Efficacy and safety of rifaximin in patients with chronic intestinal pseudo-obstruction: a randomized, double-blind, placebo-controlled, phase II-a exploratory trial.

Chronic intestinal pseudo-obstruction (CIPO) is a rare intractable disease with limited treatment options. Small intestinal bacterial overgrowth (SIBO) often co-occurs with several diseases, including CIPO. While rifaximin (RFX) is effective in treating SIBO, its efficacy for CIPO remains unclear. Here, we aimed to investigate the efficacy and safety of RFX in adult patients with CIPO. Twelve patients were randomly assigned to receive RFX (400 mg three times daily, n=8) or a placebo (PBO, n=4) for 4 weeks. The global symptom score for abdominal bloating (GSS-bloating) and an original whole gastrointestinal symptoms score (O-WGSS) were collected, and a glucose hydrogen breath test (GHBT) and abdominal computed tomography (CT) were performed. No significant differences were observed in the primary endpoint. GSS-bloating improved by 75% and 25% in the PBO and RFX groups, respectively, and O-WGSS improved by 25% in both groups. No significant differences were observed in secondary and other endpoints, including the SIBO eradication rate in the GHBT and small intestinal volume on CT. In a post hoc analysis of SIBO-positive patients with CIPO (4/4 and 4/8 in the PBO and RFX groups), SIBO was eradicated in 25% and 75% of the patients (PBO and RFX groups, respectively) at the end of treatment, indicating a high eradication rate in the RFX group. Furthermore, the small intestinal gas volume decreased in the RFX group, and no severe adverse events occurred. Although no significant improvements were observed in subjective indicators, RFX may be beneficial in alleviating SIBO and reducing the small intestinal gas volume in SIBO-positive patients with CIPO.

Prior appendectomy and cerebral infarction as potential risk factors for recurrent ischemic colitis: A retrospective observational study.

Background and Aim: Ischemic colitis (IC) is a benign disease associated with acute lower gastrointestinal bleeding and frequent recurrence. While several studies have investigated risk factors for IC onset, few have assessed the risk factors for recurrent IC. This study aimed to identify risk factors for recurrent IC. Methods: Potential risk factors for recurrence were assessed by examining medical records and laboratory findings in this single-center retrospective study. We extracted the following data from the patients' medical records: patient characteristics, clinical signs and symptoms, laboratory findings, method of treatment, length of hospital stay, disease course, and the frequency of IC morbidities. Patients with IC were selected from a total of 439 312 patients over an 11-year period. Patients were divided into recurrent and nonrecurrent IC groups. Results: In total, 225 patients met the diagnostic criteria for IC during the specified study period; of these, 204 patients (90.7%) and 21 patients (9.3%) were included in the nonrecurrent and recurrent IC groups, respectively. Univariate and multivariate analyses showed a significant association between IC recurrence and both cerebral infarction (P = 0.008, odds ratio [OR] = 6.3) and history of appendectomy (P = 0.0005, OR = 6.2). The median (interquartile range [IQR]) follow-up time for all patients was 1556 (353-2768) days; this was much longer than the median (IQR) time to recurrence of 291 (64-907) days in the recurrent IC group. Conclusion: The results of this study suggest that prior cerebral infarction and appendicectomy may be risk factors for IC recurrence.

Clinicopathological features of endoscopically treated early gastric cancer with lymphovascular infiltration.

