Recent advances in sequencing technology have allowed us to profile genome-wide mutations of various cancer types, revealing huge heterogeneity of cancer genome variations. However, its heterogeneous landscape of somatic mutations according to liver cancer progression is not fully understood. Here, we profiled the mutations and gene expressions of early and advanced hepatocellular carcinoma (HCC) related with Hepatitis B-viral infection. Integrative analysis was performed with whole-exome sequencing and gene expression profiles of the 12 cases of early and advanced HCCs and paired non-tumoral adjacent liver tissues. A total of 293 tumor-specific somatic variants and 202 non-tumoral variants were identified. The tumor-specific variants were found to be enriched at chromosome 1q particularly in the advanced HCC, compared to the non-tumoral variants. Functional enrichment analysis revealed frequent mutations at the genes encoding cytoskeleton organization, cell adhesion, and cell cycle-related genes. In addition, to elucidate actionable somatic mutations, we performed an integrative analysis of gene mutations and gene expression profiles together. This revealed the 48 mutated genes which were differentially mutated with concomitant gene expression enrichment. Of these, CTNNB1 was found to have a pivotal role in the differential progression of the HCC subgroup. In conclusion, our integrative analysis of whole-exome sequencing and transcriptome profiles could provide actionable mutations which might play pivotal roles in the heterogeneous progression of HCC.
Transferrin and alpha-1 antitrypsin are reportedly associated with liver fibrosis. We evaluated the usefulness of serum transferrin and alpha-1 antitrypsin as new liver fibrosis markers in patients with chronic hepatitis B.
The study included 293 patients with chronic hepatitis B who underwent a liver biopsy between October 2005 and June 2009, and who had no history of hepatocellular carcinoma. Serum markers and liver fibrosis stages were compared.
Univariate analysis revealed that age (P<0.001), serum platelet count (P<0.001), and serum alkaline phosphatase level (P=0.003) differed significantly between the patients with and without liver cirrhosis. Serum transferrin levels were significantly lower in advanced fibrosis than in mild fibrosis in both univariate analysis (P=0.002) and multivariate analysis (P=0.009). In addition, the serum transferrin level was significantly lower in cirrhotic patients than in noncirrhotic patients (P=0.020). However, the serum level of alpha-1 antitrypsin was not significantly associated with liver cirrhosis in patients with chronic hepatitis B.
Serum transferrin could be promising serum marker for predicting advanced liver fibrosis in patients with chronic hepatitis B.
Chronic hepatitis B; Liver cirrhosis; Transferrin; Alpha-1 antitrypsin
This retrospective study assessed the clinical outcome of a transjugular intrahepatic portosystemic shunt (TIPS) procedure for managing portal hypertension in Koreans with liver cirrhosis.
Between January 2003 and July 2013, 230 patients received a TIPS in 13 university-based hospitals.
Of the 229 (99.6%) patients who successfully underwent TIPS placement, 142 received a TIPS for variceal bleeding, 84 for refractory ascites, and 3 for other indications. The follow-up period was 24.9±30.2 months (mean±SD), 74.7% of the stents were covered, and the primary patency rate at the 1-year follow-up was 78.7%. Hemorrhage occurred in 30 (21.1%) patients during follow-up; of these, 28 (93.3%) cases of rebleeding were associated with stent dysfunction. Fifty-four (23.6%) patients developed new hepatic encephalopathy, and most of these patients were successfully managed conservatively. The cumulative survival rates at 1, 6, 12, and 24 months were 87.5%, 75.0%, 66.8%, and 57.5%, respectively. A high Model for End-Stage Liver Disease (MELD) score was significantly associated with the risk of death within the first month after receiving a TIPS (P=0.018). Old age (P<0.001), indication for a TIPS (ascites vs. bleeding, P=0.005), low serum albumin (P<0.001), and high MELD score (P=0.006) were associated with overall mortality.
A high MELD score was found to be significantly associated with early and overall mortality rate in TIPS patients. Determining the appropriate indication is warranted to improve survival in these patients.
Liver cirrhosis; Transjugular intrahepatic portosystemic shunt; Portal hypertension
Relapse has been reported after stopping nucleos(t)ide (NUC) therapy in the majority of chronic HBeAg negative hepatitis patients. However, the ideal treatment duration of HBeAg negative chronic hepatitis B (CHB) is not well known. We investigated the frequency of relapse in HBeAg negative CHB patients receiving NUC therapy.
The NUC therapy was discontinued at least 3 times undetectable level of HBV DNA leave 6 months space in 45 patients. Clinical relapse was defined as HBV DNA >2,000 IU/mL and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times of upper limit of normal range. Virological relapse was defined as HBV DNA >2,000 IU/mL.
