Jae Jun Park

Genetic polymorphisms of IL-23R and IL-17A and novel insights into their associations with inflammatory bowel disease

Background and Aims To identify the associations of genetic and epigenetic variations in IL-23R and IL-17A with inflammatory bowel diseases (IBD). Methods The promoter and exon regions of IL-23R and IL-17A were analysed in 727 subjects (201 Crohns disease, 268 ulcerative colitis and 258 healthy controls) using DNA sequencing and denaturing high performance liquid chromatography. Transcription factor binding affinity, IL-17A mRNA expression and methylation of the IL-17A promoter were evaluated in peripheral blood mononuclear cells (PBMC) and Jurkat cells. Results A case–control analysis showed that development of Crohns disease is associated with the IL-23R variant G149R (OR 0.32, 95% CI 0.15 to 0.68) and IL-17A variant IVS1+18G>C (OR 10.65, 95% CI 1.32 to 85.89). Ulcerative colitis patients showed an association with IL-23R variants G149R (OR 0.41, 95% CI 0.21 to 0.76), IVS4+17C>T (OR 2.89, 95% CI 1.20 to 6.96) and Q3H (OR 0.61, 95% CI 0.38 to 0.99), and IL-17A variants −737C>T (OR 1.50, 95% CI 1.06 to 2.13), −197G>A (OR 0.63, 95% CI 0.40 to 0.97) and IVS1+18 G>C (OR 8.93, 95% CI 1.12 to 70.99). The −877G, −737T and −444A risk alleles of IL-17A displayed higher binding affinities with the transcription factor complex and higher expression levels of IL-17A transcripts. DNA hypomethylation of the IL-17A promoter was observed in PBMC from IBD patients with a significant inverse correlation between methylation extent of IVS1+17 and IL-17A mRNA level. Finally, Jurkat cells recovered IL-17A mRNA expression after exposure to demethylating agent. Conclusions The results provide insights into the genetic and epigenetic interactions in the IL-23R/IL-17 axis that are associated with elevated expression of IL-17 and IBD pathogenesis.

Comparison of efficacies between stents for malignant colorectal obstruction: a randomized, prospective study

BACKGROUND Colonoscopic insertion of a self-expandable metallic stent (SEMS) has been widely performed for the treatment of malignant colorectal obstruction. Different types of stents could influence the efficacy and complication rate of stent use. OBJECTIVE To compare the efficacy and complication rates between two SEMSs, the uncovered WallFlex stent and the covered Comvi stent. DESIGN A prospective, randomized study. SETTING Tertiary-care academic medical center. PATIENTS Between 2007 and 2009, a total of 151 patients with malignant colorectal obstruction were enrolled. INTERVENTION Two types of colorectal SEMSs (the uncovered WallFlex stent by Boston Scientific Corp and the newly developed covered Comvi stent by Taewoong Medical Co) were inserted. MAIN OUTCOME MEASUREMENTS Technical success, clinical success, stent patency, and complication rate according to stent type. RESULTS Technical failure occurred in 2 patients (1.3%); one was in the WallFlex group and the other in the Comvi group. Clinical failure developed in 9 patients (6.0%): 6 patients from the WallFlex group and 3 from the Comvi group. Complications because of cancer infiltration occurred more frequently in the WallFlex group (14.5% vs 3.8%). However, the rate of stent migration was higher in the Comvi group (21.1% vs 1.8%). The mean patency of the stent did not differ between the two groups (P = .50). LIMITATIONS This was a single-center study. CONCLUSION Both uncovered WallFlex and covered Comvi stents were suitable for relieving malignant colorectal obstruction. Tumor ingrowth was more common in the WallFlex group, but stent migration was more common in the Comvi group.

Bifidobacterium lactis inhibits NF-κB in intestinal epithelial cells and prevents acute colitis and colitis-associated colon cancer in mice

