative rate of enhanced HCV replication was 23% at 1 year and 30% at 2 years. Conclusions: Although enhanced HCV replication is relatively common in HCV-infected patients treated with chemotherapy or immunosuppressive therapy, it does not lead to serious sequelae. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B (HB) is an infectious disease with unfavorable consequence for patients and involved in chronic inflammation of liver. The present study aimed to investigate whether High-mobility group protein B (HMGB)1/receptor for advanced glycation end products (RAGE) aggravates inflammation enhancing the expression of interleukin (IL)-17.Methods: Mild and severe HB liver tissue and peripheral blood samples were obtained intra-operatively. Histological analysis of the livers was performed by immunohistochemistry. IL-1β and IL-6 of liver tissue were detected by confocal microscopy staining. Relative mRNA expression was measured by real-time PCR and protein levels were measured by enzyme-linked immunosorbent assay.Results: HMGB1, RAGE and IL-17 expression is increased in liver of HB patients with acute on chronic liver failure (ACLF) compared to healthy controls. HMGB1 treatment induced inflammatory cytokines including IL-17 in peripheral blood cells of HB patients. IL-17 also induced the expression of RAGE and IL-1β in peripheral blood cells of HB patients with ACLF. On the other hands, the inhibitory factor of p38 and nuclear factor-kappa B reduced the expression of RAGE and IL-1β in peripheral blood cells HB patients with ACLF.Conclusions: HMGB1, RAGE and IL-17 expression is increased in liver of severe HB patients. HMGB1 and RAGE interaction may contribute to the inflammation of liver enhancing the expression of IL-17, which can be possibly restored through the decline of the HMGB1/RAGE axis. [ABSTRACT FROM AUTHOR]

Background aims. Many rodent experiments and human studies on stem cell therapy have shown promising therapeutic approaches to liver diseases. We investigated the clinical outcomes of five patients with liver failure of various causes who received autologous CD34-depleted bone marrow-derived mononuclear cell (BM-MNC) transplantation, including mesenchymal stromal cells, through the hepatic artery. Methods. CD34-depleted BM-MNCs were obtained from five patients waiting for liver transplantation by bone marrow aspiration and using the CliniMACS CD34 Reagent System (Miltenyi Biotech, Bergisch Gladbach, Germany), and autologous hepatic artery infusion was performed. The causes of hepatic decompensation were hepatitis B virus (HBV), hepatitis C virus (HCV), propylfhiouracil-induced toxic hepatitis and Wilson disease. Results. Serum albumin levels improved 1 week after transplantation from 2.8 g/dL, 2.4 g/dL, 2.7 g/dL and 1.9 g/dL to 3.3 g/dL, 3.1 g/dL, 2.8 g/dL and 2.6 g/dL. Transient liver elastography data showed some change from 65 kPa, 33 kPa, 34.8 kPa and undetectable to 46.4 kPa, 19.8 kPa, 29.1 kPa and 67.8 kPa at 4 weeks after transplantation in a patient with Wilson disease, a patient with HCV, and two patients with HBV. Ascites decreased in two patients. One of the patients with HBV underwent liver transplantation 4 months after the infusion, and the hepatic progenitor markers (cytokeratin [CD]-7, CD-8, CD-9, CD-18, CD-19, c-Kit and epithelial cell adhesion molecule [EpCAM]) were highly expressed in the explanted liver. Conclusions. Serum albumin levels, liver stiffness, liver volume, subjective healthiness and quality of life improved in the study patients. Although these findings were observed in a small population, the results may suggest a promising future for autologous CD34-depleted BM-MNC transplantation as a bridge to liver transplantation in patients with liver failure. [ABSTRACT FROM AUTHOR]

