What determines the later clinical course of patients who do not undergo colectomy at the first attack? A Japanese cohort study on ulcerative colitis.

BACKGROUND/AIMS: Several earlier studies on factors predicting the long-term outcome of ulcerative colitis only encompassed treatment failure for one severe episode, or suffered from a lack of multivariate analyses. We aimed to identify factors assessable at diagnosis or after the first induction therapy which predicted relapse or later colectomy in patients with mild to severe ulcerative colitis. METHODS: Clinical parameters (age, sex, disease extent, and disease activity at diagnosis) and laboratory data (hemoglobin, albumin, C-reactive protein, and erythrocyte sedimentation rate at diagnosis and 4 weeks after the first induction therapy) were evaluated in 296 patients (median follow-up 87 months). Factors predicting relapse and later colectomy were sought using the Cox proportional hazard model. RESULTS: The presence of moderate or severe disease at diagnosis were significant predictors of relapse [adjusted hazard ratio (95% CI) 2.07 (1.48-2.89) and 1.70 (1.06-2.72), respectively] and later colectomy [3.40 (1.09-10.54) and 6.77 (1.92-23.86)]. After the first induction therapy, hemoglobin and albumin were associated with relapse [0.87 (0.76-0.99) and 0.58 (0.41-0.83)] and later colectomy [0.60 (0.47-0.77) and 0.11 (0.06-0.22)]. CONCLUSION: Relapse and later colectomy were associated with (1) disease activity at diagnosis and (2) lower levels of hemoglobin and albumin after the first induction therapy.

[An operative case of ulcerative colitis associated with hyperthyroidism].

We encountered a rare operative case of hyperthyroidism followed by ulcerative colitis (UC). A 26-year-old mam was referred to our department to undergo an operation. We suspected the possible complication of adrenal insufficiency, since he suffered from severe weight loss, a high fever and palpitation on admission. We diagnosed hyperthyroidism, however, based on the presence of high serum free T3 and T4 levels and a decreased TSH level. After improving the symptoms and the thyroid function by administering thiamazole, we then performed a total proctocolectomy. Although a high rate of association of autoimmune thyroid diseases with UC has been suggested, only 9 cases of hyperthyroidism coexisting with UC have so far been reported in Japan. A common immunological process has been suggested to be implicated in the pathogenesis of this association, however, the exact mechanism needs to be elucidated in the future.

A randomized, double-blind, placebo-controlled clinical trial of the effectiveness of the novel serotonin type 3 receptor antagonist ramosetron in both male and female Japanese patients with diarrhea-predominant irritable bowel syndrome.

OBJECTIVE: Irritable bowel syndrome is characterized by abdominal discomfort and/or pain associated with altered bowel habits. The neurotransmitter serotonin and serotonin type 3 receptors that are extensively distributed on enteric neurons in the human gastrointestinal tract play a role in increasing the sensation of pain and affecting bowel habits in patients with irritable bowel syndrome. The aim of this study was to evaluate the efficacy and safety of the serotonin type 3 receptor antagonist ramosetron hydrochloride in Japanese patients with diarrhea-predominant irritable bowel syndrome. MATERIAL AND METHODS: In a double-blind, placebo-controlled, parallel group-comparative study with a 1-week run-in period, 539 patients with diarrhea-predominant irritable bowel syndrome meeting the Rome II diagnostic criteria received either 5 microg ramosetron hydrochloride (n=270) or placebo (n=269) once daily for 12 weeks. RESULTS: Forty-seven percent of ramosetron hydrochloride-treated patients were monthly responders in the primary end-point, "Patient-reported global assessment of relief of irritable bowel syndrome symptoms", compared with 27% for placebos (p<0.001). The most frequently reported adverse event in the ramosetron hydrochloride-treated group compared with the placebo group was hard stool. CONCLUSIONS: Ramosetron hydrochloride 5 microg once daily is effective and well tolerated in the treatment of abdominal pain, discomfort and bowel habits in patients with diarrhea-predominant irritable bowel syndrome.

[Two cases of primary unresectable and/or recurrent gastrointestinal stromal tumors of small intestine presenting hemoperitoneum caused by administration of imatinib mesylate].

