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.

Efficacy of prophylactic clip closure in reducing the risk of delayed bleeding after colorectal endoscopic submucosal dissection in patients on anticoagulant therapy: Multicenter prospective study.

OBJECTIVES: The high rate of delayed bleeding after colorectal endoscopic submucosal dissection (ESD) in patients undergoing anticoagulant therapy remains a problem. Whether prophylactic clip closure reduces the rate of delayed bleeding in these patients is unclear. This study aimed to evaluate the efficacy of prophylactic clip closure in patients receiving anticoagulants. METHODS: This multicenter prospective interventional trial was conducted at nine referral centers in Japan. Patients regularly taking anticoagulants, including warfarin potassium or direct oral anticoagulants, and undergoing ESD for colorectal neoplasms were enrolled. The discontinuation of anticoagulants was minimized according to recent guidelines. After the ESD, post-ESD ulcers were prophylactically closed using endoclips. The primary end-point was the incidence of delayed bleeding. The sample size was 45 lesions, and prophylactic clip closure was considered effective when the upper limit of the 90% confidence interval (CI) for delayed bleeding did not exceed 20%. RESULTS: Forty-five lesions were used, and three were excluded. Complete closure was achieved in 41/42 lesions (97.6%). The overall delayed bleeding rate was low, at 4.9% (2/41; 90% [CI] 0.8-14.5), which was significantly lower than that at the prespecified threshold of 20% (P = 0.007). The median closure procedure time was 17 min, and the median number of clips was nine. No massive delayed bleeding requiring transfusion, interventional radiology, or surgery was observed, and no thromboembolic events were observed. CONCLUSION: Prophylactic clip closure may reduce the risk of delayed bleeding following colorectal ESD in patients receiving anticoagulants. TRIAL REGISTRATION: UMIN Clinical Trial Registry (UMIN000036734).

Utility and advantage of the unroofing technique for gastrointestinal subepithelial tumors: A multicenter retrospective cohort study.

Background and aim: Various techniques for direct biopsy from gastrointestinal subepithelial tumors (SETs) have been reported, although no standard method has been established. A common feature of these techniques is the removal of overlaying mucosa to enable direct biopsies from the SETs. These methods have been synthesized under the collective term "unroofing technique". We conducted a multicenter retrospective study to assess its efficacy and identify potential complications. Methods: This study was conducted in 10 hospitals and involved all eligible patients who underwent unroofing techniques to obtain biopsies for gastrointestinal SETs between April 2015 and March 2021. The primary endpoint was the diagnostic accuracy of the unroofing technique, and the secondary endpoints were the incidence of adverse events and the factors contributing to the accurate diagnosis. Results: The study included 61 patients with 61 gastrointestinal SETs. The median tumor size was 20 mm, and the median procedure time was 38 min, with 82% successful tumor exposure. The rate of pathological diagnosis was 72.1%. In 44 patients with a pathological diagnosis, two showed discrepancies with the postresection pathological diagnosis. No factors, including facility experience, organ, tumor size, or tumor exposure, significantly affected the diagnostic accuracy. There was one case of delayed bleeding and two cases of perforation. Conclusion: The diagnostic yield of the unroofing technique was acceptable. The unroofing technique was beneficial regardless of institutional experience, organ, tumor size, or actual tumor exposure.

A simpler diagnostic algorithm of the Japan Esophageal Society classification for Barrett's esophagus-related superficial neoplasia.

BACKGROUND: We previously developed a Japan Esophageal Society Barrett's Esophagus (JES-BE) magnifying endoscopic classification for superficial BE-related neoplasms (BERN) and validated it in a nationwide multicenter study that followed a diagnostic flow chart based on mucosal and vascular patterns (MP, VP) with nine diagnostic criteria. Our present post hoc analysis aims to further simplify the diagnostic criteria for superficial BERN. METHODS: We used data from our previous study, including 10 reviewers' assessments for 156 images of high-magnifying narrow-band imaging (HM-NBI) (67 dysplastic and 89 non-dysplastic histology). We statistically analyzed the diagnostic performance of each diagnostic criterion of MP (form, size, arrangement, density, and white zone), VP (form, caliber change, location, and greenish thick vessels [GTV]), and all their combinations to achieve a simpler diagnostic algorithm to detect superficial BERN. RESULTS: Diagnostic accuracy values based on the MP of each single criterion or combined criteria showed a marked trend of being higher than those based on VP. In reviewers' assessments of visible MPs, the combination of irregularity for form, size, or white zone had the highest diagnostic performance, with a sensitivity of 87% and a specificity of 91% for dysplastic histology; in the assessments of invisible MPs, GTV had the highest diagnostic performance among the VP of each single criterion and all combinations of two or more criteria (sensitivity, 93%; specificity, 92%). CONCLUSION: The present post hoc analysis suggests the feasibility of further simplifying the diagnostic algorithm of the JES-BE classification. Further studies in a practical setting are required to validate these results.

