Efficacy of endoscopic submucosal resection with a ligation device for small rectal neuroendocrine tumor: study protocol of a multicenter open-label randomized control trial (BANDIT trial).

BACKGROUND: Endoscopic resection is widely accepted as a local treatment for rectal neuroendocrine tumors sized ≤ 10 mm. However, there is no consensus on the best method for the endoscopic resection of rectal neuroendocrine tumors. As a simplified endoscopic procedure, endoscopic submucosal resection with a ligation device (ESMR-L) indicates a histologically complete resection rate comparable to that of endoscopic submucosal dissection (ESD). We hypothesized that ESMR-L than ESD would be preferred for rectal neuroendocrine tumors. Hence, this trial aimed to verify whether ESMR-L is non-inferior to ESD in terms of histologically complete resection rate. METHODS: This is a prospective, open-label, multicenter, non-inferiority, randomized controlled trial of two parallel groups, conducted at the Shizuoka Cancer Center and 31 other institutions in Japan. Patients with a lesion endoscopically diagnosed as a rectal neuroendocrine tumor ≤ 10 mm are eligible for inclusion. A total of 266 patients will be recruited and randomized to undergo either ESD or ESMR-L. The primary endpoint is the rate of en bloc resection with histologically tumor-free margins (R0 resection). Secondary endpoints include en bloc resection rate, procedure time, adverse events, hospitalization days, total devices and agents cost, adverse event rate between groups with and without resection site closure, outcomes between expert and non-expert endoscopists, and factors associated with R0 resection failure. The sample size is determined based on the assumption that the R0 resection rate will be 95.2% in the ESD group and 95.3% in the ESMR-L group, with a non-inferiority margin of 8%. With a one-sided significance level of 0.05 and a power of 80%, 226 participants are required. Assuming a dropout rate of 15%, 266 patients will be included in this study. DISCUSSION: This is the first multicenter randomized controlled trial comparing ESD and ESMR-L for the R0 resection of rectal neuroendocrine tumors ≤ 10 mm. This will provide valuable information for standardizing endoscopic resection methods for rectal neuroendocrine tumors. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs042210124. Registered on Jan 6, 2022.

Utility of Combined Use of Transabdominal Ultrasonography and Fecal Immunochemical Test Examinations in Ulcerative Colitis.

This study examined the utility of the combined use of transabdominal ultrasonography (TUS) and fecal immunochemical testing (FIT) to detect mucosal inflammation, vis-a-vis the Mayo endoscopic subscore (MES), in ulcerative colitis (UC). Sixty-three UC patients who underwent TUS and FIT were retrospectively enrolled. For TUS, the colon was divided into five segments, and the bowel wall thickness was measured and evaluated. The accuracy of FIT (> 100 ng/ml) in detecting mucosal inflammation (MES>0) was 0.93, whereas that of TUS (BWT>2 mm) in each segment was 0.84-0.97. The combined use of TUS and FIT may be helpful in noninvasive treatment strategies.

Innovative submucosal injection solution for endoscopic resection with phosphorylated pullulan: a preclinical study.

BACKGROUND AND AIMS: A submucosal injection solution is used to assist in endoscopic surgery. The high viscosity of current solutions makes them difficult to inject. In the present study, we developed an extremely low-viscosity, easy-to-use submucosal injection solution using phosphorylated pullulan (PPL). METHODS: The PPL solutions were prepared at different concentrations, and their viscosities were measured. The mucosal elevation capacity was evaluated using excised porcine stomachs. Controls included 0.4% sodium hyaluronate (SH), 0.6% sodium alginate (SA), and saline. To evaluate the practicality, the catheter injectability of 0.7% PPL was measured, and EMR and endoscopic submucosal dissection (ESD) were performed using the stomach and colorectum of live pigs. As controls, 0.4% SH and saline were used. RESULTS: The PPL solutions were of extremely low viscosity compared to the solutions of 0.4% SH and 0.6% SA. Nevertheless, the mucosal elevation capacity of PPL solutions for up to 0.7% concentration was similar to that of 0.4% SH, and 0.7% PPL was less resistant to catheter infusion than 0.4% SH and 0.6% SA. In live pig experiments with endoscopic mucosal resection and ESD, snaring after submucosal injection of 0.7% PPL was easier than with 0.4% SH, ESD with 0.7% PPL produced less bubble formation than with 0.4% SH, and the procedure time tended to be shorter with 0.7% PPL than with 0.4% SH because of the shorter injection time. CONCLUSIONS: The PPL solution is an innovative and easy-to-use submucosal injection solution.

