Yoshiaki Takeuchi

Newly Developed Antibiotic Combination Therapy for Ulcerative Colitis: A Double-Blind Placebo-Controlled Multicenter Trial

OBJECTIVES:Fusobacterium varium may contribute to ulcerative colitis (UC). We conducted a double-blind placebo-controlled multicenter trial to determine whether antibiotic combination therapy induces and/or maintains remission of active UC.METHODS:Patients with chronic mild-to-severe relapsing UC were randomly assigned to oral amoxicillin 1500u2009mg/day, tetracycline 1500u2009mg/day, and metronidazole 750u2009mg/day, vs. placebo, for 2 weeks, and then followed up. The primary study end point was clinical response (Mayo score at 3 months after treatment completion) and secondary end points were clinical and endoscopic score improvements at 12 months. Anti-F. varium antibodies were measured by enzyme-linked immunosorbent assay.RESULTS:Treatment and placebo groups each had 105 subjects. At the primary end point, response rates were significantly greater with antibiotics than with placebo (44.8 vs. 22.8%, P=0.0011). Endoscopic scores significantly improved at 3 months (P=0.002 vs. placebo). Remission rates were 19.0% (antibiotics) vs. 15.8% (placebo) at 3 months (P=0.59). At the secondary end point, response rates were significantly greater with antibiotics than with placebo (49.5 vs. 21.8%, respectively, P<0.0001). Endoscopic scores were significantly improved at 12 months after antibiotic treatment (P=0.002 vs. placebo). Remission rates had improved to 26.7% with antibiotics vs. 14.9% for placebo, at 12 months (P=0.041). F. varium antibody titers decreased in responders but not in nonresponders, and more in the antibiotic than in the placebo group. More pretreatment steroid-dependent UC patients discontinued corticosteroids after treatment completion (6 months: 28.6 vs. 11.8%, respectively, P=0.046; 9 months: 34.7 vs. 13.7%, respectively, P=0.019; and 12 months: 34.7 vs. 13.7%, respectively, P=0.019). These effects were greater in the subanalysis of the active group (Mayo scores of 6–12) than in that of total cases (0–12). No serious drug-related toxicities occurred.CONCLUSIONS:The 2-week triple antibiotic therapy produced improvement, remission, and steroid withdrawal in active UC more effectively than a placebo.

Growth-promoting effect of muscarinic acetylcholine receptors in colon cancer cells

PurposeG-protein-coupled receptors are known to mediate cell growth via divergent signaling pathways. It has been reported that colon cancer cells express muscarinic acetylcholine receptor (mAChR) although their functional role is largely unknown. The aim of this study is to elucidate possible mechanisms responsible for the growth-promoting effect of mAChRs in colon cancer cells by using colon cancer cell line T84.MethodsCarbachol, a stable mAChR agonist, dose-dependently induced cell growth with a maximal effect observed at 100xa0μM, equipotent with 1xa0nM EGF. 4-DAMP, a specific antagonist of subtype 3 mAChR, inhibited the stimulatory effect by carbachol, suggesting that the growth-promoting effect was receptor-mediated. Carbachol also dose-dependently stimulated extracellular signal-regulated protein kinase (ERK) activation. This effect was inhibited by PD98059, an inhibitor of extracellular signal-regulated protein kinase kinase, which also blocked carbachol activation of cell proliferation, indicating that the p21Ras-ERK pathway is an important signaling cascade in the mitogenic effect. To investigate how mAChR activated the p21Ras-ERK pathway, transactivation of epidermal growth factor receptor (EGFR) was examined.ResultsCarbachol induced tyrosine phosphorylation of EGFR, which was abolished by an EGFR tyrosine kinase inhibitor AG1478. Transactivation by carbachol was also abrogated by a metalloproteinases (MMPs) inhibitor GM6001 or an EGFR-blocking antibody (LA-1), suggesting that binding of EGFR ligand(s) produced by MMPs may initiate transactivation in a manner dependent on EGFR tyrosine kinase. The tyrosine-phosphorylated EGFR was immunoprecipitated together with GRB2 and tyrosine-phosphorylated Shc, indicating that transactivated EGFR is able to generate downstream signals. AG 1478 and LA-1 inhibited carbachol stimulation of cell growth.ConclusionsTaken together, our results indicate that the growth-promoting effect of subtype 3 mAChR in colon cancer cells may depend on transactivated EGFR-ERK pathways. EGFR not only receives external stimuli but also serves as a scaffold for downstream signaling molecules.

