Impaired glycosylation of gastric mucins drives gastric tumorigenesis and serves as a novel therapeutic target.

BACKGROUND: Gastric cancer is often accompanied by a loss of MUC6, but its pathogenic role in gastric carcinogenesis remains unclear. METHOD: Muc6 knockout (Muc6-/-) mice and Muc6-dsRED mice were newly generated. Tff1Cre, Golph3-/-, R26-Golgi-mCherry, Hes1flox/flox, Cosmcflox/flox, A4gnt-/- mice were also used. Histology, DNAs and RNAs, proteins, and sugar chains were analyzed by whole exon DNA sequence, RNA sequence, immunohistochemistry, lectin-binding assays, and LC-MS analysis. Gastric organoids and cell lines were used for in vitro assays and xenograft experiments. RESULT: Deletion of Muc6 in mice spontaneously causes pan-gastritis and invasive gastric cancers. Muc6-deficient tumor growth was dependent on MAPK activation, mediated by Golgi stress-induced upregulation of GOLPH3. Glycomic profiling revealed aberrant expression of mannose-rich N-linked glycans in gastric tumors, detected with Banana lectin in association with lack of MUC6 expression. We identified a precursor of clusterin as a binding partner of mannose glycans. MAPK activation, Golgi stress responses, aberrant mannose expression are found in a separate Cosmc- and A4gnt-deficient mouse models which lack normal O-glycosylation. Banana lectin-drug conjugates proved an effective treatment for mannose-rich murine and human gastric cancer. CONCLUSION: We propose that Golgi stress responses and aberrant glycans are important drivers of, and promising new therapeutic targets for gastric cancer.

Association Between Vonoprazan and the Risk of Gastric Cancer After Helicobacter pylori Eradication.

BACKGROUND & AIMS: Potassium-competitive acid blockers (PCABs) have been increasingly used to treat upper gastrointestinal disorders, replacing proton pump inhibitors (PPIs). Whereas PPIs are associated with an increased risk of gastric cancer (GC) after Helicobacter pylori (Hp) eradication, it is uncertain whether PCABs carry the same risk. METHODS: Using a population-based claims database in Japan, we identified patients who were prescribed a clarithromycin-based first regimen of Hp eradication between 2015 and 2018. Patients who failed this regimen and those diagnosed with GC before or within 1 year after Hp eradication were excluded. We compared GC incidence between PCAB users and histamine type-2 receptor antagonist (H2RA) users, matching them on the basis of propensity scores calculated with considerations for age, sex, smoking, alcohol consumption, comorbidities, and co-administered medications. PCABs included only vonoprazan in this study. RESULTS: Among 54,055 patients, 568 (1.05%) developed GC during the follow-up period (mean, 3.65 years). The cumulative incidence of GC was 1.64% at 3 years, 2.02% at 4 years, and 2.36% at 5 years in PCAB users and 0.71% at 3 years, 1.04% at 4 years, and 1.22% at 5 years in H2RA users. The use of PCABs was associated with a higher GC risk (matched hazard ratio, 1.92; 95% confidence interval, 1.13-3.25; P = .016). Longer PCAB use and high-dose PCAB use were significantly associated with higher incidence of GC. Sensitivity analyses showed the risk of GC incidence among PCAB users was comparable with that of PPI users. CONCLUSIONS: The use of PCABs was associated with an increased risk of GC among Hp-eradicated patients, with duration/dose response effects.

Comparison of clinical utility of deep learning-based systems for small-bowel capsule endoscopy reading.

BACKGROUND AND AIM: Convolutional neural network (CNN) systems that automatically detect abnormalities from small-bowel capsule endoscopy (SBCE) images are still experimental, and no studies have directly compared the clinical usefulness of different systems. We compared endoscopist readings using an existing and a novel CNN system in a real-world SBCE setting. METHODS: Thirty-six complete SBCE videos, including 43 abnormal lesions (18 mucosal breaks, 8 angioectasia, and 17 protruding lesions), were retrospectively prepared. Three reading processes were compared: (A) endoscopist readings without CNN screening, (B) endoscopist readings after an existing CNN screening, and (C) endoscopist readings after a novel CNN screening. RESULTS: The mean number of small-bowel images was 14 747 per patient. Among these images, existing and novel CNN systems automatically captured 24.3% and 9.4% of the images, respectively. In this process, both systems extracted all 43 abnormal lesions. Next, we focused on the clinical usefulness. The detection rates of abnormalities by trainee endoscopists were not significantly different across the three processes: A, 77%; B, 67%; and C, 79%. The mean reading time of the trainees was the shortest during process C (10.1 min per patient), followed by processes B (23.1 min per patient) and A (33.6 min per patient). The mean psychological stress score while reading videos (scale, 1-5) was the lowest in process C (1.8) but was not significantly different between processes B (2.8) and A (3.2). CONCLUSIONS: Our novel CNN system significantly reduced endoscopist reading time and psychological stress while maintaining the detectability of abnormalities. CNN performance directly affects clinical utility and should be carefully assessed.

