Immunomodulators after the discontinuation of anti-tumor necrosis factor-alpha antibody treatment and relapse in ulcerative colitis: A multicenter cohort study.

BACKGROUND AND AIM: Strategies to reduce relapse using immunomodulators (IMs) after discontinuing anti-tumor necrosis factor-alpha (TNF-α) antibody treatment are controversial in patients with ulcerative colitis (UC). In this study, we assessed the association between IMs after discontinuing anti-TNF-α antibody treatment and relapse in patients with UC. METHODS: This retrospective, multicenter cohort study included 257 patients with UC in clinical remission. These patients discontinued anti-TNF-α antibody treatment between June 2010 and March 2019 and were followed up until March 2020. We evaluated the differences in relapse rates between patients with IMs (IM group) and those without IMs (non-IM group) after discontinuing the treatment. Relapse was defined as further undergoing an induction treatment or colectomy. Cox proportional hazards models adjusted for confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for relapse. Exploratory analyses were performed to identify other factors that could predict relapse. RESULTS: During the median follow-up period of 22 months (interquartile range: 10-41), 114 relapses occurred: 42/100 (42.0%) in the IM group and 72/157 (45.9%) in the non-IM group. In the multivariable analysis, IMs were not associated with relapse (HR, 0.95 [95% CI, 0.64-1.41]). In the exploratory analyses, discontinuation due to side effects (HR, 1.83 [95% CI, 1.18-2.82]) and younger age (HR, 0.99 [95% CI, 0.98-1.00]) predicted relapse. CONCLUSION: Immunomodulators were not associated with relapse after discontinuing anti-TNF-α antibody treatment in patients with UC. Careful patient follow-up is needed when discontinuing due to side effects or when the patient is of a younger age at the time of discontinuation.

Optimal Use of Serum Leucine-Rich Alpha-2 Glycoprotein as a Biomarker for Small Bowel Lesions of Crohn's Disease.

Introduction: A large proportion of small bowel lesions in Crohn's disease (CD) may exist beyond the reach of ileocolonoscopy and there is no gold standard imaging modality to screen them, suggesting the need for optimal biomarkers. We aimed to compare the usefulness of C-reactive protein (CRP), faecal calprotectin (FC), and leucine-rich alpha-2 glycoprotein (LRG) in determining small bowel lesions of CD. Methods: This was a cross-sectional observational study. CRP, FC, and LRG were prospectively measured in patients with quiescent CD who underwent imaging examinations (capsule or balloon-assisted endoscopy, magnetic resonance enterography, or intestinal ultrasound) selected by the physician in clinical practice. Mucosal healing (MH) of the small bowel was defined as a lack of ulcers. Patients with a CD activity index >150 and active colonic lesions were excluded. Results: A total of 65 patients (27, MH; 38, small bowel inflammation) were analysed. The area under the curve (AUC) of CRP, FC, and LRG was 0.74 (95% confidence interval: 0.61-0.87), 0.69 (0.52-0.81), and 0.77 (0.59-0.85), respectively. The AUC of FC and LRG in a subgroup of 61 patients with CRP <3 mg/L (26, MH; 32, small bowel inflammation) was 0.68 (0.50-0.81) and 0.74 (0.54-0.84), respectively. The cut-off of 16 µg/mL of LRG showed the highest positive predictive value of 1.00 with specificity of 1.00, while negative predictive value was highest (0.71) with sensitivity of 0.89 at the cut-off of 9 µg/mL. Conclusion: LRG can accurately detect and/or exclude the small bowel lesions with two cut-off values.

Factors that affect the development of acute hemorrhagic rectal ulcer syndrome and rebleeding.

