Linked color imaging improves colorectal lesion detection especially for low performance endoscopists: An international trial in Asia.

BACKGROUND AND AIM: Linked color imaging (LCI) is an image-enhanced endoscopy technique that accentuates the color difference between red and white, potentially improving the adenoma detection rate (ADR). However, it remains unclear whether LCI performance in detecting colorectal lesions differs based on endoscopists' experience levels. We aimed to evaluate the differences in LCI efficacy based on the experience levels of endoscopists by conducting an exploratory analysis. METHODS: In this post hoc analysis of an international randomized controlled trial comparing the detection of adenoma and other lesions using colonoscopy with LCI and high-definition white light imaging (WLI), we included patients from 11 institutions across four countries/regions: Japan, Thailand, Taiwan, and Singapore. We retrospectively reviewed differences in the lesion detection of LCI according to endoscopists' colonoscopy history or ADR. RESULTS: We included 1692 and 1138 patients who underwent colonoscopies performed by 54 experts (experience of ≥ 5000 colonoscopies) and by 43 non-experts (experience of < 5000 colonoscopies), respectively. Both expert and non-expert groups showed a significant improvement in ADR with LCI compared to WLI (expert, 61.7% vs 46.4%; P < 0.001; non-expert, 56.6% vs 46.4%; P < 0.001). LCI had no effect on sessile serrated lesion detection rate in non-experts (3.1% vs 2.5%; P = 0.518). LCI significantly improved detection rates in endoscopists with relatively low detection performance, defined as an ADR < 50%. CONCLUSIONS: This exploratory study analyzed data from a previous trial and revealed that LCI is useful for both experts and non-experts and is even more beneficial for endoscopists with relatively low detection performance using WLI.

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.

Daily Diet and Nutrition Risk Factors for Gastric Cancer Incidence in a Japanese Population.

Background/Aims: : Nutritional factors associated with gastric cancer (GC) are not completely understood. We aimed to determine the effect of nutrient intake on the incidence of GC. Methods: : This was a post hoc analysis of a prospective trial that evaluated modalities for GC screening in participants aged 30 to 74 years living in high-risk areas for GC in Japan between June 2011 and March 2013. The patients were followed up for GC incidence for 6 years. All participants completed a self-administered food frequency questionnaire (FFQ) upon enrollment before GC screening. Daily nutrient intake was calculated from the FFQ and dichotomized at each cutoff value using receiver operating characteristic analysis. Risk factors associated with GC incidence were investigated in terms of nutrient intake and participant characteristics using Cox proportional hazards regression analysis. Results: : Overall, 1,147 participants were included in this analysis. The median age was 62 years, and 50.7% of the participants were men. The median follow-up period was 2,184 days. GC was detected in 25 participants during the follow-up. Multivariate Cox proportional hazards regression analysis revealed that the intake of sodium (adjusted hazards ratio [aHR], 3.905; 95% confidence interval [CI], 1.520 to 10.035; p=0.005) and vitamin D (aHR, 2.747; 95% CI, 1.111 to 6.788, p=0.029) were positively associated with GC incidence, whereas the intake of soluble dietary fiber (aHR, 0.104; 95% CI, 0.012 to 0.905; p=0.040) was inversely associated with GC incidence. Conclusions: : Daily high intake of sodium and vitamin D and low soluble dietary fiber intake are associated with GC incidence.

Gastric cancer detection rates using GI endoscopy with serologic risk stratification: A randomized controlled trial.