Case1 was a 52-year-old man who had recurrence of postoperative intra-abdominal disseminations from gastrointestinal stromal tumor (GIST) of the jejunum. Case2 was a 66-year-old man who had GIST of the jejunum with multiple liver metastases. Two cases presented hemoperitoneum caused by administration of imatinib mesylate, and we conducted emergent surgery. In spite of surgically non-curative cases, it is suggested that the surgical management for GIST of high grade group with peritoneal exposure should be followed by the administration of imatinib mesylate.

Effect of weekend 5-aminosalicylic acid (mesalazine) enema as maintenance therapy for ulcerative colitis: results from a randomized controlled study.

BACKGROUND: 5-aminosalicylic acid (5-ASA) is known to be effective in the treatment of active ulcerative colitis (UC). The aim of the current study was to investigate the effect of 5-ASA enemas, as a maintenance therapy for UC, when administered twice weekly as a weekend treatment regimen, compared to daily oral 5-ASA alone. We hypothesized that the weekend enema therapy would be better tolerated by patients who worked or attended school. METHODS: Between January 2004 and August 2005, patients with UC, in whom remission of the condition had just been induced, were randomly assigned to either: the weekend 5-ASA enema group (n=11), who received 1 g 5-ASA enemas twice a week on Saturday and Sunday plus oral 5-ASA 3 g/day for 7 days, or to the daily oral 5-ASA use only group (n=13), who received only oral 5-ASA 3 g/day for 7 days. The primary endpoint of the study was defined as the incidence of relapse. The study was stopped after 24 patients had been enrolled because an interim analysis showed a significant benefit of the weekend 5-ASA enema group. RESULTS: In the weekend enema group, 2 patients (18.2%) had relapses compared with 10 (76.9%) in the oral 5-ASA only group. The multivariate hazard ratio of relapse associated with weekend 5-ASA enema, relative to the oral alone group, was 0.19 (95% confidence interval, 0.04-0.94). CONCLUSIONS: This study demonstrated the beneficial effects of adding weekend 1 g 5-ASA enema to daily 3 g oral 5-ASA as maintenance therapy for UC.

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.

[Examination of the shapes of the end of the common bile ducts after endoscopic sphincterotomy (EST)].

At the treatment of bile duct stones using EST, we sometimes experienced the difficult cases, even if the stones were small. For these cases, we tried endoscopic papillary balloon dilatation, and as a result knoches were made. And after the disappearance of the knoch, we could easily remove the stone. So we prospectively examined how often and at what cases, the knoches were made immediately after EST. As a result, knoches were present for 25% (13/52) of patients even after EST. Narrow distal segments of knoch-present patients were longer than that of knoch-absent patients, significantly. As a result, some function of sphincter was shown to be remained for a quarter of patients even after EST, and for these cases, the treatment of the stones may be difficult.

[Two cases of patients with hepatocellular carcinoma (HCC) that developed in cryptogenic cirrhosis suggestive of nonalcoholic steatohepatitis (NASH) as background liver disease after clinical courses of 26 years].

We report two cases of patients with hepatocellular carcinoma (HCC) that developed in cryptogenic cirrhosis suggestive of nonalcoholic steatohepatitis (NASH) as background liver disease. Case 1 was a 68-year-old woman, and case 2 was a 46-year-old man. They were admitted to our department for evaluation and treatment of HCC. The causes of the underlying liver disease were not determined from blood tests. However, histological analysis of non-tumor tissues of the liver revealed cirrhosis with few fat droplets. Both patients had undergone liver biopsy 26 years before the treatment of HCC. Histological review of the biopsy specimens revealed NASH (case 1) and fatty liver (case 2), respectively. It was suggested that these cases progressed from NASH and fatty liver, respectively, to NASH-related cirrhosis (so called burned-out NASH), eventually, developing HCC. These findings suggest that substantial number of burned-out NASH cases may be included in those with cryptogenic cirrhosis. These two patients are indicative cases that may reveal the long-term natural course of fatty liver and NASH.

[Carcinoma arising from ileorectal fistula in a patient with Crohn's disease].