Little is known about the role of hepatitis B virus (HBV) factors in the long-term prognosis of hepatocellular carcinoma (HCC) after resection. The objective of the present study was to identify the changing patterns of HBV levels and its effect on outcome after resection. This study recruited 188 patients with HBV-related HCC who underwent curative resection. Among the 188 patients, 115 were alive without recurrence at 12 months, and had serial measurements of viral levels. The mean age was 53 years and the mean follow-up period was 48.5 months. With multivariate analysis, tumor size > 5 cm ( P = 0.047), Child-Pugh class B ( P = 0.017), vascular invasion ( P = 0.028), and HBV DNA > 10 copies/mL at the time of resection ( P = 0.003) were independently predictive of HCC recurrence for the entire population. For the 115 patients with serial measurements of viral levels, tumor size > 5 cm, HBV DNA > 10 copies/mL at resection, and the absence of sustained HBV DNA level < 10 copies/mL, the presence of cirrhosis, and elevated aminotransferase levels (> 40 IU/L) were marginally or significantly associated with HCC recurrence and overall survival. However, on multivariate analysis, sustained HBV DNA level < 10 copies/mL was the only factor for both low recurrence ( P = 0.002; odds ratio [OR] 3.13; 95% confidence interval [CI] 1.55-6.35) and longer survival ( P = 0.002; OR 3.76; 95% CI 1.61-8.78). A high HBV replication state is among the most important predictors of adverse outcome after resection of HBV-related HCC. The sustained suppression of HBV below 10 copies/mL is a strong protective factor for long-term recurrence-free and overall survival. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated that frequent, low-dose metronomic (MET) dosing of cytotoxic agents may not only be as efficient as conventional maximum tolerated dose (MTD) chemotherapy but also less toxic. In this study, we investigated the therapeutic effect and safety of MET chemotherapy using cyclophosphamide (CTX) in rats with chemically induced hepatocellular carcinoma (HCC). Rats received weekly intraperitoneal (i.p.) injections of diethylnitrosamine during 16 weeks for induction of HCC. The rats were divided into three groups: MTD group received 40 mg/kg CTX i.p. injection on days 1, 3, and 5 of a 21-day cycle; Control and MET groups received saline and 20 mg/kg CTX i.p. injection twice a week, respectively. The growth-modulating effects and overall survival were compared between the groups. Anti-angiogenic effects were evaluated by a measurement of endothelial cell and VEGFR-2 expression. At 6 weeks of therapy, MTD and MET chemotherapy resulted in a significant reduction in tumor number and size compared with Control group. MET chemotherapy showed more prolonged survival than MTD chemotherapy and Control groups ( P < 0.05). MET chemotherapy resulted in a significant decrease in both the micro-vessel density and endothelial proliferation index ( P < 0.01). Furthermore, MET chemotherapy led to a greater decrease in VEGFR-2 expression at the mRNA and protein levels ( P < 0.01). MET scheduling not only exhibits anti-tumor and anti-angiogenic effects, but also prolongs survival without major toxicities in a rat model of HCC. Our results suggest that MET chemotherapy has a high therapeutic value and should be considered for future clinical trials. [ABSTRACT FROM AUTHOR]

Background: We evaluated the long-term effect of stereotactic body radiation therapy (SBRT) for primary small hepatocellular carcinoma (HCC) ineligible for local therapy or surgery. Methods: Forty-two HCC patients with tumors ≤ 100 cc and ineligible for local ablation therapy or surgical resection were treated with SBRT: 30-39 Gy with a prescription isodose range of 70-85% (median 80%) was delivered daily in three fractions. Median tumor volume was 15.4 cc (3.0-81.8) and median follow-up duration 28.7 months (8.4-49.1). Results: Complete response (CR) for the in-field lesion was initially achieved in 59.6% and partial response (PR) in 26.2% of patients. Hepatic out-of-field progression occurred in 18 patients (42.9%) and distant metastasis developed in 12 (28.6%) patients. Overall in-field CR and overall CR were achieved in 59.6% and 33.3%, respectively. Overall 1- year and 3-year survival rates were 92.9% and 58.6%, respectively. In-field progression-free survival at 1 and 3 years was 72.0% and 67.5%, respectively. Patients with smaller tumor had better in-field progression-free survival and overall survival rates (<32 cc vs. ≥32 cc, P < 0.05). No major toxicity was encountered but one patient died with extrahepatic metastasis and radiation-induced hepatic failure. Conclusions: SBRT is a promising noninvasive-treatment for small HCC that is ineligible for local treatment or surgical resection. [ABSTRACT FROM AUTHOR]