Low Patient Weight and Long Intubation Time Are Key Factors for Pain during Colonoscopy.

Although the clinical usefulness of colonoscopy has been established, the procedure remains painful for many patients. This study was designed to clarify the factors predicting colonoscopy-related pain. We evaluated 283 consecutive patients who completed a first-ever, total colonoscopy without sedatives or analgesics. The severity of pain symptoms was evaluated by a numeric rating scale (NRS) in a questionnaire immediately after the colonoscopy. Patient backgrounds and endoscopic findings were analyzed to evaluate their association with pain. Out of 283 patients, 53 scored their pain 0-1 on the NRS while 48 scored it 6-10. We defined the colonoscopies of the former and latter patients as painless and painful, respectively, and compared the two. Multivariate analyses revealed that low body weight (OR 4.95, 95%CI 1.89-12.99) and longer intubation time (OR 3.63, 95%CI 1.46-9.03) were significant risk factors for painful colonoscopy. To identify factors contributing to the increased intubation time, we divided subjects into short- and long-intubation-time groups based on a median insertion time of 7 min. Older age (OR 2.28, 95%CI 1.31-3.98), previous abdominal surgery (OR 1.93, 95%CI 1.13-3.32) and findings of invasive cancer (OR 10.90, 95%CI 1.34-88.90) were significant factors for longer intubation time.

Clinical course and management of adverse events after endoscopic resection of superficial duodenal epithelial tumors: Multicenter retrospective study.

OBJECTIVES: This study aimed to elucidate the clinical course and management of adverse events (AEs) after endoscopic resection (ER) for superficial duodenal epithelial tumors (SDETs). METHODS: Consecutive patients who underwent ER of SDETs between January 2008 and July 2018 at 18 Japanese institutions were retrospectively enrolled. The study outcomes included the clinical course, management, and risk of surgical conversion with perioperative AEs after ER for SDETs. RESULTS: Of the 226 patients with AEs, the surgical conversion rate was 8.0% (18/226), including 3.7% (4/108), 1.0% (1/99), and 50.0% (12/24) of patients with intraoperative perforation, delayed bleeding, or delayed perforation, respectively. In the multivariate logistic analysis, involvement of the major papilla (odds ratio [OR] 12.788; 95% confidence interval [CI] 2.098-77.961, P = 0.006) and delayed perforation (OR 37.054; 95% CI 10.219-134.366, P < 0.001) were significant risk factors for surgical conversion after AEs. Delayed bleeding occurred from postoperative days 1-14 or more, whereas delayed perforation occurred within 3 days in all cases. CONCLUSIONS: The surgical conversion rate was higher for delayed perforation than those for other AEs after ER of SDETs. Involvement of the major papilla and delayed perforation were significant risk factors for surgical conversion following AEs. In addition, reliable prevention of delayed perforation is required for 3 days after duodenal ER to prevent the need for surgical interventions.

Characteristics of synchronous and metachronous duodenal tumors and association with colorectal cancer: a supplementary analysis.

