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Purpose: The poor prognosis of hepatocellular carcinoma (HCC) is, in part, due to the high rate of recurrence even after “curative resection” of tumors. Therefore, it is axiomatic that the development of an effective prognostic prediction model for HCC recurrence after surgery would, at minimum, help to identify in advance those who would most benefit from the treatment, and at best, provide new therapeutic strategies for patients with a high risk of early recurrence.Experimental Design: For the prediction of the recurrence time in patients with HCC, gene expression profiles were generated in 65 HCC patients with hepatitis B infections.Result: Recurrence-associated gene expression signatures successfully discriminated between patients at high-risk and low-risk of early recurrence (P = 1.9 × 10−6, log-rank test). To test the consistency and robustness of the recurrence signature, we validated its prognostic power in an independent HCC microarray data set. CD24 was identified as a putative biomarker for the prediction of early recurrence. Genetic network analysis suggested that SP1 and peroxisome proliferator–activated receptor-α might have regulatory roles for the early recurrence of HCC.Conclusion: We have identified a gene expression signature that effectively predicted early recurrence of HCC independent of microarray platforms and cohorts, and provided novel biological insights into the mechanisms of tumor recurrence.

Supplementary Data from Gene Expression–Based Recurrence Prediction of Hepatitis B Virus–Related Human Hepatocellular Carcinoma

Supplementary Figures 1-5 from Identification of a Cholangiocarcinoma-Like Gene Expression Trait in Hepatocellular Carcinoma

Supplementary Tables 1-5 from Identification of a Cholangiocarcinoma-Like Gene Expression Trait in Hepatocellular Carcinoma

Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization’s goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions. We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan–Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria. Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03–1.57% among noncirrhotic males and 2.57–6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment. Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.

Scintillation crystals are commonly used for direct detection of weakly interacting massive particles (WIMPs), which are suitable candidates for a particle dark matter. It is well known that the scintillation light yields are different for electron recoil and nuclear recoil. To calibrate the energies of WIMP-induced nuclear recoil signals, the quenching factor (QF) needs to be measured, which is the light yield ratio of the nuclear recoil to electron recoil. Measurements of the QFs for Na and I recoils in a small (2 cm × 2 cm × 1.5 cm) NaI(Tl) crystal are performed with 2.43-MeV mono-energetic neutrons generated by deuteron-deuteron fusion. Depending on the scattering angle of the neutrons, the energies of the recoiled ions vary in the range of 9–152 keV for Na and 19–75 keV for I. The QFs of Na are measured at 9 points with values in the range of 10–23% while those of I are measured at 4 points with values in the range of 4–6%.

Initial performance of the UltraLo-1800 alpha particle detector at the 700 m deep Yangyang underground laboratory in Korea is described. The ionization detector uses Argon as a counting gas for measuring alpha events of a sample. We present initial calibration results and low-activity sample measurements based on the detector's pulse discrimination method and a hardware veto. A likelihood analysis that shows a separation of a bulk component from a surface component with a contamination depth from $^{210}$Po alpha particles using simulated models is presented., Comment: 14 pages, 11 figures, nima accepted

Background & AIMS Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines. Methods We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years. Results The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria. Conclusion There is great variability in CHB disease progression rates even among “lower-risk” populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.

International audience; The GBAR (Gravitational Behavior of Antihydrogen at Rest) experiment at CERN requires efficient deceleration of 100 keV antiprotons provided by the new ELENA synchrotron ring to synthesize antihydrogen. This is accomplished using electrostatic deceleration optics and a drift tube that is designed to switch from -99 kV to ground when the antiproton bunch is inside – essentially a charged particle “elevator” – producing a 1 keV pulse. We describe the simulation, design, construction and successful testing of the decelerator device at -92 kV on-line with antiprotons from ELENA.