Background: Since hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, it is still important to understand hepatocarcinogenesis mechanisms and identify effective markers for tumor progression to improve prognosis. Amplification and overexpression of Tropomyosin3 (TPM3) are frequently observed in HCC, but its biological meanings have not been properly defined. In this study, we aimed to elucidate the roles of TPM3 and related molecular mechanisms. Methods: TPM3-siRNA was transfected into 2 HCC cell lines, HepG2 and SNU-475, which had shown overexpression of TPM3. Knockdown of TPM3 was verified by real-time qRT-PCR and western blotting targeting TPM3. Migration and invasion potentials were examined using transwell membrane assays. Cell growth capacity was examined by colony formation and soft agar assays. Results: Silencing TPM3 resulted in significant suppression of migration and invasion capacities in both HCC cell lines. To elucidate the mechanisms behind suppressed migration and invasiveness, we examined expression levels of Snail and E-cadherin known to be related to epithelial-mesenchymal transition (EMT) after TPM3 knockdown. In the TPM3 knockdown cells, E-cadherin expression was significantly upregulated and Snail downregulated compared with negative control. TPM3 knockdown also inhibited colony formation and anchorage independent growth of HCC cells. Conclusions: Based on our findings, we formulate a hypothesis that overexpression of TPM3 activates Snail mediated EMT, which will repress E-cadherin expression and that it confers migration or invasion potentials to HCC cells during hepatocarcinogenesis. To our knowledge, this is the first evidence that TPM3 gets involved in migration and invasion of HCCs by modifying EMT pathway. [ABSTRACT FROM AUTHOR]

Hepatic arterial infusion chemotherapy (HAIC) has been reported to be effective in patients with advanced hepatocellular carcinoma (HCC). In this multicenter, prospective, open-labeled, clinical trial, we randomly assigned 68 patients with advanced HCC to receive either low-dose [ n = 32, 5-fluorouracil (FU), 170 mg/m2 and cisplatin, 7 mg/m2 on days 1–5] or high-dose HAIC ( n = 36, 5-FU, 500 mg/m2 on days 1–3 and cisplatin, 60 mg/m2 on day 2) every 4 weeks via an implantable port system. A total of 207 cycles of HAIC was given to the 68 patients. Overall, 6 patients (8.8%) achieved a partial response and 21 patients (30.9%) had stable disease. The objective response rate (CR + PR) was significantly improved in the high-dose group compared to the low-dose group (16.7% vs. 0%, P = 0.024). The median time to disease progression and overall survival were slightly prolonged in the high-dose group compared to the low-dose group (median survival, 193 vs. 153 days; P = 0.108; median time to disease progression, 145 vs. 90 days; P = 0.095). Multivariate analysis showed that tumor response to treatment [ P = 0.007, RR 2.27 (95% CI, 1.248–4.132)] was the only factor associated with overall survival. All adverse events were tolerable and successfully managed in both treatment groups. Both HAIC regimens are safe and effective in patients with advanced HCC. High-dose HAIC achieves a better tumor response compared to low-dose HAIC. [ABSTRACT FROM AUTHOR]

Background and Aims: The topographical distribution of hepatitis B core antigen (HBcAg) is related to the pathogenesis of liver damage caused by hepatitis B virus (HBV) infection. β-catenin plays an important role in both intracellular adhesion and Wnt signaling transduction pathways. This study investigated the intrahepatic expression of HBcAg and β-catenin in chronic HBV infection, and correlated the results with the degree of liver damage and viral replication. Method: Liver sections from 73 patients with chronic HBV infection were examined immunohistochemically for HBcAg and β-catenin. Results: The distribution of HBcAg could be classified into four types: only nucleus (C-1), both nucleus and cytoplasm (C-2), only cytoplasm (C-3) and all negative for nucleus and cytoplasm (C-4). Significant differences in serum aminotransferase level, HBV DNA and necroinflammatory score were observed among the different distribution types, and as the distribution of HBcAg changed from C-1 to C-4, fibrosis stage and hepatitis B e antigen (HBeAg) negative/anti-HBe positive rate increased concurrently. The distribution of β-catenin could be classified into two types: only membrane (B-1) and membrane with nucleus or cytoplasm (B-2). B-2 showed higher serum aminotransferase level and necroinflammatory score than B-1. Between B-1 and B-2, there was no significant difference in serum HBV DNA level or fibrosis stage. Conclusions: In chronic HBV infection, HBcAg distribution may change from C-1 to C-4 gradually, and in correlation with serum aminotransferase, and HBV DNA and HBeAg negative/anti-HBe positive rate. Nuclear or cytoplasmic distribution of β-catenin, compared with exclusive membranous distribution of β-catenin, is related to active hepatitis, but not viral replication. [ABSTRACT FROM AUTHOR]

