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Background and Aims Previous studies conducted in Europe suggested that darvadstrocel, a suspension of expanded, allogeneic, adipose-derived, mesenchymal stem cells, is safe and effective for treatment-refractory complex perianal fistulas in patients with Crohn’s disease. The aim of this study was to evaluate the efficacy and safety of darvadstrocel for the treatment of complex perianal fistulas in Japanese adults with Crohn’s disease. Methods This is a phase 3, open-label, single-arm study conducted at nine sites in Japan. Adult patients with non-active or mildly active Crohn’s disease and complex perianal fistulas received a single 24-mL intralesional injection of darvadstrocel [120 × 106 cells]. The primary endpoint was combined remission (clinically confirmed closure of all treated external openings that were draining at screening, and absence of collections >2 cm, [confirmed by magnetic resonance imaging] among treated fistulas) at Week 24. Results Between March 6, 2019 and February 1, 2021, 22 patients received darvadstrocel and completed the 52-week follow-up. The proportion of patients achieving combined remission at Week 24 was 59.1% (95% confidence interval [CI], 38.5–79.6). The effect was maintained at Week 52, with 68.2% [95% CI, 48.7–87.6] of patients achieving combined remission. Treatment-related adverse events included: one [4.5%] patient with worsening of Crohn’s disease and diarrhoea, and one [4.5%] patient with blood bilirubin increase. No new safety findings were identified in this study. Conclusions The efficacy and tolerability of darvadstrocel in Japanese adult patients with treatment-refractory complex perianal fistulas in Crohn’s disease were similar to those observed in the previous European study. ClinicalTrials.gov number, NCT03706456.

The aim of this study was to evaluate the effect of biologics on the risk of advanced-stage inflammatory bowel disease (IBD)-associated intestinal cancer from a nationwide multicenter data set.The medical records of patients with Crohn's disease (CD) and ulcerative colitis (UC) diagnosed with IBD-associated intestinal neoplasia (dysplasia or cancer) from 1983 to 2020 were included in this study. Therapeutic agents were classified into 3 types: biologics, 5-aminosalicylic acid, and immunomodulators. The pathological cancer stage was compared based on the drug used in both patients with CD and UC.In total, 1,042 patients (214 CD and 828 UC patients) were included. None of the drugs were significantly associated with cancer stage in the patients with CD. In the patients with UC, an advanced cancer stage was significantly associated with less use of biologics (early stage: 7.7% vs advanced stage: 2.0%, P0.001), 5-aminosalicylic acid, and immunomodulators. Biologic use was associated with a lower incidence of advanced-stage cancer in patients diagnosed by regular surveillance (biologics [-] 24.5% vs. [+] 9.1%, P = 0.043), but this was not the case for the other drugs. Multivariate analysis showed that biologic use was significantly associated with a lower risk of advanced-stage disease (odds ratio = 0.111 [95% CI, 0.034-0.356], P0.001).Biologic use was associated with a lower risk of advanced IBD-associated cancer in patients with UC but not with CD. The mechanism of cancer progression between UC and CD may be different and needs to be further investigated.

Background Dietary fatty acids can affect chronic intestinal inflammation and have been reported to be associated with the development of ulcerative colitis (UC), mainly in Europe and the United States. The association of dietary intake of fatty acids and the risk for UC was investigated in Japan, where dietary habits lead to lower meat and higher fish consumption than in Western countries. Methods A multicenter case-control study of 83 newly diagnosed patients with UC and 128 age- and sex-matched control patients in the hospital was conducted from 2008 to 2014. Dietary fatty acid intake in the preceding 1 month and 1 year were examined using a self-administered diet history questionnaire that was developed for Japanese people. Results About 92% of patients had experienced the first symptoms of UC within the preceding 11 months. Regarding dietary habits in the preceding year, the risk for UC was significantly decreased in patients who consumed n-6/n-3 polyunsaturated fatty acids at a ratio of ≥5.2 (odds ratio [OR] = 0.26; 95% confidence interval [CI], 0.10-0.68). Conversely, an increased risk for UC was observed in the highest tertiles of consumption of docosahexaenoic acid (OR = 7.22; 95% CI, 2.09-24.95), eicosapentaenoic acid (OR = 6.91; 95% CI, 1.88-25.44), and docosapentaenoic acid (OR = 4.83; 95% CI, 1.56-14.95). Conclusions The ratio of n-6/n-3 polyunsaturated fatty acid intake was associated with a decreased risk for UC development. However, high intakes of docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid may increase the risk for UC development.

