Tomoya Kimura

Life-event stress induced by the Great East Japan Earthquake was associated with relapse in ulcerative colitis but not Crohn's disease: a retrospective cohort study

Objective Stress is thought to be one of the triggers of relapses in patients with inflammatory bowel disease (IBD). We examined the rate of relapse in IBD patients before and after the Great East Japan Earthquake. Design A retrospective cohort study. Settings 13 hospitals in Japan. Participants 546 ulcerative colitis (UC) and 357 Crohns disease (CD) patients who received outpatient and inpatient care at 13 hospitals located in the area that were seriously damaged by the earthquake. Data on patients clinical characteristics, disease activity and deleterious effects of the earthquake were obtained from questionnaires and hospital records. Primary outcome We evaluated the relapse rate (from inactive to active) across two consecutive months before and two consecutive months after the earthquake. In this study, we defined ‘active’ as conditions with a partial Mayo score=2 or more (UC) or a Harvey-Bradshaw index=6 or more (CD). Results Among the UC patients, disease was active in 167 patients and inactive in 379 patients before the earthquake. After the earthquake, the activity scores increased significantly (p<0.0001). A total of 86 patients relapsed (relapse rate=15.8%). The relapse rate was about twice that of the corresponding period in the previous year. Among the CD patients, 86 patients had active disease and 271 had inactive disease before the earthquake. After the earthquake, the activity indices changed little. A total of 25 patients experienced a relapse (relapse rate=7%). The relapse rate did not differ from that of the corresponding period in the previous year. Multivariate analyses revealed that UC, changes in dietary oral intake and anxiety about family finances were associated with the relapse. Conclusions Life-event stress induced by the Great East Japan Earthquake was associated with relapse in UC but not CD.

MicroRNA-320 family is downregulated in colorectal adenoma and affects tumor proliferation by targeting CDK6.

AIM To investigate the microRNA (miRNA) expression during histological progression from colorectal normal mucosa through adenoma to carcinoma within a lesion. METHODS Using microarray, the sequential changes in miRNA expression profiles were compared in colonic lesions from matched samples; histologically, non-neoplastic mucosa, adenoma, and submucosal invasive carcinoma were microdissected from a tissue sample. Cell proliferation assay was performed to observe the effect of miRNA, and its target genes were predicted using bioinformatics approaches and the expression profile of SW480 transfected with the miRNA mimics. mRNA and protein levels of the target gene in colon cancer cell lines with a mimic control or miRNA mimics were measured using qRT-PCR and Western blotting. The expression levels of miRNA and target gene in colorectal tissue samples were also measured. RESULTS Microarray analysis identified that the miR-320 family, including miR-320a, miR-320b, miR-320c, miR-320d and miR-320e, were differentially expressed in adenoma and submucosal invasive carcinoma. The miR-320 family, which inhibits cell proliferation, is frequently downregulated in colorectal adenoma and submucosal invasive carcinoma tissues. Seven genes including CDK6 were identified to be common in the results of gene expression array and bioinformatics analyses performed to find the target gene of the miR-320 family. We confirmed that mRNA and protein levels of CDK6 were significantly suppressed in colon cancer cell lines with miR-320 family mimics. CDK6 expression was found to increase from non-neoplastic mucosa through adenoma to submucosal invasive carcinoma tissues and showed an inverse correlation with miR-320 family expression. CONCLUSION MiR-320 family affects colorectal tumor proliferation by targeting CDK6, plays important role in its growth, and is considered to be a biomarker for its early detection.

The Effectiveness of Self-Expandable Metallic Stent Insertion in Treating Right-Sided Colonic Obstruction: A Comparison between SEMS and Decompression Tube Placement and an Investigation of the Safety and Difficulties of SEMS Insertion in Right Colons

Objectives. Self-expandable metallic stent (SEMS) is widely used to treat malignant colonic obstruction. However, most reports about SEMS insertion have concentrated on the left colon. This study aimed to (1) investigate the effectiveness of SEMS insertion compared with conventional decompression tube for right-sided colonic obstruction and (2) compare the safety and technical success of SEMS insertion between left- and right-sided colonic obstructions. Methods. The data from thirty-seven patients who underwent SEMS or conventional decompression tube placement for malignant colonic obstruction in our hospital were analyzed retrospectively. Technical and clinical success, complications, and technical difficulties were analyzed. We compared the results between SEMS insertion and decompression tube placement in right colons and the outcomes of SEMS insertion between right- and left-sided colonic obstructions. Results. For right colons, the clinical success rate of SEMS insertion (100%) was significantly higher than that of decompression tube placement (55.9%). Concerning SEMS insertion, the technical difficulty and safety of SEMS insertion were similar between right- and left-sided colonic obstructions. Conclusion. SEMS insertion for right-sided colon is significantly more effective than conventional decompression tube placement, and this procedure was safer and less technically challenging than expected. SEMS insertion should be considered for treating right-sided malignant colonic obstruction.

