Postoperative functional outcomes and complications of partially intraanal canal anastomosis in stapled ileal pouch anal anastomosis for ulcerative colitis.

AIM: For ulcerative colitis (UC), stapled ileal pouch anal anastomosis (IPAA) reportedly results in better bowel function than does IPAA with mucosectomy. However, a potential cancer risk in the remnant mucosa has been observed. The clinical results of IPAA by double stapling technique (DS-IPAA) in which the anastomotic line was on the dentate line at posterior wall and the top of anal canal at anterior wall ("Partially intraanal canal anastomosis": PICA) to reduce the remnant mucosa were evaluated. METHODS: Clinical results of PICA were retrospectively compared with those by DS-IPAA with anastomosis at above the anal canal on 1 year after open surgery. Of 211 UC cases that underwent DS-IPAA, 146 cases (69%) with PICA who were confirmed by the squamous epithelium on the posterior part of the distal donuts were included. Sixty-five cases with anastomosis above the anal canal were evaluated as the control. One stage surgery underwent in 95% of PICA and 93% of control. RESULTS: One year after surgery, each group had six bowel movements daily. Nighttime evacuation was found in 16% of PICA and in 20% of control. Soiling was found in 1% of PICA and 4.8% of control. After one stage operation, anastomotic leakage that needed ileostomy was observed in 0.7% of PICA and 3% of control. CONCLUSION: Partially intraanal canal anastomosis (PICA) can reduce anal canal mucosa with the same postoperative bowel function and complication rate as DS-IPAA above the anal canal. This procedure may be feasible for UC patients who can tolerate this procedure in terms of decreasing postoperative cancer risk.

[A case of Crohn's disease complicated by Guillain-Barrè syndrome during ustekinumab therapy].

We herein report a case involving a 23-year-old male patient with active Crohn's disease complicated by Guillain-Barrè syndrome during ustekinumab therapy. At age 11, the patient developed an anal fistula and was found to have multiple aphthae on the rectosigmoid colon, for which he was diagnosed with Crohn's disease. At age 12, he underwent gastrojejunal anastomosis for pyrolic stenosis. At age 20, a longitudinal ulcer was found on the ascending colon, and at age 21, aphthae were found on the stomach and efferent jejunum. At age 22, adalimumab was started, but the patient noted abdominal pain and diarrhea 4 months later. Hence, adalimumab was switched to ustekinumab (2017 June). Though ustekinumab was effective, the patient noted anorexia, weakness, and bilateral lower extremity numbness 1 year later (2018 June) and was admitted to the hospital. He was then diagnosed with Guillain-Barrè syndrome after spinal tap, neurological, and hematological examinations. Immunoglobulin therapy was provided but was less effective. The patient has since been receiving physical therapy. This has been the first report regarding Guillain-Barrè syndrome as a complication during ustekinumab therapy.

Crohn's disease manifesting as ileo-urachal fistula: Two cases reports and review of literatures.

INTRODUCTION: A fistula involving a patent urachus in a patient with Crohn's disease is rare. Here we report ileourachal fistula formation in two patients with Crohn' disease. CASE PRESENTATIONS: The first patient was a 29-year-old man with Crohn's disease and ileitis, and the second patient was a 43-year-old man with Crohn's disease and ileitis. One of the patients showed pus/fecal discharge via the umbilicus. Both patients were eventually diagnosed with an ileourachal fistula associated with Crohn's disease. In the first patient, the urachal remnant was connected to the urinary bladder and a Crohn's disease-related intestinal lesion had formed a fistula to the urachus. In the second patient, a periumbilical inflammatory lesion extended to the bladder through the urachal remnant and to a longitudinal ulcer of the ileal lesion. The first patients underwent partial ileal resection, and partial cystectomy, while the second patient underwent urachal curettage, partial ileal resection, and partial cystectomy. In both. CONCLUSION: In cases of Crohn's disease with an enterocutaneous fistula or pus discharge via the umbilicus, an examination to detect an urachal remnant with a fistula from the diseased intestine should be performed.

[Diagnosis and treatment of six patients with Crohn's disease complicated by recto-perineal-urethral fistula].

Recto-perineal-urethral fistula caused by Crohn's disease is a rare, for which fundamental treatment has not been established yet. We analyzed the clinical characteristics, diagnosis, treatment, and prognosis of six male patients with anorectal lesions caused by Crohn's disease. Three patients were treated with abdominoperineal resection and the other three with rectal excision without anastomosis. Excluding one case, which presented worsening immediately after surgery, symptoms of urethral fistula improved without urethral stenosis, dysuria, or sexual dysfunction. Recto-perineal-urethral fistula is currently treated with various treatment modalities, including colostomy and drug therapy. Although the evaluation of these modalities is required, abdominoperineal resection or rectal excision without anastomosis may be a valuable treatment option because these approaches improve the urethral fistula while sparing the urethra without any significant complications.