Clinical relapse developed in 16 (35.6%) and 24 (53.3%) patients after stopping therapy at 6 months and 12 months off therapy, respectively. Virological relapse developed 22 (48.9%) and 33 (73.3%) patients at 6 months and 12 months off therapy. The factors such as age, gender, cirrhosis, baseline AST, ALT, HBV DNA levels, treatment duration, and consolidation duration were analyzed to investigate the predictive factors associated with 1 year sustained response. Of these factors, cirrhosis (86.1% in CHB, 22.2% in LC) was significantly associated with 1 year virological relapse rate. Baseline HBV DNA and total treatment duration tended to be associated with virological relapse.
Virological relapse developed in the majority (73.3%) of HBeAg negative CHB patients and clinical relapse developed in the half (53.3%) of patients at 1 year off therapy. Cirrhosis may be associated with the low rate of virological relapse.
Chronic hepatitis B; Durability; Nucleos(t)ide analogue
In patients with occlusive colorectal cancers, a complete preoperative evaluation of the colon proximal to the obstruction is often impossible. We aimed to evaluate the feasibility of preoperative colonoscopy after stent placement and to determine whether the success rate of colonoscopy differs between covered and uncovered stents.
Seventy-three patients with malignant colorectal obstruction were enrolled prospectively. In patients with a resectable cancer, a preoperative colonoscopy was performed after insertion of a self-expandable metal stent (SEMS). The success rate of complete preoperative colonoscopy was compared between covered and uncovered stents.
Forty-five of 73 patients who underwent stent placement had a resectable cancer (61.6%). A complete preoperative colonoscopy was possible in 40 of 45 patients (88.9%). The success rate of complete preoperative colonoscopy was significantly lower in the covered-stent group when the obstructing mass lesion was located in the sigmoid colon (p=0.024). Synchronous cancer was detected in one patient (2.2%). Stent migration was observed in four patients with a covered stent.
A preoperative complete colonoscopy after SEMS placement was feasible and safe in most patients with malignant colorectal obstruction. Uncovered stents seem to have more advantages than covered stents in preoperative colonoscopy proximal to the obstruction.
Colorectal neoplasms; Stents; Colonoscopy; Neoplasms, multiple primary
Endoscopic sphincterotomy (EST) combined with large-balloon dilation (LBD) has been proposed as an alternative to manage large bile duct stones. However, recent reports indicate that LBD without EST may be safe and effective in this setting.
One hundred thirty-one patients with large common bile duct (CBD) stones 12 mm in size or larger underwent LBD alone (n = 62) or EST plus LBD (n = 69) for lithotripsy. The therapeutic outcome and complications were reviewed and compared.
There were no differences between the two groups with regard to age, size and number of stones, or bile duct diameter. The LBD alone group (mean age, 70.4 years) and the EST plus LBD group (mean age, 68.2 years) had similar outcomes in terms of overall successful stone removal (96.8% vs. 95.7%, P = 0.738) and complete stone removal without the need for mechanical lithotripsy (80.6% vs. 73.9%, P = 0.360). Complications in the LBD alone and EST plus LBD groups were as follows: pancreatitis (6.5% vs. 4.3%, P = 0.593), impaction of basket and stone (0% vs. 1.4%, P = 0.341), and perforation (0% vs. 1.4%, P = 0.341).
LBD alone may be a simple, safe, and effective alternative to EST plus LBD in relatively aged patients with large CBD stones, and it can simplify the procedure compared with EST plus LBD.
Common bile duct stones; Endoscopic sphincterotomy; Large-balloon dilation
Apolipoprotein E (ApoE) plays an important role in regulating lipid and lipoprotein metabolism, and ApoE genotypes are known to affect plasma lipoprotein concentrations. We investigated whether ApoE genotype determines the disease outcome in hepatitis B virus (HBV)-infected individuals, and verified the association between ApoE genotype and the occurrence of hepatocellular carcinoma (HCC) in patients with chronic liver diseases of various etiologies.
This hospital-based, case-controlled study enrolled 156 subjects (47 healthy controls, 50 HBV-related liver cirrhosis patients, and 59 HCC patients). ApoE genotypes were determined using PCR-based ApoE genotyping kits. The biological significance of ApoE genotype was verified by measuring serum ApoE levels using an ELISA kits.
The ε3 allele was the most common allele, with allele frequencies among the entire cohort of 5.8%, 84.3%, and 9.9% for the ε2, ε3, and ε4 alleles, respectively. Significantly more of those patients carrying the ε3/3 genotype had developed liver cirrhosis compared to the control subjects. Being an ApoE4 carrier was associated with a lower probability of developing liver cirrhosis. The allele frequencies and genotype distribution of ApoE did not differ significantly between the liver cirrhosis and HCC patients. The serum level of ApoE was significantly higher in patients with liver cirrhosis than in the healthy controls, but did not differ significantly with the ApoE genotype.
