Impaired Glycosylation of Gastric Mucins Drives Gastric Tumorigenesis and Serves as a Novel Therapeutic Target.

BACKGROUND & AIMS: Gastric cancer is often accompanied by a loss of mucin 6 (MUC6), but its pathogenic role in gastric carcinogenesis remains unclear. METHODS: Muc6 knockout (Muc6-/-) mice and Muc6-dsRED mice were newly generated. Tff1Cre, Golph3-/-, R26-Golgi-mCherry, Hes1flox/flox, Cosmcflox/flox, and A4gnt-/- mice were also used. Histology, DNA and RNA, proteins, and sugar chains were analyzed by whole-exon DNA sequence, RNA sequence, immunohistochemistry, lectin-binding assays, and liquid chromatography-mass spectrometry analysis. Gastric organoids and cell lines were used for in vitro assays and xenograft experiments. RESULTS: Deletion of Muc6 in mice spontaneously causes pan-gastritis and invasive gastric cancers. Muc6-deficient tumor growth was dependent on mitogen-activated protein kinase activation, mediated by Golgi stress-induced up-regulation of Golgi phosphoprotein 3. 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. Mitogen-activated protein kinase activation, Golgi stress responses, and aberrant mannose expression are found in separate Cosmc- and A4gnt-deficient mouse models that lack normal O-glycosylation. Banana lectin-drug conjugates proved an effective treatment for mannose-rich murine and human gastric cancer. CONCLUSIONS: We propose that Golgi stress responses and aberrant glycans are important drivers of and promising new therapeutic targets for gastric cancer.

The role of gastric mucins and mucin-related glycans in gastric cancers.

Gastric mucins serve as a protective barrier on the stomach's surface, protecting from external stimuli including gastric acid and gut microbiota. Their composition typically changes in response to the metaplastic sequence triggered by Helicobacter pylori infection. This alteration in gastric mucins is also observed in cases of gastric cancer, although the precise connection between mucin expressions and gastric carcinogenesis remains uncertain. This review first introduces the relationship between mucin expressions and gastric metaplasia or cancer observed in humans and mice. Additionally, we discuss potential pathogenic mechanisms of how aberrant mucins and their glycans affect gastric carcinogenesis. Finally, we summarize challenges to target tumor-specific glycans by utilizing lectin-drug conjugates that can bind to specific glycans. Understanding the correlation and mechanism between these mucin expressions and gastric carcinogenesis could pave the way for new strategies in gastric cancer treatment.

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.

Association Between Proton Pump Inhibitors and the Risk of Intestinal Behçet Disease.

OBJECTIVE: This study aimed to investigate the association between proton pump inhibitor (PPI) use and the incidence of intestinal Behçet disease (BD) in patients with BD. METHODS: A retrospective cohort study was conducted at The University of Tokyo Hospital, including patients with BD diagnosed between April 2005 and November 2023. Cox models and Kaplan-Meier analyses were used to evaluate hazard ratios (HRs) and cumulative incidence of intestinal BD, respectively. Secondary analyses were performed to assess the duration and dose-response relationship of PPI use. RESULTS: Among 194 patients with BD, 25.3% developed intestinal BD during a mean follow-up of 12 years. PPI users had a significantly higher incidence of intestinal BD compared to nonusers (adjusted HR 2.48, 95% CI 1.38-4.47, P = 0.002), with a confirmed duration/dose-dependent relationship. The cumulative incidence of intestinal BD was markedly elevated in PPI users (log-rank P < 0.001). The result was similar to that in the propensity score-matched cohort. CONCLUSION: This study demonstrates a significant association between PPI use and increased incidence of intestinal BD in patients with BD. Caution in prescribing PPIs for patients with BD is warranted due to the potential risk of severe complications associated with intestinal BD.

Upper gastrointestinal involvement of Behçet's disease in Japan: endoscopic findings and clinical features.