A prospective analysis of the incidence of and risk factors for opportunistic infections in patients with inflammatory bowel disease

BackgroundImmunosuppressants lead to an increased risk of infection, but few prospective studies have assessed the incidence of opportunistic infections in inflammatory bowel disease (IBD) patients, a high proportion of whom are treated with immunosuppressants. The aim of this study was to assess the age distribution of Japanese IBD patients with opportunistic infections and the risk factors associated with these infections.MethodsA multicenter, prospective study of 570 IBD patients was conducted. The patients were followed for up to 12xa0months to identify any new infections. The incidence of opportunistic infections and the age distribution of patients with these infections were analyzed. We carried out a case–control study in which 2 non-infected IBD patients were selected as controls for each case (infected IBD patient); the effect of medications on the infection rate was also examined.ResultsFifty-two (9.1xa0%) of 570 IBD patients developed opportunistic infections. Herpes simplex virus and herpes zoster virus infections were observed in 29 and 16 patients, respectively. No cases of active tuberculosis were observed. The incidence of opportunistic infections in patients aged 50 years or over was significantly higher than that in the other age groups (pxa0=xa00.01). The use of steroids (pxa0=xa00.02), thiopurine (pxa0<xa00.01), and immunosuppressant combination therapy (pxa0<xa00.01) was associated with an increased rate of opportunistic infections. However, the use of infliximab was not associated with an increased rate of opportunistic infections (pxa0=xa00.62). Multivariate analysis indicated that the use of thiopurine was an independent risk factor for opportunistic infections (pxa0<xa00.01).ConclusionsAge ≥50xa0years and the use of immunosuppressants are risk factors for opportunistic infections in patients with IBD. In our cohort, tuberculosis was not seen as a complication of immunosuppressant therapy.

Comparison of Targeted vs Random Biopsies for Surveillance of Ulcerative Colitis-Associated Colorectal Cancer.

BACKGROUND & AIMSnA random biopsy is recommended for surveillance of ulcerative colitis (UC)-associated colorectal cancer. However, a targeted biopsy might be more effective. We conducted a randomized controlled trial to compare rates of neoplasia detection by targeted vs random biopsies in patients with UC.nnnMETHODSnWe performed a study of 246 patients with UC for 7 years or more, seen at 52 institutions in Japan from October 1, 2008 through December 31, 2010. Patients were randomly assigned to the random group (4 random biopsies collected every 10 cm in addition to targeted biopsies, nxa0= 122) or the target group (biopsies collected from locations of suspected neoplasia, nxa0= 124). The primary end point was the number of neoplastic lesions detected in a single surveillance colonoscopy. We estimated the ratio and difference in the mean number of neoplastic lesions between the groups. We also evaluated the non-inferiority between the groups as an exploratory study. A non-inferiority margin of 0.65 (0.13 of 0.20) was considered for the ratio of the mean number of neoplastic lesions between groups.nnnRESULTSnThe mean number of biopsies found to contain neoplastic tissue per colonoscopy was 0.211 (24 of 114) in the target group and 0.168 (18 of 107) in the random group (ratio of 1.251; 95% confidence interval, 0.679-2.306). The lower limit was above the non-inferiority margin of 0.65. Neoplasias were detected in 11.4% of patients in the target group and 9.3% of patients in the random group (Pxa0= .617). Larger numbers of biopsy samples per colonoscopy were collected in the random group (34.8 vs 3.1 in the target group; P < .001), and the total examination time was longer (41.7 vs 26.6 minutes in the target group; Pxa0<xa0.001). In the random group, all neoplastic tissues found in random biopsies were collected from areas of the mucosa with a history or presence of inflammation.nnnCONCLUSIONSnIn a randomized controlled trial, we found that targeted and random biopsies detect similar proportions of neoplasias. However, a targeted biopsy appears to be a more cost-effective method. Random biopsies from areas without any signs of present or past inflammation were not found to contain neoplastic tissues. Clinical Trial Registry: UMIN000001608.