Objectives: Acute hemorrhagic rectal ulcer syndrome (AHRUS) causes massive bleeding and often recurrent rebleeding from rectal ulcers that form immediately above the dentate line. This study aimed to determine the clinical background and risk factors contributing to rebleeding in patients with AHRUS and the most appropriate method of hemostasis treatment. Methods: This retrospective study included 93 patients diagnosed with AHRUS at Showa University Fujigaoka Hospital, Japan, between April 2009 and November 2018. Information on clinical background factors, endoscopic findings, and hemostasis was obtained from medical records. The relationship with episodes of rebleeding was analyzed by multivariate logistic regression analysis. Results: The median age was 79 years, and 84 patients (90%) had a performance status of grade 2 or higher. The patients had multiple background factors, with a median number of 5 per patient. The background factors could be classified into two major factors: those related to arteriosclerosis and those related to delayed wound healing.In the multivariate analysis, significantly more rebleeding occurred in patients with active bleeding during the initial endoscopy (odds ratio 4.88, 95% confidence interval 1.80-14.46, p = 0.003); significantly less rebleeding occurred in patients for whom hemostasis was first performed by clipping (odds ratio 0.30, 95% confidence interval 0.09-0.88, p = 0.035). Conclusions: In bedridden older individuals with poor general health, multiple combinations of arteriosclerosis-related factors and protracted wound healing factors can induce AHRUS. We strongly recommend performing hemostasis via the clipping method on suspected bleeding points, including active bleeding sites, in AHRUS.

Usefulness of colestimide for diarrhea in postoperative Crohn's disease.

Background and Aim: Crohn's disease (CD) often causes intractable diarrhea after intestinal resection. Anion exchange resins have been reported to be effective in patients with bile acid diarrhea after distal ileectomy; furthermore, bile acid metabolism has been implicated in the pathogenesis of CD. Therefore, we aimed to examine the effectiveness of colestimide in the management of postoperative CD, and to compare its impact between patients with and those without ileocecal resection. Methods: Postoperative CD patients prescribed colestimide for diarrhea between April 2017 and December 2020 were retrospectively evaluated for changes in the total Crohn's disease activity index (CDAI), each CDAI component including diarrhea frequency/week, albumin, and C-reactive protein (CRP) was evaluated before and after the administration of colestimide. Furthermore, comprehensive patient and physician assessments were reviewed from medical records during the first outpatient visit as a global clinical judgment after the initiation of colestimide therapy. Results: A total of 24 patients were included, of whom 17 had a previous history of ileocecal resection. Significant improvement was noted in CDAI and diarrhea frequency only in the ileocecal resection group (CDAI: 114.5 ± 52.7 and 95.4 ± 34.8, P < 0.05; diarrhea frequency/week 23.8 ± 14.1 and 15.4 ± 11.2, P < 0.05, respectively). There was no significant improvement in other CDAI components, albumin level, or CRP level in either group. In the global clinical judgment, 13 and 4 patients in the ileocecal and non-ileocecal resection groups, respectively, were judged as "effective," with an overall efficacy rate of 70.8%. Conclusion: Colestimide is effective for diarrhea in patients with postoperative CD, especially after ileocecal resection.

Early improvement in bowel wall thickness on transperineal ultrasonography predicts treatment success in active ulcerative colitis.

BACKGROUND: Bowel ultrasonography is a non-invasive imaging tool that can repeatedly monitor ulcerative colitis (UC) activity. AIM: This study aimed to determine whether early transabdominal or transperineal ultrasonography changes can predict subsequent clinical response to induction therapy in patients with UC. METHODS: This single-centre prospective study explored ultrasonographic predictors for clinical remission (patient-reported outcome-2 ≤ 1 with no rectal bleeding subscore) at week 8 in patients with active UC who underwent induction therapy, in comparison with faecal calprotectin and C-reactive protein (measured at baseline, week 1 and week 8). Predictive factors were assessed using multivariable regression models and receiver-operating-characteristic curve analysis. RESULTS: A total of 100 patients were analysed, of which 54 achieved remission at week 8. Baseline biomarker and ultrasonographic-parameter values were not predictive of remission. Contrastingly, change from baseline to week 1 in rectal bowel wall thickness measured using transperineal ultrasonography was an independent predictor of remission by week 8 (adjusted odds ratio is associated with a 1-mm decrease: 1.90 [95% confidence interval, 1.22-2.95]). In a subgroup analysis of the patients who did not achieve remission in 1 week, the predictive value of change in rectal bowel wall thickness remained high (AUC = 0.77 [95% confidence interval, 0.61-0.88]). CONCLUSION: Improvement in rectal bowel wall thickness measured using transperineal ultrasonography at week 1 predicts treatment success and potentially facilitates decision making during the early course of induction therapy in UC.