PURPOSE: Lymphovascular infiltration (LVI) may play a critical role in radicality and prognostic assessment of early gastric cancer (EGC). However, risk factors for LVI in endoscopically resected EGC remain unknown. This study evaluated the clinicopathological characteristics and prognoses of patients who underwent endoscopic resection of EGC to identify potential risk factors of LVI. METHODS: A cross-sectional study of patients who received gastric endoscopic submucosal dissection between February 1, 2012, and December 31, 2019, at two institutions was conducted. Among 1,462 lesions, 943 met the criteria for radical treatment considering features other than LVI and were included. The lesions were classified based on the presence of LVI. The clinicopathological characteristics of the two groups were compared. RESULTS: LVI was detected in 17 lesions (1.8%). The positivity rates of LVI were 0.7% (7/903) for intramucosal cancer and 25% (10/40) for submucosally invasive cancer. The LVI positivity rate was significantly higher for mixed-type cancer (lesions containing differentiated and undifferentiated-type carcinoma) than for non-mixed-type cancer (35.3 vs. 2.8%; P < 0.001) and for submucosally invasive cancer than for intramucosal cancer (58.8 vs. 3.2%; P < 0.001). In the multivariate logistic regression analysis, independent risk factors for LVI were mixed-type cancer (odds ratio; 95% confidence interval: 23.9; 5.0-115; P < 0.001) and submucosal invasion (58.7; 16.0-215; P < 0.001). CONCLUSIONS: Mixed-type cancer and submucosal invasion were risk factors for LVI in endoscopically resected EGC. These factors may play a critical role in the radicality and prognostic assessment of EGC.

Exploratory, multicenter, open-label study to evaluate the effects of linaclotide in patients with chronic constipation with an insufficient response to magnesium oxide: A study protocol.

Background: Chronic constipation leads to poor quality of life, and treatment remains unsatisfactory for patients. In Japan, magnesium oxide has been commonly used as the first choice of treatment for constipation; however, there are some cases of low satisfaction with magnesium oxide treatment. Linaclotide has recently been used to treat chronic constipation. In this study, we will examine whether linaclotide improves symptoms and quality of life in patients showing insufficient response to magnesium oxide. Methods: This is an exploratory multicenter open-label study. The target number of patients is 64: 32 patients with and 32 without abdominal symptoms. Patients with chronic idiopathic constipation or irritate bowel syndrome with constipation diagnosed according to the Rome-IV criteria are eligible. Patients prescribed 0.99-2 g/day of magnesium oxide for at least 4 weeks will be included. Those who consent to the study will continue taking magnesium oxide for 2-4 weeks, and defecation will be documented. Patients who meet the criteria will be prescribed linaclotide (0.5 mg) daily for 12 weeks. The primary endpoint is a change in the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL) score after 12 weeks of treatment. Conclusion: This is the first study to investigate the usefulness of linaclotide as a second-line treatment for chronic constipation. We will test the efficacy of treatment of constipation in patients with inadequate response to magnesium oxide. Trial registration: This study is registered with the Japan Registry of Clinical Trials (jRCT, jRCTs031200048).

Leukotriene Receptor Antagonist Therapy for the Chemoprevention of Human Rectal Aberrant Crypt Foci: Nonrandomized, Open-Label, Controlled Trial.

Leukotriene receptor antagonists (LTRA) are widely used drugs for treating allergic asthma, and they have recently been suggested to have a suppressive effect on carcinogenesis and cancer cell proliferation. Aberrant crypt foci (ACF) are considered a reliable surrogate biomarker of colorectal cancer. This prospective study explored the chemopreventive effect of an LTRA on colonic ACF formation and the safety of the medicine in patients as a pilot trial leading to a colorectal cancer chemoprevention trial.This was a nonrandomized, open-label, controlled trial in patients with colorectal ACFs. The participants were allocated to LTRA or observation groups. Patients in the LTRA group received 10 mg of montelukast orally daily for 8 weeks. After the intervention, colonoscopy was performed to evaluate the changes in the number of ACFs.From November 2017 to March 2020, 40 patients were enrolled. The first 30 were assigned to the LTRA group, and the remaining 10 were assigned to the observation group. In the LTRA group, the mean change in the number of ACFs per patient at 8 weeks from baseline was -2.4 ± 2.2, while the mean change in the observation group was 0.4 ± 2.3 (P = 0.002). There were no severe adverse events.This is the first study to explore the effect of LTRAs against colorectal ACF formation in humans. LTRAs are potential candidates for chemoprevention in colorectal cancer. PREVENTION RELEVANCE: We conducted the first LTRA chemoprevention trial for human rectal ACFs, which is considered a surrogate marker of colorectal carcinogenesis. 8-week treatment with LTRA suppressed ACF formation and cell proliferation in colonic epithelium. LTRAs are possible candidates for chemoprevention in colorectal cancer. See related Spotlight, p. 637.