Predictors of technical difficulty for trainees in esophageal endoscopic submucosal dissection.

BACKGROUND: Esophageal endoscopic submucosal dissection (ESD) is technically challenging, especially for trainees, and requires a safe training system. This study aimed to identify predictors of technical difficulty facing trainees performing esophageal ESD to establish such system. METHODS: This was a single-center retrospective study of patients with esophageal cancer who underwent ESD performed by trainees between January 2010 and August 2022. Technical difficulties were defined as muscularis propria exposure and long procedure time (≥ 90 min). Factors associated with these technical difficulties were investigated. RESULTS: A total of 798 lesions in 721 patients were evaluated. Muscularis propria exposure occurred in 298 lesions (37.3%), including 10 perforations (1.3%). The procedure time was ≥ 90 min in 134 lesions (16.8%). In the multivariate analysis, tumor size ≥ 20 mm, tumors ≥ 1/2 of the circumference, and those close to previous treatment scars significantly increased the incidence of both difficulties, whereas tumors in the upper esophagus significantly decreased this incidence. Furthermore, female sex and tumors in the left wall were independent predictors of muscularis propria exposure, and elevated morphology was an independent predictor of long procedure time. Muscularis propria exposure and long procedure time occurred in more than half of the cases with three or more predictors of each difficulty. CONCLUSIONS: Large tumors and tumors close to previous treatment scars increase technical difficulties for trainees in esophageal ESD. Conversely, tumors in the upper esophagus reduce these difficulties. These results enable us to predict the difficulty level preoperatively and select appropriate cases in stepwise training.

Non-Pure Intestinal Phenotype as an Indicator of Progression in Sporadic Nonampullary Duodenal Adenomas: A Multicenter Retrospective Cohort Study.

INTRODUCTION: We aimed to evaluate the natural course of sporadic nonampullary duodenal adenomas (SNDAs) and determine the risk factors of progression. METHODS: We retrospectively analyzed the follow-up outcomes of patients with biopsy-diagnosed SNDA between April 2010 and March 2016 at 13 institutions. All initial biopsy specimens were centrally evaluated. Only those diagnosed with adenomas were included. Mucinous phenotypes were classified into pure intestinal and non-pure intestinal phenotypes. Cumulative incidence rates of carcinoma and tumor enlargement were evaluated. Tumor enlargement was defined as a ≥25% or 5-mm increase in tumor size. RESULTS: Overall, 121 lesions were analyzed. Within a median observation period of 32.7 months, 5 lesions were diagnosed as carcinomas; the cumulative 5-year incidence of carcinoma was 9.5%. Male sex ( P = 0.046), initial lesion size ≥10 mm ( P = 0.044), and non-pure intestinal phenotype ( P = 0.019) were significantly associated with progression to carcinoma. Tumor enlargement was observed in 22 lesions, with a cumulative 5-year incidence of 33.9%. Initial lesion size ≥10 mm ( P < 0.001), erythematous lesion ( P = 0.002), high-grade adenoma ( P = 0.002), Ki67 negative ( P = 0.007), and non-pure intestinal phenotype ( P = 0.001) were risk factors of tumor enlargement. In a multivariate analysis, an initial lesion size ≥10 mm ( P = 0.010) and non-pure intestinal phenotype ( P = 0.046) were independent and significant risk factors of tumor enlargement. DISCUSSION: Lesion size ≥10 mm and non-pure intestinal phenotype on initial biopsy are risk factors of cancer progression and tumor enlargement in cases with SNDA. Thus, management effectiveness may be improved by focusing on lesion size and the mucinous phenotype.

Potential role of a novel endoscopic retrieval bag for large colorectal resected specimen: a proof-of-concept study.

Endoscopic submucosal dissection enables en bloc resection of large superficial colorectal neoplasms. However, it is sometimes challenging to retrieve a large resected specimen via the anus without sample fragmentation. A novel "bag-type" retrieval device has been developed to accomplish complete isolation and non-destructive delivery of oversized specimens. This single-center retrospective study was performed to demonstrate the efficacy of this device for large colorectal resected specimens. Among 17 patients, we identified 18 superficial colorectal lesions for which the use of a novel retrieval device (Endo Carry Large Type) was indicated at specimen delivery at a referral cancer institute from March 2021 to July 2022. The median (interquartile range) tumor size was 62.5 (52.0-79.5) mm. Retrieval of 17 (94%) of 18 resected specimens was performed using the Endo Carry Large Type, and 16 (89%) were successfully retrieved without sample fragmentation. The median (interquartile range) retrieval time was 4 (4-8) minutes, and no apparent adverse events were observed. The novel Endo Carry Large Type device can accomplish colorectal specimen retrieval safely and quickly without specimen damage and therefore may contribute to accurate pathological diagnosis.