A 72-year-old man was given a diagnosis of Crohn's disease in 1976 at age 44, and partial resection of is ileum was performed. In November 1982, barium enema examination revealed on ileorectal fistula. As he had no complaint, conservative therapy was chosen. In August 2003, he had high fever and CT scan revealed presacral abscess. Ileocecal resection, partial resection of is small intestine and loop sigmoid colostomy were performed. In December 2004, the serum level of CEA was gradually elevated and he complained of anal mucus discharge. Endoscopic examination showed a fistula orifice in the rectum and biopsy of the fistula revealed mucinous adenocarcinoma. We performed abdominoperineal resection of the rectum with partial resection of the sacrum. We thought that careful observation helped the detection of such a rare case of carcinoma arising from a fistula tract.

Evidence-based clinical practice guidelines for management of colorectal polyps.

BACKGROUND: Recently in Japan, the morbidity of colorectal polyp has been increasing. As a result, a large number of cases of colorectal polyps that are diagnosed and treated using colonoscopy has now increased, and clinical guidelines are needed for endoscopic management and surveillance after treatment. METHODS: Three committees [the professional committee for making clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators] were organized. Ten specialists for colorectal polyp management extracted the specific clinical statements from articles published between 1983 and September 2011 obtained from PubMed and a secondary database, and developed the CQs and statements. Basically, statements were made according to the GRADE system. The expert panel individually rated the clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than seven on a nine-point scale from the panel was regarded as valid. RESULTS: The professional committee created 91CQs and statements for the current concept and diagnosis/treatment of various colorectal polyps including epidemiology, screening, pathophysiology, definition and classification, diagnosis, treatment/management, practical treatment, complications and surveillance after treatment, and other colorectal lesions (submucosal tumors, nonneoplastic polyps, polyposis, hereditary tumors, ulcerative colitis-associated tumor/carcinoma). CONCLUSIONS: After evaluation by the moderators, evidence-based clinical guidelines for management of colorectal polyps have been proposed for 2014.

Multicenter randomized controlled trial for the treatment of ulcerative colitis with a leukocytapheresis column.

The administration of steroids is not always effective for the treatment of ulcerative colitis (UC). Their long-term use often causes adverse effects which sometimes result in their stoppage and acute exacerbation. Therefore, an alternative treatment is necessary in order to decrease steroid dosage and avoid the clinical problems associated with steroids. Methods The effectiveness and adverse effects of a leukocytapheresis (LCAP) were investigated in a controlled multicenter trial with randomized assignment of 76 active-stage UC patients in two groups. In the LCAP group (39 patients), LCAP weekly for 5 weeks as an intensive therapy was added to the on-going drug therapy, while steroids were maintained but not increased, and then LCAP was gradually reduced to once every 4 weeks as a maintenance therapy. In the high dose prednisolone (h-PSL) group (37 patients), PSL was added or increased 30 approximately 40 mg/day for moderately severe and 60 approximately 80 mg/day for severe patients and then gradually tapered. Findings The LCAP group showed a significantly higher effectiveness (74% vs. 38%; p=0.005) and lower incidence of adverse effects (24% vs. 68%; p<0.001). The patients were able to continue the trial for a longer period in the LCAP group than the h-PSL group (p=0.012). Clinical activity and endoscopic indexes showed the LCAP group had better improvements than the h-PSL group. Interpretation The results of the trial show that LCAP permits a reduction in total PSL dosage and is more effective and safer than high-dose PSL administration for intensive therapy, and LCAP may maintain remission longer than PSL.

Clinical course and longterm prognosis of Japanese patients with Crohn's disease: predictive factors, rates of operation, and mortality.