Residual Short-Segment Distal Inflammation Has No Significant Impact on the Major Relapse of Extensive Ulcerative Colitis.

BACKGROUND: Mucosal healing is a treatment target for patients with ulcerative colitis. However, the relevance of proactive treatment for residual inflammation limited to the distal colon is unclear. MATERIALS AND METHODS: Patients with ulcerative colitis who had extensive colitis in clinical remission and underwent colonoscopy were retrospectively enrolled and followed up for 2 years. Patients with complete endoscopic remission (CER; Mayo endoscopic subscore [MES] of 0) and those with short-segment distal inflammation (SS; active inflammation only in the sigmoid colon and/or rectum with a proximal MES of 0) were compared for the incidence of minor (only symptomatic) and major (need for induction treatments or hospitalization) relapses. RESULTS: A total of 91 patients with CER and 54 patients with SS were identified and 63 relapses (47 minor and 16 major) were analyzed. Univariate analysis showed that minor relapses were significantly more frequent in the SS group than in the CER group (hazard ratio [HR], 2.22; 95% confidence interval [CI], 1.25-3.97), but major relapses were not more frequent in the SS group than in the CER group (HR, 1.78; 95% CI, 0.65-4.83). Multivariable analysis showed that SS was the only risk factor significantly associated with minor relapse (HR, 2.38; 95% CI, 1.31-4.36). When the SS group was stratified by MES of 1 vs 2/3, minor relapses were significantly more frequent in the subgroup with MES of 2/3 than in the CER group, whereas the incidence of major relapse remained similar. CONCLUSIONS: Residual short-segment distal inflammation is not a risk factor for major relapses as long as endoscopic remission is achieved in the proximal colon. Therefore, reactive but not proactive treatment may be appropriate for such lesions.

Determining the usefulness of Capsule Scoring of Ulcerative Colitis in predicting relapse of inactive ulcerative colitis.

BACKGROUND AND AIM: The usefulness of second-generation colon capsule endoscopy (CCE2) in ulcerative colitis (UC), especially in clinically inactive patients, has been reported. Capsule Scoring of Ulcerative Colitis (CSUC) was developed as a severity index for UC. We aimed to determine whether CSUC is useful for predicting relapse during clinical remission. METHODS: Forty-one UC patients in clinical remission who underwent CCE2 were prospectively registered from April 2016 to August 2019. Patients' CSUC score was obtained; those with subsequent relapse were followed up retrospectively. The correlation of CSUC with white blood cell count, platelet count, albumin, C-reactive protein, fecal calprotectin and fecal lactoferrin levels, and fecal immunochemical test results was evaluated; their predictive values for future relapse were compared. RESULTS: The correlations of CSUC with white blood cell, platelet, albumin, C-reactive protein, fecal calprotectin, fecal immunochemical test, and fecal lactoferrin values were rs  = 0.13, 0.27, -0.25, 0.15, 0.50, 0.43, and 0.50, respectively. CSUC was higher in 12 patients who relapsed within 1 year than in 29 patients who remained in clinical remission (2.83 ± 1.95 vs 0.72 ± 1.00, P < 0.01). Receiver operator characteristic curve analysis showed that CSUC ≥ 1 was a predictor of relapse (area under the curve of 0.82, sensitivity of 83.3%, specificity of 58.6%) and maybe superior to fecal biomarkers. In the univariate analysis, patients with CSUC of 0 had a lower relapse rate than those with CSUC of ≧ 1 (P = 0.03, log-rank test). After analyzing patients who underwent CCE2 within 6 months after the successful induction treatment, results showed that those with CSUC of ≤ 1 remained in clinical remission for a year. CONCLUSION: CSUC predicts relapse within 1 year in UC patients in clinical remission, especially when used 6 months after induction treatment.