Background: The aim of this study was to investigate the antiinflammatory effects of Bifidobacterium lactis on intestinal epithelial cells (IECs) and on experimental acute murine colitis and its tumor prevention effects on colitis‐associated cancer (CAC) in mice. Methods: Human HT‐29 cells were stimulated with IL‐1&bgr;, lipopolysaccharides, or tumor necrosis factor‐&agr; with and without B. lactis, and the effects of B. lactis on nuclear factor kappa B (NF‐&kgr;B) signaling in IEC were examined. For in vivo study, dextran sulfate sodium (DSS)‐treated mice were fed with and without B. lactis. Finally, we induced colonic tumors in mice by azoxymethane (AOM) and DSS and evaluated the effects of B. lactis on tumor growth. Results: B. lactis significantly suppressed NF‐&kgr;B activation, including NF‐&kgr;B‐binding activity and NF‐&kgr;B‐dependent reporter gene expression in a dose‐dependent manner, and suppressed I&kgr;B‐&agr; degradation, which correlated with the downregulation of NF‐&kgr;B‐dependent gene products. Moreover, B. lactis suppressed the development of acute colitis in mice. Compared with the DSS group, the severity of DSS‐induced colitis as assessed by disease activity index, colon length, and histological score was reduced in the B. lactis‐treated group. In the CAC model, the mean number and size of tumors in the B. lactis‐treated group were significantly lower than those in the AOM group. Conclusions: Our data demonstrate that B. lactis inhibits NF‐&kgr;B and NF‐&kgr;B‐regulated genes in IEC and prevents acute colitis and CAC in mice. These results suggest that B. lactis could be a potential preventive agent for CAC as well as a therapeutic agent for inflammatory bowel disease. (Inflamm Bowel Dis 2010)

Negative capsule endoscopy without subsequent enteroscopy does not predict lower long-term rebleeding rates in patients with obscure GI bleeding

BACKGROUND Capsule endoscopy (CE) is now widely accepted as a first-line diagnostic modality for obscure GI bleeding (OGIB). However, the clinical implications of negative results of CE studies remain unclear. OBJECTIVE To investigate long-term (>1 year) outcomes for patients undergoing CE for OGIB and to identify risk factors associated with rebleeding. DESIGN AND SETTING Retrospective study in a tertiary care hospital. METHODS A total of 57 consecutive patients who had undergone CE for OGIB were enrolled and their pre- and post-CE clinical data were collected. Specific treatments were defined as treatments directly aimed at presumed bleeding causes including hemostasis and disease-specific medical therapy, whereas nonspecific treatments were defined as symptomatic treatments for anemia. RESULTS Of the 57 patients, the indication for CE was obscure-overt bleeding in 46 patients and obscure-occult bleeding in 11 patients. Among 51 patients for whom long-term data were available, significant (P2) lesions were found in 23 (45.1%) patients. The overall rebleeding rate was 35.3% during a median follow-up duration of 31.7 months (range 12.8-58.0 months). There was no statistically significant difference in the cumulative rebleeding rate between patients with positive and negative CE results (34.8% vs 35.7%, respectively; P = .989). However, specific treatments after CE (hazard ratio, 0.111; 95% CI, 0.013-0.980; P = .043) significantly decreased rebleeding. LIMITATIONS Small number of patients, retrospective study design. CONCLUSIONS The rebleeding rate for patients with OGIB and negative CE results was substantial, indicating that these patients should be closely observed. However, specific treatment after CE significantly reduced the incidence of recurrent bleeding.

Interactions between IL17A, IL23R, and STAT4 polymorphisms confer susceptibility to intestinal Behcet's disease in Korean population.

AIMS Although polymorphisms in IL23R have recently been proposed to predispose to Behcets disease (BD), associations between IL23R polymorphisms and intestinal BD have yet to be elucidated. We therefore performed a study to evaluate whether IL17A, IL23R, and STAT4 polymorphisms are associated with susceptibility to intestinal BD in the Korean population. MAIN METHODS Single nucleotide polymorphisms (SNP) in the IL17A, IL23R, and STAT4 genes were analyzed using DNA sequencing, denaturing high performance liquid chromatography, and TaqMan genotyping assays. KEY FINDINGS Individual polymorphism analysis revealed that the TT genotype of IL17A rs8193036 (odds ratio (OR) 2.10, 95% confidence interval (CI) (1.12-3.92), p=0.021), and GG+GT genotype of IL23R rs1884444 (OR 1.92, 95% CI (1.03-3.57), p=0.034) was associated with the development of intestinal BD. When these two genotypes were combined, the risk of BD increased compared to that of patients with no-risk or one-risk genotype (OR 2.21, 95% CI (1.13-4.34), p=0.021). Furthermore, statistically significant gene-gene interactions were observed between G149R in IL23R vs. rs11685878 in STAT4, rs2275913 in IL17A vs. rs7574865 in STAT4, and rs11889341 in STAT4 vs. rs2275913 in IL17A. The haplotypes of IL17A had a positive association with intestinal BD risks, whereas those of IL23R were protective for disease development. SIGNIFICANCE Our results indicate that the interaction of specific IL17A, IL23R, and STAT4 SNPs modulate susceptibility to intestinal BD in the Korean population, suggesting that the IL-17/23 axis plays a significant role in disease pathogenesis.