Patients with longstanding inflammatory bowel disease are at high risk of developing intestinal cancers. In this study, we aimed to elucidate the differences between intestinal cancers associated with ulcerative colitis and Crohn's disease.Intestinal cancers in ulcerative colitis and Crohn's disease patients treated between 1983 and 2020 at 43 Japanese institutions were retrospectively analyzed..A total of 1505 intestinal cancers in 1189 ulcerative colitis and 316 Crohn's disease patients were studied. Almost all of ulcerative colitis-associated cancers (99%) were in the colon and rectum, whereas half of Crohn's disease-associated cancers (44%) were in the anus, with 11% in the small intestine. Ulcerative colitis-associated cancers were diagnosed more frequently by surveillance (67% vs. 25%, P 0.0001) and at earlier stages (stages 0-1, 71% vs. 27%, P 0.0001) compared with Crohn's disease-associated cancers. Colorectal cancers associated with Crohn's disease showed a significantly worse 5-year overall survival rate than those associated with ulcerative colitis (stage 2, 76% vs. 89%, P = 0.01, stage 3, 18% vs. 68%, P = 0.0009, and stage 4, 0% vs. 13%, P = 0.04). Surveillance correlated with earlier diagnoses for ulcerative colitis- and Crohn's disease-associated intestinal cancers, whereas shorter intervals between endoscopic examinations correlated with an earlier cancer diagnosis in ulcerative colitis patients but not in Crohn's disease patients.The clinical and oncological features of ulcerative colitis- and Crohn's disease-associated cancers were very different. Crohn's disease-associated cancers were diagnosed at more advanced stages and were detected less frequently by surveillance. Additionally, they showed a significantly poorer prognosis.

To determine the effectiveness of surveillance colonoscopy (SC) and optimize its use by assessing real-world surgically resected cases of ulcerative colitis (UC)-associated colorectal cancer (CRC) and dysplasia.Clinicopathological data of 406 (238 CRC and 168 dysplasia) patients who underwent surgical resection in 10 UC specialized institutions were retrospectively reviewed. The overall survival (OS) rates were compared between the SC and non-SC groups. The incidence of and risk factors for early-onset CRC (8 years after UC onset) were identified. The distribution of CRC lesions was also assessed.Cancer stages were significantly more advanced in the non-SC group than in the SC group (P0.001). The patients in the SC group showed significantly better OS than those in the non-SC group (5-year OS: 89% vs 70%; log-rank test: P = 0.001). Seventeen percent of patients developed CRC within 8 years after UC onset. The age at UC onset was a risk factor and a good predictor of early-onset CRC (8 years) (P0.01; AUC: 0.85). The most common sites of CRC were the rectum (51%) and sigmoid colon (20%). Multiple CRC was identified in 16% of patients.Surveillance colonoscopy was effective and improved the OS in patients with UC. We recommend that patients with late-onset UC (40 years) undergo SCs earlier because of the high incidence of CRC within 8 years of UC onset. Moreover, the rectum and sigmoid colon should be more thoroughly examined.

Background Recently, the prevalence of venous thromboembolism (VTE) in Asian patients with inflammatory bowel disease (IBD) is gradually increasing. IBD surgery is a well-recognized risk factor for VTE. However, there are no prospective studies about VTE after surgery for ulcerative colitis (UC) in Asia. This multicenter prospective study aimed to clarify the prevalence and risk factors for perioperative VTE in UC surgery in Japan. Methods A total of 134 patients with UC were included from January 1, 2013 to December 31, 2014. Preoperative screening was performed in all patients. In the perioperative period, standard VTE prophylaxis based on risk assessment was administered. The prevalence of pre- and postoperative VTE, its risk factors, and mortality rates were investigated. Results Perioperative deep vein thrombosis and pulmonary embolism were diagnosed in 15 (11.1%) and 1 patient (0.7%), respectively. All patients were asymptomatic. No surgery-related deaths were found (mortality rate 0%). Seven patients (5.2%) were diagnosed, and 8 (6.4%) during postoperative follow-up by ultrasonography or computed tomography. Forty-seven percent of VTE cases was developed preoperatively. A preoperative hospital length stay of over 5 days was a significant risk factor [P = 0.04; odds ratio: 8.26 (1.06–64.60)] for preoperative VTE. Postoperative deep vein thrombosis occurred in 8 of the 127 patients (6.4%). Six out of these 8 (75.0%) occurred after postoperative day 14. Perioperative blood transfusion was a significant risk factor [P = 0.04; odds ratio: 8.26 (1.06–64.60)] for postoperative VTE. Conclusion A VTE-conscious perioperative management is as necessary in Asia as in Western countries.

Background: Early detection of ulcerative colitis-associated neoplasia (UCAN) is often difficult. The aim of this study was to clarify the morphology of initial UCAN. Methods: White-light colonoscopy images obtained within the 2 years before UCAN diagnosis were retrospectively reviewed. The primary endpoint was the frequency of visible or invisible neoplasia on the endoscopic images before UCAN diagnosis. The secondary endpoints were comparisons of (1) visible or invisible neoplasia on initial endoscopic images of early-stage and advanced cancers, (2) the clinical backgrounds of patients in whom neoplasia was visible or invisible on initial endoscopic images, and (3) the clinical backgrounds of patients with distinct and indistinct UCAN borders. Results: Of the 27 UCAN lesions (11 early-stage, 16 advanced-stage), 25.9% (n = 7) were initially visible and 74.1% (n = 20) were invisible. The mean interval between the last surveillance colonoscopy and UCAN diagnosis was 14.5 ± 6.7 months. Of early-stage cancers, 18.2% (n = 2) were visible and 81.8% (n = 9) were invisible. Of advanced-stage cancers, 31.3% (n = 5) were visible and 68.8% (n = 11) were invisible. Invisible lesions were significantly more common in the rectum (p = 0.011) and tended to be more common in patients with inflammation and left-sided colitis (p = 0.084, p = 0.068, respectively). Patients with indistinct UCAN borders were significantly more likely to present with inflammation than those with distinct UCAN borders (p = 0.021). Conclusion: More careful surveillance is needed because rectum lesions and inflammation are difficult to identify as neoplasia even within the 2 years before a UCAN diagnosis.