COSINE-100 is a dark matter detection experiment that uses NaI(Tl) crystal detectors operating at the Yangyang underground laboratory in Korea since September 2016. Its main goal is to test the annual modulation observed by the DAMA/LIBRA experiment with the same target medium. Recently DAMA/LIBRA has released data with an energy threshold lowered to 1 keV, and the persistent annual modulation behavior is still observed at 9.5 σ . By lowering the energy threshold for electron recoils to 1 keV, COSINE-100 annual modulation results can be compared to those of DAMA/LIBRA in a model-independent way. Additionally, the event selection methods provide an access to a few to sub-GeV dark matter particles using constant rate studies. In this article, we discuss the COSINE-100 event selection algorithm, its validation, and efficiencies near the threshold.

Background There are many studies on emphasizing the importance of quitting smoking, but the smoking status was based on baseline status without subsequent status. Since a significant percentage of patients who have received coronary revascularization change their smoking status, it is necessary to confirm the clinical consequences of smoking status after revascularization. Purpose In this study, we aimed to investigate the impact of smoking status after revascularization on long-term clinical outcomes, using large population based study from the Korean National Health Insurance System. Methods Among 74,004 patients who received coronary revascularization (PCI or CABG) from 1 January 2007 to 21 December 2013 and underwent regular health check-up within 2 years after index PCI, examined for death, MI, revascularization and stroke. Results Within patients who underwent revascularization, 33,800 (45.7%) of patients were self-reported non-smoker, 28,603 (38.7%) were ex-smoker, 11601 (15.6%) were current smokers at first regular health check-up after revascularization. Current smokers were associated with higher risks for death (HR: 1.497; 95% CI: 1.366–1.641), MI (HR: 1.498; 95% CI: 1.302–1.723) and revascularization (HR: 1.088; 95% CI: 1.018–1.164) than non-smokers. Compared with non-smokers, more than 30PY ex-smokers and current smokers showed higher incidence of major adverse cardiovascular and cerebrovascular events (MACCE), defined as a composite of death, MI, revascularization and stroke. Regarding smoking tendency, maintaining non-smokers were lower risk for MACCE than maintaining smokers (Figure 1). Quitters tended to lower MACCE compared to patients who continued to smoke (HR: 0.823; 95% CI: 0.762–0.888). Especially, maintaining non-smokers and quitters significantly showed lower mortality than patients who continued to smoke. Conclusion Smoking is associated with poor clinical outcomes after coronary revascularization especially more than 30PY ex-smokers and current smokers. These results also emphasized that smoking cessation after revascularization also important for mortality benefit. Figure 1 Funding Acknowledgement Type of funding source: None

Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization's goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions.We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan-Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria.Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03-1.57% among noncirrhotic males and 2.57-6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment.Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.

Purpose Presence of antibodies to donor specific human leukocyte antigens (HLA) is a well-known risk factor associated with outcome in heart transplantation (HTx). Recent studies have suggested that non-HLA antibodies could also be associated with outcomes. We sought to assess the combined effect of donor specific HLA antibodies and non-HLA anti-vimentin antibodies on graft outcome in Korean HTx patients. Methods Pre-transplant serum was analyzed in 192 adult patients who underwent HTx from January 2014 to December 2016 in four large transplant centers in Korea. Demographic and outcome data were obtained from the Korean Organ Transplantation Registry (KOTRY), an organization established in 2014 to collect data on transplant patients. Results Donor specific HLA antibodies (DSA) were present in 28 (14.6%) patients, while anti-vimentin antibodies were present in 98 (51.0%) patients. Anti-vimentin antibodies were more prevalent in males (p=0.029), but there were no significant differences in other demographic factors. Positive DSA was associated with a significantly higher rate of 3-month graft failure (log-rank p=0.001). Anti-vimentin antibody positivity was also an independent predictor for 3-month and 1-year graft failure (HRadjust 5.21, 95% CI 1.66-16.37, p=0.005; HRadjust 3.45, 95% CI 1.47-8.09, p=0.004, respectively). In DSA(+) patients, anti-vimentin antibody positivity further discriminated 1-year graft survival (long-rank p=0.002). Conclusion In our analysis of Korean HTx patients, presence of DSA and anti-vimentin antibodies were both associated with increased risk of graft failure at 1 year. Additionally, anti-vimentin antibody positivity further discriminated outcome in pre-sensitized patients. Pre-transplant assessment of anti-vimentin antibodies could help predict outcome and tailor immunotherapy in specific populations.