Special Issue: The Role of Gut Microbiota in Gastrointestinal Cancers-From Pathogenesis to Therapeutic Perspectives.

Associations between the gut microbiota and gastrointestinal carcinogenesis have been intensively studied [...].

Association of probiotic use with nivolumab effectiveness against various cancers: A multicenter retrospective cohort study.

BACKGROUND: Previous studies have revealed an association between probiotic use and effectiveness of immune checkpoint inhibitors in renal and lung cancers. However, little is known regarding other cancers, including gastrointestinal cancer. METHODS: To address this issue, we conducted a multicenter retrospective cohort study and the duration of nivolumab treatment for various cancers was compared between probiotic users and non-users. RESULTS AND CONCLUSIONS: In total, 488 patients who received nivolumab therapy were included. In all cancers, no significant differences in treatment duration of nivolumab were observed between probiotic users and non-users (median 62.0 vs. 56.0, hazard ratio = 1.02, p = 0.825), whereas probiotic use, compared with non-use, in patients with gastric cancer was significantly associated with a longer duration of nivolumab treatment (55.0 vs. 31.0 days, hazard ratio = 0.69, p = 0.039). In conclusion, probiotics may improve the response to nivolumab and potentially prolong progression-free survival in patients with gastric cancer.

The Association between Diverticular Rebleeding and Early-Morning Blood Pressure and Surge: A Prospective Observational Trial.

INTRODUCTION: Colonic diverticular bleeding is the major cause of lower gastrointestinal bleeding. Hypertension is a major risk factor for diverticular rebleeding. Direct evidence of an association between actual 24-h blood pressure (BP) and rebleeding is lacking. Therefore, we analyzed the association between 24-h BP and diverticular rebleeding. METHODS: We performed a prospective observational cohort trial involving hospitalized patients with colonic diverticular bleeding. We performed 24-h BP measurements (ambulatory BP monitoring [ABPM]) in the patients. The primary outcome was diverticular rebleeding. We evaluated the 24-h BP difference and the morning and pre-awaking BP surge between rebleeding and non-rebleeding patients. Morning BP surge was defined as early-morning systolic BP minus the lowest night systolic BP >45 mm Hg (highest quartile of morning BP surge). The pre-awaking BP surge was defined as the difference between morning BP and pre-awaking BP. RESULTS: Of 47 patients, 17 were excluded, leaving 30 who underwent ABPM. Of the 30 patients, 4 (13.33%) had rebleeding. The mean 24-h systolic and diastolic BP were 125.05 and 76.19 mm Hg in rebleeding patients and 129.98 and 81.77 mm Hg in non-rebleeding patients, respectively. Systolic BP at 5:00 (difference -23.53 mm Hg, p = 0.031) and 11:30 (difference -31.48 mm Hg, p = 0.006) was significantly lower in rebleeding patients than in non-rebleeding patients. Diastolic BP at 2:30 (difference -17.75 mm Hg, p = 0.023) and 5:00 (difference -16.12 mm Hg, p = 0.043) was significantly lower in rebleeding patients than in non-rebleeding patients. A morning surge was observed in one rebleeding patient and no non-rebleeding patients. The pre-awaking surge was significantly higher in rebleeding patients (28.44 mm Hg) than in non-rebleeding patients (9.30 mm Hg) (p = 0.015). CONCLUSION: Lower BP in the early-morning and a higher pre-awaking surge were risk factors for diverticular rebleeding. A 24-h ABPM can identify these BP findings and reduce the risk of rebleeding by enabling interventions in patients with diverticular bleeding.

Gastric squamous metaplasia observed by image-enhanced endoscopy.

