Randomized controlled trial of remimazolam compared with placebo in Japanese patients undergoing upper gastrointestinal endoscopy: Phase III investigator-initiated clinical trial.

OBJECTIVES: To assess the effectiveness of remimazolam against normal saline (placebo) as a sedative agent for endoscopy in a multicenter, randomized, double-blind, investigator-initiated phase III controlled trial. METHODS: We included 48 Japanese patients undergoing upper gastrointestinal endoscopy. For the procedure, an initial remimazolam dose of 3 mg and additional doses of 1 mg were administered, as determined in the phase II clinical study. The primary study end-point was the successful sedation rate during gastrointestinal endoscopy, determined as a Modified Observer's Assessment of Alertness/Sedation score ≤4 before the start of endoscopy, the completion of gastrointestinal endoscopy, and two or fewer additional doses per 6 min. RESULTS: The successful endoscopy sedation rates were 91.9% and 9.1% in the remimazolam and placebo groups, respectively (P < 0.01). The time from the end of endoscopy to arousal was 0.0 (0.0-0.0) min for both groups. The number of additional doses required to achieve sedation was lower in the remimazolam group than that in the placebo group (P < 0.01). CONCLUSIONS: Remimazolam demonstrated a significantly higher sedation effect during upper gastrointestinal endoscopy in Japanese patients with safe and fast recovery compared with placebo.

A single-center prospective study on pain alleviation during peroral upper endoscopy with an ultrathin endoscope.

BACKGROUND: The efficacy of transnasal endoscopy using an ultrathin endoscope has been reported in several studies. However, few studies regarding peroral endoscopy with ultrathin endoscopes with high resolution have been reported. This study investigates the pain alleviation of peroral endoscopy with an ultrathin endoscope. METHODS: Patients with a history of peroral endoscopy using a conventional, normal-diameter scope with no sedation who underwent peroral esophagogastroduodenoscopy (EGD) using a thin scope between April-July 2022 were included in this study. After the procedure, the patients completed a questionnaire evaluating pain during the examination and willingness to repeat the procedure. The physicians were surveyed regarding their level of satisfaction. The primary endpoint was patient satisfaction, which corresponded to the rate of patients who rated the thin endoscope as more comfortable or somewhat more comfortable than the previously-used, conventional endoscope. RESULTS: One hundred and forty-five patients were included in the analyses. Patient satisfaction was achieved in 86.2% (125/145) of patients. The median visual analog scale pain score was 3 (0-7) points in this study, which is significantly lower than the pain score after the previous endoscopy (5 (0-10) points; p < 0.001). In addition, 96% (24/25) of patients who underwent EGD by an expert and 95.8% (115/120) who underwent EGD by a non-expert were willing to repeat endoscopy using the thin scope (p = 0.69). CONCLUSION: Peroral endoscopy using a thin scope reduces patient pain regardless of the endoscopist's experience.

Management of colorectal high-grade dysplasia or cancer resected by cold snare polypectomy: a multicenter exploratory study.

BACKGROUND: The clinical course and surveillance strategy for patients who undergo cold snare polypectomy (CSP) for high-grade dysplasia (HGD) or cancer is unclear. We investigated the management of colorectal HGDs and cancers following CSP. METHODS: This Japanese nationwide multicenter exploratory study was retrospectively conducted on patients who had undergone CSP for colorectal HGDs or cancers and follow-up colonoscopy at least once from 2014 to 2020. We investigated the detection rate of CSP scars, local recurrence rate (LRR), risk factors for local recurrence, and follow-up strategy. This study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000043670). RESULTS: We included 155 patients with 156 lesions. CSP scars were identified in 22 (31.4%), 41 (54.7%), and 10 (90.9%) patients with curative, borderline, and non-curative resection, respectively. Among them, residual tumors were observed in one (4.5%), six (14.6%), and three (30.0%) cases, respectively. The total LRR was 13.7% (95% confidence interval: 6.8-23.8). R1 resection cases (either horizontal or vertical margins positive for tumors) were associated with local recurrence (p = 0.031). Salvage endoscopic and surgical resections were performed on 21 and 10 patients, respectively. Among them, the proportion of endoscopically suspected residual tumors was significantly higher (p < 0.001) in the residual tumor-positive group (100%) than in the residual tumor-negative group (28.6%). CONCLUSIONS: LRR after CSP for HGDs or cancers was 13.7% based on scar-identified cases. Salvage endoscopic or surgical resection should be performed according to the curability of the lesion and endoscopic findings during colonoscopic surveillance.