Background Donor-specific antibodies (DSA) are measured at the time of transplantation to predict renal allograft outcome, but pretransplantation DSA are sometimes not adequate to predict antibody-mediated rejection (AMR). We previously developed a flow cytometric assay that could measure the number of antibody-secreting cells (ASCs) instead of DSA. Here, we evaluated the performance of the flow cytometric ASC assay in predicting renal allograft rejection and compared it with that of the enzyme-linked immunospot (ELISpot) assay. Methods We enrolled 25 patients who received renal transplantation between May 2017 and August 2017 at Seoul National University Hospital. Mononuclear cells separated from patient peripheral blood obtained on pretransplantation day 1 were incubated with CpG 2006, human CD40L, interleukin-21, and donor or autologous lymphocyte lysates for 6 days. Flow cytometry and ELISpot assay (Mabtech) were performed to measure the ASCs and their association with graft rejection. Results The number of donor-reactive ASCs, as measured by flow cytometry, was higher in the rejection group than in the nonrejection group (mean ± standard deviation [SD], 3688.9 ± 3875.3 vs 257.9 ± 297.3, P = .014), and no significant difference was observed in the ELISpot assay. Multiple linear regression analysis showed that the number of donor-reactive ASCs measured by flow cytometry was independently and negatively associated with the number of rejection-free days (P = .008, partial R2 = 0.368, adjusted R2 = 0.496). Conclusion After renal transplantation, an increased number of donor-reactive ASCs, as measured by flow cytometry, was associated with allograft rejection. This may be useful to predict renal allograft rejection by measuring the sensitization status of patients who are awaiting renal transplantation.

Background High levels of lipids and lipid variability are established risk factors for atherosclerotic cardiovascular disease. We investigated their roles in the development of atrial fibrillation (AF). This is the largest cohort study yet on the association between lipid levels and AF, and the first study on the association between lipid variability and AF. Methods A nationwide population-based cohort of 3,828,652 adults (mean age 43.9 years) from the Korean National Health Insurance Service database without prevalent AF, not on lipid-lowering medication, and with at least 3 measurements of each lipid parameter at 1–2 year intervals over a 4-year period were included. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured, and lipid variability was calculated using variability independent of mean. The cohort was divided into quartiles by baseline lipid levels and lipid variability, and followed up for incident AF. Results During median 3.4 years of follow-up, AF was newly diagnosed in 13,240 (0.35%). AF development was inversely associated with TC and LDL-C levels (for top vs. bottom quartile; TC, hazard ratio [HR] 0.76, 95% confidence interval [95% CI] 0.72–0.80); LDL-C, HR 0.78, 95% CI 0.74–0.82) in both sexes, and with TG levels in men (HR 0.85, 95% CI 0.80–0.90). Meanwhile, AF development was associated with higher LDL-C and HDL-C variability (for top vs. bottom quartile; LDL-C, HR 1.16, 95% CI 1.10–1.22; HDL-C, HR 1.08, 95% CI 1.03–1.14) in both sexes, and with TC variability in men (HR 1.16, 95% CI 1.10–1.22). Conclusions Lower cholesterol levels (TC, LDL-C) and higher cholesterol variability (LDL-C, HDL-C) were associated with higher risk for AF. Low TG levels and high TC variability were also associated with AF incidence in men. These findings support the “cholesterol paradox” in AF, and suggest that cholesterol variability is also a risk factor for AF development.