Background/aim The aim of the study was to analyze the postoperative survival of colitis-associated colorectal cancer (CAC) with ulcerative colitis (UC), and the risk factors affecting it. Patients and methods A questionnaire including postoperative survival was sent to 88 hospitals that reported CAC patients in the literature up until January, 2006 and to members of the Research Group of Intractable Inflammatory Bowel Disease. Results The 5-year postoperative overall survival (OS) of 170 CAC patients was 74.2% which was similar to sporadic colorectal cancer in Japan (72.1%). Pathologic TNM stage, histological type, type of surgical procedure (proctocolectomy, segmental resection), and preoperative cancer surveillance were statistically significant factors for OS. By Cox regression analysis, pathologic TNM stage and proctocolectomy were statistically significant prognostic factors for OS. Conclusion In CAC with UC, the postoperative OS was similar to sporadic colorectal cancer. Pathologic TNM stage and proctocolectomy were confirmed as important prognostic factors.

After colectomy for ulcerative colitis (UC), very severe and sometimes lethal enteritis can develop. However, the clinical features remain uncertain because of the low incidence, diversity of symptoms, and undefined diagnostic criteria. The aim of this study was to define postoperative ulcerative colitis-related severe enteritis (UCRSE) and to investigate its clinical features. A retrospective multicenter study was performed as a survey of major medical facilities utilizing surgical supplies for inflammatory bowel disease in Japan from 2001 to 2014. UCRSE was defined as a case with massive intestinal bleeding, intestinal perforation, high-output stoma, and/or a requirement for medications, such as steroids and biologics. Patients with gastroduodenal lesions or pouchitis alone were excluded. The incidence, symptoms, involvement of bacteria, cytomegalovirus reactivation, treatment, and prognosis were examined for patients with UCRSE after colectomy. Forty-two (0.8%) out of 5284 cases met the criteria for UCRSE. Major symptoms were massive intestinal bleeding (76.2%), which required a median of 3850 (560–18900) mL blood transfusion; high-output stoma (38.1%) with excretion of fluid of 5000 (2000–7800) mL/day; and intestinal perforation (7.1%). Hypovolemic shock (35.7%) and/or disseminated intravascular coagulation (31.0%) developed as serious complications. Tests for cytomegalovirus reactivation were positive in 26.2% of cases. The presence of pathogenic bacteria was confirmed in only 5 cases. Corticosteroids or infliximabs were effective in half of the patients. Thirteen cases (31.0%) were treated surgically and 22 cases (56.4%) required maintenance therapy. The mortality rate was 11.9%. UCRSE is a rare but serious complication after colectomy and is sometimes life-threatening.

Objectives One of the characteristics of colorectal cancer complicating Crohn's disease (CD) in the Japanese population is that it frequently occurs in the lower anorectal site. This study aimed to examine CD patients biopsied in the lower anorectal sites to investigate the significance and problems associated with this method of cancer surveillance. Methods Among 116 patients with CD duration of ≥10 years, we examined patients diagnosed with cancer using histological examination of the lower anorectal site (287 times). We also evaluated the detection rates of cancer and atypical cells using this method. Results Of the 116 patients, neoplastic lesions were detected through biopsy in 22 (19.0%), of which 18 had carcinomas and 4 had atypical cells. The clinicopathological traits of the cancer patients were early-age onset and chronic disease duration of CD before cancer diagnosis. Histologic findings were characterized by a high frequency of poorly differentiated adenocarcinoma and mucinous carcinoma. The 18 patients with cancer were assigned to groups A and B depending on the presence or absence of cancer-related symptoms, and their characteristics were compared. Of these, 5 patients whose cancer was detected without symptoms (group A) had better prognosis than those detected with symptoms (group B) based on survival curves. We next examined 103 patients for surveillance after excluding 13 patients who were diagnosed with cancer-related symptoms from the 116 patients and found a 5.8% (6 patients) detection rate of cancer and atypical cells. Conclusions Our results suggest the effectiveness of transanal histological testing for the surveillance of anorectal cancer with CD.

