Danbi Lee

HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability

Objective Little is known about the long-term clinical outcome and durability of HBsAg seroclearance following nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB). Design During a median follow-up period of 6 years (33 567 patient-years) of 5409 CHB patients who were initially treated with lamivudine or entecavir, a total of 110 achieved HBsAg seroclearance (0.33% annual seroclearance rate) and were included in this study. Results Baseline alanine aminotransferase (ALT) level >5 times of upper limit of normal was associated with higher probability of HBsAg seroclearance (HR 1.80, p<0.01), while HBeAg positivity (HR 0.46, p<0.01), high HBV DNA level (log10 IU/mL; HR 0.61, p<0.01), and cirrhosis (HR 0.48, p<0.01) were inversely associated with the probability of HBsAg seroclearance by multivariable analysis. During follow-up for 287 patient-years after HBsAg seroclearance, only two patients with baseline cirrhosis developed hepatocellular carcinoma (HCC) or died (0.7% annual risk), which was of a significantly lower rate compared with propensity score-matched patients without HBsAg seroclearance (HR 0.09, p<0.01). HBsAg reversion and/or HBV DNA reversion occurred in 18 patients, most of which were transient with extremely low serum levels of HBsAg (0.05–1.00 IU/mL) and HBV DNA (17-1818 IU/mL). None required retreatment. The cumulative probability of anti-HBs seroconversion (detection of anti-HBs) at 4 years was 67.4% by Kaplan–Meier analysis. Selection for lamivudine-resistance HBV mutants during treatment was not associated with composite reversion (p=0.66). Conclusions HBsAg seroclearance achieved after NUC treatment was associated with favourable clinical outcomes and was durable in most cases during long-term follow-up.

Incidence of hepatocellular carcinoma after HBsAg seroclearance in chronic hepatitis B patients: A need for surveillance

BACKGROUND & AIMS Little is known about whether surveillance for hepatocellular carcinoma (HCC) is worthwhile in chronic hepatitis B virus (HBV)-infected patients who have achieved HBsAg seroclearance. METHODS A retrospective analysis of 829 patients (mean age: 52.3 years; 575 males; 98 with cirrhosis) achieving HBsAg seroclearance was performed at a tertiary hospital in Korea between 1997 and 2012. We evaluated incidence rates of HCC, and validated CU-HCC score based on data at the time of HBsAg seroclearance. RESULTS During a follow-up of 3464 patient-years, 19 patients developed HCC (annual rate: 0.55%). Liver cirrhosis (hazard ratio [HR]: 10.80; 95% confidence interval [CI]: 4.25-27.43), male gender (HR: 8.96; 95% CI: 1.17-68.80), and age ⩾50 years at the time of HBsAg seroclearance (HR: 12.14; 95% CI: 1.61-91.68) were independently associated with HCC. The estimated annual incidence of HCC was 2.85% and 0.29% in patients with and without cirrhosis, respectively. Among the non-cirrhotic patients, the annual rate of HCC was higher in the male patients than in the females (0.40% vs. 0%, respectively), and all the HCCs developed after age 50. The time-dependent area under the receiver operating characteristic curves for the CU-HCC score for 5 year and 10 year HCC prediction were 0.85 and 0.74, respectively. CONCLUSIONS HCC surveillance should be considered for cirrhotic patients and non-cirrhotic male patients over age 50, even after HBsAg seroclearance, especially those infected with HBV genotype C. HBsAg seroclearance at age ⩾50years was also an independent predictor for HCC.

Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma†

Sorafenib currently sets the new standard for advanced hepatocellular carcinoma (HCC). It has been suggested that Asian patients with HCC have increased susceptibility to hand‐foot skin reaction (HFSR) related to sorafenib therapy. The authors investigated the association between sorafenib‐induced HFSR and genetic polymorphisms in Korean patients with HCC.

Transforming growth factor beta 1 overexpression is closely related to invasiveness of hepatocellular carcinoma.