Acceptability of endoscopic submucosal dissection for sessile serrated lesions: comparison with non-sessile serrated lesions.

Background and study aims Sessile serrated lesions (SSL) are major precursor lesions of serrated pathway cancers, and appropriate treatment may prevent interval colorectal cancer. Studies have reported the outcomes of endoscopic mucosal resection (EMR) for SSL; however, there are insufficient reports on endoscopic submucosal dissection (ESD). We examined the characteristics and outcomes of SSL and compared them to those of non-SSL in ESD. Patients and methods We reviewed 370 consecutive cases in 322 patients who underwent colorectal ESD between January 2016 and March 2020 at our hospital. There were 267 0-IIa lesions that were stratified into 41 SSL and 226 non-SSL (intramucosal cancer, adenoma) cases. We used propensity matching to adjust for the variances in the factors affecting treatment between the SSL and non-SSL groups. Results In the baseline cases, young women and proximal colon tumor location were significantly more common in the SSL group. There were no statistically significant differences between the SSL and non-SSL groups in terms of en bloc resection rate (97.6 % vs. 99.6 %; P  = 0.28), R0 resection rate (92.7 % vs. 93.4 %; P  = 0.74), perforation (0 % vs. 0.9 %; P  > 0.99), and postoperative bleeding (2.4 % vs. 1.8 %; P  = 0.56). Thirty-eight pairs were matched using propensity score, and the median dissection speed (12 vs. 7.7 cm 2 /h; P  = 0.0095) was significantly faster in the SSL than in the non-SSL group. Conclusions ESD for SSL was safely performed, and SSL was smoother to remove than non-SSL. ESD might be an acceptable endoscopic treatment option for SSL.

Efficacy and suitable indication of colorectal endoscopic submucosal dissection using a balloon-assisted endoscope.

BACKGROUND AND AIM: Cases of colorectal endoscopic submucosal dissection (ESD) with poor maneuverability are often encountered. We aimed to evaluate the efficacy of balloon-assisted endoscopy (BAE) for such cases. METHODS: We confirmed maneuverability preoperatively in 400 consecutive cases of colorectal ESD performed at a single center from April 2011 to April 2018. A total of 83 deep colon cases judged as having poor maneuverability were retrospectively reviewed; 54 cases underwent BAE with a single balloon endoscope (group B), and 29 cases underwent conventional procedures without BAE (group C). Tumor size, procedure duration, dissection speed, en bloc resection rate, histology, and associated complications were compared between groups. RESULTS: The mean tumor size, tumor invasiveness, fibrosis, and complications did not differ between groups. Although the en bloc resection rate did not differ (both 98%), the groups significantly differed with regard to the R0 resection rate (B: 96%; C: 83%; P = 0.048). Overall, the procedure duration (B: 51 min; C: 70 min; P = 0.17) and dissection speed (B: 19.4 mm2/min; C: 17.4 mm2/min; P = 0.13) were not significantly different between groups. However, the dissection speed for lesions in the cecum/ascending colon was significantly faster in group B than in group C (B: 22.3 mm2/min; C: 11.3 mm2/min; P = 0.037). CONCLUSIONS: In cases of colorectal ESD with poor maneuverability, the use of BAE contributed to an improvement in the R0 resection rate. In addition, BAE contributed to a quicker dissection speed for lesions located in the cecum/ascending colon.

A case of rectal neuroendocrine carcinoma in a patient with long-standing ulcerative colitis involving alterations of the p16-Rb pathway.