Phase 1 Clinical Study of siRNA Targeting Carbohydrate Sulphotransferase 15 in Crohn's Disease Patients with Active Mucosal Lesions.

BACKGROUND AND AIMS: Carbohydrate sulphotransferase 15 [CHST15] is a specific enzyme biosynthesizing chondroitin sulphate E that binds various pathogenic mediators and is known to create local fibrotic lesions. We evaluated the safety of STNM01, a synthetic double-stranded RNA oligonucleotide directed against CHST15, in Crohn's disease [CD] patients whose mucosal lesions were refractory to conventional therapy. METHODS: This was a randomized, double-blind, placebo-controlled, concentration-escalation study of STNM01 by a single-dose endoscopic submucosal injection in 18 CD patients. Cohorts of increasing concentration of STNM01 were enrolled sequentially as 2.5nM [n = 3], 25nM [n = 3], and 250nM [n = 3] were applied. A cohort of placebo [n = 3] was included in each concentration. Safety was monitored for 30 days. Pharmacokinetics was monitored for 24h. The changes from baseline in the segmental Simple Endoscopic Score for CD [SES-CD] as well as the histological fibrosis score were evaluated. RESULTS: STNM01 was well tolerated and showed no drug-related adverse effects in any cohort of treated patients. There were no detectable plasma concentrations of STNM01 at all measured time points in all treatment groups. Seven of nine subjects who received STNM01 showed reduction in segmental SES-CD at Day 30, when compared with those who received placebo. Histological analyses of biopsy specimens revealed that STNM01 reduced the extent of fibrosis. CONCLUSION: Local application of STNM01 is safe and well tolerated in CD patients with active mucosal lesions.

A case of Crohn's disease complicated with simultaneous double cancers of the small bowel.

A case of Crohn's disease complicated with simultaneous double cancers of the small bowel is reported. The patient is a 66-year-old man who had suffered from Crohn's disease for 20 years. He underwent surgery to identify the source of repeated episodes of intestinal obstruction. Two short segments of strictures and proximal dilatations were found in the distal ileum. Therefore, we performed an en bloc resection of the two stenotic sections instead of strictureplasty. Histological examination of the resected specimen revealed not only Crohn's disease but also a well-differentiated adenocarcinoma within each of the two strictures. One had invaded to the muscular layer and the other to the subserosal layer. In cases of Crohn's disease with longstanding stenosis, the probability of carcinoma should be considered.

Coping Strategies for Possible Flare-Ups and Their Perceived Effectiveness in Patients With Inflammatory Bowel Disease.

The study objective was to investigate the nature and perceived effectiveness of strategies that patients with inflammatory bowel disease (IBD) use in response to worsening symptoms. Questionnaires to investigate the use and perceived effectiveness of 11 types of strategies for coping with possible flare-ups were mailed to 1,641 members of the Crohn's and Colitis Foundation of Japan. The responses were analyzed separately by disease type: ulcerative colitis (UC) and Crohn disease (CD). A total of 400 questionnaires were analyzed from 260 UC and 140 CD patients. The strategies used most by both patient groups were "change contents of meals" and "get more sleep." In addition, "skip some meals" was commonly used by CD patients. The most effective strategies were "use extra topical corticosteroids" (30 of the 56 subjects, 53.6%) among UC patients, and "skip some meals" (70 of the 114 subjects, 61.4%), and "take/add to the elemental diet" (53 of 89 subjects, 59.6%) among CD patients. The coping strategies used most by patients with IBD involved lifestyle modifications. However, the additional use of medications was regarded as the most effective, despite the small number of patients who used this strategy. Additional use of topical medications for UC patients and diet modifications for CD patients should be emphasized in self-management education for patients.

[Recent advances in medical and surgical treatment of ulcerative colitis].

Recent advances in both medical and surgical treatment of ulcerative colitis have been remarkable. Changes in medical treatment are mainly good results of therapy with the anti-TNF-α antibody, tacrolimus, and those in surgical treatment are an expansion of the surgical indications to include patients with intractable disease, such as treatment refractoriness and chronic corticosteroid dependence, by a better postoperative clinical course after pouch surgery, improred selection of surgical procedures and the timing of surgery in elderly patients. To offer the optimal treatment for patients with ulcerative colitis, new medical therapies should be analyzed from the standpoint of the efficacy and limitations of effect. Long postoperative clinical course of surgical patients including colitic cancer, prevention of postoperative complications should be also analyzed.

[Long-term outcomes of ileal pouch-anal canal anastomosis in children with ulcerative colitis].