Objectives: The study was aimed to investigate the relationship between plasma transforming growth factor beta 1 (TGF-β1) expression and the characteristics of hepatocellular carcinoma (HCC). Methods: Five hundred and seventy-one patients with HCC were subjected. Plasma TGF-β1 levels were measured by enzyme-linked immunosorbent assay at diagnosis and compared in accordance with clinical and radiological characteristics. Results: Plasma TGF-β1 levels were significantly higher in the diffuse infiltrative type (n = 159) than in the nodular type of HCC (n = 412; 3.94 ± 0.34 vs. 3.79 ± 0.29 log10 pg/ml; p < 0.001). They were much higher in patients with portal vein thrombosis or extrahepatic metastasis than in those without (3.88 ± 0.34 vs. 3.81 ± 0.29 log10 pg/ml, p = 0.008; 3.94 ± 0.35 vs. 3.82 ± 0.30 log10 pg/ml, p = 0.013, respectively). Also, plasma TGF-β1 levels showed a positive correlation with the size of HCC (r = 0.014, p < 0.001). Additionally, plasma TGF-β1 levels were inversely related to the survival periods (p < 0.001). Conclusion: TGF-β1 was overexpressed in invasive types of HCC and it may be involved in the rapid progression of HCC.

Prevalence and Prediction of Coronary Artery Disease in Patients With Liver Cirrhosis A Registry-Based Matched Case–Control Study

Background— There is conflict regarding the prevalence of coronary artery disease (CAD) in patients with liver cirrhosis. This study aimed to investigate the prevalence of silent CAD in comparison with the general population, and to identify the relevant risk factors in patients with liver cirrhosis. Methods and Results— This retrospective study included 1045 prospectively registered consecutive patients with liver cirrhosis without any history of chest pain or CAD, who underwent computerized coronary angiography as a pretransplant workup. These were matched with 6283 controls with healthy livers, based on propensity scores according to established cardiovascular risk factors. Obstructive CAD was defined as ≥50% luminal narrowing in any artery. A matched analysis of 853 pairs showed that the proportion of subjects with obstructive CAD did not differ significantly between the cirrhotic and control groups (7.2% versus 7.9%, P=0.646), in agreement with the outcome of multivariate analysis for its predictors, with an adjusted odds ratio for liver cirrhosis of 1.06 (P=0.690). Nonobstructive CAD was more prevalent in the matched cirrhotic cases (30.6% versus 23.4%, P=0.001). In the pooled cirrhotic cohort, older age, male sex, hypertension, diabetes mellitus, and alcoholic cirrhosis were independently associated with obstructive CAD (adjusted odds ratios, 1.07, 2.74, 1.69, 2.37, and 2.17, respectively; P<0.05 for all), whereas liver function and coagulation parameters were not. Conclusions— Asymptomatic cirrhotic patients and nonhepatic subjects are similar in terms of the prevalence of occult obstructive CAD. Traditional cardiovascular risk factors are related to critical coronary stenosis in cirrhotic patients, and thus may be helpful indicators for more careful preoperative evaluation of coronary risk.

Comparison of chemoembolization with and without radiation therapy and sorafenib for advanced hepatocellular carcinoma with portal vein tumor thrombosis: a propensity score analysis.