The patient was a 54-year-old male who had been suffering from extensive ulcerative colitis (UC) for 17 years. Colonoscopy revealed an elevated lesion in the affected rectum, and its biopsy demonstrated neuroendocrine carcinoma (NEC). The surgical specimen obtained on laparoscopic high anterior resection showed extensive active inflammatory and dysplastic lesions and three grossly visible multifocal malignant lesions: a polypoid fungating tumor of NEC (type 1, 20 mm in diameter, pT3) that had been preoperatively noticed, a polypoid fungating tumor of adenocarcinoma (type 1, 22 mm, pT2) and a protruded sessile polypoid tumor (0-Is, 5 mm, pTis) of adenocarcinoma. The NEC was adjacently accompanied by dysplasia-carcinoma sequential lesions and showed a diffuse immunohistochemical overexpression of p53 and p16 proteins and the loss of Rb with no abnormal immunohistochemical staining of microsatellite instability markers and no KRAS mutations. Fifteen months later, the patient showed liver metastasis from the NEC component, followed by bone and spinal metastasis; he died 22 months after the initial diagnosis. A rare case of lethal NEC arising from long-standing extensive UC was reported. The NEC appeared to be UC-related, not incidental, and complicated by progression from dysplasia to carcinoma involving alterations of the p16-Rb pathway.

Life-threatening emphysematous liver abscess associated with poorly controlled diabetes mellitus: a case report.

BACKGROUND: Emphysematous liver abscesses are defined as liver abscesses accompanied by gas formation. The fatality rate is extremely high at 27%, necessitating prompt intensive care. CASE PRESENTATION: The patient was a 69-year-old Japanese man with type 2 diabetes. He visited the emergency outpatient department for fever and general malaise that had been ongoing for 2 weeks. Abdominal computed tomography revealed an abscess 5 cm in diameter accompanied by gas formation in the right hepatic lobe. Markedly impaired glucose tolerance was observed with a blood sugar level of 571 mg/dL and a glycated hemoglobin level of 14.6%. The patient underwent emergency percutaneous abscess drainage, and intensive care was subsequently initiated. Klebsiella pneumoniae was detected in both the abscess cavity and blood cultures. The drain was removed 3 weeks later, and the patient was discharged. CONCLUSION: Emphysematous liver abscesses are often observed in patients with poorly controlled diabetes, and the fatality rate is extremely high. Fever and malaise occasionally mask life-threatening infections in diabetic patients, necessitating careful examination.

Severe refractory Clostridium difficile infection with good response to fecal microbiota transplantation: a case report.

A 49-year-old woman diagnosed with pseudomembranous enterocolitis was transferred to our hospital for medical treatment. She responded poorly to treatment with vancomycin hydrochloride and metronidazole, so she underwent fecal microbiota transplantation. Treatment effects were observed the next day, and the diarrhea disappeared within 3 days. Colonoscopy 4 days later revealed the resolution of pseudomembranes, and no recurrences were reported within the first year after discharge.

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

BACKGROUND AND AIM: Calprotectin is an abundant protein in neutrophils, which infiltrate the mucosa during inflammation. Fecal calprotectin (FC) level has shown correlation with disease activity in ulcerative colitis (UC) patients. Additionally, FC level is expected to indicate mucosal healing (MH). This study was to see the significance of FC for predicting MH in patients with quiescent UC. METHODS: A total of 112 patients with quiescent UC were included. After taking blood and stool samples, patients underwent total colonoscopy, and the Mayo endoscopic subscore was recorded. FC was measured by fluorescence enzyme immunoassay. C-reactive protein, hemoglobin, erythrocyte sedimentation rate, and serum albumin were measured as conventional biomarkers. MH was defined as Mayo 0 or 0 and 1, and receiver-operator characteristic analyses were undertaken to determine the significance levels of measurements. RESULTS: Data from 105 patients were available. Eleven patients showed Mayo ≥ 2. The median (interquartile range) of FC level of all patients was 115 µg/g (45.4-420). The area under the curve (AUC) in receiver operator characteristic analysis of FC to predict Mayo 0 and 1 was 0.869 with a cut-off value of 200 µg/g yielding 67% sensitivity and 91% specificity, which were the best among all biomarkers. However, the power of FC to predict Mayo 0 was modest; the AUC was 0.639 and cut-off value 194 µg/g with 71% sensitivity and 58% specificity. CONCLUSIONS: Based on the findings of this study, we believe that FC is a clinically relevant biomarker of MH in patients with quiescent UC. Other favorable features of FC test include feasibility and non-invasiveness.