Comparison of the diagnostic performance of NBI, Laser-BLI and LED-BLI: a randomized controlled noninferiority trial.

BACKGROUND AND AIMS: New image-enhanced endoscopy (IEE), blue Light Imaging (LED-BLI) is launched in USA and Europe, whereas Blue Laser Imaging (Laser-BLI) is available only Asian and some countries. No studies have directly compared the diagnostic accuracy of narrow band imaging (NBI), Laser-BLI and LED-BLI for colorectal tumors. The present study aimed to compare the diagnostic accuracy of the three methods for colorectal tumor using the NBI international colorectal endoscopic (NICE) classification and the Japanese NBI Expert Team (JNET) classifications. METHODS: This was a multi-center evaluator-blinded, randomized control trial of patients who underwent endoscopic colorectal tumor resection. The patients were randomly assigned to NBI, Laser-BLI or LED-BLI. Cropped images were sent to blinded external evaluators and diagnosed according to NICE and JNET classifications. The diagnostic accuracy of each endoscopy system was compared with non-inferiority test. RESULTS: A total of 619 colonic tumors were resected from 230 patients and evaluated by external four evaluators. The diagnostic accuracy of NBI for NICE 1, NICE 2, NICE 3 was 90.6%, 90.3% and 99.5%, respectively and for JNET 1, JNET 2A, JNET 2B and JNET 3, it was 94.6%, 72.0%, 79.2% and 99.1%, respectively. In non-inferiority test, Laser-BLI and LED-BLI revealed non-inferiority to NBI in all NICE and JNET categories (p<0.001). CONCLUSIONS: Laser-BLI and LED-BLI had high diagnostic accuracy and non-inferiority of NBI, especially for hyperplastic polyp/sessile serrated lesion and low-grade dysplasia. This is first trial to compare the diagnostic accuracy with NBI, Laser-BLI and LED-BLI and useful to understand the position of each IEE. This trial was registered as UMIN000032107.

Severe acute respiratory syndrome coronavirus 2 prevalence in saliva and gastric and intestinal fluid in patients undergoing gastrointestinal endoscopy in coronavirus disease 2019 endemic areas: Prospective cross-sectional study in Japan.

OBJECTIVES: Gastrointestinal endoscopy (GIE) is useful for the early detection and treatment of many diseases; however, GIE is considered a high-risk procedure in the coronavirus disease 2019 (COVID-19) pandemic era. This study aimed to explore the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity in saliva and gastrointestinal fluids to which endoscopy medical staff are exposed. METHODS: The study was a single-center cross-sectional study. From June 1 to July 31, 2020, all patients who underwent GIE at Yokohama City University Hospital were registered. All patients provided 3 mL of saliva. For upper GIE, 10 mL of gastric fluid was collected through the endoscope. For lower GIE, 10 mL of intestinal fluid was collected through the endoscope. The primary outcome was the positive rate of SARS-CoV-2 in saliva and gastrointestinal fluids. We also analyzed serum-specific antibodies for SARS-CoV-2 and patients' background information. RESULTS: A total of 783 samples (560 upper GIE and 223 lower GIE samples) were analyzed. Polymerase chain reaction (PCR) on saliva samples did not show any positive results in either upper or lower GIE samples. However, 2.0% (16/783) of gastrointestinal fluid samples tested positive for SARS-CoV-2. No significant differences in age, sex, purpose of endoscopy, medication, or rate of antibody test positivity were found between PCR positive and PCR negative cases. CONCLUSIONS: Asymptomatic patients, even those with no detectable virus in their saliva, had SARS-CoV-2 in their gastrointestinal tract. Endoscopy medical staff should be aware of infection when performing procedures. The study was registered as UMIN000040587.

