Hyo-Jong Kim

Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis

BACKGROUND Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis. METHODS We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. RESULTS Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P<0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score ≤2 and no subscore >1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups. CONCLUSIONS Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).

Interleukin-1B (IL-1B) polymorphisms and gastric mucosal levels of IL-1β cytokine in Korean patients with gastric cancer

Interleukin‐1B and IL‐1 receptor antagonist gene polymorphisms are associated with an increased risk of gastric cancer (GC) in Caucasian populations. However, recent studies could not find any association between IL‐1B‐511T polymorphism and the risk of GC in Asians. We tested for an association between IL‐1 loci polymorphisms with increased gastric mucosal levels of IL‐1β and an increased risk of developing GC in a Korean population. Polymorphisms of IL‐1A‐889, IL‐1B‐31, IL‐1B‐511 and IL‐1RN were genotyped in 434 controls and 234 patients with GC. Mucosal IL‐1β cytokine was measured using an ELISA. The frequencies of IL‐1A, IL‐1B‐511, IL‐1B‐31 and IL‐1RN were not statistically different between controls and all patients with GC. After subclassification of GC, only patients with intestinal‐type GC showed a higher frequency of IL‐1B‐31T homozygotes (OR = 2.2; 95% CI = 1.1–4.3) compared with controls. Risk was also significantly increased in these patients for IL‐1B‐31T homozygotes compared with patients with diffuse‐type GC (OR = 3.4; 95% CI = 1.5–7.7). As in Caucasian populations, linkage disequilibrium between IL‐1B‐31 and IL‐1B‐511 was nearly complete, but the pattern of haplotype related to the risk of GC (IL‐1B‐31T/IL‐1B‐511C) was opposite (IL‐1B‐511T/IL‐1B‐31C). Mucosal IL‐1β levels in H. pylori‐infected GC patients were higher in patients homozygous for IL‐1B‐31T compared with IL‐1B‐31C/T and IL‐1B‐31C/C. Thus, the combined effects of H. pylori infection and IL‐1B‐31T/IL‐1B‐511C polymorphisms with enhanced mucosal IL‐1β production contributed to the development of intestinal‐type GC in this Korean population.

The incidence and clinical characteristics of symptomatic propylthiouracil-induced hepatic injury in patients with hyperthyroidism: a single-center retrospective study

OBJECTIVES:Although symptomatic propylthiouracil (PTU)-induced hepatic injury is known to be rare, there have been few reports about its exact incidence in patients with hyperthyroidism. We tried to evaluate its incidence in a single center and its clinical course.METHODS:Medical records of 912 hyperthyroid patients who had been diagnosed between March 1990 and December 1998 were reviewed about clinical characteristics, management, and laboratory findings. Symptomatic PTU-induced hepatic injury was defined as the development of jaundice or hepatitis symptoms with at least a 3-times elevation of liver function tests (LFT) without other causes.RESULTS:Four hundred ninety-seven patients (age 42.6 ± 10.7 yr, male/female 140/357) were included. Clinically overt hepatitis developed in six patients (1.2%; age, 43.7 ± 14.8 yr; male:female ratio, 3:3) between 12 and 49 days after PTU administration. Jaundice and itching developed in five patients, fever in two, rash in two, and arthralgia in one. Bilirubin, ALT, and ALP increased in five, four, and six patients, respectively (293 ± 288 μmol/L, 143 ± 111 U/L, and 265 ± 81 U/L; normal, <117 U/L). The type of hepatic injury was cholestatic in three, hepatocellular in one, and mixed in two patients. None resulted from viral hepatitis. There were no statistical differences in age, sex, PTU dose, or T4 and T3 levels at initial diagnosis between patients with and without hepatic injury. LFT normalized in all patients between 16 and 145 (72.8 ± 46.4) days after the PTU withdrawal.CONCLUSIONS:Symptomatic hepatic injury develops usually within the first few months of PTU administration with rare frequency, but its clinical course is relatively benign once the drug is withdrawn. However, it may be difficult to predict its development, so all patients should be monitored for rise in LFTs at regular intervals, especially during the early period.