Randomized controlled trial comparing conventional and traction endoscopic submucosal dissection for early colon tumor (CONNECT-C trial).

OBJECTIVES: Endoscopic submucosal dissection (ESD) is a widely used treatment for early gastrointestinal cancer. However, colon ESD remains challenging. Previous studies on colon ESD using the traction method used a small sample, single-center design, providing insufficient evidence of this procedure's efficacy. We thus aimed to investigate the efficacy and safety of the traction method in colon ESD in this multicenter randomized trial. METHODS: We conducted a prospective, multicenter, randomized, two-arm controlled trial at 10 facilities in Japan. A 1:1 allocation was conducted for the conventional ESD (C-ESD) and traction ESD (T-ESD) groups. The primary end-point was ESD procedure time. RESULTS: We included 128 C-ESD and 123 T-ESD cases from April 2020 to August 2021. The median procedure times for C-ESD and T-ESD were 61 (40-100) and 53 (40-76) min (P = 0.18), respectively, and no significant differences were observed between the groups. Subgroup analysis showed that the median procedure times for patients with a lesion diameter of ≥30 mm in the C-ESD and T-ESD groups were 89 (57-80) and 69 (50-104) min (P = 0.05), respectively, and for nonexpert operators were 81 (62-120) and 64 (52-109) min (P = 0.07), respectively. CONCLUSIONS: The traction method did not contribute to a significantly shortened ESD procedure time. However, this method may be useful when the tumor diameter is large or if the procedure is conducted by nonexpert endoscopists.

First dose-ranging study of remimazolam in Japanese patients undergoing gastrointestinal endoscopy: Phase II investigator-initiated clinical trial.

OBJECTIVES: Remimazolam, an ultra-short-acting benzodiazepine, has been used for procedural sedation in the United States. We conducted an investigator-initiated clinical trial to determine the appropriate dose of remimazolam required for sedation during gastrointestinal endoscopy in Japanese subjects. METHODS: In this single-center, open-label, uncontrolled, phase II trial, a three-stage cohort investigated the appropriate initial and additional doses of remimazolam required for gastrointestinal endoscopy. This study was designed with advice from the Pharmaceuticals and Medical Devices Agency. The initial and additional doses were 2 mg and 1 mg/dose, 3 mg and 1 mg/dose, and 5 mg and 2 mg/dose in cohorts 1, 2, and 3, respectively. Each cohort included 10 cases of upper gastrointestinal endoscopy and colonoscopy. The primary end-point was the success rate of sedation during gastrointestinal endoscopy. RESULTS: Sedation was successful in all gastrointestinal endoscopies in cohorts 1 and 2. In cohort 1, sedation was achieved in five (25.0%) and 10 (50.0%) participants with the initial dose and total dose (initial dose + additional dose ≤ the initial dose of the next cohort), respectively, before endoscopy. In cohort 2, sedation was achieved in 11 (55.0%) and 18 (90.0%) participants with the initial dose and total dose, respectively, before endoscopy. No patient in either cohort lost consciousness or required flumazenil or manual ventilation. CONCLUSION: Initial and additional doses of 3 mg and 1 mg/dose of remimazolam, respectively, were shown to be effective and safe for sedation during gastrointestinal endoscopy in Japanese patients.

Self-completion method of endoscopic submucosal dissection using the Endosaber for treating colorectal neoplasms (with video).