Fecal calprotectin is a clinically relevant biomarker of mucosal healing in patients with quiescent ulcerative colitis.

Calprotectin is an abundant protein in neutrophils, which infiltrate the mucosa during inflammation. Fecal calprotectin (FC) level has shown correlation with disease activity in ulcerative colitis (UC) patients. Additionally, FC level is expected to indicate mucosal healing (MH). This study was to see the significance of FC for predicting MH in patients with quiescent UC.

The impact of disease activity of Crohn’s disease during pregnancy on fetal growth

Although it is known that women with inflammatory bowel disease have an increased risk of adverse outcome of pregnancy, the relationship between disease activity during pregnancy and the adverse outcome is not well known. A 29-year-old woman with Crohn’s disease presented with flare-up at the end of the first trimester. Although the disease had been rendered inactive by maintenance infusion of infliximab, the drug was discontinued at the time of conception because of the patient’s fear of the adverse effects of infliximab. Because retardation of fetal growth was observed at the flare-up, we re-started infliximab therapy. As disease activity reduced with therapy, the retardation of fetal growth subsequently improved. The patient finally delivered a newborn of 2550xa0g in weight and no adverse outcome was noted. The case supports the notion that disease activity is a risk factor for adverse outcome in pregnancy and that infliximab may be safely used in pregnancy.

A multicentre randomised trial to compare the efficacy of omeprazole versus rabeprazole in early symptom relief in patients with reflux esophagitis

BackgroundProton pump inhibitors (PPIs) are affected by cytochrome P450 2C19 (CYP2C19) polymorphisms. This study compared the effect of two PPIs on early symptom relief in Japanese patients with reflux esophagitis, classified by the CYP2C19 phenotype.MethodsPatients with reflux esophagitis were randomised to treatment with omeprazole 20xa0mg or rabeprazole 10xa0mg once daily. The CYP2C19 phenotype [homozygous extensive metaboliser (homoEM), heterozygous extensive metaboliser (heteroEM) or poor metaboliser (PM)] of each patient was determined. The primary efficacy endpoint was early, sufficient (Global Overall Symptom scale score 1 or 2), sustained (maintained for ≥7xa0days) reflux symptom relief.ResultsOf the 199 patients included in this analysis, the proportion achieving sufficient, sustained reflux symptom relief was higher with omeprazole than with rabeprazole on dayxa01 (35.6 vs. 22.4xa0%; pxa0=xa00.041) and dayxa02 (43.6 vs. 28.6xa0%; pxa0=xa00.028); there was no significant difference between the two groups on daysxa03–7. Among patients with the CYP2C19 PM phenotype, sufficient, sustained reflux symptom relief was higher with omeprazole than with rabeprazole on daysxa04–7 (62.5–66.9 vs 31.6xa0%; pxa0≤xa00.03); differences were not significant on days 1–3, or among those with the homoEM or heteroEM phenotypes on daysxa01–7.ConclusionsIn Japanese patients with reflux esophagitis, omeprazole 20xa0mg is more effective than rabeprazole 10xa0mg at achieving early, sufficient, sustained reflux symptom relief in individuals with the CYP2C19 PM phenotype, and is similarly effective to rabeprazole 10xa0mg in those with heteroEM or homoEM phenotypes.