Effects of colorectal endoscopic submucosal dissection on postoperative abdominal symptoms: a prospective observational study.

BACKGROUND: Endoscopic submucosal dissection (ESD) is an effective procedure to resect large superficial gastrointestinal neoplasms. In gastric ESD, several studies showed the relationship between postoperative abdominal symptoms and endoscopic treatment. However, the influence of colorectal ESD on abdominal symptoms after treatment is still unknown. To the best of our knowledge, this is the first prospective multicenter study performed to investigate the impact of colorectal ESD on postoperative abdominal symptoms. This study aimed to clarify the association between change of abdominal symptoms and ESD. METHODS: This study was a prospective multicenter observational trial that enrolled 141 out of 171 patients who underwent colorectal ESD and answered the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire from March 2015 to August 2019. We evaluated abdominal symptoms in the patients using the GSRS questionnaire before ESD and a few weeks after ESD. RESULTS: Comparing the GSRS before and after ESD, overall scores changed from 1.58 ± 0.58 to 1.48 ± 0.48, and the five subscales (reflux syndrome, abdominal pain, indigestion syndrome, diarrhea syndrome, and constipation syndrome) were slightly improved. Overall scores, indigestion syndrome, and constipation syndrome were statistically significantly different before and after ESD (P < 0.05). CONCLUSIONS: In GSRS, a score of ≥ 3 is often treated as a clinically significant symptom. Therefore, our findings indicated that there was no clinically significant difference. For this reason, colorectal ESD does not affect postoperative abdominal symptoms and is considered a minimally invasive treatment. The analysis of the impact of colon ESD on gastrointestinal symptoms UMIN000016914.

A prospective interventional trial on the effect of periodontal treatment on Fusobacterium nucleatum abundance in patients with colorectal tumours.

Fusobacterium nucleatum is associated with the progression of colorectal cancer. Thus, the possibility of preventing colorectal cancer or its progression by targeting F. nucleatum has been explored. As F. nucleatum is associated with periodontitis, we analysed whether treating periodontitis could influence F. nucleatum abundance in the colon. Patients with colorectal tumours who underwent colonoscopy were recruited. Patients diagnosed with periodontitis by a dentist were treated for approximately 3 months. Endoscopic resection of colorectal tumours was performed after periodontitis treatment, and resected tumours were pathologically classified as high-(HGD) or low-grade dysplasia (LGD). Saliva and stool samples were collected before and after the treatment. Of the 58 patients with colorectal tumours, 31 were included in the study, 16 showed improvement in periodontitis, and 11 showed no improvement. Stool F. nucleatum levels before treatment were significantly lower in the LGD group than in the HGD group. A significant decrease in faecal F. nucleatum levels was observed in patients who underwent successful treatment but not in those whose treatment failed. Salivary F. nucleatum levels were not altered in patients despite periodontal treatment. Thus, successful periodontitis treatment reduces stool F. nucleatum levels and may aid research on periodontitis and suppression of colorectal cancer development.

Efficacy of sedation with dexmedetomidine plus propofol during esophageal endoscopic submucosal dissection.