Endoscopic submucosal dissection (ESD) is effective for the treatment of colorectal neoplasms. We have developed a self-completion ESD (S-ESD) using Endosaber without requiring additional instruments or assistance. This prospective cohort study was conducted to investigate the feasibility of S-ESD for colorectal neoplasms. Patients with colorectal neoplasms measuring 20-40 mm in size were enrolled. A single operator, without assistance, performed ESD using only the Endosaber. The primary outcome was the success rate of S-ESD. Secondary outcomes included procedure time, the rates of en bloc, complete, and curative resection, and complication rates, including the incidence of perforation and delayed bleeding. In total, 15 patients with 15 lesions were enrolled. The median size of the resected lesions was 28 mm (interquartile range 25-29 mm). S-ESD success rate of 100% was achieved. The median procedure time was 44 min (29.5-53.5 min). We observed en bloc, complete, and curative resection rates of 100%, 93.3%, and 86.7%, respectively, and a complication rate of 6.7% (perforation: 0%, delayed bleeding: 6.7%). S-ESD for colorectal neoplasms was successfully performed with favorable treatment outcomes and low complication rates. S-ESD reduces the number of devices and extent of assistance, making S-ESD a simple and cost-effective procedure.

Efficacy and timing of gastrografin administration after ileus tube insertion in patients with adhesive small bowel obstruction.

BACKGROUND AND STUDY AIMS: Gastrografin administration (GA) is performed for adhesive small bowel obstruction (ASBO) in cases when decompression therapy using an ileus tube fails to relieve the obstruction. This study evaluated the efficacy of GA and optimized its timing after ileus tube insertion. PATIENTS AND METHODS: In this retrospective study, we evaluated data from patients with ASBO admitted between January 2014 and August 2018 and included patients who underwent ileus tube intubation and GA. The patients were classified as those treated with GA within 48 h after admission (early GA [EGA]) and those treated later with GA (delayed GA [DGA]). Propensity score matching was performed to compensate for differences between the groups. Short-term outcomes were compared between the two groups. RESULTS: We included 67 and 80 patients in the EGA and DGA groups, respectively, and 55 pairs with similar background characteristics were matched. The rates of successful conservative management were 87.3% (48/55) in the EGA group, 96.4% (53/55) in the DGA group, and 91.8% (101/110) in the entire sample. The median period of ileus tube insertion in the DGA group was significantly lower than that in the EGA group, whereas other outcomes did not significantly differ between the groups. Aspiration pneumonia occurred in one patient in the EGA group. CONCLUSIONS: GA with an ileus tube achieved a high rate of successful conservative management. Follow-up using decompression with an ileus tube for at least 48 h after admission is recommended in patients with ASBO.

The Ideal Helicobacter pylori Treatment for the Present and the Future.

BACKGROUND: Helicobacter pylori eradication treatments are widely performed to improve gastric mucosal inflammation, promote ulcer healing, and reduce the incidence of gastric cancer. However, there are several issues associated with H. pylori eradication treatment. First, various treatment regimens are currently used worldwide, and the standard treatment varies with region and country. Second, the antimicrobial resistance of H. pylori is increasing due to indiscriminate antibiotic use. Finally, gut microbiota dysbiosis is potentially induced by H. pylori treatment. SUMMARY: Based on current international guidelines and a network meta-analysis comparing the effects of various treatment regimens, nonbismuth quadruple therapies for 10-14 days and vonoprazan-based triple therapy for 7 days are the currently recommended H. pylori treatment regimens. These regimens show good eradication rates of approximately 90%, even in areas where antimicrobial-resistant strains are highly prevalent. However, these regimens still have inherent drawbacks that may promote further increases in antimicrobial resistance and induce gut microbiota dysbiosis because of the empiric use of multiple antibiotics. Key Message: The ideal concept for the present and future H. pylori eradication treatment involves "a simple, cost-effective strategy that fosters compliance without having a negative impact on the gut microbiota or contributing to future antimicrobial resistance." One interesting possibility that may fulfill this concept is a dual therapy involving vonoprazan and amoxicillin. This is the simplest treatment regimen that provides acceptable eradication rates, improves safety and tolerability, and minimizes the potential for increasing antimicrobial resistance or causing gut microbiota dysbiosis.

Diagnostic Ability of High-definition Imaging Using Ultraslim Endoscopes in Early Gastric Cancer.