Original articleClinical endoscopyComparison of efficacies between stents for malignant colorectal obstruction: a randomized, prospective study

BACKGROUND Colonoscopic insertion of a self-expandable metallic stent (SEMS) has been widely performed for the treatment of malignant colorectal obstruction. Different types of stents could influence the efficacy and complication rate of stent use. OBJECTIVE To compare the efficacy and complication rates between two SEMSs, the uncovered WallFlex stent and the covered Comvi stent. DESIGN A prospective, randomized study. SETTING Tertiary-care academic medical center. PATIENTS Between 2007 and 2009, a total of 151 patients with malignant colorectal obstruction were enrolled. INTERVENTION Two types of colorectal SEMSs (the uncovered WallFlex stent by Boston Scientific Corp and the newly developed covered Comvi stent by Taewoong Medical Co) were inserted. MAIN OUTCOME MEASUREMENTS Technical success, clinical success, stent patency, and complication rate according to stent type. RESULTS Technical failure occurred in 2 patients (1.3%); one was in the WallFlex group and the other in the Comvi group. Clinical failure developed in 9 patients (6.0%): 6 patients from the WallFlex group and 3 from the Comvi group. Complications because of cancer infiltration occurred more frequently in the WallFlex group (14.5% vs 3.8%). However, the rate of stent migration was higher in the Comvi group (21.1% vs 1.8%). The mean patency of the stent did not differ between the two groups (P = .50). LIMITATIONS This was a single-center study. CONCLUSION Both uncovered WallFlex and covered Comvi stents were suitable for relieving malignant colorectal obstruction. Tumor ingrowth was more common in the WallFlex group, but stent migration was more common in the Comvi group.

Nonsteroidal anti‐inflammatory drugs suppress cancer stem cells via inhibiting PTGS2 (cyclooxygenase 2) and NOTCH/HES1 and activating PPARG in colorectal cancer

Cancer stem cells (CSCs) play a pivotal role in cancer relapse or metastasis. We investigated the CSC‐suppressing effect of nonsteroidal anti‐inflammatory drugs (NSAIDs) and the relevant mechanisms in colorectal cancer. We measured the effect of NSAIDs on CSC populations in Caco‐2 or SW620 cells using colosphere formation and flow cytometric analysis of PROM1 (CD133)+CD44+ cells after indomethacin treatment with/without prostaglandin E2 (PGE2) or peroxisome proliferator‐activated receptor γ (PPARG) antagonist, and examined the effect of indomethacin on transcriptional activity and protein expression of NOTCH/HES1 and PPARG. These effects of indomethacin were also evaluated in a xenograft mouse model. NSAIDs (indomethacin, sulindac and aspirin), celecoxib, γ‐secretase inhibitor and PPARG agonist significantly decreased the number of colospheres formation compared to controls. In Caco‐2 and SW620 cells, compared to controls, PROM1 (CD133)+CD44+ cells were significantly decreased by indomethacin treatment, and increased by 5‐fluorouracil (5‐FU) treatment. This 5‐FU‐induced increase of PROM1 (CD133)+CD44+ cells was significantly attenuated by combination with indomethacin. This CSC‐inhibitory effect of indomethacin was reversed by addition of PGE2 and PPARG antagonist. Indomethacin significantly decreased CBFRE and increased PPRE transcriptional activity and their relative protein expressions. In xenograft mouse experiments using 5‐FU‐resistant SW620 cells, the 5‐FU treatment combined with indomethacin significantly reduced tumor growth, compared to 5‐FU alone. In addition, treatment of indomethacin alone or combination of 5‐FU and indomethacin decreased the expressions of PROM1 (CD133), CD44, PTGS2 (cyclooxygenase 2) and HES1, and increased PPARG expression. NSAIDs could selectively reduce the colon CSCs and suppress 5‐FU‐induced increase of CSCs via inhibiting PTGS2 (cyclooxygenase 2) and NOTCH/HES1, and activating PPARG.