Summary: Background/Objective: Mixed-type early gastric cancer (differentiated and undifferentiated components) incurs a higher risk of lymph node metastasis than pure-type early gastric cancer (only differentiated or only undifferentiated components). Therefore, we investigated the expansion of lymph node metastasis in mixed-type submucosal invasive gastric cancer in order to establish the most appropriate treatment for mixed-type cancer. Methods: We retrospectively analyzed 279 consecutive patients with submucosal invasive gastric cancer who underwent curative gastrectomy for gastric cancer between 1996 and 2015. We classified the patients into the mixed-type and pure-type groups according to histologic examination and evaluated the expansion of lymph node metastasis. Results: The rate of lymph node metastasis was 23.7% (66/279) in the total patients, 36.4% (36/99) in the mixed-type group, and 16.6% (30/180) in the pure-type group. The significant independent risk factors for lymph node metastasis were tumor size ≥2.0 cm (P = 0.014), mixed-type gastric cancer (P

Background Few studies have investigated surgical outcomes following a colectomy in pediatric patients with ulcerative colitis (UC). Purpose This study aimed to determine long‐term outcomes in a large cohort of pediatric patients who underwent proctocolectomy with ileal pouch‐anal anastomosis (IPAA) for UC. Methods Pediatric patients (

The prevention of postoperative recurrence is a critical issue in surgery for Crohn’s disease. Prospective randomized trials in Western countries have shown that the postoperative use of anti-tumor necrosis factor α-antibodies was effective in reducing the recurrence rate. We investigated the efficacy of infliximab (IFX) for the prevention of postoperative Crohn’s disease recurrence. We performed a prospective randomized multicenter study. Patients who underwent intestinal resection were assigned to groups treated with or without IFX. Immediately after surgery, patients in the IFX group received IFX at 5 mg/kg at 0, 2, and 6 weeks, followed by every 8 weeks for 2 years. The primary study outcome was the proportion of patients with endoscopic and/or clinical recurrence at 2 years after surgery. Thirty-eight eligible patients participated in this study: 19 in the IFX group and 19 in the non-IFX group. The disease recurrence rate in the IFX group was 52.6% (10/19), which was significantly lower than that in the non-IFX group (94.7% [18/19]). The postoperative use of IFX is effective in preventing Crohn’s disease recurrence for 2 years.

Small bowel obstruction (SBO) often occurs after total proctocolectomy and ileal pouch anal anastomosis with diverting loop‐ileostomy for ulcerative colitis. Little is known about the association between SBO and surgical procedures for diverting loop‐ileostomy. We conducted a multicenter, retrospective questionnaire survey. Unlinkable anonymized data on ileostomy procedures and ileostomy‐related complications including SBO were collected from institutions specializing in surgery for inflammatory bowel disease. In total, 515 patients undergoing total proctocolectomy and ileal pouch anal anastomosis with loop‐ileostomy among 1022 patients with ulcerative colitis undergoing surgery during a 3‐year period between 2012 and 2014 were analyzed. Twenty‐nine patients without information on complications were excluded. Incidence of ileostomy‐related complications and factors associated with the development of small bowel obstruction were determined in 486 patients. The most common complications were parastomal dermatitis (n=169, 34.8%), SBO (n=111, 22.8%), mucocutaneous dehiscence (n=59, 12.1%), stoma prolapse (n=21, 4.3%), parastomal hernia (n=12, 2.5%), and stoma retraction (n=11, 2.3%). Incidence of small bowel obstruction was significantly higher in patients with distance from the ileal pouch to the ileostomy of less than 30 cm and in patients undergoing laparoscopic surgery. Procedures for diverting loop‐ileostomy after surgery for ulcerative colitis varied among institutions. Incidence of small bowel obstruction was high after total proctocolectomy and ileal pouch anal anastomosis with diverting loop‐ileostomy. Shorter distance between the pouch and the stoma and the laparoscopic surgery were risk factors for SBO in univariate analysis.

We evaluated the recent incidence of surgery and the changing surgery trends for ulcerative colitis (UC) in Japan due to the increasing use of anti-tumor necrosis factor (TNF) agents. A questionnaire survey was performed to assess the number of surgeries, surgical indications, surgical timing, and immunosuppressive treatments before surgery between 2007 and 2017. A total of 3801 surgical cases were reported over 11 years. The prevalence of UC surgery decreased over the period studied. The rate of prednisolone (PSL) use did not change. The prevalence of both calcineurin inhibitors (CNIs) and anti-TNF agents increased during the period studied (p

Chemotherapy for advanced colitis-associated colorectal cancer (CAC) has been insufficiently evaluated. The goal of this study was to clarify the efficacy and safety of chemotherapy for CAC in Japan. CAC patients who were treated with chemotherapy between 2005 and 2015 were retrospectively examined. Twenty-nine patients (median age, 48 years; 23 men) were assessed. Eighteen patients had ulcerative colitis, and 11 had Crohn's disease. Three ulcerative colitis and four Crohn's disease patients were in the active disease phase. Primary tumors were located in the rectum/anus (n=16), the left colon (n=9), or the right colon (n=4). Palliative or adjuvant chemotherapy was performed in 13 and 16 patients, respectively. First-line palliative chemotherapy regimens were as follows: fluorouracil, leucovorin, and oxaliplatin (FOLFOX; n=6), FOLFOX+bevacizumab (n=3), and others (n=4). Adjuvant chemotherapy regimens were S-1 (n=7), oxaliplatin-based (n=4) and others (n=5). In palliative chemotherapy, the objective response rate was 15%, and the median progression-free survival and overall survival were 182 and 315 days, respectively. In adjuvant chemotherapy, the 5-year relapse-free survival rate was 78%. Grade 3/4 adverse events (AEs) were observed in 16 patients (55%). Active and remission inflammatory bowel disease patients suffered grade 3/4 nonhematological AEs at an incidence of 71 and 23%, respectively (P