Background Bodyweight fluctuation is a risk factor for cardiovascular events and death. We investigated whether bodyweight variability is also a risk factor for atrial fibrillation (AF) development. Methods A nationwide population-based cohort of 8,091,401 adults from the Korean National Health Insurance Service database without previous history of AF and with at least 3 measurements of bodyweight over a 5-year period was followed up for incident AF. Intra-individual bodyweight variability was calculated using variability independent of mean, and high bodyweight variability was defined as the quartile with highest bodyweight variability (Q4) with Q1–3 as reference. Results During median 8.1 years of follow-up, AF was newly diagnosed in 158,347 (2.0%). Increasing bodyweight variability was associated with AF development after adjustment for baseline bodyweight, height, age, sex, lifestyle factors and comorbidities: each increase of 1-SD in bodyweight variability was associated with 5% increased risk of AF development (hazard ratio [HR] 1.05, 95% confidence interval [CI] 1.04–1.05), and subjects with highest bodyweight variability (Q4) showed 14% increased risk of AF development compared to those in the quartile with lowest bodyweight variability (HR 1.14, 95% CI 1.12–1.15). When the cohort was grouped by body mass index (BMI) into underweight, normal weight, overweight, obese (Figure 1A), subjects with high bodyweight variability showed a shallow U-shaped relationship of BMI with AF incidence, with the highest incidence rate of AF in the underweight group. On the other hand, subjects with reference bodyweight variability showed a proportional increase of AF incidence with BMI, with the highest AF incidence in the obese group. High bodyweight variability was significantly associated with AF development in all BMI groups except in the very obese (BMI≥30) in multivariable analysis, and this association was stronger in subjects with lower bodyweight. In underweight subjects, high bodyweight variability was associated with 16% increased risk of AF development (HR 1.16, 95% CI 1.08–1.24). Obese subjects with high bodyweight variability compared to those with reference variability showed lower crude AF incidence rates, but after multivariable analysis, AF risk was increased (obese stage I) or comparable (obese stage II). When the cohort was grouped by total bodyweight change (Figure 1B), subjects with high bodyweight variability showed higher AF incidence and elevated AF risk on multivariable analysis in all weight change groups. Subjects with overall weight loss (≥-5%) and high bodyweight variability showed the highest AF incidence and AF risk (HR 1.12, 95% CI 1.09–1.15). Figure 1 Conclusions Fluctuation in bodyweight was independently associated with higher risk of AF development. The association of high bodyweight variability with AF development was especially stronger in subjects with lower bodyweight, and in subjects with overall weight loss (≥-5%)

For the GBAR (Gravitational Behaviour of Antihydrogen at Rest) experiment at CERN's Antiproton Decelerator (AD) facility we have constructed a source of slow positrons, which uses a low-energy electron linear accelerator (linac). The driver linac produces electrons of 9 MeV kinetic energy that create positrons from bremsstrahlung-induced pair production. Staying below 10 MeV ensures no persistent radioactive activation in the target zone and that the radiation level outside the biological shield is safe for public access. An annealed tungsten-mesh assembly placed directly behind the target acts as a positron moderator. The system produces $5\times10^7$ slow positrons per second, a performance demonstrating that a low-energy electron linac is a superior choice over positron-emitting radioactive sources for high positron flux., published in NIM A. 33 pages 9 figures

INTRODUCTION: Spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the functional cure of hepatitis B infection, occurs rarely. Prior original studies are limited by insufficient sample size and/or follow-up, and recent meta-analyses are limited by inclusion of only study-level data and lack of adjustment for confounders to investigate HBsAg seroclearance rates in most relevant subgroups. Using a cohort with detailed individual patient data, we estimated spontaneous HBsAg seroclearance rates through patient and virologic characteristics. METHODS: We analyzed 11,264 untreated patients with chronic hepatitis B with serial HBsAg data from 4 North American and 8 Asian Pacific centers, with 1,393 patients with HBsAg seroclearance (≥2 undetectable HBsAg ≥6 months apart) during 106,192 person-years. The annual seroclearance rate with detailed categorization by infection phase, further stratified by hepatitis B e antigen (HBeAg) status, sex, age, and quantitative HBsAg (qHBsAg), was performed. RESULTS: The annual seroclearance rate was 1.31% (95% confidence interval: 1.25–1.38) and over 7% in immune inactive patients aged ≥55 years and with qHBsAg 55 years: aHR = 1.21), negative HBeAg (aHR = 6.34), and genotype C (aHR = 1.82) predicted higher seroclearance rates, as did lower hepatitis B virus DNA and lower qHBsAg (P < 0.05 for all), and inactive carrier state. DISCUSSION: The spontaneous annual HBsAg seroclearance rate was 1.31%, but varied from close to zero to about 5% among most chronic hepatitis B subgroups, with older, male, HBeAg-negative, and genotype C patients with lower alanine aminotransferase and hepatitis B virus DNA, and qHBsAg independently associated with higher rates (see Visual Abstract, Supplementary Digital Content 2, http://links.lww.com/CTG/A367).