BACKGROUND: We previously reported outcomes of endoscopic resection for duodenal tumors in a large cohort. This study investigated the frequency and characteristics of synchronous and metachronous lesions, and their association with colorectal advanced adenoma (CAA) and colorectal cancer (CRC). METHODS: Patients underwent duodenal endoscopic resection during January 2008 to December 2018. Background and characteristics, incidence of synchronous and metachronous lesions, and incidence of CAA and CRC were investigated. Patients without synchronous lesions were classified as the single group, and those with synchronous lesions as the synchronous group. Patients were also classified as the metachronous and non-metachronous groups. The characteristics among the groups were compared. RESULTS: We included 2658 patients with 2881 duodenal tumors: 2472 (93.0%) patients had single, 186 (7.0%) had synchronous, and 54 (2.0%) had metachronous lesions. The 5-year cumulative incidence of metachronous lesions was 4.1%. In total, 208 (7.8%) had CAA and 127 (4.8%) patients had CRC, and colonoscopy was performed in 936 (35.2%) patients. The incidence of CAA in the synchronous groups tended to be higher compared with that in the single groups (11.8% vs 7.5%, adjusted risk ratio 1.56), and the incidence of CRC in the metachronous groups tended to be higher compared with that in the non-metachronous groups (13.0% vs 4.6%, adjusted risk ratio 2.75), but there was no difference after adjusting for colonoscopy. CONCLUSIONS: This study showed the incidence of synchronous and metachronous duodenal lesions. There was no significant difference in incidence of CAA and CRC among each group, but further studies are warranted.

Usefulness of Intestinal Ultrasound to Detect Small Intestinal Stenosis in Patients With Crohn's Disease.

OBJECTIVES: Double balloon enteroscopy (DBE) with retrograde contrast is useful as a monitoring tool for small intestinal lesions in Crohn's disease (CD), but these are burdensome for patients. Intestinal ultrasound (IUS) can be used with ease in daily clinical practice, but there is less evidence regarding the accuracy of detection of small intestinal stenosis in CD. This study aimed to examine the diagnostic power of IUS for small intestinal stenosis in patients with CD. METHODS: The findings of DBE and IUS in 86 patients with CD with small intestinal lesions were evaluated. Using DBE as the reference standard, we examined the detection rate of IUS for small intestinal stenosis. We evaluated three parameters: luminal narrowing, prestenotic dilation, and to-and-fro movement for determining stenosis using IUS. In addition, we compared the characteristics between the stenosis-detectable and stenosis-undetectable groups by IUS. RESULTS: Of the 86 patients, 30 had small intestinal stenosis. In IUS findings, when lesions that met two or more of the three parameters were judged as stenosis, the detection rate was 70.0% for sensitivity, 98.2% for specificity, and 88.4% for accuracy. Moreover, there were patients with a younger age at diagnosis (P < 0.05) and more ileocolonic disease location (P < 0.05) in the stenosis-detectable group by IUS. The stenoses detected by IUS were significantly longer than those undetected by IUS (14.1 mm versus 5.2 mm, P < 0.05). CONCLUSIONS: IUS delivered reliable results for clinically important small intestinal stenosis of CD with high diagnostic accuracy.

Erratum: Prospective multicenter study of the efficacy and safety of cold forceps polypectomy for ≤ 6-mm non-ampullary duodenal low-grade adenomas.

[This corrects the article DOI: 10.1055/a-1793-9439.].

Prospective multicenter study of the efficacy and safety of cold forceps polypectomy for ≤ 6-mm non-ampullary duodenal low-grade adenomas.