Background and Aim: This study investigated the clinical variables that predict hepatitis B e antigen (HBeAg) loss in lamivudine-resistant patients receiving adefovir therapy. Methods: Fifty-six consecutive HBeAg-positive patients treated with adefovir for at least 12 months were enrolled in this study. All had serum alanine aminotransferase (ALT) levels over twice the upper limit of normal (ULN) as a result of lamivudine resistance. Predictors of HBeAg loss after switching from lamivudine to adefovir were examined. Results: During the follow-up period, 18 (32.1%) of 56 patients showed a loss of HBeAg. The estimated rates of HBeAg loss at 6, 12, and 18 months were 11.5%, 26.8%, and 42.9%, respectively. Univariate analysis revealed that pretreatment ALT levels >10 × ULN ( P = 0.029), a viral load at 3 months of therapy ( P = 0.017), and viral decline by >3 log10 from baseline at 3 months ( P < 0.001) were significantly associated with the loss of HBeAg within 12 months of therapy. With multivariate analysis using the stepwise logistic regression model, pretreatment ALT > 10 × ULN (odds ratio [OR], 4.22; 95% confidence interval [CI], 1.09–19.44; P = 0.044) and viral suppression >3 log10 at 3 months (OR, 10.39; 95% CI, 1.86–58.07; P = 0.008) were identified as the two independent predictors of HBeAg loss. Conclusions: Pretreatment ALT levels and the initial pattern of post-treatment viral decline are the strongest predictors of the early achievement of HBeAg loss following treatment with adefovir in lamivudine-resistant patients. These results may provide useful information for the optimal timing of adefovir rescue as well as for better monitoring after treatment. [ABSTRACT FROM AUTHOR]