BACKGROUND AND AIM: During endoscopic submucosal dissection for superficial esophageal cancer, patient body movement can sometimes occur, which may cause discontinuation of the procedure. Propofol and dexmedetomidine have recently been found to be useful sedatives for endoscopic submucosal dissection. This study investigated whether sedation using propofol plus dexmedetomidine can suppress the patient's body movements during esophageal endoscopic submucosal dissection and compared this combination with sedation using propofol alone. METHODS: This was a prospective double-blind randomized controlled trial. Patients with superficial esophageal cancers who underwent esophageal endoscopic submucosal dissection at Yokohama City University Hospital were prospectively enrolled and were randomly assigned to the propofol and the propofol plus dexmedetomidine groups. The primary endpoint was the incidence of restlessness. The secondary endpoints were the satisfaction score, maintenance dose of propofol, and number of rescue propofol injections. RESULTS: Sixty-six patients (propofol group: n = 33; combination group: n = 33) were included. The combination group had a significantly lower incidence of restlessness than the propofol group (3.0% vs 27.3%, P = 0.02). In the combination group, the satisfaction scores of the endoscopists were significantly higher, the maintenance dose of propofol was significantly lower, and the number of rescue propofol injections was lower than those in the propofol group (3.0% vs 18.2%, P < 0.001). Although the incidence of bradycardia was significantly higher in the combination group (30.3% vs 3.0%, P < 0.01), no serious adverse effects occurred. CONCLUSION: The propofol plus dexmedetomidine combination provided excellent sedation that effectively suppressed the patient's body movements during esophageal endoscopic submucosal dissection.

The efficacy of aspirin and metformin combination therapy in patients with rectal aberrant crypt foci: a double-blinded randomized controlled trial.

BACKGROUND: The incidence and mortality rates of colorectal cancer (CRC) continue to increase worldwide. Therefore, new preventive strategies are needed to lower the burden of this disease. Previous studies reported that aspirin could suppress the development of sporadic colorectal adenoma. In addition, metformin is a biguanide derivative that is long widely used for the treatment of diabetes mellitus and has recently been suggested to have a suppressive effect on carcinogenesis and cancer cell growth. Both drugs exhibit a chemopreventive effect, but their efficacy is limited. Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and stain more darkly with methylene blue than normal crypts, are more prevalent in patients with cancer and adenomas, and considered a reliable surrogate biomarker of CRC. Thus, we designed a prospective trial as a preliminary study prior to a CRC chemoprevention trial to evaluate the chemopreventive effect of aspirin combined with metformin on colorectal ACF formation in patients scheduled for polypectomy. METHODS: This study is a double-blind randomized controlled trial that will be conducted in patients with both colorectal ACF and colorectal polyps scheduled for polypectomy. Eligible patients will be recruited for the study and the number of ACF in the rectum will be counted at the baseline colonoscopy. Then, the participants will be allocated to one of the following two groups; the aspirin plus placebo group or the aspirin plus metformin group. Patients in the aspirin plus placebo group will receive oral aspirin (100 mg) and placebo for 8 weeks, and those in the aspirin plus metformin group will receive oral aspirin (100 mg) and metformin (250 mg) for 8 weeks. After 8 weeks of administration, polypectomy will be performed to evaluate changes in the number of ACF, and the cell-proliferative activity in the normal colorectal mucosa and colorectal polyps. DISCUSSION: This is the first study proposed that will explore the effect of aspirin combined with metformin on the formation of colorectal ACF in humans. TRIAL REGISTRATION: This trial has been registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000028259 . Registered 17 July 2017.

Difference in Defecation Desire Between Patients With and Without Chronic Constipation: A Large-Scale Internet Survey.

INTRODUCTION: Defecation desire (DD) is an important physiological component of normal defecation. However, knowledge of DD in the general population and in individuals with chronic constipation (CC) is lacking. We aimed to assess the prevalence of DD in the general population and individuals with CC and to understand the impact of treatment on DD among individuals with CC. METHODS: We conducted an online questionnaire survey targeting the Japanese general population in 2019. DD was reported as never, rarely, usually, or always. Individuals who self-reported constipation and met the Rome IV criteria for functional constipation but did not for irritable bowel syndrome were included in the CC group, while the same number of age-/sex-matched controls who met neither functional constipation nor irritable bowel syndrome criteria was included in the non-CC group. Individuals who reported DD as rarely or never were defined as having loss of DD (LODD). RESULTS: Of the 20,986 participants, 2,587 were included in the CC group (12.3%). LODD was significantly higher in the CC individuals than in the non-CC controls (57.4% vs 8.3%, respectively, P < 0.001, odds ratio 14.84 [95% confidence interval 12.65-17.42]). Satisfaction with treatment for constipation was lower in individuals with persistent LODD (25.9%) compared with those with improved LODD (56.5%) on treatment (P < 0.001, odds ratio 2.48 [1.39-4.43]). DISCUSSION: LODD is common in CC and is associated with decreased satisfaction to treatment. Greater attention should be paid to DD when treating patients with CC.