Endoscopic features of gastric neuroendocrine carcinoma.

BACKGROUND AND AIM: The endoscopic features of gastric neuroendocrine carcinoma (G-NEC) have not been clarified; therefore, they were investigated in relation to clinicopathological findings. METHODS: Consecutive patients with G-NECs who had undergone endoscopic or surgical resection at our institution between January 2005 and March 2022 were included in this retrospective study. The endoscopic and clinicopathological findings of the lesions were analyzed to provide information of diagnostic value. In addition, cases of gastric neuroendocrine tumor (G-NET) and common-type gastric adenocarcinoma treated in the same study period were identified to compare the endoscopic findings between each G-NEC versus G-NET, and G-NEC versus common-type gastric adenocarcinoma. Patients with common-type gastric adenocarcinoma were matched for age, sex, tumor size, and depth of tumor invasion in 1:3 ratio. RESULTS: Among 15 patients with 15 G-NECs, submucosal tumor-like marginal elevation (87%), adherent white coat (67%), and ulceration with a distinct border (60%) were characteristic endoscopic findings in white-light images. Magnifying narrow-band imaging endoscopy revealed an absent microsurface (MS) pattern plus disrupted irregular microvessel (MV) in five (71%) of seven cases with evaluable MS and MV patterns. The area with an absent MS pattern plus disrupted irregular MV corresponded to the histological finding of NEC component in all five cases. These endoscopic features were all significantly more frequent in G-NECs than G-NETs (n = 22) or common-type gastric adenocarcinomas (n = 45). CONCLUSIONS: These endoscopic features should be taken into consideration to increase the index of suspicion and to improve the accuracy of target biopsies for G-NEC.

Multiple foci of dilated vessels as a new predictor of metachronous esophageal cancer.

OBJECTIVES: Prediction of the risk of esophageal squamous cell carcinoma (SCC) by endoscopic findings without iodine staining, which is irritating to the esophagus, would be beneficial. In a previous retrospective study, we found that multiple foci of dilated vascular areas (MDV) of the esophageal mucosa, seen in narrow-band imaging (NBI)/blue laser imaging (BLI), are associated with iodine-unstained lesions and, thus, may be a predictor of esophageal SCC. This prospective study aimed to investigate the association between MDV and metachronous esophageal SCC. METHODS: Patients with a history of endoscopic resection for esophageal SCC were included in the study. First, evaluation of the MDV using NBI or BLI was conducted during the initial endoscopy. The patients were then monitored for metachronous esophageal SCC by endoscopic surveillance. The association between the number of MDV and incidence of metachronous esophageal SCC was investigated. RESULTS: From February 2018 to May 2019, 206 patients were enrolled and 201 patients were included in the analysis. Patients were followed up until October 2022. The median (interquartile range) endoscopic follow-up period was 1260 (1105-1348) days. The incidence of metachronous esophageal SCC at 2 years was 7.1% in patients with MDV ≤4 and 13.9% in patients with MDV ≥5 (P < 0.01). In the multivariate analysis, MDV was an independent predictor of metachronous esophageal SCC, with an odds ratio (95% confidence interval) of 2.37 (1.06-5.31). CONCLUSION: Multiple foci of dilated vascular area is a useful predictor for stratifying the risk of metachronous esophageal SCC.

Endoscopic resection for local residual or recurrent cancer after definitive chemoradiotherapy or radiotherapy for esophageal squamous cell carcinoma.

Chemoradiotherapy (CRT) and radiotherapy (RT) are treatment options for esophageal squamous cell carcinoma (ESCC), but local residual/recurrent cancer after CRT/RT is a major problem. Endoscopic resection (ER) is an effective treatment option for local residual/recurrent cancer. To ensure the efficacy of ER, complete removal of endoscopically visible lesions with cancer-free vertical margins is desired. This study aimed to identify the endoscopic parameters associated with the complete endoscopic removal of local residual/recurrent cancer. In this single-center, retrospective study, we used a prospectively maintained database to identify esophageal lesions that were diagnosed as local residual/recurrent cancer after CRT/RT and treated by ER between January 2012 and December 2019. We evaluated the associations of endoscopic R0 resection with findings on conventional endoscopy and endoscopic ultrasonography (EUS). In total, 98 lesions (83 cases) were identified from our database. The rate of endoscopic R0 resection was higher for flat lesions (100% versus 77%, P = 0.00014). EUS was performed for 24 non-flat lesions, and endoscopic R0 resection was achieved for 94% of lesions with an uninterrupted fifth layer. Flat lesions on conventional endoscopy and lesions with an uninterrupted fifth layer on EUS are good candidates for ER.