Background and study aims Because the endoscopic treatment for non-ampullary duodenal adenoma (NADA) has a non-negligible risk of adverse events (AEs), a safe and easy treatment for NADA is desirable. This was a multicenter prospective trial evaluating the efficacy and safety of cold forceps polypectomy (CFP) for diminutive NADAs. Patients and methods This study was prospectively conducted at six general hospitals and one university hospital. The inclusion criteria were histologic and endoscopic diagnosis of low-grade NADA measuring ≤ 6 mm. A second endoscopy was scheduled for 1 month after CFP. After confirmation of the success of CFP, 6-month and 12-month surveillance endoscopies were scheduled. The primary endpoint was the endoscopic and histologic disease disappearance rates at the 12-month endoscopy. Results Thirty-nine lesions from 38 patients were prospectively included. Median tumor size at enrollment was 5 mm (range 3-6 mm). There were four cases of remnant lesions at the second endoscopy, and the lesion disappearance rate of single CFP was 89.7 % (35 /39; 95 % confidence interval (CI), 76.9 %-97.9 %). In three cases, complete removal of the lesion was achieved with a single re-CFP, but one case required four repeat CFPs. The lesion disappearance rate at 12-month endoscopy was 97.4 % (38 /39; 95 %CI, 86.8 %-99.5 %). During the follow-up period, no AEs related to CFP were observed. Conclusions CFP for NADA ≤ 6 mm was safe and effective in this study. This common endoscopic method to remove lesions may be an option for treatment of diminutive NADAs.

Modified line-assisted complete closure of the defect after gastric endoscopic full-thickness resection: a pilot study in porcine models.

Background and study aims Closure after endoscopic full-thickness resection (EFTR) is challenging. We previously developed a simple endoscopic closure method: line-assisted complete closure (LACC). We performed a pilot study using porcine models to evaluate the feasibility of modified LACC after gastric EFTR. Patients and methods Six live pigs were included. EFTR (greater curvature of the gastric antrum [n = 3] and anterior wall of the gastric body [n = 3]) was performed under general anesthesia and the defect after EFTR was closed by modified LACC. The pigs were observed until postoperative day 4 (Day 4). The closure site was endoscopically evaluated and the presence or absence of peritonitis and fluid leakage was evaluated. The outcomes were the success rate of modified LACC on the day of the procedure, maintenance of defect closure, presence of peritonitis or leakage, and clinical course. Results Once complete closure was successfully achieved in all cases, maintenance of closure on Day 4 was not achieved. However, there was neither peritonitis nor fluid leakage. The defect was completely covered by surrounding tissues on Day 4 and the clinical course was good in all cases. Conclusions The feasibility of modified LACC after gastric EFTR was demonstrated in porcine models. Further improvement is needed to maintain defect closure.

Resection depth for small colorectal polyps comparing cold snare polypectomy, hot snare polypectomy and underwater endoscopic mucosal resection.

Background and study aims Small colorectal polyps are removed by various methods, including cold snare polypectomy (CSP), hot snare polypectomy (HSP), and underwater endoscopic mucosal resection (UEMR), but the indications for using these methods are unclear. We retrospectively assessed the efficacy of CSP, HSP, and UEMR for small polyps, focusing on the depth of the resected specimens. Patients and methods Outpatients with non-pedunculated small polyps (endoscopically diagnosed as 6 to 9 mm), resected by two endoscopists between July 2019 and September 2020, were enrolled. We histologically evaluated the specimens resected via CSP, HSP, and UEMR. The main outcome was the containment rate of the muscularis mucosa (MM) and submucosa (SM) tissues. Results Forty polyps resected via CSP (n = 14), HSP (n = 12), or UEMR (n = 14) were enrolled after excluding 13 polyps with resection depths that were difficult to determine. The rates of specimens containing MM and SM tissue differed significantly (57 % and 29 % for CSP, 92 % and 83 % for HSP, and 100 % and 100 % for UEMR, respectively ( P  = 0.005 for MM and P  < 0.001 for SM tissue). Multiple logistic regression analysis showed UEMR was an independent factor relating to the containment of SM tissue. The thickness of SM tissue by CSP, HSP, and UEMR were 52 µm, 623 µm, and 1119 µm, respectively ( P  < 0.001). The thickness by CSP was significantly less than those by HSP and UEMR ( P  < 0.001, Bonferroni correction). Conclusions UEMR could be the best method to contain SM tissue without injection. Further studies are needed to evaluate the indication of UEMR for small polyps.