Purpose We aimed to investigate prognosis of heart transplanted (HTx) patients who experienced RRT in perioperative period. Methods Korean Organ Transplant Registry (KOTRY) is nationwide, organ transplant registry in Korea. We reviewed 501 HTx patients prospectively enrolled in KOTRY. Among them, 13 patients who underwent combined heart and kidney transplantation (HKTx). Remaining patients were grouped as follows; Gr 1: Patients who were free of periop RRT. Gr 2: patients who required preop RRT but not postop RRT. Gr 3: patients who were free of preop RRT but necessitated postop RRT, Gr 4: patients who needed both preop and postop RRT. Postoperative RRT was defined as the need for dialysis after HTx during postoperative management. The primary outcome was dialysis dependent end-stage renal disease (ESRD). The secondary outcome was overall mortality. Results Follow up duration was 22 months (9-39 month). Gr 4 pateints had significantly more ischemic heart disease, but less idiopathic DCMP. Patients who needed preop RRT (Gr 2 and 4) had higher incidence of DM. Significantly more patients who needed preop RRT (Gr 2 and Gr 4) experienced preHTx mechanical cardiac support and ventilator (p Conclusion We suggested that HF patients on HTx waiting list with severe kidney dysfunction requiring RRT still should be considered for HTx. Among patients who needed preopRRT, those who did not require postop RRT showed comparable survival rates to pateints who were free of periop RRT. Also, those with ischemic HF and DM with severe renal dysfunction requiring preoperative RRT should be considered for HKTx to improve post HTx outcome.

Introduction Shift work is known to have a negative impact on a wide range of health problems such as sleep disturbance, cognitive impairment, and emotional disorders (e.g., anxiety and depression). It is important to understand underlying mechanisms for negative impact of shift work on health problems. This study aimed to investigate psychological and neural mechanisms associated with shift work. Methods Thirty six shift workers (28 females, age = 29.9 ± 7.4) and 35 non-shift workers (20 females, age = 30.5 ± 5.5) participated in this study. They were performing the word Stroop task during fMRI scanning. This task included sleep-related words and negative words to investigate neural substrates associated with sleep-related information and emotional information processing. Neutral words were included as control stimuli. The participants also completed questionnaires assessing sleep-related problems such as Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale, and emotion-related problems such as Beck Depression Inventory and Beck Anxiety Inventory. Two-sample t-tests were conducted to find group differences in self-report measures and neural response to sleep-related words and negative words compared to neutral words. Results Relative to non-shift workers, shift workers showed greater sleep disturbance (i.e., higher PSQI), but they did not show any evidence of emotion-related problems. Shift workers also demonstrated greater neural response to negative words (vs. neutral words) in several prefrontal regions (e.g., dorsal anterior cingulate cortex and dorsolateral prefrontal cortex), anterior insula and caudate compared to non-shift workers. However, shift workers did not show significantly different neural response to sleep-related words (vs. neutral words) compared to non-shift workers. Conclusion The result from this study provides supporting evidence that shift work is associated with subjective sleep disturbance. Shift workers’ heightened neural response to negative information may reflect their increased sensitivity to negative information, that may contribute to sleep disturbance. Support Brain Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (Study No.: 2016M3C7A1904338 and NRF-2018R1D1A1B07049704).

BackgroundJapanese cedar pollen (JCP) is the major outdoor allergen for spring pollinosis and seasonal allergic rhinitis (SAR) caused by JCP is the most common disease in Jeju Island, South Korea and in Japan. Prior to our research, JCP counts were strongly temperature dependent and were significantly associated with the JCP sensitization rate and JC pollinosis. This event may still be ongoing due to the effects of global climate change, such as increasing temperature.Methods and FindingFor these reasons, we are studying the correlation among increasing temperatures, the JCP counts in the atmosphere and the JCP sensitization rate.ConclusionsIn this study, our data show that increasing temperatures in January and April might lead to earlier and longer JCP seasons and that earlier and longer JCP seasons lead to an increase in the JCP sensitization rate, which influences the prevalence of JC pollinosis.