Incidence and characteristics of the 2009 influenza (H1N1) infections in inflammatory bowel disease patients

BACKGROUNDnIn 2009, influenza A (H1N1) infections spread worldwide. Because the use of immunomodulators is associated with an increased risk of infection, inflammatory bowel disease (IBD) patients who are on immunomodulators might be concerned about H1N1 influenza infections. The aim of this study was to investigate the age distribution and risk factors associated with H1N1 influenza of IBD patients in 2009-2010.nnnMETHODSnA multicenter, prospective study was conducted, and 570 IBD patients were enrolled. Patients were followed up for 10 months to identify any new infections. The incidence and age distribution of the H1N1 influenza infections were analyzed. IBD patients with H1N1 influenza infections and 2 matched, noninfected IBD patients were selected to assess the effect of specifying the medication on the incidence of infections.nnnRESULTSnA total of 38 patients (6.7%) developed H1N1 influenza infections. The incidence of H1N1 influenza infections in patients aged less than 20 years was significantly higher than that among patients in other age groups (p<0.01). The age distribution for H1N1 influenza infections in IBD patients was comparable to those in the general population. No patients needed hospitalization due to influenza infection. A total of 29 patients (76%) recovered from the H1N1 influenza symptoms within 7 days and 20 patients (53%) received antiviral treatment. The percentage of patients who used steroids or thiopurine was comparable between the cases of H1N1 influenza infection and the control group.nnnCONCLUSIONnOur prospective study showed that younger IBD patients were frequently infected with the influenza A (H1N1) virus as well as general population. Admission and fatal cases due to H1N1 influenza infections were not observed.

Development of hepatocellular carcinoma following treatment with6-mercaptopurine for ulcerative colitis: investigation of chromosomal aberration by comparative genomic hybridization

In a 64-year-old man who had been treated with prednisolone (PSL) and 6-mercaptopurine (6MP) for a long period, for ulcerative colitis (UC), hepatocellular carcinoma (HCC) was detected incidentally. The UC was in remission with these medications. After he had been taking these medications for about 8 years, HCC was detected by computed tomography (CT), done for the evaluation of an other disease. Blood chemistry examination results were normal, except that the protein induced by vitamin K antagonist (PIVKA)-II level was 7940u2009AU/ml. We performed resection of liver segment V. With comparative genomic hybridization, chromosomal aberrations were recognized; these were gains of 1q, 3ptel-21, 8p12, and 22q11.23–22q13.1. Generally, HCC is associated with hepatitis virus infection in most cases, but in this patient, the HCC was not related to hepatitis C virus (HCV) or HBV. It is presumed that this case was related to the immunosuppressive therapy for UC and was associated with the gains of 1q, 3p, and 8p.

Long-Term Enteral Immunonutrition Containing Lactoferrin in Tube-Fed Bedridden Patients: Immunological and Nutritional Status

Objective: The aim of this study was to examine the efficacy and safety of a novel immune-enhancing enteral formula, Prem-8, which contains lactoferrin as an immunonutrient. Design, Setting, Patients: A multicenter, randomized controlled trial was conducted in 5 hospitals in Japan, and 71 tube-fed bedridden patients with serum albumin concentrations between 2.5 and 3.5 g/dL were allocated to Prem-8 (n = 38) or control formula (n = 33) groups for an observation period of 12 weeks. Measures of Outcome: Efficacy was evaluated by comparing immunological (natural killer cell activity, neutrophil-phagocytic activity, neutrophil-sterilizing activity, and C-reactive protein), and nutritional (anthropometric measurements and serum levels of nutritional assessment proteins and total cholesterol) variables. Safety was assessed by comparing the incidence of adverse events. In a secondary analysis, patients were subgrouped according to the amount of protein supplemented (1 g/kg/d) so that immunological and nutritional variables and safety could be further compared. Results: Natural killer activity and neutrophil functions were normal for both groups throughout the study period, without significant between-group differences at any point. Nutritional status was stably maintained in both groups, although the body mass index at 12 weeks was marginally lower in the Prem-8 group than in the control group (p < 0.01). The incidence of adverse events were comparable between both groups, but the incidence of fever in the Prem-8 group (7/14) was significantly lower than in the control group (10/11) in a subgroup of patients whose supplemented protein was less than 1 g/kg/d (p < 0.05). Conclusion: Prem-8 did not demonstrate superiority to the control formula with respect to immunological and nutritional variables, whereas the body mass index of patients in the Prem-8 group marginally decreased. However, Prem-8 had a favorable effect on the incidence of fever in a subgroup of patients with low protein intake.