PURPOSE: It is unclear whether high-definition (HD) imaging improves visibility and diagnostic ability in early gastric cancer (EGC) compared with standard-definition (SD) imaging. We aimed to compare the diagnostic performance and visibility scores of HD and SD ultraslim endoscopes in EGC. MATERIALS AND METHODS: We used HD and SD ultraslim endoscopes to obtain 60 images with similar compositions of gastric environments. Of the 60 images, 30 showed EGC (15 images for each modality) and 30 showed no EGC (15 images for each modality). Seventeen endoscopists evaluated the presence and location of the lesions in each image. Diagnostic ability was compared between modalities. The color difference between a lesion and the surrounding mucosa (ΔE) was measured and compared between the modalities. RESULTS: The ability of HD to detect EGC was significantly higher than that of SD (accuracy: 80.8% vs. 71.6%, P=0.017; sensitivity: 94.9% vs. 76.5%, P<0.001; positive predictive value, 76.2% vs. 55.3%, P<0.001; and negative predictive value (NPV), 94.1% vs. 73.5%, P<0.001). The ability of HD to determine the horizontal extent of EGC was significantly higher than that of SD (accuracy: 71.0% vs. 57.8%, P=0.004; sensitivity: 75.3% vs. 49.0%, P<0.001; NPV, 72.9% vs. 55.9%, P<0.001; and area under the curve: 0.891 vs. 0.631, P=0.038). The mean ΔE was significantly higher for HD than for SD (10.3 vs. 5.9, P=0.011). CONCLUSIONS: The HD ultraslim endoscope showed a higher diagnostic performance in EGC than the SD endoscope because it provided good color contrast.

Efficacy of macrogol 4000 plus electrolytes in bowel preparation for colonoscopy in patients with chronic constipation.

BACKGROUND: Chronic constipation is a significant factor in poor bowel preparation for colonoscopy. Macrogol 4000 plus electrolytes (Movicol, EA Pharma, Tokyo, Japan), containing polyethylene glycol (PEG) and electrolytes, have been used recently to treat patients with constipation. However, prospective studies on the use of macrogol 4000 for bowel cleansing for colonoscopy are lacking. This study aimed to investigate the efficacy and safety of macrogol 4000 in addition to PEG administered in patients with chronic constipation. METHODS: This single-center, single-arm prospective study enrolled patients with chronic constipation who were scheduled to undergo colonoscopy. The primary endpoint was the proportion of good bowel preparation assessed using the Boston bowel preparation scale (BBPS) (6 or more points). The secondary endpoints were the time from when pPEG (MoviPrep, EA Pharma, Tokyo, Japan) was taken until colonoscopy could be started, amount of PEG taken, number of defecations, whether additional PEG doses were taken, and adverse events. Endoscopy-related endpoints included cecal intubation rate, insertion time, observation time, adenoma detection rate (ADR), and polyp detection rate (PDR). The tolerability of PEG and macrogol 4000 was assessed using a questionnaire. RESULTS: Forty patients were included in the analysis. The median BBPS was 7 (range 3-9) and ≥ 6 points in 37 cases (92.5%). The median time until colonoscopy can be started was 210 min (90-360 min), the median volume of PEG taken was 1500 mL (1000-2000 mL), and the median number of defecations was 7 (3-20). No adverse events were observed. Fourteen patients required an additional dose of PEG. Cecal intubation was achieved in all cases, the median insertion time was 6.0 min (range 2.3-22 min), and the median observation time was 8.8 min (range 4.0-16.0 min). The ADR and PDR were 60.0% and 75.0%, respectively. A proportion of patients rated the tolerability of macrogol 4000 and PEG as 95.0% and 50.0%, respectively. CONCLUSIONS: Intake of macrogol 4000 in addition to PEG is effective and safe for colonoscopy in patients with chronic constipation. Clinical trial registration statement This study was registered in the UMIN-CTR database (UMIN-ID000038315).

Long term impact of vonoprazan-based Helicobacter pylori treatment on gut microbiota and its relation to post-treatment body weight changes.