Recent data have shown that the clinical outcome of hepatitis C virus (HCV) infection may be influenced by the host genetic factor. The aim of this study was to investigate whether particular human leukocytes antigen (HLA) molecules are associated with the susceptibility to HCV infection in the Korean population. Methods: One hundred and thirty-seven patients with chronic HCV infection and 206 normal individuals were examined for HLA class I and II molecules. Results: In class I antigens, the frequencies of HLA-A3 (relative risk (RR)=3.5, P<0.04), HLA-B35 (RR=2.0, P<0.03), and HLA-B46 (RR=2.5, P<0.02) significantly increased in chronic HCV carriers compared with the controls. The frequencies of DRB1*0803, DQB1*0601 and DQB1*0604 were significantly higher in chronic HCV carriers than in controls (RR=2.5, P<0.005; RR=1.8, P<0.05; RR=1.9, P<0.04, respectively). On the other hand, the frequencies of DRB1*0301, DQA1*0501 and DQB1*0201 were significantly lower in chronic HCV carriers than in normal controls (RR=0.2, P<0.03; RR=0.4, P<0.004; RR=0.5, P<0.02, respectively). The haplotype DRB1*0803−DQB1*0601 significantly increased (RR=2.5, P<0.02) while the DQA1*0501−DQB1*0201 significantly decreased (RR=0.2, P<0.03) in chronic HCV carriers compared with normal controls. In stratification analysis to investigate the interrelationships among the associated alleles, DRB1*0803 and DQB1*0601 were associated with HLA-B46, particularly in patients with chronic HCV carriers. Conclusions: These results suggest that particular HLA alleles may have an influence on chronic HCV infection as a host genetic factor in the Korean population. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate retrospectively the long-term effects of lamivudine in 461 Korean patients with chronic hepatitis B who were treated for more than 12 months. Methods: The annual rates of virological response and breakthrough were examined and the predictive factors for post-treatment relapse in 114 patients who achieved hepatitis B e antigen (HBeAg) loss or seroconversion after lamivudine therapy were also analyzed. Results: During follow-up, the rates of HBeAg seroconversion after 1, 2, 3, 4 and 5 years of treatment were 22.9, 33.2, 47.6, 54.2 and 58.8%, respectively, while those for virological breakthrough at 1, 2, 3 and 4 years were 8.2, 41.7, 55.7 and 64.8%, respectively. Ninety-five patients (20.6%) had HBeAg seroconversion and 19 (4.1%) showed HBeAg loss alone with disappearance of hepatitis B virus DNA in serum. Seroconversion was higher with prolonged treatment in patients who had elevated serum alanine aminotransferase. The cumulative relapse rates in the seroconversion group were 52.0 and 55.7% 1 and 2 years after treatment, respectively. Age and the duration of additional treatment were significant predictive factors for post-treatment relapse. Patients aged ≤40 who had additional treatment for >12 months after seroconversion had the lowest relapse rate (p < 0.001). Conclusions: These results suggest that additional treatment for over 12 months after HBeAg seroconversion in younger patients may produce a better long-term outcome. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: Previous studies have shown that a treatment regimen using epirubicin, cisplatin, and 5-fluorouracil (5-FU) (ECF) has a survival benefit for gastric cancer patients. Based on these results and the hypothesis that a combination modality has a better therapeutic advantage over a single mode of therapy, the efficacy of multimodal combination therapy using a transarterial infusion of epirubicin and cisplatin, systemic infusion of 5-FU, and additional percutaneous ethanol injection (PEI) for unresectable hepatocellular carcinoma (HCC) was investigated in this study in comparison with conventional transarterial chemoembolization (TACE). Patients and methods: From July 1997 to September 1998, a total of 52 patients with unresectable HCC who underwent at least two cycles of transarterial chemotherapy were enrolled in this study. Among the 52 patients, 30 (ECF group) received a multimodal combination therapy comprising transarterial infusion of epirubicin (50 mg/m2) and cisplatin (60 mg/m2), systemic infusion of 5-FU (200 mg/m2), and additional PEI every 4 weeks, and the remaining 22 (ADR group) received conventional TACE using Adriamycin (ADR, 50 mg) and Gelfoam every 8 weeks. Results: During the follow-up period (mean 13.8±8.5 months), the objective tumor response of the ECF group was significantly higher than that of the ADR group (53.3 vs 22.7%, P=0.044). The median survival time was 13.5 months for the ECF group and 10.5 months for the ADR group (P=0.026). The cumulative survival rates at 6, 12, 18, and 24 months, respectively, were 90, 57, 27, and 17% for the ECF group and 73, 37, 7, and 0% for the ADR group. Univariate analysis showed five prognostic factors including tumor number, tumor morphology, portal vein thrombosis, Child-Pugh classification, and tumor response. With multivariate analysis, portal vein thrombosis and tumor response were identified as the two independent factors for survival. No serious adverse effect was observed in the ECF group, while there was a higher tendency for hepatic complications in the ADR group. Conclusions: Combination therapy comprising transarterial infusion of epirubicin and cisplatin, systemic infusion of 5-FU, and additional PEI appears to be feasible and promising as a multimodal approach for unresectable HCC. Furthermore, it may provide a survival benefit for patients with more advanced disease. [ABSTRACT FROM AUTHOR]

Background/Aims Pegylated interferon (PEG-IFN) treatment with a high rate of off-therapy host immune control is still an attractive treatment for chronic hepatitis B virus (HBV) infection. There remains uncertain about the prognosis of sustained responder after PEG-IFN treatment who do not need nucleos(t)ides (NAs). We investigated the long-term outcomes of PEG-IFN treatment focused on tolerant patients without NAs up to 13 years. Methods A consecutive 172 patients treated with PEG-IFN for chronic hepatitis B or compensated liver cirrhosis between 2005 and 2014 were enrolled and finally 122 patients who fully completed PEG-IFN treatment were analyzed. The definition of response for PEG-IFN treatment at 6months posttreatment were as follows: hepatitis B e antigen (HBeAg) positive patients, achieve both virologic response (VR; <2,000 IU/mL of HBV DNA) and serologic response (HBeAg loss or seroconversion); HBeAg negative patients, reach VR. During follow-up period, we analyzed the number of patients with HBsAg loss, starting NAs due to viral activation and disease progression including liver cirrhosis and hepatocellular carcinoma (HCC). Results The median follow-up period of 122 patients were 7.2 years (range, 1.1 to 13.2 years). Of 122 patients, 43 patients (35.2%) had a response at 6 months posttreatment. During follow-up, 69 patients (56.6%) started NAs and the patients who had a response for PEG-IFN significantly lower rate of starting NAs (14/43 vs 55/79, p<0.001). HBsAg loss occurred in nine patients (7.4%) and sustained responders without further NAs treatment had significantly high rate of HBsAg loss compared to the patients with starting NAs (13.2% vs 2.9%, p=0.01). Eight patients (6.6%) developed disease progression including HCC (n=3). All of them were nonsustained responders who started NAs after PEG-IFN therapy compared to sustained responders (p=0.03). Conclusions Sustained responders without further NAs treatment after PEG-IFN treatment had a favorable clinical outcome in HBsAg loss and no disease progression up to 13 years. [ABSTRACT FROM AUTHOR]

