Tsuneo Fukushima

Development of consensus statements for the diagnosis and management of intestinal Behçet's disease using a modified Delphi approach

BackgroundAlthough intestinal Behçets disease has been treated anecdotally with various therapeutic modalities, clinical evidence regarding management of intestinal Behçets disease is lacking. The objective of this study was to develop consensus-based practice guidelines for diagnosis and treatment of intestinal Behçets disease by using a modified Delphi approach.MethodsThree groups of Japanese gastroenterology specialists were involved in the study: moderators, an expert panel, and a professional group. Clinical statements for ratings were extracted from relevant literature, a survey of the professional group, and by discussion among the expert panel. The expert panel rated the clinical statements according to a nine point scale. After the first round of ratings, a panelist meeting was held to discuss areas of disagreement and to clarify areas of uncertainty. The list of clinical statements was revised after the panelist meeting, and a second round of rating was conducted.ResultsThirty-two relevant articles were selected in a literature search, and 35 clinical statements were extracted. An additional 209 clinical statements were developed from the survey and discussion among gastroenterology specialists. In the first and second rounds, 56% and 60% of statements, respectively, received median scores ≥7. The range of scores decreased considerably from the first to the second round.Conclusions5-Aminosalycylic acid, corticosteroids, immunosuppressants, enteral nutrition, total parenteral nutrition, and surgical therapy were considered standard therapy for intestinal Behçets disease. Infliximab, colchicines, thalidomide, other pharmacological therapy, endoscopic therapy, and leukocytapheresis were deemed experimental therapy. Based on a two-round modified Delphi approach, practice guidelines for diagnosis and treatment of intestinal Behçets disease were developed.

No Mycobacterium paratuberculosis detected in intestinal tissue, including Peyer's patches and lymph follicles, of Crohn's disease.

Abstract: To clarify the etiologic significance of Mycobacterium paratuberculosis in Crohns disease, we investigated whether M. paratuberculosis was detected in intestinal tissues, including Peyers patches, where M. paratuberculosis invades, and colonic lymph follicles, where early lesions appear. Fifty-one samples of intestinal tissues, either therapeutically resected or biopsied, including 34 specimens from 30 patients with Crohns disease, were studied. Four Peyers patches and eight lymph follicles were included in the intestinal tissue samples of Crohns disease. They were visualized by acetic acid fixation. DNA extracted from intestinal tissues by proteinase K treatment was used for nested polymerase chain reaction (PCR) for detection of IS900, which is specific for M. paratuberculosis. PCR products were analyzed by agarose gel electrophoresis and subsequent Southern blot analysis. Our amplification system could detect 7.5 fg of M. paratuberculosis DNA. None of the tissue samples showed positive IS900 amplification, whereas they all showed amplification of the positive control human leukocyte antigen (HLA)-DQA DNA. Spiked experiments of tissue samples with M. paratuberculosis demonstrated that inhibitors of IS900 amplification were not present in the samples. Our study does not support the etiologic significance of M. paratuberculosis in Crohns disease.

Systemic and local evidence of increased Fas-mediated apoptosis in ulcerative colitis

Abstract. Background and aims: Recent studies suggest that Fas-mediated apoptosis is involved in the pathogenesis of inflammatory bowel disease (IBD). This study was conducted to clarify whether soluble forms of Fas (sFas) and Fas ligand (sFasL) are concerned with inflammation in IBD. Methods and patients: Concentration of serum sFas and sFasL was measured by enzyme-linked immunosorbent assay in 10 patients with ulcerative colitis (UC), 10 with Crohns disease (CD) in both active and remission stages, and 20 controls. Expression of Fas and sFas in colonic mucosa was examined by western blot. Distribution of Fas and FasL in colonic mucosa was examined by immunohistochemistry in 20 UC, 20 CD, and 10 non-IBD colitis patients and in 10 controls. Apoptotic cells were examined by TUNEL. Results: Concentration of systemic sFas was significantly lower in active UC than controls. The number of FasL-containing cells was significantly higher in active UC than in remission UC, non-IBD colitis, and controls. Apoptotic cells were increased in active UC. Conclusions: Our results demonstrate that systemic and local Fas-mediated apoptosis is promoted in UC, which might be involved in the pathogenesis in UC.