A Comparison of Short- and Long-Term Therapeutic Outcomes of Infliximab- versus Tacrolimus-Based Strategies for Steroid-Refractory Ulcerative Colitis

Background/Aims. Antitumor necrosis factor antibodies and calcineurin inhibitors have shown good therapeutic efficacy for steroid-refractory ulcerative colitis (UC). Although some studies have compared the efficacy of infliximab (IFX) and cyclosporin A, there are no published studies comparing IFX and tacrolimus (Tac). This study aimed to compare therapeutic efficacies between IFX- and Tac-based strategies for steroid-refractory UC. Methods. Between July 2009 and August 2013, 95 patients with steroid-refractory UC received either IFX (n = 48) or Tac (n = 47) in our hospital. In the IFX group, the patients continued to receive maintenance treatment with IFX. In the Tac group, patients discontinued Tac treatment up to 3 months and subsequently received thiopurine. We retrospectively compared the therapeutic outcomes between the groups. Results. There was no significant difference in the colectomy-free rate, clinical remission rate, and clinical response rate at 2 months between the groups. However, relapse-free survival was significantly higher in the IFX group than in the Tac group (p < 0.001; log-rank test). The proportions of serious adverse events did not differ between the groups. Conclusion. The findings of our study showed that IFX and Tac have similar short-term therapeutic efficacy for steroid-refractory UC. Maintenance treatment with IFX, however, yields better long-term outcomes than Tac-thiopurine bridging treatment.

ATP-binding cassette subfamily B member 1 1236C/T polymorphism significantly affects the therapeutic outcome of tacrolimus in patients with refractory ulcerative colitis

Tacrolimus is now considered to be one of the main therapeutic options for refractory ulcerative colitis. Both cytochrome P‐450 3A5 (CYP3A5) and ATP‐binding cassette subfamily B member 1 (ABCB1) associated with tacrolimus metabolism are known to have several genetic polymorphisms. However, it remains controversial whether these polymorphisms affect the therapeutic efficacy for ulcerative colitis. We aimed to investigate the influence of both CYP3A5 and ABCB1 polymorphisms on the efficacy of tacrolimus in ulcerative colitis treatment under the tight dose‐adjusting strategy.

Tacrolimus Dose Optimization Strategy for Refractory Ulcerative Colitis Based on the Cytochrome P450 3A5 Polymorphism Prediction Using Trough Concentration after 24 Hours.

Background: In the tacrolimus treatment for refractory ulcerative colitis (UC), dose adjustment is necessary because the required doses to keep appropriate drug concentrations are significantly different among individuals. Cytochrome P450 (CYP) 3A5 polymorphism affects tacrolimus blood concentrations. However, it is difficult to obtain genetic information in real clinical practice. In the present study, we investigated possible factors that may predict CYP3A5 polymorphism and proposed a dose optimization strategy based on the obtained predicting factors. Summary: We retrospectively analyzed 41 patients who underwent remission induction therapy with tacrolimus for UC in our hospital. First, we performed a correlation analysis of CYP3A5 polymorphism and pharmacokinetics. In the CYP3A5 non-expressers, the dose of tacrolimus (mg/kg) was lower and dose-adjusted trough levels (ng/mL per mg/kg) were higher compared with those in expressers. Next, we investigated factors that could predict CYP3A5 polymorphism. Trough concentration 24 h following tacrolimus administration was extracted as a significant factor. When the trough cutoff value at 24 h was set to 2.6 ng/mL, sensitivity and specificity for estimation of CYP3A5 polymorphism were 63 and 96% respectively. Therefore, when the trough concentration 24 h after administration is ≤2.6 ng/mL, the patient can be estimated as a CYP3A5 expresser and an increase in dose should be proposed. Key Message: The trough concentration 24 h after the first tacrolimus administration appears to be a useful predictor of CYP3A5 polymorphism. Performing dose optimization strategy based on the prediction of CYP3A5 polymorphism can lead to earlier and safer remission induction.