PURPOSE To compare efficacy of transarterial chemoembolization with and without radiation therapy (RT) versus sorafenib for advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). MATERIALS AND METHODS This single-center retrospective study involved 557 patients with HCC with PVTT who initially received chemoembolization (1997-2002; n = 295), chemoembolization and RT (2003-2008; n = 196), or sorafenib (2009-2012; n = 66) according to eligibility criteria among an initial population of 617. The three groups were divided into three pairs (chemoembolization vs chemoembolization/RT, chemoembolization vs sorafenib, and chemoembolization/RT vs sorafenib), and time to progression (TTP) and overall survival (OS) were compared by propensity-score analyses. RESULTS The chemoembolization/RT group had longer median TTP and OS than the chemoembolization-alone and sorafenib groups (P < .001). Multivariate Cox analysis revealed that chemoembolization/RT treatment was an independent predictor of favorable TTP and OS. In the matched cohort, median TTP and OS were significantly longer in the chemoembolization/RT group than the chemoembolization-alone group (102 pairs; TTP, 8.7 mo vs 3.6 mo [P < .001]; OS, 11.4 mo vs 7.4 mo [P = .023]) or the sorafenib group (30 pairs; TTP, 5.1 mo vs 1.6 mo [P < .001]; OS, 8.2 mo vs 3.2 mo [P < .001]), in agreement with the inverse probability of treatment weighted (IPTW) outcomes. In matching analyses, the chemoembolization-alone group had longer median TTP and OS than the sorafenib group (46 pairs; TTP, 3.4 mo vs 1.8 mo [P < .001]; OS, 5.9 mo vs 4.4 mo [P = .003]). There was no significant difference in terms of OS with the IPTW approach (P = .108), but there was one in terms of TTP (P < .001). CONCLUSIONS Within the limitation of a retrospective study, the present data indicate that transarterial chemoembolization combined with RT could be considered as an alternative to the standard sorafenib in the treatment of patients with advanced-stage HCC with PVTT.

Reappraisal of serum alpha-foetoprotein as a surveillance test for hepatocellular carcinoma during entecavir treatment.

The aim of this study was to re‐evaluate the diagnostic performance of alpha‐foetoprotein (AFP) as a surveillance test for hepatocellular carcinoma (HCC) in patients with hepatitis B virus‐related chronic liver disease who were treated with entecavir (ETV).

Clinical Implications of Arrest-Defective Protein 1 Expression in Hepatocellular Carcinoma: A Novel Predictor of Microvascular Invasion

Objective: The associations between arrest-defective protein 1 (ARD1) gene expression and the clinicopathological characteristics and clinical outcomes of 94 patients undergoing hepatectomy for hepatocellular carcinoma (HCC) were investigated. Methods: ARD1 mRNA levels in HCC and corresponding non-cancerous tissues were quantified by real-time PCR. The gene expression of the tumor relative to that in the non-tumor tissues was calculated using the 2–ΔΔCT method. The subjects were classified into high expression (2–ΔΔCT > 1, n = 38) and low expression (2–ΔΔCT ≤ 1, n = 56) groups. Results: The HCCs did not differ from matched liver tissues in terms of ARD1 mRNA levels. The high expression group had more often microvascular invasion than the low expression group (32 vs. 14%; p = 0.045). The two groups did not differ significantly in terms of other patient or tumor variables. The median follow-up period was 92.1 months. The 5-year recurrence-free and overall survival rates were 34 and 76% for the high expression group, respectively, which were similar to the rates of the low expression group (46 vs. 73%, p = 0.98 and p = 0.52, respectively). Conclusions: Intratumoral ARD1 mRNA overexpression was involved in the microvascular invasion process in patients with HCC, although it did not associate strongly with postresectional outcomes.

Recurrences of hepatocellular carcinoma following complete remission by transarterial chemoembolization or radiofrequency therapy: Focused on the recurrence patterns

In this study, we analyzed the rates and patterns of recurrences in hepatocellular carcinoma (HCC) patients who had achieved complete remission (CR) by transarterial chemoembolization (TACE) or radiofrequency ablation (RFA), and also examined the differences of recurrence patterns between TACE‐treated and RFA‐treated groups.

Single nucleotide polymorphisms associated with metastatic tumour antigen 1 overexpression in patients with hepatocellular carcinoma

Metastatic tumour antigen 1 (MTA1) promotes angiogenesis by stabilizing hypoxia‐inducible factor‐1α (HIF‐1α), which is closely associated with frequent postoperative recurrence and poor survival in patients with HCC. In this study, we determined single nucleotide polymorphisms (SNPs) in angiogenesis‐related genes that are associated with MTA1 overexpression in HCC tissues.