Altered expression of angiogenic factors in the VEGF-Ets-1 cascades in inflammatory bowel disease

BackgroundThe VEGF-Ets-1 cascades play important roles in angiogenesis by converting endothelial cells to an angiogenic phenotype. The aim of this study was to clarify whether the VEGF-Ets-1 cascades are involved in the pathogenesis of inflammatory bowel disease (IBD).MethodsColonic specimens were taken from 42 patients with ulcerative colitis (UC), 37 with Crohn’s disease (CD), 8 with non-IBD colitis, and 21 normal controls. (1) Expression of vascular endothelial growth factor (VEGF), VEGF receptors (Flt-1, KDR), and Ets-1 proteins in colonic mucosa was immunohistochemically examined using specific antibodies. (2) Expression of Ets-1 protein or VEGF, Flt-1, KDR, and Ets-1 mRNA in colonic mucosa was measured by Western blot or RT-PCR.Results(1) The number of VEGF-containing cells was significantly increased in active UC (P < 0.05). The numbers of positive blood vessels (mean ± SE /mm2) to Flt-1, KDR, and Ets-1 antibodies were significantly increased in active UC (Flt-1: 4.0 ± 0.84; KDR: 2.4 ± 0.37; Ets-1: 5.5 ± 0.77) compared to active CD (Flt-1: 0.6 ± 0.30; KDR: 0.77 ± 0.28; Ets-1: 2.0 ± 0.56) (P < 0.01), non-IBD colitis (Flt-1: 1.0 ± 0.45; KDR: 1.83 ± 0.54; Ets-1: 3.0 ± 1.0), and controls (Flt-1: 0.88 ± 0.40; KDR: 0.60 ± 0.22; Ets-1: 1.67 ± 0.47) (P < 0.01). The numbers of positive cells to these antibodies were also increased in active UC. (2) Expression of Ets-1 protein and Flt-1, KDR, and Ets-1 mRNA was increased in active UC.ConclusionsAngiogenic factors in the VEGF-Ets-1 cascades were upregulated in UC, but they were relatively downregulated in CD. These alterations might be involved in the pathogenesis of both diseases.

The incidence and outcome of pelvic sepsis following handsewn and stapled ileal pouch anal anastomoses.

The incidence and outcome of pelvic sepsis was analyzed in 210 patients who underwent restorative proctocolectomy for ulcerative colitis (UC) in 197 patients, and for familial adenomatous polyposis (FAP) in 13 patients. Pelvic sepsis developed in 18 patients (8.6%) and a significantly higher incidence was seen in men than in women, at 13.6% vs 3.7%, respectively (P < 0.05). The incidence of pelvic sepsis in patients with UC complicated by toxic megacolon and/or fulminant colitis was significantly higher that in those without any preoperative complications, at 36.4% vs 7.4% (P < 0.05). The incidence of pelvic sepsis following handsewn anastomosis was significantly higher than that following stapled anastomosis, at 15.6% vs 5.5% (P < 0.05). The outcome of pelvic sepsis in patients with a stapled anastomosis was better than that in those with a handsewn anastomosis. The prognosis of women who developed pelvic sepsis was better than that of men who developed pelvic sepsis. The risk factors predisposing to pelvic sepsis were UC, especially when complicated by toxic megacolon and/or fulminant colitis, and male sex, while a handsewn anastomosis was more vulnerable than a stapled anastomosis.

Feasibility of a novel weekday-on/weekend-off oral UFT schedule as postoperative adjuvant chemotherapy for colorectal cancer

Purpose: When oral anticancer agents are used for adjuvant chemotherapy of colorectal cancer, compliance and feasibility become issues because of the long treatment time. Appropriate studies of these issues are lacking. We investigated compliance and feasibility during a weekday-on/weekend-off schedule of oral UFT (uracil-tegafur) over a period of 1 year administered as adjuvant chemotherapy to patients with colorectal cancer. Patients and methods: A UFT dose of 600 mg/day was prescribed according to a weekday-on/weekend-off schedule to 87 patients after potentially curative resection. Compliance was investigated in three ways: physician interview, patient self-report, and chemical analysis of urine. The results were compared with the dose prescribed. Feasibility was evaluated on the basis of two indices: relative performance (RP), which was the ratio of the actual total dose taken to the total dose planned, and individual dose intensity (IDI), which was the ratio of the actual dose taken to the dose planned during a given period. Results: The compliance assessed by physician interview and by patient self-report conformed well with the prescribed dose, the rate of agreement among the three compliance measures being more than 94%. Chemical analysis of urine in 38 of the patients revealed that they were actually taking the drug. The RP was 0.72, and the IDI was 0.8. Conclusion: From these results, the feasibility of the weekday-on/weekend-off schedule was judged to be good. It is suggested that the feasibility would be even better if the dose of UFT was set according to body surface area.