Clinicopathological Characteristics of Superficial Barrett's Adenocarcinoma in a Japanese Population: A Retrospective, Multicenter Study.

Objective Although Barrett's adenocarcinoma (BA) remains a minor disease in Japan, its incidence has been gradually increasing. We analyzed the characteristics of BA in Japanese populations. Methods We retrospectively reviewed medical records and analyzed the clinicopathological differences between short-segment Barrett's esophagus (SSBE) and long-segment Barrett's esophagus (LSBE), as well as metastasis. Local recurrence and metachronous lesions were analyzed only in patients who underwent endoscopic resection (ER). Patients Consecutive patients who had pathological T1 BAs resected by ER or surgery from January 2003 to December 2017. Results A total of 168 patients were analyzed, including 139 with SSBE and 29 with LSBE. In total, 67% of the SSBE lesions and 32% of the LSBE lesions were located between 0 and 3 o'clock (p=0.0014). No patients who achieved pathological margin-free resection (pR0) and 17% of patients who did not achieve pR0 experienced local recurrence (p=0.0131). None of the patients without lymphovascular involvement, a poorly differentiated component, lesion size of >30 mm, and submucosal invasion of >500 µm experienced metastasis. The 5-year cumulative incidence rate of metachronous BA after ER was 0% in patients with SSBE and 40% in patients with LSBE (p=0.0005). Conclusion Superficial BA was likely to be detected at the right anterior wall of SSBE in the Japanese population. The risk for metachronous BA after ER was high in Japanese patients with LSBE, as in Western patients.

Fever and electrocoagulation syndrome after colorectal endoscopic submucosal dissection for patients with immunosuppressants and steroids.

Objectives: Transient fever and electrocoagulation syndrome after colorectal endoscopic submucosal dissection (ESD) remain a challenge. The aim of this study was to assess the risk factors of post-ESD fever and post-ESD coagulation syndrome (PECS), focusing on the involvement of immunosuppressive drugs and steroids (IM). Methods: This retrospective analysis included 510 patients who underwent colorectal ESD at Okayama University Hospital from 2015 to 2020. The incidence rate, clinical outcome, and factors associated with post-ESD fever and PECS were investigated. Results: Post-ESD fever and PECS occurred in 63 patients (12.4%) and 43 patients (8.4%), respectively. In multivariate analysis, the American Society of Anesthesiologists Physical Status ≥3, the use of immunosuppressants or prednisolone ≥5mg (IM group), and injury to muscle layer/perforation were significantly associated with post-ESD fever. In PECS, IM group, tumors located on the right side, treatment time ≥60 min, injury to the muscle layer, and multiple lesions were independent risk factors. Both post-ESD fever and PECS improved conservatively in the IM group, and no serious complication was observed. Conclusions: The use of IM was a risk factor for both post-ESD fever and PECS. However, there were no serious complications in colorectal ESD for patients taking IM.

The Colon Wall Thickness Measured Using Transabdominal Ultrasonography Is Useful for Detecting Mucosal Inflammation in Ulcerative Colitis.

Objective Transabdominal ultrasonography (TUS) is a non-invasive procedure that is reportedly useful for managing ulcerative colitis (UC) and assessing bowel wall thickness (BWT), the most common measure of mucosal inflammation. However, the exact range of BWT that reflects disease activity remains undetermined. The present study clarified the BWT due to disease activity by comparing the use of TUS in each segment of the colon versus using colonoscopy (CS) and determined the usefulness of TUS in patients with UC. Methods We divided the colon into five segments and measured the BWT using TUS. The results were then compared to the Mayo endoscopic subscore (MES) classification to determine the accuracy of BWT measurement. Patients Eighty patients with UC who underwent TUS within 14 days of CS were retrospectively registered. Results We evaluated a total of 268 images depicting each segment among 80 patients with UC. The BWT was positively correlated with endoscopic activity (0.69, p<0.0001). In each segment, the relationship between a BWT>2 mm and an MES>0 had the highest sensitivity, specificity, and accuracy (0.85-1.00, 0.67-0.92, and 0.81-0.97, respectively). Conclusion This study concluded that TUS was a useful method of detecting an MES>0, which indicates the presence of inflammation and its location among UC patients. MES>0 was found to be highly accurate when a BWT>2 mm was considered positive. This non-invasive method may help control disease activity in patients with UC.