Do Patients with Ulcerative Colitis Diagnosed at a Young Age Have More Severe Disease Activity than Patients Diagnosed when Older

Background/Aims: To compare the clinical features and disease behavior of ulcerative colitis (UC) according to the age at onset. Methods: This retrospective study included 455 patients with UC who were diagnosed and treated between 1990 and 2008 at a single tertiary institution in Korea. The patients were divided into 2 groups according to their age at diagnosis of UC: an elderly group (≧40 years) and a young group (<40 years). Clinical findings at diagnosis, extent of disease, treatment modalities used, cumulative admission rates, cumulative relapse rates, and surgery rates were analyzed according to these age groups. Results: Two hundred and forty-two patients with UC (53.2%) were diagnosed before the age of 40 years. Disease severity at initial presentation as assessed by diarrhea frequency, the presence of pancolitis, and the use of steroids were higher in the young group; however, clinical disease course including cumulative admission rates, cumulative relapse rates, and surgery rates were not significantly different between the 2 groups. Conclusions: Certain clinical features and the extent of disease in UC patients appear to be more severe when the disease is diagnosed at younger age; however, their disease course and prognosis might not be different from those of their older counterparts.

Risk Factors for Treatment Failure and Recurrence after Metronidazole Treatment for Clostridium difficile-associated Diarrhea

BACKGROUND/AIMS The incidence of treatment failure or recurrence of Clostridium difficile-associated diarrhea (CDAD) following metronidazole treatment has increased recently. We studied the treatment failure, recurrence rate, and risk factors predictive of treatment failure and recurrence after metronidazole treatment for CDAD. METHODS We retrospectively identified consecutive patients who were admitted and treated for CDAD at a single tertiary institution in Korea over a recent 10-year period (i.e., 1998-2008). RESULTS Metronidazole was administered as the initial treatment to 111 of 117 patients (94.9%) with CDAD. Fourteen patients (12.6%) had no clinical response to the metronidazole treatment, and in 13 patients (13.4%) CDAD recurred after successful metronidazole treatment. Diabetes mellitus (p=0.014) and sepsis (p=0.002) were independent risk factors for metronidazole treatment failure. Patients who had received surgery within 1 month before CDAD developed were more likely to experience a recurrence after metronidazole treatment (p=0.032). Vancomycin exhibited a higher response rate after treatment failure, and metronidazole showed a reasonable response rate in the treatment of recurrence. Treatment failure and recurrence rates increased with time after metronidazole treatment for CDAD over the 10-year study period. CONCLUSIONS Our data suggest that diabetes mellitus and sepsis are independent risk factors for metronidazole treatment failure, and that operation history within 1 month of development of CDAD is a predictor of a recurrence after metronidazole treatment.

Advanced synchronous adenoma but not simple adenoma predicts the future development of metachronous neoplasia in patients with resected colorectal cancer.

Background Patients with resected colorectal cancer remain at a high risk for developing metachronous neoplasia in the remnant colorectum. The aim of this study was to identify baseline clinical and colonoscopic features predictive of metachronous neoplasia after curative resection of colorectal cancer. Methods The baseline clinical and colonoscopic data and follow-up details of 503 patients who had colonoscopic surveillance after curative colorectal resection between January 2000 and October 2005 in a single tertiary institution were analyzed. Univariate and multivariate analyses were done to identify risk factors for metachronous adenoma. Results Metachronous adenomas were diagnosed in 176 patients (35.0%) and advanced adenomas in 39 (7.8%) during the follow-up period (35.7±20.9 mo). Among the clinical and colonoscopic factors at baseline, advanced age (≥60 y) (odds ratio (OR)=3.64; 95% confidence intervals (CI), 1.55-8.52), the presence of advanced synchronous adenoma (OR=4.38; 95% CI, 1.77-10.85), and longer total follow-up period (OR=1.03; 95% CI, 1.01-1.04) were independently correlated with developing advanced metachronous adenoma. Patients who had synchronous tubular adenoma without advanced features at baseline were not found to have an increased risk for future development of advanced metachronous adenoma compared with those in the synchronous adenoma-free group (OR=1.75; 95% CI, 0.69-4.43, P=0.650). Conclusions Our data showed that patients with advanced synchronous adenoma at baseline were identified to have an increased risk of advanced metachronous neoplasia during a longer follow-up period but those with tubular adenoma without advanced features at baseline were not.