The ApoE ε3/3 genotype frequency was higher in patients with HBV-associated liver cirrhosis than in the controls.
Apolipoprotein E; Hepatitis B virus; Genotype; Liver cirrhosis
The association of a single nucleotide polymorphism of interleukin (IL)-10RB codon 47 with the chronic hepatitis B virus (HBV) infection has been reported in two ethnic populations with different results, but not in a Korean population. IL-10RB is a subunit of receptor complexes for interferon-lambda (IFN-λ) and IL-22, which have antiviral and hepatocyte-protective activity, respectively. This study examined the association of IL-10RB K47E with the outcomes of HBV infection in Korean subjects and the cellular response to these cytokines.
Genotypes of IL-10RB and the outcomes of HBV infection were analyzed in 1,000 Korean patients. The effect of IFN-λ or IL-22 on HBV replication and cell viability was assessed in hepatoma cells expressing IL-10RB K47 or E47. The transcript level of IL-10RB was examined in Epstein Barr virus-transformed B cells and hepatoma cells.
IL-10RB K47E was associated with chronic HBV infection but not with hepatoma in the Korean population. IL-10RB K47E was associated with the transcript level of IL-10RB in transformed B cells but not with the responses in hepatoma cells to IFN-λ or IL-22. HBV replication or 5-fluorouracil-induced cell death was suppressed by treatment of IFN-λ or IL-22 in an IL-10RB K47E-independent manner.
IL-10RB K47E is related to chronic HBV infection in a Korean population, but not to cellular responsiveness to IFN-λ and IL-22.
Electronic supplementary material
The online version of this article (doi:10.1007/s12072-012-9361-8) contains supplementary material, which is available to authorized users.
Chronic hepatitis B; HBV replication; IFN-λ; IL-10R2; IL-22; Single nucleotide polymorphism
The placement of self expandable metal stent (SEMS) is one of the palliative therapeutic options for patients with unresectable malignant biliary obstruction. The aim of this study was to compare the effectiveness of a covered SEMS versus the conventional plastic stent.
We retrospectively evaluated 44 patients with unresectable malignant biliary obstruction who were treated with a covered SEMS (21 patients) or a plastic stent (10 Fr, 23 patients). We analyzed the technical success rate, functional success rate, early complications, late complications, stent patency and survival rate.
There was one case in the covered SEMS group that had failed technically, but was corrected successfully using lasso. Functional success rates were 90.5% in the covered SEMS group and 91.3% in the plastic stent group. There was no difference in early complications between the two groups. Median patency of the stent was significantly prolonged in patients who had a covered SEMS (233.6 days) compared with those who had a plastic stent (94.6 days) (p=0.006). During the follow-up period, stent occlusion occurred in 11 patients of the covered SEMS group. Mean survival showed no significant difference between the two groups (covered SEMS group, 236.9 days; plastic stent group, 222.3 days; p=0.182).
The patency of the covered SEMS was longer than that of the plastic stent and the lasso of the covered SEMS was available for repositioning of the stent.
Malignant biliary obstruction; Self-expandable metal stent; Plastic stent
Although the prevalence of chronic hepatitis B has decreased considerably in recent years due to widespread use of the hepatitis B virus (HBV) vaccine, its prevalence still remains high in adults, and this can place a significant burden on health care in areas with endemic HBV. Since the introduction of nucleos(t)ide analogues (NUCs), there has been marked improvement in the care of patients with chronic hepatitis B, resulting in increased survival. However, the emergence of drug resistance in patients treated with NUCs is a major concern. The number of multi-drug resistant patients is increasing, and many patients may not respond to the currently available drugs. In this review, we describe the current status of NUC therapy for antiviral-naïve and -resistant patients.
Chronic hepatitis B; Nucleos(t)ide analogue; Drug resistance; Hepatitis B virus
This study is the first to examine the increased apoptosis in the adult rat ovary after lactational exposure to coumestrol (COU), a potent phytoestrogen. Lactating dams were gavaged at doses of 0.01, 0.1, 1, and 10 mg/kg COU during the lactation period and the reproductive effects of female pups were investigated in young adults. Rats were sacrificed at postnatal days (PND) 81–84. Ovarian weights were reduced significantly at 0.1 and 1.0 mg/kg COU. The reduction in the ovarian weight occurred in parallel with an increase in the apoptosis at PND 135–140. A marked dose-dependent increase in the expressions of active caspase-3 and -7 was observed in ovarian granulosa cells. Immunostaining for active caspase-3 and the TUNEL staining of apoptotic cells were also increased in ovaries exposed to COU in a dose-dependent manner. These results suggest new sights into the effect of lactational exposure to COU on the female reproductive health.
Ovarian apoptosis; Coumestrol; Lactational exposure; Caspase-3