Background & Aims Patients with Crohn’s disease (CD) can require multiple intestinal operations. We examined time trends and risk factors for reoperation in patients with CD who underwent intestinal surgery, focusing on the effects of post-operative medical treatments. Methods We performed a retrospective analysis of 1871 patients with CD who underwent initial intestinal resection at 10 tertiary care institutions in Japan, with initial operative date after May 1982. We collected data on background characteristics of all patients, including Montreal Classification, smoking status, and medical therapy after surgery (tumor necrosis factor antagonists [anti-TNF agents] or immunomodulators). The primary outcome was requirement for first reoperation. Rate of reoperation was estimated using the Kaplan-Meier method, and risk factors for reoperation were identified using the Cox regression model. Results The overall cumulative 5- and 10-year reoperation rates were 23.4% and 48.0%, respectively. Multivariable analysis revealed that patients who underwent the initial operation after May 2002 had a significantly lower rate of reoperation than patients who were operated on before April 2002 (hazard ratio [HR], 0.72; 95% CI, 0.61–0.86). Preoperative smoking (HR 1.40; 95% CI, 1.18–1.68), perianal disease (HR, 1.50; 95% CI, 1.27–1.77), and ileocolic type of CD (HR, 1.42; 95% CI, 1.20–1.69) were significant risk factors for reoperation. Post-operative use of immunomodulators (HR, 0.60; 95% CI, 0.44–0.81) and anti-TNF therapy (HR, 0.71; 95% CI, 0.57–0.88) significantly reduced the risk. Anti-TNF was effective in the bio-naive subgroup. Conclusions The rate of reoperation in patients with CD significantly decreased after May 2002. Post-operative use of anti-TNF agents might reduce the reoperation rate for bio-naive patients with CD.

Background In this study, survival and cause of death were investigated in patients with Crohn’s disease (CD) at a tertiary referral center. Methods A database was created based on the medical records of 1108 CD patients who had a history of visiting our hospital to investigate background characteristics, cumulative survival rates from diagnosis, causes of death, and the standardized mortality ratio (SMR) for each cause of death. A follow-up questionnaire survey of patients followed up inadequately was also conducted. The cumulative survival rate from diagnosis was determined using the life table method and compared with that of a sex- and age-matched population model from the year 2000. Results The study included 1108 patients whose mean age at diagnosis was 25.6 ± 10.8 years. The mean duration of follow-up was 14.6 ± 9.4 years, and there were 52 deaths. The cumulative survival rate was significantly lower 25 years after the diagnosis of CD (91.7%) than in the standard population model (95.7%). SMRs for both all causes [3.5; 95% confidence interval (CI): 2.7–4.6] and CD-specific causes (36.7; 95% CI 26.1–51.6) were high. Among the CD-specific causes, SMRs were especially high for small intestine and colorectal cancers, gastrointestinal diseases including intestinal failure (IF), perioperative complications, and amyloidosis. Conclusion The SMRs for both all causes and CD-specific causes were high in CD patients. CD-specific causes including intestinal cancer, IF, perioperative complications, and amyloidosis showed especially high SMRs.

Although several complications capable of causing pouch failure may develop after restorative proctocolectomy (RPC) for ulcerative colitis (UC), the incidences and causes are conflicting and vary according to country, race and institution. To avoid pouch failure, this study aimed to evaluate the rate of pouch failure and its risk factors in UC patients over the past decade via a nationwide cohort study. We conducted a retrospective, observational, multicenter study that included 13 institutions in Japan. Patients who underwent RPC between January 2005 and December 2014 were included. The characteristics and backgrounds of the patients before and during surgery and their postoperative courses and complications were reviewed. A total of 2376 patients were evaluated over 6.7 ± 3.5 years of follow-up. Twenty-seven non-functional pouches were observed, and the functional pouch rate was 98.9% after RPC. Anastomotic leakage (odds ratio, 9.1) was selected as a risk factor for a non-functional pouch. The cumulative pouch failure rate was 4.2%/10 years. A change in diagnosis to Crohn’s disease/indeterminate colitis (hazard ratio, 13.2) was identified as an independent risk factor for pouch failure. The significant risk factor for a non-functional pouch was anastomotic leakage. The optimal staged surgical procedure should be selected according to a patient’s condition to avoid anastomotic failure during RPC. Changes in diagnosis after RPC confer a substantial risk of pouch failure. Additional cohort studies are needed to obtain an understanding of the long-standing clinical course of and proper treatment for pouch failure.