A 61-year-old Helicobacter pylori-positive female with gastroesophageal reflux disease has undergone surveillance endoscopy every year for 13 years at Tokyo Medical University Hospital. At the first surveillance in 2009, conventional white light endoscopy showed a 10-mm whitish slightly depressed lesion at the lesser curvature of the gastric cardia. This lesion gradually increased in size to 15 mm over the 13-year observational period. Indigo carmine chromoendoscopy, narrow band imaging, and texture and color enhancement imaging in both mode 1 and mode 2 clearly emphasized the presence of a depressed whitish mucosa around the gastric mucosa compared with white light imaging. None of the three image-enhanced endoscopy techniques showed any abnormality in the vascular or structural pattern. Pathological findings showed squamous epithelium without atypia and revealed no evidence of malignancy in the stomach. We thus report a case of gastric squamous metaplasia without gastric neoplastic lesion in the gastric cardia whose lesions were endoscopically observed to change the size for more than 10 years and whose lesions were endoscopically evaluated with a texture and color enhancement imaging mode 1 and mode 2 and narrow band imaging.

Improved Object Detection Artificial Intelligence Using the Revised RetinaNet Model for the Automatic Detection of Ulcerations, Vascular Lesions, and Tumors in Wireless Capsule Endoscopy.

The use of computer-aided detection models to diagnose lesions in images from wireless capsule endoscopy (WCE) is a topical endoscopic diagnostic solution. We revised our artificial intelligence (AI) model, RetinaNet, to better diagnose multiple types of lesions, including erosions and ulcers, vascular lesions, and tumors. RetinaNet was trained using the data of 1234 patients, consisting of images of 6476 erosions and ulcers, 1916 vascular lesions, 7127 tumors, and 14,014,149 normal tissues. The mean area under the receiver operating characteristic curve (AUC), sensitivity, and specificity for each lesion were evaluated using five-fold stratified cross-validation. Each cross-validation set consisted of between 6,647,148 and 7,267,813 images from 217 patients. The mean AUC values were 0.997 for erosions and ulcers, 0.998 for vascular lesions, and 0.998 for tumors. The mean sensitivities were 0.919, 0.878, and 0.876, respectively. The mean specificities were 0.936, 0.969, and 0.937, and the mean accuracies were 0.930, 0.962, and 0.924, respectively. We developed a new version of an AI-based diagnostic model for the multiclass identification of small bowel lesions in WCE images to help endoscopists appropriately diagnose small intestine diseases in daily clinical practice.

Risk and preventive factors of early-onset colorectal neoplasms: endoscopic and histological database analysis.

BACKGROUND AND AIM: The incidence of early-onset colorectal neoplasms has been increasing in both Western and Eastern countries. However, the risks and preventive factors for these neoplasms in Eastern countries remain unclear. METHODS: The data of 5580 patients who underwent colonoscopy between 2016 and 2021 were retrospectively evaluated. The primary outcome was advanced colorectal neoplasm (ACRN), defined as advanced adenomas (adenoma ≥10 mm, or with high-grade dysplasia or villous component) or adenocarcinoma. The clinical factors associated with ACRNs were determined for each age category (≤50 and >50 years), and the differences between the two categories were assessed. Odds ratios adjusted for age and sex were calculated. RESULTS: Among 1001 patients (age ≤50 years), ACRN was found in 94 (9.4%). In this younger category, male sex (adjusted odds ratio [aOR]:2.34, 95% confidence interval [CI]:1.51-3.63) and a family history of colorectal cancer (aOR:2.14, 95% CI:1.17-3.89) were significantly associated with higher odds of developing ACRNs. ACRNs were detected in 726 (15.9%) of 4579 patients (age >50 years). In the older age category, smoking (aOR:1.32, 95% CI:1.08-1.63) was significantly associated with a higher risk of ACRNs. Exercise of >3.5 metabolic equivalent of task (METs) (aOR,0.80; 95% CI:0.67-0.96) was significantly associated with a lower risk of ACRNs. CONCLUSION: The development of early-onset ACRNs was primarily associated with congenital factors, whereas that of late-onset ACRNs was associated with acquired ones. Colonoscopy is recommended for young male patients, particularly for those with a family history of colorectal cancer.

Improvement of dyspeptic symptoms after Helicobacter pylori eradication therapy in Japanese patients.