Role of Helicobacter pylori infection among offspring or siblings of gastric cancer patients

A positive family history is an increased risk factor for gastric cancer within family members, and one of the possible causes of this is the intrafamilial clustering of Helicobacter pylori infection. Our study examined the prevalence of H. pylori infection, serum antibodies to CagA and VacA and atrophic gastritis and/or intestinal metaplasia in the offspring or siblings of gastric cancer patients. A total of 726 subjects included 300 relatives of 300 separate gastric cancer patients and 426 controls. All subjects underwent upper gastrointestinal endoscopic examination with a rapid urease test. Blood samples were obtained to test for the presence of serum antibodies to the CagA and VacA proteins of H. pylori. The prevalence of H. pylori infection was higher in relatives of cancer patients (75.3%) than in controls (60.1%), and the adjusted odds ratio was 2.1 (95% CI 1.5–2.9). When either siblings or 2 or more family members were gastric cancer patients, the prevalence of H. pylori infection was much higher compared to the prevalence in controls. There was no specific relationship between CagA and VacA, and H. pylori infection. Atrophic gastritis and/or intestinal metaplasia were more frequently found in H. pylori‐infected relatives of cancer patients (26.1%) than in H. pylori‐infected controls (12.9%). These results strongly support a role for H. pylori infection in familial aggregation of gastric cancer. The prophylactic eradication of H. pylori infection in the offspring or siblings of gastric cancer patients may be clinically beneficial.

Genome-Wide Association Study of Ulcerative Colitis in Koreans Suggests Extensive Overlapping of Genetic Susceptibility With Caucasians

Background:Recent genome-wide association studies and meta-analyses have identified 47 susceptibility loci for ulcerative colitis (UC) in Caucasian populations. A previous genome-wide association study of UC in a Japanese population suggested marginal sharing of susceptibility loci between Caucasian and Asian populations. We performed a genome-wide association studies to identify UC susceptibility loci in a Korean population and further comparative study. Methods:We analyzed 581,060 autosomal single-nucleotide polymorphisms (SNPs) in 388 individuals with UC and 739 control subjects in the discovery stage. For the validation, 64 suggestive SNPs were analyzed in an additional 417 affected individuals and 732 control subjects. Results:Three genetic loci were validated for significant association, and all were previously reported in Caucasians including the major histocompatibility complex region (top SNP, rs9271366; P = 1.03 × 10−18, odds ratio [OR] = 2.10), 16q24.1 (rs16940186; P = 4.39 × 10−10, OR = 1.56), and RNF186-OTUD3-PLA2G2E at chromosome arm 1p36.13 (top SNP, rs4654903 in OTUD3; P = 7.43 × 10−9, OR = 0.64). Although failed to reach genome-wide statistical significance, 2 additional loci previously reported in Caucasians including rs17085007 at chromosome arm 13q12 and JAK2 at chromosome arm 9p24 were significant after Bonferroni correction (Pcorrected = 0.0016 and Pcorrected = 0.0056, respectively). FOS, UBE2L3, the JAK2 gene region, and rs1297265 at chromosome arm 21q21.1 likely play a role in both Crohn’s disease and UC. Conclusions:Our data support the biologic significance of the overlapping loci for UC between Caucasian and Korean populations. Our data suggest that genetic associations for UC tend to overlap more extensively among different ethnic groups than those for Crohn’s disease, which shows well-established dependence on ethnicity.

Dedifferentiation of conditionally immortalized hepatocytes with long-term in vitro passage.

The rat hepatocytes were immortalized using a temperature-sensitive mutant of SV40 large T antigen (tsT) to develop as a possible substitute for primary hepatocytes. Four rat hepatocyte lines that have been developed and maintained more than passage 50, were characterized for their cellular morphology, T antigen and p53 expression, chromosomes, liver-specific differentiation, telomerase activity and anchorage independent growth. All of four cell lines showed a typical epithelial cell morphology, but the population-doubling time became short with passage: 18 to 60%. T antigen expression was increased with passage about 3 to 65 times at permissive temperature but decreased significantly at non-permissive temperature. The expression level of p53 unchanged during passages was also decreased at non-permissive temperature. The distribution of chromosome number changed somewhat with passage. The production levels of albumin and urea in four cell lines were 2.4 to 13.0% and 7.5 to 19.9% of those produced in primary hepatocytes, respectively and were decreased to an undetectable level with passage. Telomerase activity was increased 10 fold following immortalization of cells, but anchorage independent growth of cells did not develop. These results indicate that conditionally immortalized hepatocytes become dedifferentiated with in vitro passage, which may be caused by marked chromosomal damages that occur with compulsive and continuous replications by the increment of T antigen content with passage and its sequential inhibition of p53 function.