The efficacy of a leukotriene receptor antagonist in the treatment of human rectal aberrant crypt foci: a nonrandomized, open-label, controlled trial.

BACKGROUND: Leukotriene receptor antagonists (LTRAs) are broadly used for the management of allergic asthma and have recently been indicated to inhibit carcinogenesis and cancer cell growth. In colorectal cancer (CRC) chemoprevention studies, the occurrence of adenoma or CRC itself is generally set as the trial endpoint. Although the occurrence rate of CRC is the most confident endpoint, it is inappropriate for chemoprevention studies because CRC incidence rate is low in the general population and needed for long-term monitoring. Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and darker in methylene blue staining than normal crypts, are regarded to be a fine surrogate biomarker of CRC. Therefore, this prospective study was designed to explore the chemopreventive effect of LTRA on colonic ACF formation and the safety of the medicine in patients scheduled for a poly resection as a pilot trial leading the CRC chemoprevention trial. METHODS: This study is a nonrandomized, open-label, controlled trial in patients with colorectal ACF and polyps scheduled for a polypectomy. Participants meet the inclusion criteria will be recruited, and the number of ACF in the rectum will be counted at the baseline colonoscopic examination. Next, the participants will be assigned to the LTRA or no treatment group. Participants in the LTRA group will continue 10 mg of oral montelukast for 8 weeks, and those in the no treatment group will be observed without the administration of any additional drugs. At the end of the 8-week LTRA intervention period, a polypectomy will be conducted to evaluate the changes in the number of ACF, and cell proliferation in the normal colorectal epithelium will be analyzed. DISCUSSION: This will be the first study to investigate the effect of LTRAs on colorectal ACF formation in humans. TRIAL REGISTRATION: This trial has been registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000029926 . Registered 10 November 2017.

The benefit of elobixibat in chronic constipation is associated with faecal deoxycholic acid but not effects of altered microbiota.

BACKGROUND: Elobixibat, a novel inhibitor of apical sodium-dependent bile acid transporter for treating chronic constipation, increases colonic bile acid concentrations, stimulating bowel function. However, it is not clear which bile acids are altered, or whether altered gut microbiota are associated with functional effects that may alter bowel function. AIMS: To investigate the effects of elobixibat on changes in the faecal concentrations of total and individual bile acids and in faecal microbiota. METHODS: This was a prospective, single-centre study. After baseline period, patients received 10 mg daily of elobixibat for 2 weeks. We evaluated the effects on bowel function, changes in faecal bile acid concentrations and composition of gut bacteria, before and after elobixibat administration. RESULTS: In the 30 patients analysed, the frequency of pre- and post-treatment bowel movements per fortnight was 7 and 10 (P < 0.001), respectively. The pre-treatment faecal bile acid concentration increased significantly from 10.9 to 15.0 µg/g stool post-treatment (P = 0.030), with a significant increase in faecal deoxycholic acid (pre-treatment 3.94 µg/g stool to post-treatment 5.02 µg/g stool, P = 0.036) and in glycine-conjugated deoxycholic and chenodeoxycholic acids. Shannon index was significantly decreased, but there were no significant changes at the genus and phylum levels. CONCLUSIONS: Short term treatment with elobixibat increased the concentrations of total bile acids and deoxycholic acid and decreased the diversity of faecal microbiota. The biological effects of elobixibat are associated with its effects on secretory bile acids, rather than the structural changes of an altered faecal microbiota.