BACKGROUND: Vonoprazan-based Helicobacter pylori (H. pylori) treatment is highly effective in eradicating the target bacteria; however, its post-1-year impact on gut microbiota is unknown. This study evaluated the impact of vonoprazan-based H. pylori therapy on gut microbiota 1-year post-therapy and investigated the relationship between body weight changes and post-therapy gut microbiota perturbations. MATERIALS AND METHODS: Between March and May 2019, 43 patients with H. pylori infections received either vonoprazan/amoxicillin (VA) or vonoprazan/amoxicillin/clarithromycin (VAC) therapy. Fecal samples were collected prior to treatment and 1 year after treatment. The alpha and beta diversities and the bacterial taxa composition ratios were determined using polymerase chain reaction amplification of the V3-V4 region of the 16S ribosomal RNA gene. The correlation between body weight changes and relative abundances of genera post-therapy was also analyzed. RESULTS: Among the 43 patients, 18 received VA therapy and 21 received VAC therapy. One year after treatment, the alpha diversity was significantly higher in both the treatment groups (p < .001, using observed operational taxonomic units and Chao1 index), and beta diversity was significantly different in both the groups (p = .001, using unweighted UniFrac distance) compared with baseline findings. Significant positive correlations were found between body weight changes and the relative abundances of Coprococcus spp. (p = .037) and Odoribacter spp. (p = .022) post-therapy. CONCLUSION: Vonoprazan-based H. pylori therapies are associated with long-term impacts on gut microbiota, including effects on bacterial species richness, and potentially affect metabolism by altering the microbiota. TRIAL REGISTRATION NUMBER: UMIN000040025.

Lower impact of vonoprazan-amoxicillin dual therapy on gut microbiota for Helicobacter pylori eradication.

BACKGROUND AND AIM: Helicobacter pylori eradication can disrupt the gut microbiome. Here, we investigated the short-term impact of minimum antibiotic treatment-a 7-day vonoprazan and low-dose amoxicillin regimen (VA-dual therapy)-on gut microbiota and compared it with that of vonoprazan-based triple therapy (VAC-triple therapy). METHODS: Fifty-nine patients with H. pylori infection were recruited (UMIN000034140) from March to May 2019 and randomly assigned to the VAC-triple therapy or VA-dual therapy groups, according to the first-line H. pylori treatment received. Fecal samples were collected before treatment initiation and 1 and 8 weeks after eradication therapy completion. The composition ratios of the bacterial taxa and the alpha and beta diversities were evaluated in both groups via polymerase chain reaction amplification of the V3-V4 region of the 16S rRNA gene and sequencing using the MiSeq system. RESULTS: Nineteen patients were assigned to the VA-dual group and 24 to the VAC-triple group. Compared with baseline, the alpha diversity reduced significantly 1 and 8 weeks after VAC-triple therapy. However, for VA-dual therapy, the alpha diversities at 1 and 8 weeks after the treatment did not change significantly compared with those at baseline. Additionally, the beta diversity differed significantly between baseline and 1 and 8 weeks after VAC-triple therapy. VAC-triple therapy led to significant alteration in the relative abundance of Actinobacteria at the phylum level and Collinsella, Blautia, and Streptococcus at the genus level. CONCLUSIONS: Compared with VAC-triple therapy, VA-dual therapy induced minimal changes in the diversity and relative abundance of gut microbiota.

Efficacy and safety of grasping forceps-assisted endoscopic resection for gastric neoplasms: A multi-centre retrospective study.

BACKGROUND: Endoscopic submucosal dissection (ESD) is widely accepted for early gastric cancer (EGC) without lymph node metastasis, although ESD is challenging, even for small lesions, in the greater curvature (GC) of the upper (U) and middle (M) thirds of the stomach. Grasping forceps-assisted endoscopic resection (GF-ER) is a type of endoscopic mucosal resection that is performed via a double-channel endoscope. AIM: To investigate the safety and efficacy of GF-ER vs ESD in the GC of the stomach's U and M regions. METHODS: We retrospectively reviewed the medical records of 506 patients who underwent ER of 522 EGC lesions in the stomach's U and M regions in three institutions between January 2016 and May 2020. Nine lesions from eight patients who underwent GF-ER for EGC (the GF-ER group) were compared to 63 lesions from 63 patients who underwent ESD (the ESD group). We also performed a subgroup analysis of small lesions (≤ 10 mm) in 6 patients (7 lesions) from the GF-ER group and 20 patients (20 lesions) from the ESD group. RESULTS: There were no statistically significant differences between the GF-ER and ESD groups in the en bloc resection rates (100% vs 100%) and the R0 resection rates (100% vs 98.4%). The median procedure time in the GF-ER group was shorter than that in the ESD group (4.0 min vs 55.0 min, P < 0.01). There were no adverse events in the GF-ER group, although five perforations (8.0%) and 1 case of postoperative bleeding (1.6%) were observed in the ESD group. When we only considered lesions that were ≤ 10 mm, the median procedure time in the GF-ER group was still shorter than that in the ESD group (4.0 min vs 35.0 min, P < 0.01). There were no adverse events in the GF-ER group, although 1 case of perforation (1.6%) were observed in the ESD group. CONCLUSION: These findings suggest that GF-ER may be an effective therapeutic option for small lesions in the GC of the stomach's U and M regions.