Frequent epigenetic inactivation of hSRBC in gastric cancer and its implication in attenuated p53 response to stresses.

hSRBC is a putative tumor suppressor located at 11p15.4, at which frequent genomic loss has been observed in several human malignancies. To explore the candidacy of hSRBC as a suppressor of gastric tumorigenesis, we analyzed the expression and mutation status of hSRBC in gastric tissues and cell lines. hSRBC transcript was expressed in all normal and benign tumor tissues examined, but undetectable or very low in 73% (11/15) cancer cell lines and 41% (46/111) primary tumors. Loss or reduction of hSRBC expression was tumor‐specific and correlated with stage and grade of tumors. While allelic loss or somatic mutations of the gene were infrequent, its expression was restored in tumor cells by 5‐aza‐2′‐deoxycytidine treatment and aberrant hypermethylation of 23 CpG sites in the promoter region showed a tight association with altered expression. Transient or stable expression of hSRBC led to a G1 cell cycle arrest and apoptosis of tumor cells, and strongly suppresses colony forming ability and xenograft tumor growth. In addition, hSRBC elevated apoptotic sensitivity of tumor cells to genotoxic agents, such as 5‐FU, etoposide and ultraviolet. Interestingly, hSRBC increased the protein stability of p53 and expression of p53 target genes, such as p21Waf1, PUMA and NOXA, while hSRBC‐mediated cell cycle arrest and apoptosis were abolished by blockade of p53 function. Our findings suggest that hSRBC is a novel tumor suppressor whose epigenetic inactivation contributes to the malignant progression of gastric tumors, in part, through attenuated p53 response to stresses.

Risks for opportunistic tuberculosis infection in a cohort of 873 patients with inflammatory bowel disease receiving a tumor necrosis factor-α inhibitor.

Abstract Objective. Real-world epidemiological data on tuberculosis (TB) infection in patients with inflammatory bowel disease (IBD) receiving TNF-α inhibitors are scarce. We investigated the risks for and case characteristics of TB in a large cohort of IBD patients treated with TNF-α inhibitors in Korea, where TB is endemic. Materials and methods. We performed an observational study on all TB cases identified in a cohort of 873 IBD subjects treated with TNF-α inhibitors from January 2001 to December 2013. The standardized incidence ratio (SIR) of TB was calculated using data from the matched general population. Results. A total of 25 newly developed TB cases were identified in the cohort (pulmonary TB, 84% [21/25]; extrapulmonary TB, 16% [4/25]). The adjusted SIR of TB was 41.7 (95% confidence interval, 25.3–58.0), compared with that of the matched general population. Nineteen of the 25 patients (76%) developed TB within 2–62 months of initiation of TNF-α inhibitor treatment despite screening negative for latent TB infection (LTBI), whereas three patients with LTBI (12%, 3/25) developed TB 3 months after completion of chemoprophylaxis. The outcomes of TB treatment were mostly favorable, although one death from peritoneal TB was noted. The type of TNF-α inhibitor prescribed (infliximab) was a significant predictor of TB (p = 0.033). Conclusions. TNF-α inhibitor treatment strikingly increases the risk of TB infection in an IBD population from a TB endemic area. Continuous evaluation of the development of de novo TB infection in IBD patients subjected to long-term TNF inhibitor therapy is mandatory.

The Risk of Tuberculosis in Korean Patients with Inflammatory Bowel Disease Receiving Tumor Necrosis Factor-α Blockers

The aims of this study were to assess the risk of tuberculosis (TB) and the status of latent tuberculosis infection (LTBI) in Korean patients with inflammatory bowel disease (IBD) receiving tumor necrosis factor (TNF)-α blockers. We reviewed medical records of 525 Korean IBD patients (365 TNF-α blocker naïve and 160 TNF-α blocker exposed) between January 2001 and December 2013. The crude incidence of TB was significantly higher in IBD patients receiving TNF-α blockers compared to TNF-α-blocker-naïve patients (3.1% vs. 0.3%, P=0.011). The mean incidence of TB per 1,000 patient-years was 1.84 for the overall IBD population, 4.89 for TNF-α blocker users, and 0.45 for TNF-α-blocker-naïve patients. The adjusted risk ratio of TB in IBD patients receiving TNF-α blocker was 11.7 (95% confidence interval, 1.36-101.3). Pulmonary TB was prevalent in patients treated with TNF-α blockers (80.0%, 4/5). LTBI was diagnosed in 17 (10.6%) patients, and none of the 17 LTBI patients experienced reactivation of TB during treatment with TNF-α blockers. Treatment with TNF-α blockers significantly increased the risk of TB in IBD patients in Korea. De novo pulmonary TB infection was more prevalent than reactivation of LTBI, suggesting an urgent need for specific recommendations regarding TB monitoring during TNF-α blocker therapy. Graphical Abstract

Amelioration of trinitrobenzene sulfonic acid‐induced colitis in mice by liquiritigenin

The anti‐inflammatory effects of liquiritigenin, a major flavonoid isolated from Glycyrrhizae uralensis, have been reported in many inflammation models. However, its protective effects have not been reported in a colitis model. This study investigated the anti‐inflammatory effect and mechanism of liquiritigenin for trinitrobenzene sulfonic acid (TNBS)‐induced colitis in mice.