AIM: Behçet's disease (BD) can involve any gastrointestinal (GI) tract site. We analyzed the characteristics, risk factors, and treatment responses to upper GI (UGI) involvement in patients with BD. METHODS: This retrospective cohort study analyzed UGI findings in 101 patients with BD who underwent endoscopy between April 2005 and December 2022 at the University of Tokyo Hospital. The patients were divided into two groups based on the presence or absence of UGI findings. Patient backgrounds, clinical symptoms, colonoscopy (CS) findings, and blood test findings were compared between the groups. RESULTS: In total, 18.8% (19/101) of the patients had UGI lesions. The prevalence rates in the esophagus, stomach, and duodenum were 6.9%, 6.9%, and 8.9%, respectively. Of these 19 patients, BD treatment were intensified in 10 (52.6%) patients after esophagogastroduodenoscopy (EGD), and all showed improvement in symptoms or endoscopic findings. In the multivariate analysis, symptoms (OR: 37.1, P < 0.001), CRP > 1 mg/dL (OR: 11.0, P = 0.01), and CS findings (OR: 5.16, P = 0.04) were independent predictors of UGI involvement in BD patients. The prediction model for UGI involvement using these three factors was highly accurate, with an AUC of 0.899 on the ROC curve. In the subgroup analysis of intestinal BD, symptoms (OR: 12.8, P = 0.01) and ESR > 20 mm/h (OR: 11.5, P = 0.007) were independent predictors. CONCLUSIONS: EGD should be conducted in BD patients with high CRP, GI symptoms, and lower GI involvement, which leads to better management of BD in terms of improving symptoms and endoscopic findings.

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.

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.

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.

Machine learning-based personalized prediction of gastric cancer incidence using the endoscopic and histologic findings at the initial endoscopy.

BACKGROUND AND AIMS: Accurate risk stratification for gastric cancer is required for optimal endoscopic surveillance in patients with chronic gastritis. We aimed to develop a machine learning (ML) model that incorporates endoscopic and histologic findings for an individualized prediction of gastric cancer incidence. METHODS: We retrospectively evaluated 1099 patients with chronic gastritis who underwent EGD and biopsy sampling of the gastric mucosa. Patients were randomly divided into training and test sets (4:1). We constructed a conventional Cox proportional hazard model and 3 ML models. Baseline characteristics, endoscopic atrophy, and Operative Link on Gastritis-Intestinal Metaplasia Assessment (OLGIM)/Operative Link on Gastritis Assessment (OLGA) stage at initial EGD were comprehensively assessed. Model performance was evaluated using Harrel's c-index. RESULTS: During a mean follow-up of 5.63 years, 94 patients (8.55%) developed gastric cancer. The gradient-boosting decision tree (GBDT) model achieved the best performance (c-index from the test set, .84) and showed high discriminative ability in stratifying the test set into 3 risk categories (P < .001). Age, OLGIM/OLGA stage, endoscopic atrophy, and history of malignant tumors other than gastric cancer were important predictors of gastric cancer incidence in the GBDT model. Furthermore, the proposed GBDT model enabled the generation of a personalized cumulative incidence prediction curve for each patient. CONCLUSIONS: We developed a novel ML model that incorporates endoscopic and histologic findings at initial EGD for personalized risk prediction of gastric cancer. This model may lead to the development of effective and personalized follow-up strategies after initial EGD.

Chemoprevention of Oesophageal Squamous-Cell Carcinoma and Adenocarcinoma: A Multicentre Retrospective Cohort Study.

BACKGROUND: Oesophageal cancer comprises 2 different histological variants: oesophageal squamous-cell carcinoma (ESCC) and adenocarcinoma (EAC). While there are multiple therapeutic options for both types, patients with advanced or metastatic oesophageal cancer still suffer from poor prognosis. AIMS: The study aimed to examine the association between the risk of oesophageal cancer and medications and to estimate the chemopreventive effects of commonly used drugs. METHODS: A multicentre retrospective cohort study was conducted using data from 9 hospital databases of hospitalized patients between 2014 and 2019. The primary outcomes were ESCC and EAC. The association of oesophageal cancer with drug use and clinical factors was evaluated. Odds ratios (ORs) were adjusted for age, sex, Charlson comorbidity index scores, and smoking with/without gastro-oesophageal reflux disease. RESULTS: The use of proton pump inhibitors (PPIs) (adjusted OR [aOR] 0.48, p < 0.0001), aspirin (aOR 0.32, p < 0.0001), cyclooxygenase-2 inhibitor (COX2I) (aOR 0.70, p = 0.0005), steroid (aOR 0.19, p < 0.0001), statin (aOR 0.43, p < 0.0001), and metformin (aOR 0.42, p < 0.0001) was associated with a lower risk of ESCC than that in non-use. The use of aspirin (aOR 0.33, p = 0.0006) and steroids (aOR 0.54, p = 0.022) was associated with a lower risk of EAC than that in non-use. CONCLUSION: COX2Is, statins, metformin, and PPIs could help in prevention of ESCC, and aspirin and steroids may be chemopreventive for both types of oesophageal cancer.