Feasibility of underwater endoscopic mucosal resection for endoscopic management of gastric neoplasms in patients with familial adenomatous polyposis.

BACKGROUND: Underwater endoscopic mucosal resection (UEMR) has been developed as an effective endoscopic intervention for colon, rectum, and duodenum neoplasms. However, there are no comprehensive reports regarding the stomach, and its safety and efficacy are unknown. We aimed to examine the feasibility of UEMR for gastric neoplasms in patients with familial adenomatous polyposis (FAP). METHODS: We retrospectively extracted data of patients with FAP who underwent endoscopic resection (ER) for gastric neoplasms at Osaka International Cancer Institute from February 2009 to December 2018. Elevated gastric neoplasms of ≤ 20 mm in diameter were extracted, and conventional endoscopic mucosal resection (CEMR) and UEMR were compared. Furthermore, outcomes after ER until March 2020 were examined. RESULTS: 91 endoscopically resected gastric neoplasms were extracted from 31 patients with 26 pedigrees, and 12 neoplasms underwent CEMR and 25 neoplasms underwent UEMR was compared. The procedure time was shorter for UEMR than for CEMR. There was no significant difference between en bloc resection and R0 resection rates by EMR methods. CEMR and UEMR showed postoperative hemorrhage rates of 8% and 0%, respectively. Residual/local recurrent neoplasms were identified in four lesions (4%), but additional endoscopic intervention (three UEMR and one cauterization) resulted in a local cure. CONCLUSION: UEMR was feasible in gastric neoplasms of FAP patients, especially in elevated lesions and those of ≤ 20 mm in diameter.

A single-center prospective study evaluating the usefulness of artificial intelligence for the diagnosis of esophageal squamous cell carcinoma in a real-time setting.

BACKGROUND: Several pre-clinical studies have reported the usefulness of artificial intelligence (AI) systems in the diagnosis of esophageal squamous cell carcinoma (ESCC). We conducted this study to evaluate the usefulness of an AI system for real-time diagnosis of ESCC in a clinical setting. METHODS: This study followed a single-center prospective single-arm non-inferiority design. Patients at high risk for ESCC were recruited and real-time diagnosis by the AI system was compared with that of endoscopists for lesions suspected to be ESCC. The primary outcomes were the diagnostic accuracy of the AI system and endoscopists. The secondary outcomes were sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and adverse events. RESULTS: A total of 237 lesions were evaluated. The accuracy, sensitivity, and specificity of the AI system were 80.6%, 68.2%, and 83.4%, respectively. The accuracy, sensitivity, and specificity of endoscopists were 85.7%, 61.4%, and 91.2%, respectively. The difference between the accuracy of the AI system and that of the endoscopists was - 5.1%, and the lower limit of the 90% confidence interval was less than the non-inferiority margin. CONCLUSIONS: The non-inferiority of the AI system in comparison with endoscopists in the real-time diagnosis of ESCC in a clinical setting was not proven. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs052200015, 18/05/2020).

Predictors of stricture after non-circumferential endoscopic submucosal dissection of the esophagus and single-dose triamcinolone injection immediately after the procedure.

BACKGROUND AND AIMS: Local triamcinolone (TA) injection is widely used to prevent stricture formation after endoscopic submucosal dissection (ESD). However, stricture develops in up to 45% of patients despite this prophylactic measure. We therefore conducted a single-center prospective study to identify predictors of stricture after esophageal ESD and local TA injection. METHODS: Patients who underwent esophageal ESD and local TA injection and who were comprehensively assessed for lesion- and ESD-related factors were included in the study. Multivariate analyses were conducted to identify the predictors of stricture. RESULTS: A total of 203 patients were included in the analysis. Multivariate analysis identified residual mucosal width ≤5 mm (odds ratio [OR], 29.0; P < .0001) or 6 to 10 mm (OR, 3.7; P = .04), history of chemoradiotherapy (OR, 5.1; P = .045), and tumor in the cervical or upper thoracic esophagus (OR, 3.8; P = .018) as independent predictors of stricture. Based on the ORs of the predictors, patients were stratified into 2 groups according to stricture risk: patients in the high-risk group (residual mucosal width ≤5 mm or 6-10 mm with another predictor) had a stricture rate of 52.5% (31 of 59 cases), and patients in the low-risk group (residual mucosal width ≥11 mm or 6-10 mm without other predictors) had a stricture rate of 6.3% (9 of 144 cases). CONCLUSIONS: We identified predictors of stricture after ESD and local TA injection. Local TA injection prevented stricture formation after ESD in low-risk patients but was not sufficient to prevent stricture in high-risk patients. Additional interventions should thus be considered in high-risk patients. (University Hospital Medical Network Clinical Trials Registry number: UMIN 000028894.).