The present study investigated the long-term outcomes of restorative proctocolectomy in pediatric patients with ulcerative colitis (UC). We report a series of 25 patients who underwent total proctocolectomy with ileal pouch-anal canal anastomosis (IACA). Surgery was performed for medically intractable colitis and severe colitis in 14 and 11 patients, respectively. Early and late complications were observed in 6 (24%) and 14 (56%) patients, respectively. The long-term quality of life outcomes were satisfactory, including both bowel function and social function. Growth retardation was observed in 6 patients. Five patients exhibited catch-up growth and 3 patients overcame growth retardation. Patients with growth retardation tended to have a younger onset and longer duration of UC, as well as a longer duration and higher total dose of steroid use. In conclusion, the long-term outcomes of pediatric patients with UC undergoing IACA are satisfactory. Furthermore, to minimize the risk of growth retardation, surgery should be performed without delay.

Molecular cloning reveals nearly half of patients with Crohn's disease have an antibody to peroxiredoxin 6-like protein.

BACKGROUND AND AIM: Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) of unknown etiology. We aimed to identify the etiological agent of CD using a molecular cloning strategy that was particularly focused on identifying agents causing immune abnormalities and infectious agents. METHODS: We constructed a cDNA library derived from the inflamed intestinal tissue of a CD patient, and screened 1.5 million clones in this library with the serum from another typical CD patient. The expressed cDNA clones that positively reacted with the serum were then expressed as fusion proteins with glutathione S-transferase, and western blotting was performed using the sera of 22 CD, 13 ulcerative colitis (UC), and 16 non-IBD patients. RESULTS: We identified nine positive clones that did not contain any viral or bacterial genomic DNA. Of these, we selected one clone (clone 50) with which the typical CD patient's serum most strongly reacted. Clone 50 is highly homologous to the antioxidant protein peroxiredoxin 6. In western blotting, the sera of 47.6% CD patients (small intestine type 80%, large and small intestine type 43%, large intestine type 0%) showed strong reactivity to clone 50, none of the UC patients were reactive to clone 50, and 18.8% of non-IBD patients were very weakly reactive to it. We also found that the expression of peroxiredoxin 6 was significantly increased in inflamed intestinal epithelia of CD. CONCLUSION: The present study first showed that some CD patients have an antibody against peroxiredoxin 6-like protein, which may be involved in the pathogenesis of CD.

Hypoglycemia-like symptoms after restorative proctocolectomy for UC: a preliminary study.

This study was conducted to explore the hypoglycemia-like symptoms sometimes noted after proctocolectomy for ulcerative colitis. Eighty-three patients who underwent restorative proctocolectomy at least 1 year before December 2001 (staged procedure, n = 50; one-staged procedure, n = 33) were requested to answer three questionnaires at the stage of temporary diverting ileostomy and/or after completion of the operation (after stoma closure). The questionnaires evaluated the presence of 18 items of hypoglycemia-like symptoms, subject recognition of the cause, and whether the symptoms were improved after eating or drinking. Seven subjects (14%) experienced at least one of the three items considered to be specific symptoms of hypoglycemia ("cold sweats," "trembling of hands," and "extreme desire for sweets") at the stage of temporary ileostomy. Ten (20%) and 9 (27.3%) subjects experienced those specific symptoms at the stage after completion of the operation by staged procedure and by one-staged procedure, respectively. There was no significant difference between the stages. Hypoglycemia-like symptoms were found to be experienced in a considerable number of patients after proctocolectomy for ulcerative colitis.

[Reconstruction of proctocolectomy: which is the best surgical procedure?].

Total proctocolectomy is commonly performed in patients with ulcerative colitis or familial adenomatosis coli. The standard surgical procedure for reconstruction is the ileal pouch anal anastomosis with rectal mucosal stripping (IPAA), which is radical treatment for the disease, or stapled ileal pouch anal anastomosis with preserved anal canal (stapled IPAA), which results in a lower incidence of soiling with a high possibility of one-stage surgery. Postoperative cancer surveillance colonoscopy is recommended in patients with stapled IPAA, and patients with IPAA have also at risk for cancer in the anastomotic site, although at very low incidence. Quality of life (QOL) studies (SF36, etc.) found good QOL after surgery in patients who underwent both procedures. Patients with permanent ileostomy for preoperative anal dysfunction also had good QOL. The surgical procedure for reconstruction should be determined based on surgical indications, preoperative anal function, and patient's request. For improved QOL in the future, pouch surgery should have a lower incidence of diverting ileostomy and result in fewer bowel movements and a lower incidence of soiling, with optimal management of pouchitis.