Assistant skill in gastric endoscopic submucosal dissection using a clutch cutter.

BACKGROUND: A clutch cutter is a scissor-type knife used in endoscopic submucosal dissection (ESD) for gastrointestinal tract tumors. The assistant during the ESD using a clutch cutter (ESD-C) needs to rotate the device and grasp the target tissue appropriately; therefore, the assistant's skill may affect the technical outcomes of ESD-C. AIM: To determine how assistant skill level affected the technical outcomes of gastric ESD-C using an ex vivo porcine training model. METHODS: In this pilot study, mock lesions of 15-30 mm in diameter were created in the middle or lower third of the porcine stomach. A total of 32 ESD-C procedures were performed by 16 trainees. Each trainee operator performed two ESD-C procedures; one ESD-C was assisted by an expert (ESD-C-E), and the other was assisted by a non-expert (ESD-C-NE). The total procedure time of the ESD was set as the primary outcome, and en bloc resection rate, complete procedure rate, perforation rate, and each procedure time/speed for mucosal incision or submucosal dissection were set as the secondary outcomes. In addition, we investigated factors associated with the difficulty of ESD including incompletion of ESD procedure, a long procedure time (≥ 20 min) or intraoperative perforation. RESULTS: The median total procedure time of the ESD-C-E was significantly shorter than that of the ESD-C-NE (12.9 min vs 21.9 min, P = 0.001). The en bloc resection rate was 100% in both groups. Complete resection rates of the ESD-C-E and ESD-C-NE groups were 100% and 93.8%, respectively. No intraoperative perforation was observed in both groups. In the multivariate analysis, assistant skill was significantly associated with the difficulty of ESD, with the highest odds ratio of 16.5. CONCLUSION: Assistance by an expert is an important factor when trainees perform ESD-C procedures.

High Body Mass Index Is Correlated with the Success of Vonoprazan-Based Second-Line Therapy for Helicobacter Pylori Infection.

Eradication of Helicobacter pylori (Hp) is necessary for preventing peptic ulcers and stomach cancer. The potassium-competitive acid blocker vonoprazan is a gastric acid secretion inhibitor that improves the success rate of Hp eradication through its immediate and persistent inhibition of acid excretion. In Japan, first-line treatment involves a regimen in which vonoprazan is combined with amoxicillin and clarithromycin, while second-line treatment involves vonoprazan combined with amoxicillin and metronidazole. However, in contrast to the vonoprazan-based first-line therapy, no studies have investigated the factors influencing the success of vonoprazan-based second-line therapy. In this study, we therefore aimed to investigate factors related to the success of vonoprazan-based second-line therapy. We analyzed the association between the success of Hp eradication and patient factors including metronidazole/amoxicillin minimal inhibitory concentrations (MICs). MICs were measured using the Hp isolated from each patient. A receiver operating characteristic (ROC) analysis was conducted to examine continuous variables and eradication success. We reviewed the records of 33 patients (age: 34-79 years, male/female: 22/11, and body mass index (BMI): 16.1-28.8 kg/m2) who underwent vonoprazan-based second-line therapy after failure of first-line therapy at seven Japanese facilities between October 2018 and June 2019. The eradication success rate was 81.8% (27/33). ROC analysis revealed an area under the curve and BMI cutoff value of 0.796 and 23.8 kg/m2, respectively. The eradication success rate was higher in patients with high BMI than in those with low BMI (p = 0.007). Our findings indicate that higher BMI is correlated with the success of vonoprazan-based second-line therapy.