BACKGROUND AND AIMS: Efforts have been made to develop an endoscopic screening system incorporating serologic gastric cancer (GC) risk stratification (ABC classification) alongside annual population-based GC screening using barium. We conducted a randomized controlled trial (RCT) to compare GC detection rates between the Ba-Endo group, which underwent annual barium tests for primary screening followed by detailed endoscopic examinations, and the ABC-Endo group, where endoscopy intervals were determined based on individual gastric cancer risk in the ABC classification. METHODS: In total, 1206 individuals from Yurihonjo and Nikaho City, Akita Prefecture, were randomized through the minimization method using sex and age as allocation factors. The intervention study was conducted for both groups over 5 years. The Ba-Endo group received annual barium tests, and the ABC-Endo group underwent EGD at different intervals: group A, EGD only at entry; group B, EGD once every 3 years; group C, EGD once every 2 years; and group D, EGD every year. RESULTS: There were 24 detected GC lesions, with a GC detection rate of 1.9%. GC detection rates in the Ba-Endo and ABC-Endo groups were 2.0% and 1.8%, respectively, with no significant differences between groups (P = 1.0). However, the rate of GC cured by endoscopic resection alone was 41.6% in the Ba-Endo group and was significantly higher at 90.9% in the ABC-Endo group (P = .02). CONCLUSIONS: There were no differences between the Ba-Endo and ABC-Endo groups in GC detection rates. However, the rate of detected GCs that could be cured by endoscopic resection alone was significantly higher in the ABC-Endo group. (Clinical trial registration number: UMIN000005962.).

Randomized controlled trial comparing the costs of gastric cancer screening systems between serological risk-based upper gastrointestinal endoscopy and the existing barium photofluorography: gastric cancer screening labeled by serum examination in place of aged gastric cancer organized screening systems (GALAPAGOS study).

BACKGROUND: Although the risk of gastric cancer can be stratified according to Helicobacter pylori (H. pylori) IgG antibody titer and pepsinogen levels (ABC classification), a population-based gastric cancer screening system combining serological tests and endoscopy has not been introduced. This study aimed to compare the total testing cost per participant between the ABC classification method and the existing protocol. METHODS: Using the minimization method with sex and age as allocation factors, 1206 participants were randomly assigned to the following two methods for a 5-year intervention: barium photofluorography as primary examination followed by detailed examination with upper gastrointestinal endoscopy (Ba-Endo) and risk-based upper gastrointestinal endoscopy by ABC classification (ABC-Endo). The primary endpoint was the total testing cost per participant over a 5-year period. The secondary endpoint was the expense required to detect one gastric cancer. RESULTS: The total testing cost per participant was 39,711 yen in Ba-Endo (604 participants) and 45,227 yen in ABC-Endo (602 participants), with the latter being significantly higher (p < 0.001). During the intervention period, gastric cancer was found in 11 and eight participants in Ba-Endo and ABC-Endo, respectively. The expenses required to detect one gastric cancer were 2,240,931 yen in Ba-Endo and 3,486,662 yen in ABC-Endo. CONCLUSIONS: The testing cost per participant turned out to be higher in the ABC-Endo group than in the Ba-Endo group. This superiority trial, based on the hypothesis that the cost of testing is lower for ABC-Endo than for Ba-Endo, was rejected.

Association of direct oral anticoagulant and delayed bleeding with pharmacokinetics after endoscopic submucosal dissection.

BACKGROUND AND AIMS: Pharmacokinetic parameters, such as drug plasma level at trough, time to maximum plasma concentration (Tmax), and coagulation factor Xa (FXa) activity generally predict factors for the anticoagulant effects of direct oral anticoagulants (DOACs). Although GI bleeding is a major adverse event after endoscopic submucosal dissection (ESD), little is known about the association between post-ESD bleeding in patients taking DOACs and the pharmacologic parameters. This study aimed to evaluate pharmacologic risk factors for post-ESD bleeding in patients taking DOACs. METHODS: We prospectively evaluated the incidence of post-ESD bleeding in patients taking DOACs between April 2018 and May 2022 at 21 Japanese institutions and investigated the association with post-ESD bleeding and pharmacologic factors, including plasma concentration and FXa activity at trough and Tmax. RESULTS: The incidence of post-ESD bleeding was 12.8% (14 of 109; 95% confidence interval [CI], 7.2-20.6). Although plasma DOAC concentration and plasma level/dose ratio at trough and Tmax varied widely among individuals, a significant correlation with plasma concentration and FXa activity was observed (apixaban: correlation coefficient, -0.893; P < .001). On multivariate analysis, risk factors for post-ESD bleeding in patients taking DOACs were higher age (odds ratio [OR], 1.192; 95% CI, 1.020-1.392; P = .027) and high anticoagulant ability analyzed by FXa activity at trough and Tmax (OR, 6.056; 95% CI, 1.094-33.529; P = .039). CONCLUSIONS: The incidence of post-ESD bleeding in patients taking DOACs was high, especially in older patients and with high anticoagulant effects of DOACs. Measurement of pharmacokinetic parameters of DOACs may be useful in identifying patients at higher risk of post-ESD bleeding.

Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression.

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152 IMs) across 692 subjects from a prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell and spatial profiles highlight changes in tissue ecology and IM lineage heterogeneity, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes of IM associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to transform to GC. By highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression, our results raise opportunities for GC precision prevention and interception.

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.

Treatment with vonoprazan for 3 weeks is not inferior to 8 weeks for the management of gastric ESD: a multicenter noninferiority randomized study.

BACKGROUND: Vonoprazan, a potassium-competitive acid blocker (VPZ), significantly reduces postoperative bleeding after gastric ESD; however, there is no consensus on the appropriate treatment duration. We conducted a randomized controlled study to demonstrate that the 3-week administration of VPZ is not inferior to the 8-week administration for ulcer healing. METHODS: This is a prospective, open-label multicenter randomized controlled trial. Patients aged 20-85 years undergoing gastric ESD were included in this study. The key exclusion criteria were patients with bleeding tendencies and those taking NSAIDs, steroids, PPIs, or VPZ medications. Eligible patients were randomly assigned to the VPZ 3w or 8w treatment group. The primary endpoint was the proportion of patients with complete closure of the post-ESD wound at 24 weeks after ESD. The key secondary endpoints included the proportion of patients with complete closure of the post-ESD wound at 8 weeks and the proportion of bleeding or perforation more than 3 weeks after ESD. RESULTS: From May 2018 to October 2020, 234 patients were included. The proportion of patients with complete ulcer closure was significantly lower in the 3w group than in the 8w group (70.8% vs. 90.6%) at 8 weeks post-treatment. The complete closure rates at 24 weeks in the 3w and 8w groups were 99.1% and 99.2%, respectively. The absolute difference in the closure rate at 24 weeks was - 0.059% [95% confidence interval (CI) -3.4% to 3.2], and the lower limit of the 95% CI exceeded -10%, the preset threshold. None of the patients developed delayed bleeding 3 weeks after ESD. CONCLUSION: This multicenter randomized study demonstrated that 3 weeks of treatment with VPZ is sufficient for ulcer healing. Trial registry number. UMIN000031564.

Clinical characteristics and long-term prognosis of type 1 gastric neuroendocrine tumors in a large Japanese national cohort.

OBJECTIVES: Optimal management of type 1 gastric neuroendocrine tumors (T1-GNETs) remains unknown, with few reports on their long-term prognosis. This study investigated the clinical characteristics and long-term prognosis of T1-GNETs. METHODS: We reviewed the medical records of patients diagnosed with T1-GNET during 1991-2019 at 40 institutions in Japan. RESULTS: Among 172 patients, endoscopic resection (ER), endoscopic surveillance, and surgery were performed in 84, 61, and 27, respectively, including 27, 77, and 2 patients with pT1a-M, pT1b-SM, and pT2 tumors, respectively. The median tumor diameter was 5 (range 0.8-55) mm. Four (2.9%) patients had lymph node metastasis (LNM); none had liver metastasis. LNM rates were significantly higher in tumors with lymphovascular invasion (LVI) (15.8%; 3/19) than in those without (1.1%; 1/92) (P = 0.016). For tumors <10 mm, LVI and LNM rates were 18.4% (14/76) and 2.2% (2/90), respectively, which were not significantly different from those of tumors 10-20 mm (LVI 13.3%; 2/15, P = 0.211; and LNM 0%; 0/17, P = 1.0). However, these rates were significantly lower than those of tumors >20 mm (LVI 60%; 3/5, P = 0.021; and LNM 40%; 2/5, P = 0.039). No tumor recurrence or cause-specific death occurred during the median follow-up of 10.1 (1-25) years. The 10-year overall survival rate was 97%. CONCLUSIONS: Type 1 gastric neuroendocrine tumors showed indolent nature and favorable long-term prognoses. LVI could be useful in indicating the need for additional treatments. ER for risk prediction of LNM should be considered for tumors <10 mm and may be feasible for tumors 10-20 mm. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Information Network (UMIN) under the identifier UMIN000029927.