Prevention and restoration of hepatic fibrosis from chronic liver injury is essential for the treatment of patients with chronic liver diseases. Vitamin C is known to have hepatoprotective effects, but their underlying mechanisms are unclear, especially those associated with hepatic fibrosis. Here, we analyzed the impact of vitamin C on bile acid induced hepatocyte apoptosis in vitro and lithocholic acid (LCA)-induced liver injury in vitamin C-insufficient Gulo(-/-) mice, which cannot synthesize vitamin C similarly to humans. When Huh-BAT cells were treated with bile acid, apoptosis was induced by endoplasmic reticulum stress-related JNK activation but vitamin C attenuated bile acid-induced hepatocyte apoptosis in vitro. In our in vivo experiments, LCA feeding increased plasma marker of cholestasis and resulted in more extensive liver damage and hepatic fibrosis by more prominent apoptotic cell death and recruiting more intrahepatic inflammatory CD11b(+) cells in the liver of vitamin C-insufficient Gulo(-/-) mice compared to wild type mice which have minimal hepatic fibrosis. However, when vitamin C was supplemented to vitamin C-insufficient Gulo(-/-) mice, hepatic fibrosis was significantly attenuated in the liver of vitamin C-sufficient Gulo(-/-) mice like in wild type mice and this hepatoprotective effect of vitamin C was thought to be associated with both decreased hepatic apoptosis and necrosis. These results suggested that vitamin C had hepatoprotective effect against cholestatic liver injury.

Background and Aim A uniform staging system for hepatocellular carcinoma (HCC) is needed. In this study, the discrimination abilities of HCC staging systems (American Joint Committee on Cancer [AJCC], Barcelona Clinic Liver Cancer [BCLC], Cancer of the Liver Italian Program, and Okuda stage) were compared during the course of untreated HCC. Methods We included consecutive 80 patients diagnosed with HCC, but were not treated for HCC, at a single medical center in Korea. In addition, 177 treated patients matched by prognostic factors were included to evaluate the survival gain owing to locoregional treatment. Results The mean age of untreated patients was 58.7 years. During the observation period (median = 41.1 months), 72 patients died (median survival = 2.1 months; range = 1.6–33.7 months). Among various staging systems, the BCLC system had the best discrimination ability (linear trend χ2 = 16.35). Multivariate analysis indicated that the intrahepatic tumor classification (AJCC T classification) was an independent predictor of overall survival (OS) (P = 0.001). However, either node or metastasis classification failed to affect the OS significantly (both P > 0.05). Patients undergoing intrahepatic tumor control with locoregional therapy showed prolonged survival in those patients with nodal involvement (hazard ratio = 0.315; P = 0.004) and extrahepatic metastasis (hazard ratio = 0.658; P = 0.258), respectively, after adjustment for independent prognostic factors. Compared with untreated patients, BCLC stage A and B patients had > 1 year of survival gain but those with stage C and D did not, owing to locoregional therapy. Conclusion The BCLC system had the best discrimination among untreated HCC patients. However, re-evaluation of the clinical importance of nodal and metastasis classification might be required.

PURPOSE To evaluate the incidence and risk factors of post-treatment intracranial hemorrhage of brain metastases from hepatocellular carcinoma (HCC). MATERIALS AND METHODS Medical records of 81 patients who have been diagnosed of brain metastases from HCC and underwent surgery, radiosurgery and/or whole brain radiotherapy (WBRT) between January 2000 and December 2013 were retrospectively reviewed. RESULTS Intracranial hemorrhage was present in 64 patients (79%) at the time of diagnosis. Median value of alpha-fetoprotein (AFP) level was 1,700 ng/mL. The Eastern Cooperative Oncology Group (ECOG) performance status for 20 patients was greater than 2. Fifty-seven patients underwent WBRT and the others were treated with surgery and/or radiosurgery without WBRT. During follow-up, 12 events of intracranial hemorrhage after treatment were identified. Three-month post-treatment hemorrhage rate was 16.1%. Multivariate analyses revealed that ECOG performance status, AFP, and WBRT were associated with post-treatment hemorrhage (p = 0.013, 0.013, and 0.003, respectively). Kaplan-Meier analysis showed that 3-month post-treatment hemorrhage rate of new lesion was higher in patients treated without WBRT, although statistical significance was not reached. (18.6% vs. 4.6%; p = 0.104). Ten of 12 patients with post-treatment hemorrhage died with neurologic cause. CONCLUSION WBRT should be considered to prevent post-treatment hemorrhage in the treatment of brain metastases from HCC.