BACKGROUND: The purpose of this study was to clarify the long-term course of Crohn's disease (CD) and predictors of its prognosis in Japan. METHODS: This was a historical cohort study of 276 patients with CD who had been diagnosed between 1965 and 1998. The clinical course was evaluated by the course of the CD score (CCDS) according to the required treatments. The predictive factors were examined by stepwise regression test. The cumulative rates of operation and survival were calculated by the Kaplan-Meier method. RESULTS: Patients with colitis-type CD had significantly lower annual and cumulative operation rates than those with other types, and showed significantly better progress, estimated by the CCDS, than patients with ileocolitis type. Reliable predictors for the 2- to 5-year clinical course after starting treatment were the CCDS, the presence of laparotomy during the initial year, and onset at age 30 years or more. The predictors for the 6- to 10-year clinical course were the duration of symptoms at diagnosis and onset at age 16 years or less. The predictors for the 11- to 15-year clinical course were the CCDS, the maximum International Organization of the Study of Inflammatory Bowel Disease (IOIBD) assessment score during the first year after starting treatment, and the effectiveness of the initial treatment. Relative survival rates at 5, 10, 15, and 20 years after the onset were 98.9%, 98.1%, 97.7%, and 94.9%, respectively. CONCLUSIONS: CD patients with colitis type showed a better clinical course and had significantly different clinical features compared with the patients with ileitis and ileocolitis type. Prediction of the longterm course of CD is possible by using clinical factors during the first year after starting treatment. The relative survival rates in Japanese patients with CD are not different from those seen in Western countries. The purpose of this study was to clarify the long-term course of Crohn's disease (CD) and predictors of its prognosis in Japan.

Microsatellite instability and loss of heterozygosity in the nondysplastic colonic epithelium of ulcerative colitis.

Background. A major longterm risk for patients with ulcerative colitis (UC) is the development of colorectal dysplasia and cancer. Microsatellite instability (MI) has now been reported not only in colitic cancers but also in dysplasias, and even in nondysplastic inflamed mucosa. With the conventional microdissection technique, however, contamination by nonepithelial cells cannot be prevented and this could produce less reliable results than other methods. Therefore, we examined the condition of MI and loss of heterozygosity (LOH) of UC epithelium using a crypt isolation technique. Methods. One hundred and twenty-nine biopsy samples from 21 patients with UC were investigated for histology and microsatellite status, using nine microsatellite markers. A total of 1031 polymenase chain reaction (PCR) products were evaluated. Results. We found that no microsatellite markers displayed instability, but LOH at the 3p locus was detected in the nondysplastic epithelium of one patient with longstanding UC. Conclusions. Our study strongly suggests that MI does not contribute to the progression of the colitis-dysplasia sequence.

High Ki-67 labeling index in human colorectal cancer with microsatellite instability.

BACKGROUND: In the present study, we examined the relationships between microsatellite status and Ki-67 labeling index, a proliferative marker, in colorectal cancers in order to clarify the common biological profiles of familial and sporadic cases of MSI (microsatellite inability)-positive tumors. PATIENTS AND METHODS: Seventy-eight invasive colorectal carcinomas were studied. Five microsatellite loci were analyzed by polymerase chain reaction, while Ki-67 was studied by immunohistochemistry. RESULTS: The MSI was found in 15 (19.2%) of the 78 tumors, and the Ki-67 labeling index was significantly higher in the 15 MSI-positive tumors than that in the 15 MSI-negative ones (p = 0.0181). Moreover, the Ki-67 labeling index was significantly higher in the 7 tumors with MSI at more than 2 loci (MSI-H; high-frequency MSI) than that in the MSI-negative ones (p = 0.0082). CONCLUSION: The present study demonstrates that colorectal cancers with MSI show high Ki-67 labeling index irrespective of hereditary or nonfamilial cancer types, suggesting their common biological aspects distinct from MSI-negative ones.

Correlative polymorphism of NAD(P)H: quinone oxidoreductase (NQO1) with telomere shortening in colorectal cancer.

AIM: The aim of this study was to examine whether and relationships could be found among polymorphism of the NQO1 gene, telomere length and telomerase activity in colorectal cancers. MATERIALS AND METHODS: Fifty-one invasive colorectal cancers were studied. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was undergone to detect mutation of the NQO1 gene. Telomere length was examined by Southern blot analysis. Telomerase activity was assayed by telomeric repeat amplification protocol with minor modifications. RESULTS: Of the 51 tumors, 20 (39.2%) and 9 (17.6%) were heterozygous and homozygous for the mutation, respectively. Most of the cases homozygous for the mutation (88.9%) showed short telomeres and its frequency was significantly higher than in those heterozygous (p = 0.0432). However no relationship was found between the telomerase activity and mutation in the NQO1 gene. CONCLUSION: Our data suggest that oxidative stress by the lack of NQO1 activity could result in telomere shortening through colorectal cancinogenesis.