Risk factors associated with postoperative recurrence and repeat surgery in Japanese patients with Crohn’s disease

PurposeTo avoid frequent surgery in patients with Crohn’s disease, it is important to identify the risk factors for postoperative recurrence or repeat surgery. However, there have so far been few studies on this topic from Asian countries. In addition, the recent development of anti-tumor necrosis factor (TNF) therapy may have changed the risk factors. We aimed to identify the factors associated with postoperative recurrence and repeat surgery.MethodsThe postoperative courses of 168 patients were reviewed. We analyzed the cumulative postoperative recurrence and repeat surgery rates and identified the factors affecting these rates.ResultsPostoperative recurrence was observed in 70 patients, and the 1-, 3-, and 5-year cumulative recurrence rates were 17.1, 40.1, and 54.9%, respectively. The recurrence rate was significantly higher in patients with anal lesions and lower in patients newly treated with anti-TNF agents following surgery. In a multivariate analysis, the new introduction of anti-TNF agents was identified as an independent suppressor (hazard ratio 0.50, 95% confidence interval 0.28–0.88). Twenty-four patients underwent repeat surgery, and the 1-, 3-, and 5-year cumulative repeat surgery rates were 4.6, 11.2, and 18.7%, respectively. The surgery rate was significantly higher in patients with penetrating-type disease. In a multivariate analysis, penetrating-type disease (6.98, 2.37–23.35), anal lesions (4.40, 1.14–30.53), and first-time surgery (5.28, 1.17–17.93) were identified as independent risk factors.ConclusionsAnti-TNF agents have the potential to prevent postoperative recurrence. The new introduction, dose escalation, or switching of anti-TNF agents is recommended in patients with some risk factors.

Allele-specific DNA methylation of disease susceptibility genes in Japanese patients with inflammatory bowel disease

Background Inflammatory bowel disease (IBD) has an unknown etiology; however, accumulating evidence suggests that IBD is a multifactorial disease influenced by a combination of genetic and environmental factors. The influence of genetic variants on DNA methylation in cis and cis effects on expression have been demonstrated. We hypothesized that IBD susceptibility single-nucleotide polymorphisms (SNPs) regulate susceptibility gene expressions in cis by regulating DNA methylation around SNPs. For this, we determined cis-regulated allele-specific DNA methylation (ASM) around IBD susceptibility genes in CD4+ effector/memory T cells (Tem) in lamina propria mononuclear cells (LPMCs) in patients with IBD and examined the association between the ASM SNP genotype and neighboring susceptibility gene expressions. Methods CD4+ effector/memory T cells (Tem) were isolated from LPMCs in 15 Japanese IBD patients (ten Crohns disease [CD] and five ulcerative colitis [UC] patients). ASM analysis was performed by methylation-sensitive SNP array analysis. We defined ASM as a changing average relative allele score (ΔRAS¯) >0.1 after digestion by methylation-sensitive restriction enzymes. Among SNPs showing ΔRAS¯ >0.1, we extracted the probes located on tag-SNPs of 200 IBD susceptibility loci and around IBD susceptibility genes as candidate ASM SNPs. To validate ASM, bisulfite-pyrosequencing was performed. Transcriptome analysis was examined in 11 IBD patients (seven CD and four UC patients). The relation between rs36221701 genotype and neighboring gene expressions were analyzed. Results We extracted six candidate ASM SNPs around IBD susceptibility genes. The top of ΔRAS¯ (0.23) was rs1130368 located on HLA-DQB1. ASM around rs36221701 (ΔRAS¯ = 0.14) located near SMAD3 was validated using bisulfite pyrosequencing. The SMAD3 expression was significantly associated with the rs36221701 genotype (p = 0.016). Conclusions We confirmed the existence of cis-regulated ASM around IBD susceptibility genes and the association between ASM SNP (rs36221701) genotype and SMAD3 expression, a susceptibility gene for IBD. These results give us supporting evidence that DNA methylation mediates genetic effects on disease susceptibility.

Long-term course of inflammatory bowel disease after the Great East Japan Earthquake: Long-course of IBD after the earthquake

This study analyzed inflammatory bowel disease activity for 2 years after the Great East Japan Earthquake.

Clinical and genetic risk factors for decreased bone mineral density in Japanese patients with inflammatory bowel disease: Risk factors of low BMD in Japanese IBD

Patients with inflammatory bowel disease (IBD) are at a high risk of low bone mineral density (BMD). Reportedly, clinical and genetic factors cause low BMD in Caucasians; however, studies in non‐Caucasian populations remain scarce.