Background and Aim There have been very few reported investigations on the standardized incidence ratio (SIR) of intestinal cancer and all cancers other than intestinal cancer with Crohn's disease (CD) by organ in Japan. This study examined the risk of developing cancer (i.e. SIR) that occurs in association with CD. Methods The subjects were 770 CD patients managed at our hospital department, which specializes in inflammatory bowel disease, during the approximately 25 years from July 1985 to August 2010. The number of expected cancer patients in a healthy population matched for sex and age with the CD patients in our hospital was then calculated. The relative risk, or SIR, was also calculated. Results The total observation period was 10 552 person-years, during which 19 cases (2.5%) of cancer were discovered in 770 subjects. The cancer cases included nine cases of colorectal cancer (CRC), one case of small bowel cancer, one case of stomach cancer, three cases of acute myeloid leukemia, two cases of endometrial cancer, one case of lung cancer, one case of skin cancer, and one case of thyroid cancer. The SIR for cancers in Japan in 2003 was 0.87 (95% confidence interval [CI] 0.52–1.35) for all cancers, 2.79 (95% CI 1.28–5.29) for CRC, and 6.94 (95% CI 1.43–20.3) for leukemia. Conclusions Among the cancers in CD patients in our hospital, no significant difference was seen in the risk for all cancers in comparison with the standard population. However, the risks for CRC and leukemia were significantly higher than in the standard population.

Cancer of the intestinal tract (small and large intestine) associated with Crohn's disease has a low incidence but can be fatal if it develops. Thus, the key question is how to deal with this type of cancer. The current study surveyed major medical facilities that treat inflammatory bowel disease (IBD) surgically in Japan in order to examine the clinical features of cancer of the intestinal tract associated with Crohn's disease and explore ways to deal with this cancer in the future.Sixteen major medical facilities that treat IBD surgically were surveyed regarding cancer of the intestinal tract associated with Crohn's disease. The medical facilities had treated 3,454 patients with Crohn's disease, 122 of whom had developed intestinal cancer. The medical facilities were surveyed regarding those 122 patients.The incidence of intestinal cancer associated with Crohn's disease has increased yearly. Cancer most often developed in the left side of the colon and, particularly, in the rectum and anal canal. Seventy-six percent of cases were diagnosed preoperatively, 4% were diagnosed intraoperatively, while the remaining 20% were diagnosed pathologically after surgery. The most prevalent histological type of cancer was mucinous carcinoma (50%). Forty-two percent of cancers were differentiated, with 4% being poorly differentiated. The surgical procedure performed most often (67%) was abdominoperineal resection. The 5-year survival rate by stage was 88% for Stage I, 68% for Stage II, 71% for Stage IIIa, 25% for Stage IIIb and 0% for Stage IV. Overall, the 5-year survival rate was 52%.Gastrointestinal (GI) cancer associated with Crohn's disease had an incidence of 3.5%, but also involved a poor prognosis with a 5-year survival rate of 52%. Early detection through surveillance is crucial to improving the prognosis for patients. However, surveillance of the intestinal tract with endoscopy or contrast studies is technically and diagnostically hampered by Crohn's disease and intestinal strictures. A biopsy of the anal canal, a common site of cancer, can readily be performed and constitutes the first step in surveillance.

This study used a multicenter questionnaire survey to evaluate the morphology and progression of the initial lesion in cases of colitis-associated colorectal neoplasia (CRN).Endoscopic images of lesions that had been definitively diagnosed as CRN by pathological examination were retrospectively reviewed.This resulted in the identification of 54 initial lesions in 49 patients. The 54 initial lesions fell into the following categories: 22 endoscopically visible localized lesions consisting of 18 elevated lesions and 4 depressed lesions, as well as 32 lesions that were not endoscopically visible as localized and consisted of 20 active-phase mucosal lesions and 12 remission-phase mucosal lesions. Nineteen of the lesions eventually became advanced cancers, while 35 lesions eventually became early-stage cancers. The final lesions were 40 elevated lesions, 5 flat or depressed lesions and 9 stenotic lesions. The form of growth of the advanced cancers was progressive stenosis or increased elevation. For approximately 69% of the early-stage cancers, the growth form was increasing elevation or development of elevation. For 73.6% of the advanced cancers, the initial lesion underwent rapid growth and became advanced cancer within 3 years; they accounted for 25.9% of the total cancers. Approximately 40% of the initial lesions of CRN were endoscopically visible as localized lesions, while approximately 60% were judged to be inflammatory mucosal lesions.It will be necessary to proactively take biopsy inflammatory mucosal lesions in order to discover tumors early and periodic surveillance should be performed with the knowledge that tumors may grow very quickly.

Aim: We assessed the long-term outcome of infliximab (IFX) therapy in patients with Crohn's disease (CD) and investigated the efficacy of concomitant endoscopic balloon dilation (EBD) for intestinal stricture during treatment. Methods: The effectiveness of maintenance therapy with IFX was retrospectively evaluated in 185 patients with CD in a single center (median observation period 24 months). IFX effectiveness with and without immunomodulators (IMM) and enteral nutrition (EN), as well as cumulative surgery-free rates, were compared. The efficacy of concomitant EBD in patients with obstructive symptoms and high-level stricture was evaluated. Results: In 185 patients receiving the maintenance therapy, the long-term efficacy rate was 84.9% at 24 months and 79.0% at 48 months. The cumulative surgery-free rate was significantly higher in the maintenance group (P