Successful conservative treatment of emphysematous gastritis.

Emphysematous gastritis is an extremely rare disease with an unfavorable prognosis. To date, very few studies have been conducted regarding the intragastric recovery process based on endoscopic findings. We herein report a case of emphysematous gastritis that improved with long-term (five months) conservative treatment in which we were able to observe the intragastric recovery process endoscopically. In cases in which emphysematous gastritis is suspected, it is important to provide prompt diagnostic imaging (including CT) and early appropriate treatment in order to improve the prognosis.

Small intestinal obstruction caused by anisakiasis.

Small intestinal anisakiasis is a rare disease that is very difficult to diagnose, and its initial diagnosis is often surgical. However, it is typically a benign disease that resolves with conservative treatment, and unnecessary surgery can be avoided if it is appropriately diagnosed. This case report is an example of small intestinal obstruction caused by anisakiasis that resolved with conservative treatment. A 63-year-old man admitted to our department with acute abdominal pain. A history of raw fish (sushi) ingestion was recorded. Abdominal CT demonstrated small intestinal dilatation with wall thickening and contrast enhancement. Ascitic fluid was found on the liver surface and in the Douglas pouch. His IgE (RIST) was elevated, and he tested positive for the anti-Anisakis antibodies IgG and IgA. Small intestinal obstruction by anisakiasis was highly suspected and conservative treatment was performed, ileus tube, fasting, and fluid replacement. Symptoms quickly resolved, and he was discharged on the seventh day of admission. Small intestinal anisakiasis is a relatively uncommon disease, the diagnosis of which may be difficult. Because it is a self-limiting disease that usually resolves in 1-2 weeks, a conservative approach is advisable to avoid unnecessary surgery.

Gastric- and intestinal-type marker expression in invasive ductal adenocarcinoma of the pancreas.

BACKGROUND: Although invasive ductal adenocarcinoma of the pancreas (PDAC) manifests as a relatively uniform histomorphological feature of the pancreatobiliary type, it may be complicated by metaplastic changes and heterogeneous gastric and intestinal elements. This study aimed to investigate the complication rate and clinicopathological significance of such heterogeneous elements. METHODS: Fifty-nine patients who underwent resection of PDAC were examined in this study. Immunohistochemically, tumors showing high expression (>25%) of the intestinal-type (INT) marker CDX2 were classified as PDAC with INT. Those with high expression (>25%) of the gastric-type (GAS) marker MUC5AC were classified as PDAC with GAS, while those with high expression of both markers were classified as PDAC with INT/GAS. These patients were compared with those with PDAC of the negative group in which neither markers was highly expressed to examine their clinicopathological significance. RESULTS: In the 59 patients, 31 (52.5%) showed high CDX2 or MUC5AC expression. Twenty-eight patients (47.5%) belonged to a negative group, 11 (18.6%) to a PDAC with INT group, 15 (25.4%) to a PDAC with GAS group, and 5 (8.5%) to a PDAC with INT/GAS group. No significant differences were observed for age, gender, size, localization, T classification, or prognosis among the four groups. Although the PDAC with GAS group had well differentiated types significantly more than the other groups, the rate of lymph node metastasis in this group was significantly higher (PDAC with GAS: 73%; other groups: 36%). CONCLUSION: Complications with heterogeneous elements are not uncommon in PDAC, and this should be considered during the diagnosis and treatment of PDAC along with histogenesis of the disease.