Entecavir (ETV) plus adefovir (ADV) combination therapy is one of the useful treatment option for the patients with chronic hepatitis B (CHB) who had failed on prior nucleos(t) ide analogue (NA) treatments. This study compared the efficacies of the combinations of ETV 0.5 mg plus ADV and ETV 1.0 mg plus ADV in patients who had failed on prior multiple NA treatments. This retrospective analysis included 148 consecutive patients with CHB infection in Korea (n = 37 with ETV 0.5 mg plus ADV and n = 111 with ETV 1.0 mg plus ADV). The virological and biochemical responses were compared between the two groups. The cumulative probability of viral suppression of ETV 0.5 mg plus ADV was not inferior to that of ETV 1.0 mg plus ADV (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.38–1.08; P = 0.094). The changes in serum HBV DNA level in the ETV 0.5 mg plus ADV group were not different between the two groups over 12 months. Moreover, no significant difference was observed in acquiring ETV-resistant variants between the two groups during the treatment (HR, 0.95; P = 0.953). This study suggests the proof-of-concept that the lower dose of NA in combination with other NA might be the theoretical option for rescue combination therapy in patients with CHB who had failed on prior multiple NA treatments in order to reduce systemic exposure and possible side effects of NA. J. Med. Virol. 87:999–1007, 2015. © 2015 Wiley Periodicals, Inc.

Although oral nucleos(t)ide analogues can lead to suppression of serum hepatitis B virus (HBV) DNA to undetectable levels efficiently, they usually fail to achieve seroclearance of hepatitis B surface antigen (HBsAg), which indicates eradication of HBV infection. In this study, the efficacy of therapeutic vaccination in patients with chronic HBV infection was evaluated by comparing to the control patients. Patients who had achieved complete virologic response following oral nucleos(t)ide analogue treatment for at least 6 months were included. Vaccinated patients were given three intramuscular injections of hepatitis B vaccine that each contains 20 µg of HBsAg. The efficacy of vaccination was assessed by testing for HBsAg seroclearance. A total of 32 consecutive patients were analyzed, which included 15 vaccinated patients and 17 control patients. At month 6, 1 out of 15 vaccinated patients (6.7%) and 1 out of 17 control patients (5.9%) were determined to clear HBsAg from their sera (P = 1.000). A baseline HBsAg titer of ≤100 IU/mL tended to be predictive of HBsAg seroclearance, but the relationship was not significant (P = 0.097). During the follow-up period, virologic relapse occurred in 29 patients, and 9 patients developed hepatitis flare. The cumulative incidences of virologic relapse and hepatitis flare were similar between the vaccinated and control patients (P = 0.077 and P = 0.667, respectively). In conclusion, therapeutic HBV vaccination in patients who had stopped nucleos(t)ide analogue treatment showed limited efficacy for HBsAg seroclearance. To enhance the efficacy and safety of therapeutic HBV vaccination, rational patient selection and novel therapeutic approaches are needed. J. Med. Virol. 87:575–582, 2015. © 2015 Wiley Periodicals, Inc.