Background: Previous studies have shown various risk factors for the initial and/or the second operation for Crohn's disease (CD). However, limited data are available with regard to the risk factors for a third operation. We aimed to clarify the risk factors for a third operation for CD. Methods: A total of 200 CD patients who underwent a second intestinal surgery at 13 institutions were examined. We performed univariate and multivariate analyses to examine the influence of independent variables on the cumulative rate of needing a third operation. Results: A total of 95 patients underwent a third operation. The overall 5-year and 10-year cumulative rates for the third operation were 42.2% and 71.0%, respectively. In univariate analysis, the interval between the initial and the second operation (P = 0.0069), postoperative administration of infliximab (P = 0.0030), and the anatomical site of the disease (P = 0.0132) were significant risk factors for the third operation. In multivariate analysis, the interval between the initial and the second operation (P = 0.0287) and postoperative administration of infliximab (P = 0.0297) remained significant risk factors for the third operation. The cumulative 5-year third operation rate was significantly higher in patients with an interval of less than 5 years between the first and second operations than for those with an interval of 5 years or more (47.8% versus 35.2%, P = 0.0232). Conclusions: An interval of less than 5 years between the first and the second operations is a significant risk factor for a third operation in patients with CD. (Inflamm Bowel Dis 2011;)

Background: Although rare, duodenal lesions have been reported in association with ulcerative colitis (UC); however, there have been very few reports on small bowel lesions, and many aspects of their pathology and frequency remain unknown. This study determined whether small bowel lesions are present in UC by using wireless capsule endoscopy (WCE). Patients and Methods: WCE was performed on 20 patients with active UC and 10 who had undergone proctocolectomy. Results: Small bowel lesions (e.g. edema or ulcers) were observed in 11 of the 30 patients (36.6%): in eight (40%) of the 20 patients with active UC and in three (33.3%) of the 10 post-proctocolectomy patients. Ulcers that extended over a long segment or whole tertile of the small bowel were observed in five patients, and the disease type was extensive colitis in three of these and pouchitis in the other two. Age at onset was significantly lower in the 20 active UC patients that had small bowel lesions. Conclusion: WCE revealed the presence of ulcers that extended over a long segment or a whole tertile in the small bowel in active extensive colitis and pouchitis. In future, it will be necessary to assess the clinical significance of small bowel lesions in UC in detail.

The combination of an oral fluoropyrimidine derivative, S-1, and irinotecan is expected to be a promising regimen for advanced colorectal cancer. This study was performed to determine the maximum tolerated dose (MTD) and recommended dose (RD) of irinotecan combined with S-1 in a 3-week cycle regimen and to observe the safety and efficacy for patients with previously untreated advanced colorectal cancer. Eighty milligrams per m2 of S-1 was given orally for 14 consecutive days and escalated doses of irinotecan were administered on days 1 and 8 every 3 weeks in the phase I trial. Forty patients were treated at the RD during the phase II trial. Forty-three patients were enrolled between February 2005 and March 2007. The dose-limiting toxicity was diarrhea and abdominal pain. The MTD of irinotecan was 100 mg/m2 and the RD was determined to be 80 mg/m2 of irinotecan combined with 80 mg/m2 of S-1. The phase II trial showed that 22 of 40 patients achieved a complete or partial response and eight had stable disease. The overall response rate was 55.0%. The median progression-free survival time and median survival time were 6.7 and 21 months, respectively. There were no treatment-related deaths. The main toxicities were leukopenia, neutropenia, anorexia and diarrhea. This study suggests the combination of irinotecan and S-1 repeated every 3 weeks is tolerable and effective for patients with previously untreated advanced colorectal cancer. (Cancer Sci 2010; 101: 2591–2595)

Background and Aim: Ulcerative colitis (UC) is not only characterized by pathological lesions localized to colonic mucosa, but also to various complications involving other organs, including postoperative pouchitis. Among these complications, diffuse gastroduodenitis with lesions resembling colonic lesions has been reported, albeit rarely. The aim of the present study was to attempt to characterize the lesions of the upper gastrointestinal tract occurring as a complication of UC, and to assess the frequency and clinical course of these lesions. Methods: A total of 322 UC patients who had undergone upper gastrointestinal endoscopy were retrospectively analyzed. We assessed the frequency of endoscopic findings, including diffuse gastroduodenal lesions resembling colonic lesions. Ulcerative gastroduodenal lesion (UGDL) associated with UC was diagnosed if lesions satisfied the following criteria: (i) improvement of the lesions with treatment of UC; and/or (ii) resemblance to UC in pathological findings. Results: UGDL satisfying the aforementioned criteria was found in 15 (4.7%) of 322 patients. All the 15 patients had UGDL accompanied by pancolitis or after proctocolectomy. Frequency in 146 patients with pancolitis was 6.2% (nine patients) and that in 81 patients who had undergone proctocolectomy was 7.4% (six patients). Four patients with diffuse ulcerative upper-gastrointestinal mucosal inflammation (DUMI) had pouchitis. In all patients except one, the lesions resolved easily with medical treatment. Conclusions: In more than half of the post-proctocolectomy patients, UGDL was related to the occurrence of pouchitis. The existence of characteristic UGDL must be taken into account in the diagnosis and treatment of UC, and UGDL is possibly related to the occurrence of pouchitis.