Background/Aims Transarterial radioembolization (TARE) is a form of radiation therapy performed by selective intra-arterial injection of microspheres loaded with Yttrium-90. TARE is known to be effective in the management of unresectable hepatocellular carcinoma (HCC). The aim of this study is to identify prognostic factors for overall survival (OS) and time to progression (TTP) in patients with HCC undergoing TARE. Methods This study included 73 consecutive HCC patients who underwent TARE from July 2009 to January 2018. The tumor responses to TARE were assessed according to modified Response Evaluation Criteria in Solid Tumors. Results The patients' baseline characteristics were as follows: median age was 66 years, 74% of male. The median tumor size was 9 cm and 41% of the patients had tumors larger than 10 cm. Multifocal HCCs identified in 58% and 26% of the patients showed infiltrative tumor. Sixty-three percent of the patients did not have portal vein tumor thrombus (PVTT), 10% had VP 1-2, and 27% had VP 3-4 of PVTT. Among 73 patients, five (7%) obtained complete response and 25 (34%) showed partial response at 3 months after TARE. Median OS was 27.6 months and TTP was 3.2 months. Multivariate analysis revealed that the absence of PVTT (hazard ratio [HR], 0.137; 95% confidence interval [CI], 0.057 to 0.331; p<0.001) was independent factor for OS. The absence of PVTT (HR, 0.330; 95% CI, 0.172 to 0.632; p=0.001) and tumor diameter ≤10 cm (HR, 0.287; 95% CI, 0.135 to 0.611, p=0.001) were independent prognostic factors for TTP. Conclusions TARE is an effective therapy for patients with advanced HCC. Absence of PVTT before TARE is an independent predictive factor for both OS and TTP. [ABSTRACT FROM AUTHOR]

Background/Aims Drug-induced liver injury (DILI) is liver injury caused by the interplay between drugs, their metabolites and host immune response. The aim of this study is to characterize liver infiltrating immune cells in DILI and to evaluate the correlation between infiltrating immune cells and clinical outcome. Methods From January 2017 to February 2019, 23 patients with DILI were prospectively enrolled in this study. Diagnosis of DILI was based on patient medication history after exclusion of other etiology (virus, alcohol, autoimmune, ischemic hepatitis or extrahepatic obstruction of the bile duct). Liver biopsy was performed, and immunohistochemical stain for CD3, CD68, CD20, and CD38 was done. Experienced pathologist confirmed the pathologic and immunohistochemical findings. Results The causes included health foods or dietary supplements (n=8, 34.8%), folk remedies (n=6, 26.1%), medications (n=4, 17.4%), herb (n=3, 13.0%). Eighteen patients (78.3%) treated with steroid. Two patients progressed to hepatic failure and recovered after steroid treatment. All patients were completely recovered from DILI at 1 month after diagnosis, whether they were treated with steroid or not. The frequency of infiltrated T cells, macrophages, and B cells was quantified by immunohistochemistry. The amounts of T cells, showed linearly ascending correlation with total bilirubin (r=0.370, p=0.030) and Model for End-Stage Liver Disease (MELD) score (r=0.340, p=0.047). The amounts of macrophages showed linearly ascending correlation with total bilirubin (r=0.401, p=0.020), aspartate aminotransferase (r=0.445, p=0.010), and MELD score (r=0.402, p=0.020). Conclusions In this study, we found the positive correlation between the amounts of T cells and macrophages infiltrations and deterioration of liver function in DILI. Favorable responses to steroid therapy suggest that vigorous innate and adaptive immune responses play critical roles in DILI. [ABSTRACT FROM AUTHOR]