Background/Aims. Hepatitis B virus (HBV) can form immune complexes which may result in various types of glomerulonephritis (GN). However, proteinuria can occur because of other kidney diseases besides HBV-related GN (HBV-GN). The aim of this study is to elucidate the causes of proteinuria and report on the clinical outcomes of HBV-GN.Methods. We reviewed the medical records of patients positive for serum hepatitis B surface antigen who underwent renal biopsies due to proteinuria at a tertiary medical center in Korea.Results. A total of 55 patients were included. HBV-GN was diagnosed in 20 (36.4%) of the patients by confirming the presence of immune complexes (12 of 13 membranoproliferative glomerulonephritis, 7 of 8 membranous glomerulonephritis, and 1 of 13 immunoglobulin A nephropathy). Twenty-one patients had other types of GN. A total of 13 (65%) HBV-GN patients were treated with antiviral agents for a median of 11 months. However, the degrees of proteinuria were not significantly reduced in the antiviral intervention group when compared to the control group.Conclusions. Proteinuria can be caused by various glomerular diseases and HBV-GN accounts for one-third of total GN cases. Well-designed prospective study is needed to assess whether antiviral therapy against HBV infection may improve the prognosis of HBV-GN.

Liver cancer is one of the most drug-resistant cancer types, and cancer stem cells are related to drug resistance. c-Jun-N-terminal kinase (JNK) signaling is involved in drug resistance, and the side population of cells (SP cells) can be used as a model to study liver cancer stem cells. We sought to evaluate the relationship between SP cells and JNK signaling in hepatocarcinoma cells. For this purpose, we examined cell proliferation and the SP cell ratio following treatment of Huh7 cells with the anticancer drugs 5-fluorouracil (5-FU) and paclitaxel. The expression of phospho-stress-activated protein kinase (SAPK)/JNK in the treated cells was evaluated using immunoblotting. 5-FU and paclitaxel treatment increased the number of SP cells and JNK phosphorylation, and decreased cell survival. Huh7 and HepG2 cells were also treated with SP600125, a JNK inhibitor, to study the relationship between SP cells and JNK signaling. The increase in the number of SP cells and the SAPK/JNK and c-Jun phosphorylation was reverted by SP600125 treatment in these cells. We also used immunohistochemistry and showed that SAPK/JNK and c-Jun phosphorylation are increased in hepatocarcinoma tissues. In conclusion, our results demonstrate that the number of SP cells and SAPK/JNK phosphorylation are increased upon treatment with anticancer drugs, and that this increase is blocked by inhibition of JNK signaling. These findings suggest that drug resistance in liver cancer may involve an increase in the number of SP cells following JNK activation.

Background & Aims Accurate prognostication of acute-on-chronic liver failure (ACLF) is essential for therapeutic decisions. Our aim was to validate a novel scoring system for predicting mortality, the chronic liver failure-sequential organ failure assessment (CLIF-SOFA), in a population of Asian patients with ACLF. Methods A total of 345 patients with acutely decompensated alcoholic cirrhosis were selected for study, comparing areas under the receiver operating characteristic (AUROC) curves of CLIF-SOFA and five existing scoring systems for end-stage liver disease [model for end-stage liver disease (MELD), MELD-Na, Refit-MELD, Refit-MELD-Na, and Child-Turcotte-Pugh]. Results CLIF-SOFA displayed the highest AUROC of 0.943 significantly outperforming all five reference methods in predicting short-term mortality at Week 4 (all P

The aim of this study is to evaluate prognostic factors of brain metastases from hepatocellular carcinoma. Medical records of 95 patients who have been diagnosed of brain metastases from hepatocellular carcinoma between January 2000 and December 2011 were retrospectively reviewed. The median age at diagnosis of brain metastases is 56.1 years. Eighty-two patients were male. Median interval from diagnosis of hepatocellular carcinoma to brain metastases was 29.5 months. Eighty-eight patents had extracranial metastases, and the lung was the most frequent involved organ. Motor weakness was the most frequent presenting symptom (49.5 %). Intracranial hemorrhage was present in 71 patients (74.7 %). Brain metastases were treated with whole brain radiation therapy (WBRT) alone in 57 patients, radiosurgery alone in 18, surgery and WBRT in 6, surgery and radiosurgery in 3, surgery alone in 3, radiosurgery and WBRT in 2, and conservative management only in 6. Median overall survival was 3.0 months. Multivariate analysis showed ECOG performance status, Child-Pugh class, AFP level, number of brain lesions, and treatment modality were associated with survival (p