Background and Aim: Helicobacter pylori eradication therapy effectively improves the abdominal symptoms and bowel habits of patients. Patients in whom dyspepsia is under control by 6 to 12 months after successful H. pylori eradication are defined as having H. pylori-associated dyspepsia, and patients with dyspepsia that is refractory to successful eradication are defined as having functional dyspepsia. Here, we aimed to investigate the association between H. pylori eradication and improvement of dyspepsia in the short and long term after eradication therapy. Methods: Dyspeptic symptoms before treatment and at 2 and 12 months after eradication were evaluated using the Gastrointestinal Symptom Rating Scale (GSRS) in 282 H. pylori-positive Japanese patients who underwent eradication therapy. Results: Of the Japanese H. pylori-positive patients, 48.2% (136/282) had upper abdominal symptoms. Eradication improved dyspepsia in 34.5% (47/136) of the patients at 2 months post eradication, which continued to be under control up to 12 months. A significant decrease at 2 and 12 months after eradication, compared with before eradication, was observed in total GSRS (from 25.7 ± 10.4 [before eradication, n = 249] to 23.3 ± 7.2 [after 2 months, n = 249] and 24.8 ± 7.8 [after 12 months, n = 81]; P = 0.014 and 0.321, respectively), gastric pain score (from 4.1 ± 1.9 to 3.7 ± 1.3 and 3.7 ± 1.2; P = 0.025 and 0.047), and constipation score (from 5.9 ± 3.1 to 5.2 ± 2.3 and 5.9 ± 3.0; P < 0.021 and 0.862). Conclusion: H. pylori-positive dyspepsia patients should be recommended to undergo H. pylori eradication to alleviate dyspepsia-associated symptoms.

Third-Generation High-Vision Ultrathin Endoscopy Using Texture and Color Enhancement Imaging and Narrow-Band Imaging to Evaluate Barrett's Esophagus.

It remains unclear whether texture- and color-enhancement imaging (TXI) and narrow-band imaging (NBI) provide an advantage over white-light imaging (WLI) in Barrett's esophagus. We compared endoscopic findings and color differences between WLI and image-enhanced endoscopy (IEE) using a third-generation ultrathin endoscope. We retrospectively enrolled 40 patients who evaluated Barrett's esophagus using WLI, TXI, and NBI. Color differences determined using the International Commission on Illumination 1976 (L∗, a∗, b∗) color space among Barrett's epithelium, esophageal, and gastric mucosa were compared among the endoscopic findings. As the secondary outcome, we assessed the subjective visibility score among three kinds of endoscopic findings. The prevalence of Barrett's esophagus and gastroesophageal reflux disease (GERD) in WLI was 82.5% and 47.5%, respectively, and similar among WLI, TXI, and NBI. Color differences between Barrett's epithelium and esophageal or gastric mucosa on NBI were significantly greater than on WLI (all p < 0.05). However, the color difference between Barrett's epithelium and esophageal mucosa was significantly greater on NBI than TXI (p < 0.001), and the visibility score of Barrett's epithelium detection was significantly greater on TXI than NBI (p = 0.022), and WLI (p = 0.016). High-vision, third-generation ultrathin endoscopy using NBI and TXI is useful for evaluating Barrett's epithelium and GERD compared with WLI alone.

Investigation of the New Advantages of Colonoscope Insertion with an Endoscopic Position Detection Unit.

BACKGROUND: The use of an endoscopic position detection unit (UPD) enables better and more objective understanding of the shape and position of the colonoscope. Here, we investigated the reproducibility of the insertion of a colonoscope with UPD. MATERIALS AND METHODS: Study participants were 122 patients who received a colonoscopy with UPD twice for the purpose of large bowel screening and surveillance. The mean age of participants was 69.7 ± 10.4 years, and the male-to-female ratio was 9.2:1. The colonoscope insertion technique was primarily based on the shaft-holding, shortening insertion method. The cecal intubation time was recorded; the method used for passing through the sigmoid/descending colon junction (SDJ) and the hepatic flexure. RESULTS: The mean cecal intubation time was 990 ± 511 s. The cecal intubation time and the patterns for passing through the SDJ and hepatic flexure were significantly correlated between the first and second colonoscopies. CONCLUSION: Use of a UPD revealed good reproducibility of colonoscope insertion. This is the first time we have proved that both time and pattern are inserted in much the same way for the first and second times. In patients' conducted UPD combination TCS after the second time, it was suggested that individual tailor-made insertions are possible based on the information from the first time.

Effectiveness and safety of chemotherapy for patients with malignant gastrointestinal obstruction: A Japanese population-based cohort study.