Dietary fat attenuates the benefits of an elemental diet in active Crohn's disease: a randomized, controlled trial.

OBJECTIVES: Although an elemental diet has been established as the primary treatment for patients with Crohn's disease, the influence of dietary fat on the elemental diet remains unclear. We have designed the first randomized, controlled trial for elemental diets containing different fat percentages in patients with active Crohn's disease. METHODS: Each patient was randomized to receive one of three dose levels of fat in an elemental diet (Elental) for 4 weeks: 10 patients received low fat (3.06 g/day), 10 patients received medium fat (16.56 g/day) and eight patients received high fat (30.06 g/day). The additional fat was composed of long-chain fatty acids. All patients were evaluated using the International Organization of Inflammatory Bowel Disease rating, plus C-reactive protein level and erythrocyte sedimentation rate, which were measured at weekly intervals. RESULTS: Although the International Organization of Inflammatory Bowel Disease rating, C-reactive protein level and erythrocyte sedimentation rate in the low-fat group decreased, the values in the medium- and high-fat groups fluctuated during the study. The remission rate after 4 weeks in each group was 80%, 40% and 25% for patients in the low-, medium- and high-fat groups, respectively. CONCLUSIONS: When the fat consisted of long-chain triglycerides, a high amount of this fat in the elemental diet formula decreased its therapeutic effect against active Crohn's disease.

Telomere shortening of peripheral blood mononuclear cells in coronary disease patients with metabolic disorders.

OBJECTIVE: Telomere shortening is correlated with cell turnover and aging, but it has been recently suggested to occur not only by aging but by several biochemical factors of metabolic disorders predisposing to atherosclerosis. PATIENTS AND METHODS: We compared telomere length of peripheral blood mononuclear cells of patients with the metabolic disorders, hypercholesterolemia (HC) and diabetes mellitus (DM), according to the presence or absence of coronary diseases. RESULTS: The results demonstrated that HC and/or DM patients with coronary diseases have significantly shorter telomere length than healthy controls (p = 0.0014). CONCLUSION: Telomere shortening may be involved in the mechanisms that promote coronary diseases under some circumstances of metabolic disorders.

Rupture of rectal varices treated with endoscopic variceal ligation.

We report here 3 cases of rectal varices treated with endoscopic variceal ligation and discuss the pathogenesis, treatment, and prognosis of rectal varices with referring to previous reports. Of the 3 patients, 2 had been diagnosed as liver cirrhosis and 1 as extrahepatic portal hypertension. All of the 3 patients had previously undergone treatment of esophagogastric varices. The rupture of rectal varices appeared to have some relationship with the treatment of esophageal varices. In previous reports, 73% of patients with ruptured rectal varices treated with endoscopic injection sclerotherapy or endoscopic variceal ligation had undergone treatments of esophageal varices. The endoscopic treatments resulted in a favorable prognosis in 2 patients. Although no fatality from endoscopic injection sclerotherapy or endoscopic variceal ligation has been reported, 1 of the present 3 cases died of liver failure.

[Usefulness of percutaneous endoscopic gastrostomy (PEG) in home health care--investigation from the viewpoint of cost effectiveness].

The use of percutaneous endoscopic gastrostomy (PEG) has widely spread in recent years, even in Japan. In our hospital, we have performed this procedure in over 20 patients per year recently. In this study, we investigated the usefulness of PEG in home health care from the view point of cost effectiveness. We found that medical expenses decreased remarkably when patients underwent PEG because they could switch from hospital care to home health care, shortening there by the period of hospital care. The role of PEG in home health care will be more important also from cost effectiveness.

[Usefulness of percutaneous endoscopic gastrostomy (PEG) in home health care--investigation from the viewpoint of cost effectiveness].

The use of percutaneous endoscopic gastrostomy (PEG) has widely spread in recent years, even in Japan. In our hospital, we have performed this procedure in over 20 patients per year recently. In this study, we investigated the usefulness of PEG in home health care from the view point of cost effectiveness. We found that medical expenses decreased remarkably when patients underwent PEG because they could switch from hospital care to home health care, shortening there by the period of hospital care. The role of PEG in home health care will be more important also from cost effectiveness.