Efficacy of treatment with chimeric monoclonal antibody (Infliximab) to tumor necrosis factor-α for Crohn's disease in Japan: Evaluation by rapid turnover proteins, and radiologic and endoscopic findings

Background: Several studies have reported that the chimeric monoclonal antibody to tumor necrosis factor (TNF)‐α (Infliximab) is extremely valuable in the treatment of Crohns disease. The aim of this study was to clarify the efficacy of this treatment in Japanese patients with Crohns disease.

Effects of cyclosporin A on active Crohn’s disease

SummarySeven patients with active Crohn’s disease were treated with cyclosporin A orally for 16 weeks. The initial dose was 8 mg/kg/day and the subsequent dose was adjusted to maintain the plasma concentration of cyclosporin A of approximately 200 ng/ml. The mean value of the Crohn’s disease activity index before treatment was 194.3±57.4. It was gradually decreased reaching a nadir at 12 weeks (139.0±45.6, p< 0.05) and one enterocutaneous fistula was closed. White blood cell counts, hemoglobin and α-2-globulin did not significantly improve during treatment. Cyclosporin A could be indicated when steroids, sulfasalazine or azathioprine are not effective or not tolerated.

Restorative proctocolectomy for pediatric patients with ulcerative colitis.

PurposeA restorative proctocolectomy has become an elective surgical treatment for patients with ulcerative colitis (UC). In children with UC, however, the role of this procedure has not yet been well evaluated. We investigated the postoperative status of pediatric patients with UC regarding the side effects of steroids, postoperative complications, and growth.MethodsThe medical records of 15 patients with UC who underwent a restorative proctocolectomy between August 1993 and October 2003 were retrospectively reviewed.ResultsTheir mean age was 12.6 ± 3.4 years (range 5.7–15.7; boys: 9, girls: 6). All patients had total colitis, except for one who had left-sided colitis. The mean cumulative dose of preoperative prednisolone was 6201 ± 7980 mg (mean ± SD). The operative indications were an unsuccessful response to medical treatments in 12 patients (80%) and severe colitis in 3 patients (20%). Surgery was performed in one stage in 6 patients and in two stages in 9 patients. Seven patients (47%) demonstrated growth retardation at the time of operation. Steroid-related complications were seen in 3 cases, i.e., steroid myopathy, glaucoma, and cataracts, respectively. As early postoperative complications, an intestinal obstruction was seen in 2 patients, peritonitis in 1, and pancreatitis in 1. As late complications, anastomotic stenosis was observed in 5 patients, pouchitis in 4, residual proctitis in 3, and anal or proctovaginal fistula in 2. An intestinal obstruction, peristomal pyoderma gangrenosum, and dehydration each was seen in 1 patient. A growth “catch-up” was obtained for all but one patient. All patients became free of corticosteroids.ConclusionA restorative proctocolectomy was found to be an effective treatment alternative even in children with UC when conservative therapy proves to be ineffective.

Report on the first annual survey of home parenteral nutrition in Japan

An annual survey of the current national status of home parenteral nutrition (HPN) in Japan was begun in 1991, with a total of 231 registered patients from 142 institutions providing adequate data for evaluation and analysis. HPN was given for an average of 683±764 days to 93 patients with malignant diseases and 138 with benign disease, including 53 with inflammatory bowel disease and 79 with short bowel syndrome, 107 (46.3%) of whom were successfully rehabilitated. By the end of 1990, 61% of the patients investigated were still on HPN, 7% had already completed HPN, and 26% had died, the deceased accounting for 54% of the patients with malignant disease and 7% of those with benign diseases. A total of 321 catheters had been used by all 231 patients, the most common being the subcutaneously implanted type, accounting for 33% of all catheters. By the end of 1990, 32% of these 321 catheters were still in place, 18% had been removed on the termination of HPN and 44% had been removed due to complications of total parenteral nutrition, including 20% for catheter fever. Rehospitalization was required in 62% of the patients, the cause being HPN-related in 21% of the total patients. Metabolic complications were experienced by 60% of the patients, but none of these were severe although 6% required hospitalization. Thus, the total population of HPN patients and the success rate of rehabilitation in Japan were close to those reported in Europe, while the indications for HPN and its outcome were similar to those documented in the USA OASIS report, except that the incidence of rehospitalization from HPN-related causes in the Japanese survey was lower.