Metformin ameliorates chronic colitis in a mouse model by regulating interferon-γ-producing lamina propria CD4+ T cells through AMPK activation.

Metformin, a commonly prescribed drug for type 2 diabetes mellitus, has been shown to activate AMP-activated protein kinase (AMPK). Notably, AMPK activation has recently been observed to be associated with anti-inflammatory responses. Metformin is also reported to elicit anti-inflammatory responses in CD4+ T cells, resulting in improvement in experimental chronic inflammatory diseases, such as systemic lupus erythematosus. To investigate the effect of metformin on inflammatory bowel disease (IBD), we developed a T cell-transfer model of chronic colitis in which SCID mice were injected with CD4+ CD45RBhigh T cells to induce colitis. We examined the effects of metformin via in vitro and in vivo experiments on lamina propria (LP) CD4+ T cells. We observed that metformin suppresses the frequency of interferon (IFN) -γ-producing LP CD4+ T cells in vitro, which were regulated by AMPK activation, a process possibly induced by the inhibition of oxidative phosphorylation. Furthermore, we examined the effects of metformin on an in vivo IBD model. Metformin-treated mice showed AMPK activation in LP CD4+ T cells and ameliorated colitis. Our study demonstrates that metformin-induced AMPK activation in mucosal CD4+ T cells contributes to the improvement of IBD by suppressing IFN-γ production. Moreover, our results indicate that AMPK may be a target molecule for the regulation of mucosal immunity and inflammation. Thus, AMPK-activating drugs such as metformin may be potential therapeutic agents for the treatment of IBD.

Optimization of insufflation and pressure control in third-space endoscopy.

BACKGROUND: Third-space endoscopy requires a delicate and accurate insufflation technique to secure the endoscopic visualization and maintain the working space. However, optimal third-space insufflation parameters have yet to be determined. The aim of this study was to assess: (1) the diversity of endoluminal third-space pressure by manual insufflation, and (2) the performance of the insufflation settings for third-space endoscopy. METHODS: A submucosal tunnel was created in the upper posterior wall of the porcine stomach. Using two-channel esophagogastroduodenoscopy, one channel was used for insufflation and the other was used for pressure measurement. Experiment 1 Endoluminal submucosal tunnel pressure was measured in a 10-cm submucosal tunnel of a single porcine. Six board-certified endoscopists in turn maintained what they considered sufficient exposure under manual insufflation. Experiment 2 Endoluminal submucosal tunnel pressure and number of insufflations were measured using the pressure-regulated insufflation device; the differences in the submucosal tunnel length (long: 10-cm, short: 4-cm) and the insufflation route diameter (large: 3.8-mm, small: 2.2-mm) were compared. RESULTS: Experiment 1 The endoluminal submucosal tunnel pressure profiles during third-space endoscopy varied between endoscopists. Experiment 2 Longer submucosal tunnels and larger insufflation route diameters lead to stable endoluminal submucosal tunnel pressure. The gap with the preset pressure of the insufflator and endoluminal pressure narrowed, and the required number of insufflations decreased with longer tunnel length and larger route diameter. CONCLUSIONS: The pressure dynamics in third-space endoscopy differed among endoscopists. Longer submucosal tunnels and larger insufflation route diameters lead to stable endoluminal submucosal tunnel pressure.