Comparison of complete resection rates in cold snare polypectomy using two different wire diameter snares: A randomized controlled study.

BACKGROUND AND AIM: Cold snare polypectomy (CSP) is a standard treatment for small colorectal polyps. This study examined the effect of different snare wire diameters on complete histological resection rate, resection depth, and CSP safety. METHODS: This randomized controlled trial was conducted at two institutions between June 2019 and March 2021. Eligible colorectal polyps (≤10 mm) were randomly assigned in a 1:1 ratio to receive either CSP with a conventional snare made of normal-diameter wire (0.40 mm) or CSP with a dedicated snare made of thin wire (0.23 mm). The primary endpoint was the complete resection rate determined on histological assessment of the resected specimen. RESULTS: In total, 254 lesions in 152 patients were included, with 128 and 126 lesions assigned to the normal-diameter wire snare group and the thin-wire snare group, respectively. No significant differences were observed in patient characteristics between the two groups. The histological complete resection rate was significantly higher in the thin-wire snare group than in the normal-diameter wire snare group (70.0% vs 81.0%, P = 0.04). The normal-diameter wire snare group had significantly more cases of unclear horizontal margin evaluation than the thin-wire snare group (28.1% vs 15.9%, P = 0.02). No significant differences were observed between the two groups in the muscularis mucosa and submucosa of the resected specimens or the thickness of the submucosa in the resected specimens. CONCLUSIONS: CSP with a dedicated thin-wire snare provides more specimens that can be evaluated at the horizontal end and increases the histological complete resection rate.

Linked-Color Imaging Detects More Colorectal Adenoma and Serrated Lesions: An International Randomized Controlled Trial.

BACKGROUND & AIMS: Effects of linked-color imaging (LCI) on colorectal lesion detection and colonoscopy quality remain controversial. This study compared the detection rates of adenoma and other precursor lesions using LCI vs white-light imaging (WLI) during screening, diagnostic, and surveillance colonoscopies. METHODS: This randomized controlled trial was performed at 11 institutions in 4 Asian countries/regions. Patients with abdominal symptoms, a primary screening colonoscopy, positive fecal immunochemical test results, or undergoing postpolypectomy surveillance were recruited and randomly assigned in a 1:1 ratio to either the LCI or high-definition WLI group. The primary outcome was adenoma detection rate (ADR). Secondary outcomes were polyp detection rate, advanced ADR, sessile serrated lesion (SSL) detection rate, and the mean number of adenomas per colonoscopy. The recommended surveillance schedule distribution after trial colonoscopy was analyzed. RESULTS: Between November 2020 and January 2022, there were 3050 participants (LCI, n = 1527; WLI, n = 1523) recruited. The LCI group ADR was significantly higher than the WLI group ADR using intention-to-treat (58.7% vs 46.7%; P < .01) and per-protocol analyses (59.6% vs 46.4%; P < .01). The LCI group polyp detection rates (68.6% vs 59.5%; P < .01), SSL detection rates (4.8% vs 2.8%; P < .01), and adenomas per colonoscopy (1.48 vs 1.02; P < .01) also were significantly higher. However, the advanced ADR was not significantly different (13.2% vs 11.0%; P = .06). Significantly more patients in the LCI group had shorter recommended surveillance schedules than the WLI group (P < .01). CONCLUSIONS: Compared with WLI, LCI improved adenoma and other polyp detection rates, including SSLs, resulting in alteration of the recommended surveillance schedule after screening, diagnostic, and postpolypectomy surveillance colonoscopies. TRIAL REGISTRATION NUMBER: UMIN000042432 (https://www.umin.ac.jp/ctr/index.htm).

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.