Background/Aims Cancer stem cells play a key role in cancer invasion and metastasis. Among CSCs, CD44 has known as important modulators of epithelial-mesenchymal transition (EMT) together with transforming growth factor beta 1. EMT is epithelial cells lose their polarity and acquire mesenchymal cell migratory characteristics. microRNAs (miRNA) could lead to either EMT through the regulation of various transcription factors. This study aimed to investigate the role of miR-148a-5p regulating the EMT as well as CD44 in hepatocellular carcinoma (HCC). Methods We sorted CD44- and CD44+ cells by fluorescence-activated cell sorting in transforming growth factor beta 1 (TGF-β1)-positive SNU-368 cells and TGF-β1-negative SNU-354 cells. The miRNAs expression profiles of CD44 sorted cells and TGF-β1-treated cells were analyzed through next-generation sequencing. miR-148a-5p mimic and inhibitor were transfected into HCC cells. The expression of mRNA and protein were detected by quantitative real-time PCR and Western blot. Results FACS analysis showed high expression of CD44 in two HCC cell lines. SNU-354 CD44+ cells with no TGF-β1 expression only showed increased N-cadherin. However, TGF- β1-stimulated SNU-354 cells and SNU-368 CD44+ cells exhibited lower E-cadherin and higher N-cadherin. We identified different miRNAs between two groups (CD44- vs CD44+ cells and con vs TGF-β1-treated cells), among which miR-148a-5p was up-regulated in SNU-354 CD44+ cells and was downregulated in SNU-354 TGF-β1-stimulated cells. Similarly, miR-148a-5p expression was also down-regulated in SNU-368 CD44+ cells. The Inhibition of miR-148a-5p in SNU-354 cells induced EMT and cell migration. In contrast, overexpression of miR-148a-5p in SNU-368 cells reduced mesenchymal marker and cell migration as well as down-regulation of CD44. Also, TGF-β1 stimulation after miR-148a-5p overexpression induced neither the mesenchymal phenotype nor cell migration. Conclusions Overexpression of miR-148a-5p suppressed EMT. The results suggest that miR-148a-5p may serve as specific biomarkers and therapeutic targets for HCC. [ABSTRACT FROM AUTHOR]

Background/Aims While it has long been known that hepatitis B virus (HBV) integrates into the host genome, the biological role of HBV integration in hepatocarcinogenesis still remains uncertain. The study aimed to localize HBV integrants throughout the host genome by high-throughput sequencing method. Methods Next-generation sequencing (NGS)-based target enrichment sequencing was performed to detect HBV integration in paired tumor/non-tumor tissues from 33 hepatocellular carcinoma (HCC) patients. The Illumina NGS workflow was conducted in the following steps: gDNA sonication to generate DNA libraries, HBV sequence capture using HBV probes, followed by high-throughput sequencing. Chimeric count >10 and AVG_MQ >20 was regarded as true signal. Results HBV integration was identified in all (25/25, 100%) HBsAg-positive and two (2/8, 25%) HBsAg-negative patients with HCC. Two patients who lost HBsAg before HCC development also harbored HBV integration. The average number of integration sites in HBV-related HCC and adjacent non-tumor tissues was 12.45 and 24.04 per sample, respectively. HBV integration most frequently occurred in chromosomes 5 and 10. Recurrent target genes for HBV integration included TERT, MLL4, and PREX2 for tumor and FN1 for non-tumor. The major hotspot breakpoints of host and HBV genomes were located at upstream of hTERT gene and nt 1,600-1,800 of HBV genome, respectively. Integrations in tumor were over-presented in promoter or exon and less presented in intergenic region. Gene-annotation analysis indicated that the recurrent HBV integrations are enriched in cancer-associated genes. HBV integration breakpoints were validated by Sanger sequencing in twelve randomly selected tumor tissues. Conclusions Our study reports a new NGS-based high-throughput targeted sequencing with high detection ability to identify HBV integration in the human genome. This cost-effective method facilitates a survey of HBV integration in a large number of samples in an unbiased way and helps in investigating the oncogenic role of HBV integration in HCC. [ABSTRACT FROM AUTHOR]