自験例139例のCrohn病肛門部病変の長期経過を検討した（平均観察期間178.2カ月）．最終的には129例，92.8％に肛門部病変を合併した．長期経過の中でいずれの病変も増加し，なかでも痔瘻，膿瘍の増加が顕著で複雑多発化の傾向がみられた．外科治療としては，痔瘻根治術に比べseton法ドレナージの経過が良好であり，痔瘻，膿瘍に対して第1に選択すべき治療法と思われる．肛門部病変に起因した人工肛門造設例は29例，20.9％で，14例の直腸切断術のうち4例が癌合併であった．若年で発症するCD患者の長期経過の中で肛門部病変はQOLを左右する重要な因子であり，QOLの保持を第1に，癌合併も含めた長期経過を考慮した治療法の選択が肝要である．

"Pouchitis" is a term for nonspecific mucosal inflammation of the pouch after total proctocolectomy and ileal pouch-anal anastomosis for ulcerative colitis. Pouchitis is the most frequent complication of the pelvic pouch at the late stage. To improve the accuracy of the pouchitis diagnosis, sets of clinical symptoms and endoscopic findings (with or without histology of biopsy samples) have previously been evaluated. Endoscopic findings are central to the diagnosis, and a universal consensus of various endoscopic findings must be the initial step toward an objective diagnosis of pouchitis. Since a proper signpost for the endoscopic evaluation of pouchitis has been absent, we developed this pouchitis atlas to minimize the diagnostic variation inherent among individual endoscopists. We also propose new criteria for the diagnosis of pouchitis: the Japanese criteria for diagnosis of pouchitis. These criteria are based on clinical symptoms and endoscopic findings that are clearly categorized in the atlas, and exclude infectious enteritis, anastomotic insufficiency, pelvic infection, anal dysfunction, and Crohn's disease. Advantages of the new criteria include ease of bedside diagnosis, without the calculation of points required by the other criteria for pouchitis. This pouchitis atlas, together with our new criteria, should contribute to the establishment of a clear-cut diagnosis for pouchitis and promote better evaluation and treatment of this novel intestinal inflammation.

Perianal lesions are a frequent complication of Crohn's disease (CD) and include fistula, abscess, anal ulcer, skin tag, anal stricture, and carcinoma. Perianal fistula is the most commonly observed condition and exhibits multiple incidence and intractable characteristics. The starting point for the management of perianal fistula is an accurate diagnosis, which requires careful exploration during an EUA. The condition is treated with medications such as antibiotics, immunosuppressants, or anti-tumor necrosis factor agents. However, it is difficult to maintain long-term remission. Surgical therapy is selected according to the type of fistula and can include conventional fistulotomy, seton drainage, diverting stoma, and anorectal amputation. After fistulotomy, recurrence is frequent and there is an increased risk of incontinence. Seton drainage is the preferred treatment to improve symptoms and preserve anal function. Stoma is useful to relieve symptoms but difficult to indicate for young patients. The optimum treatment for perianal fistula associated with CD remains controversial. Currently, the goal of therapy for these patients has shifted from complete fistula closure to reducing drainage from the fistula to improve their quality of life. Ongoing careful management is important to control anal symptoms and maintain long-term anal function in the treatment of patients with CD, while monitoring them to detect possible progression to anorectal carcinoma.

The aim of the study is to assess the relationship between the introduction of biologic and immunosuppressant therapy and the number of patients undergoing surgery for ulcerative colitis (UC). A questionnaire survey about patients undergoing surgery for UC was sent to 26 teaching hospitals throughout Japan. The questionnaire period spanned from 2008 to 2013, to account for the introduction of tacrolimus (2009) and infliximab (2010). The total number of patients who underwent surgery was 297, 291, 273, 255, 300, and 305 in 2008, 2009, 2010, 2011 2012, and 2013, respectively. The emergency surgery rate remained stable at 32–34 % each year. The proportion of patients who underwent surgery for cancer increased from 13.8 % in 2008 to 20 % in 2013. In 2013, 41, 38, and 6 % of patients who underwent surgery had received treatment with a biologic, tacrolimus, and cyclosporine, respectively. No institution reported an increase in postoperative complications among patients treated with immunosuppressive drugs. The number of patients undergoing surgery decreased temporarily soon after infliximab and tacrolimus first became widely available, but subsequently increased again. The emergency surgery rate remained unchanged throughout the study period. These data show that immunosuppressive drugs have had little effect on the risk of postoperative complications.

乳腺原発悪性リンパ腫は稀であり,中でもきわめて稀なT細胞性の1例を経験したので報告する.症例は49歳の女性で,主訴は左乳房腫瘤触知である.術前の画像所見では乳癌と診断した.術中迅速病理診断にて,悪性リンパ腫と診断し,胸筋温存乳房切除術を行い,術後化学療法(VEPA)を加えた.術後8カ月目に脛骨,腋窩リンパ節,鎖骨上リンパ節に転移をきたした.化学療法(VEPA+VP16)を行い,一時的に症状の改善と画像上病変の縮小を認めたが,最終的には多発性骨転移にて,術後2年8カ月目死亡した. T細胞性悪性リンパ腫は,化学療法にも抵抗性であることが多く,予後不良である.