BACKGROUND: The impacts of chemotherapy on patients with malignant gastrointestinal obstructions remain unclear, and multicenter evidence is lacking. AIM: To evaluate the effectiveness and safety of chemotherapy in patients with unresectable malignant gastrointestinal obstructions. METHODS: We conducted a multicenter retrospective cohort study that compared the chemotherapy group who received any chemotherapeutics after interventions, including palliative surgery or self-expandable metal stent placement, for unresectable malignant gastrointestinal obstruction vs the best supportive care (BSC) group between 2014 and 2019 in nine hospitals. The primary outcome was overall survival, and the secondary outcomes were patency duration and adverse events, including gastrointestinal perforation and gastrointestinal bleeding. RESULTS: In total, 470 patients in the chemotherapy group and 652 patients in the BSC group were analyzed. During the follow-up period of 54.1 mo, the median overall survival durations were 19.3 mo in the chemotherapy group and 5.4 mo in the BSC group (log-rank test, P < 0.01). The median patency durations were 9.7 mo [95% confidence interval (CI): 7.7-11.5 mo] in the chemotherapy group and 2.5 mo (95%CI: 2.0-2.9 mo) in the BSC group (log-rank test, P < 0.01). The perforation rate was 1.3% (6/470) in the chemotherapy group and 0.9% (6/652) in the BSC group (P = 0.567). The gastrointestinal bleeding rate was 1.5% (7/470) in the chemotherapy group and 0.5% (3/652) in the BSC group (P = 0.105). CONCLUSION: Chemotherapy after interventions for unresectable malignant gastrointestinal obstruction was associated with increased overall survival and patency duration.

Efficacy of Early Video Capsule Endoscopy for Acute Overt Lower Gastrointestinal Bleeding with Colonic Diverticulosis: A Prospective Observational Study.

BACKGROUND/AIMS: Although most patients with presumptive colonic diverticular bleeding (CDB) do not undergo a small bowel investigation in clinical practice, no prospective study supports this management. We evaluated the utility of early small bowel capsule endoscopy (CE) after negative colonoscopy results. METHODS: This prospective study evaluated the diagnostic yield of early small bowel CE (≤3 days from visit) for consecutive patients with acute-onset hematochezia, when colonoscopy found colonic diverticulosis but did not identify the definite bleeding source (n = 51; presumptive CDB). As a matched control for comparing clinical outcomes, presumptive CDB patients without CE (n = 51) were retrospectively extracted. RESULTS: On CE for the prospective cohort, the rates of total positive findings, P2 findings (high bleeding potential according to the P classification), and blood pooling in the colon were 57%, 12% (ulceration, 8%; angioectasia, 4%), and 24%, respectively. The rates of rebleeding within 30 and 365 days were 16% and 29% in the prospective cohort with CE, respectively, and were not significantly different from those in the retrospective cohort without CE (10% and 25%, respectively). In addition, thromboembolism and mortality within 30 and 365 days were not significantly different between those with and without CE. CONCLUSION: Early CE detected a suspected small bowel bleeding source in 12% of acute-onset presumptive CDB patients but did not significantly improve major clinical outcomes. Therefore, routine CE is unnecessary for presumptive CDB patients after colonoscopy (UMIN000026676).

Linked color imaging effectively detects the endoscopic atrophic border in transnasal endoscopy.

In oral endoscopy, linked color imaging (LCI) detects atrophic border and gastric mucosal diseases better than white light imaging (WLI), but its usefulness in transnasal endoscopy has not been fully investigated. Here, we retrospectively compared WLI and LCI using the L*a*b* color space in images from 57 patients aged ≥20 years who had undergone transnasal endoscopy as part of a health check-up from May 2016 to January 2017. We measured color differences at the atrophic/non-atrophic and fundic/pyloric mucosal borders. Gastritis severity scored using the Kyoto classification of gastritis was similar between the two techniques. However, in patients with current and with past Helicobacter pylori infection, color difference at the atrophic border was greater with LCI (21.58 ±â€…6.97 and 27.34 ±â€…10.32, respectively) than with WLI [14.42 ±â€…5.95 (p = 0.004) and 17.9 ±â€…8.48 (p<0.001)]; in those never infected with Helicobacter pylori, color difference at the fundic/pyloric mucosal border was greater with LCI than with WLI (p<0.001). Because of its enhancement of atrophic border detection, we recommend linked color imaging as the method of choice for transnasal endoscopy in health check-ups, particularly for identifying people at high risk of gastric cancer.