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

BACKGROUND: Although intestinal Behçet's disease has been treated anecdotally with various therapeutic modalities, clinical evidence regarding management of intestinal Behçet's disease is lacking. The objective of this study was to develop consensus-based practice guidelines for diagnosis and treatment of intestinal Behçet's disease by using a modified Delphi approach. METHODS: Three 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. RESULTS: Thirty-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 > or =7. The range of scores decreased considerably from the first to the second round. CONCLUSIONS: 5-Aminosalycylic acid, corticosteroids, immunosuppressants, enteral nutrition, total parenteral nutrition, and surgical therapy were considered standard therapy for intestinal Behçet's 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 Behçet's disease were developed.

[Clinical experiences of five cases with ulcerative colitis and recto- or anovaginal fistula].

Clinical aspects, treatment and outcome of five patients with ulcerative colitis recto- or anovaginal fistula and were studied retrospectively. All patients had total colitis (relapse and remission type) and more than a 5 year history of ulcerative colitis. They all had anorectal complications, such as periproctal abscess, stenosis of fistula. Four patients had total colectomy with an ileal pouch anal canal anastomosis for intractability or dysplasia. One was treated conservatively. Complete closure of fistula was obtained in two patients;in one patient rectum was resected below the fistula and in one patient defect of the vaginal posterior wall was reconstructed by using a gluteal fold flap following colectomy. Recto- or anovaginal fistula complicating ulcerative colitis is rare but may occur in the patients with severe rectal inflammation and they can be managed by restorative proctocolectomy with an ileal pouch anal or anal canal anastomosis.

Restorative proctocolectomy for pediatric patients with ulcerative colitis.

PURPOSE: A 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. METHODS: The medical records of 15 patients with UC who underwent a restorative proctocolectomy between August 1993 and October 2003 were retrospectively reviewed. RESULTS: Their 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. CONCLUSION: A restorative proctocolectomy was found to be an effective treatment alternative even in children with UC when conservative therapy proves to be ineffective.

Incidence and outcome of complications following restorative proctocolectomy.

BACKGROUND: Complications were analyzed in 296 patients with ulcerative colitis who underwent restorative proctocolectomy. METHODS: In 96.3% of patients, the pouch was anastomosed using the double stapling method. A total of 44.6% of patients underwent restorative proctocolectomy in 1 stage without ileostomy and 53% in 2 stages. Complications were divided into 2 stages: early (within 1 month) and late (after 1 month); moreover, the annual incidences were calculated, mean onset time, and pouch survival rate. RESULTS: The overall incidence of complications was 52.7%. Early complications (13.2%) occurred significantly less often than late complications (46.3%) (P < .05). Thirty-five (17.7%) of 198 complications required surgery. The cumulative 5- and 10-year pouch survival rate was 99%, respectively. CONCLUSIONS: The rate of complications after restorative proctocolectomy was almost equivalent to that in other reports, but the pouch survival rate was very high.

[Surgical treatment for ulcerative colitis--recent advances].

Surgical indication for ulcerative colitis is fulminant colitis, intractability, cancer or dysplasia. New surgical indication should be established because new medical treatment such as leucocytoapheresis or intravenous cyclosporine treatment developed. Standard surgical procedure is ileal pouch anal anastomosis with rectal mucosal stripping and stapled ileal pouch anal anastomosis. Postoperative bowel function and QOL are satisfactory in both of them. Surgical treatment should be performed without any delay for the patients who do not respond medical treatment.

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

BACKGROUND: The 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). METHODS: Colonic 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. CONCLUSIONS: Angiogenic 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.

CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells.

It is well known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only active suppression by regulatory T cells plays an important role in the normal intestinal homeostasis, but also its dysregulation leads to the development of inflammatory bowel disease. In this study, we demonstrate that the CD4(+)CD25(bright) T cells reside in the human intestinal lamina propria (LP) and functionally retain regulatory activities. All human LP CD4(+) T cells regardless of CD25 expression constitutively expressed CTLA-4, glucocorticoid-induced TNFR family-related protein, and Foxp3 and proliferate poorly. Although LP CD4(+)CD25(-) T cells showed an activated and anergic/memory phenotype, they did not retain regulatory activity. In LP CD4(+)CD25(+) T cells, however, cells expressing CD25 at high levels (CD4(+)CD25(bright)) suppressed the proliferation and various cytokine productions of CD4(+)CD25(-) T cells. LP CD4(+)CD25(bright) T cells by themselves produced fewer amounts of IL-2, IFN-gamma, and IL-10. Interestingly, LP CD4(+)CD25(bright) T cells with regulatory T activity were significantly increased in patients with active inflammatory bowel disease. These results suggest that CD4(+)CD25(bright) T cells found in the normal and inflamed intestinal mucosa selectively inhibit the host immune response and therefore may contribute to the intestinal immune homeostasis.