Chemoprevention for Colorectal Cancers: Are Chemopreventive Effects Different Between Left and Right Sided Colorectal Cancers?

BACKGROUND AND AIMS: Recent studies have suggested that right- and left-sided colorectal cancers (CRCs) are molecularly distinct. In this study, we examined the association between the risk of right- and left-sided CRC and drug use to estimate their chemopreventive effects METHODS: This multicenter retrospective cohort study was conducted using the data of hospitalized patients between 2014 and 2019 from nine hospital databases. The primary outcomes were right- and left-sided CRC. We evaluated the association of CRCs with drug use and clinical factors. Odds ratios adjusted for age, sex, Charlson Comorbidity Index scores, and smoking status were calculated. We also compared the transcriptional profiling in precancerous lesions, including sessile serrated lesions (SSLs) RESULTS: A total of 307,938 patients, including 2745 with right-sided CRC and 4819 with left-sided CRC, were analyzed. The use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, cyclooxygenase-2 inhibitors, and steroids was associated with a lower risk of both right- and left-sided CRCs. In contrast, statins, other lipid-lowering agents, and metformin were associated with a lower risk of left-sided CRC. Transcriptomic analysis showed that SSL, which predominantly develops in the right colon, was associated with a lower expression of lipid metabolism-related genes. CONCLUSIONS: Targeting lipid metabolism may be useful for chemoprevention of left-sided CRCs, while development of right-sided CRCs may be independent of this pathway.

Risk factors of poor prognosis and impairment of activities of daily living in patients with hemorrhagic gastroduodenal ulcers.

BACKGROUND: Impairment of activities of daily living (ADL) due to hemorrhagic gastroduodenal ulcers (HGU) has rarely been evaluated. We analyzed the risk factors of poor prognosis, including mortality and impairment of ADL, in patients with HGU. METHODS: In total, 582 patients diagnosed with HGU were retrospectively analyzed. Admission to a care facility or the need for home adaptations during hospitalization were defined as ADL decline. The clinical factors were evaluated: endoscopic features, need for interventional endoscopic procedures, comorbidities, symptoms, and medications. The risk factors of outcomes were examined with multivariate analysis. RESULTS: Advanced age (> 75 years) was a significant predictor of poor prognosis, including impairment of ADL. Additional significant risk factors were renal disease (odds ratio [OR] 3.43; 95% confidence interval [CI] 1.44-8.14) for overall mortality, proton pump inhibitor (PPIs) usage prior to hemorrhage (OR 5.80; 95% CI 2.08-16.2), and heart disease (OR 3.05; 95% CI 1.11-8.43) for the impairment of ADL. Analysis of elderly (> 75 years) subjects alone also revealed that use of PPIs prior to hemorrhage was a significant predictor for the impairment of ADL (OR 8.24; 95% CI 2.36-28.7). CONCLUSION: In addition to advanced age, the presence of comorbidities was a risk of poor outcomes in patients with HGU. PPI use prior to hemorrhage was a significant risk factor for the impairment of ADL, both in overall HGU patients and in elderly patients alone. These findings suggest that the current strategy for PPI use needs reconsideration.

Wet Beriberi Associated with Hikikomori Syndrome.

Wet beriberi, characterized by high cardiac output with predominantly right-sided heart failure and lactic acidosis, is a disease caused by thiamine deficiency, and is rarely seen in modern society. However, patients with social withdrawal syndrome, also known as hikikomori syndrome, may be a new population at risk of thiamine deficiency. Hikikomori syndrome, first recognized in Japan, is becoming a worldwide issue. A 39-year-old Japanese patient was brought to our hospital, with a 3-week history of progressive shortness of breath and generalized edema. The patient had right-sided high-output heart failure, lactic acidosis, and Wernicke-Korsakoff syndrome. Because of his history of social isolation, we diagnosed hikikomori syndrome according to the Japanese government's definition, which is as follows: lifestyle centered at home; no interest or willingness to attend school or work; persistence of symptoms beyond 6 months; and exclusion of other psychiatric and developmental disorders. Considering his diagnosis of hikikomori syndrome and social isolation, we suspected malnutrition, particularly thiamine deficiency, and successfully treated him. Clinicians should be aware of the potential risk of thiamine deficiency associated with hikikomori syndrome and initiate thiamine replacement in cases of high-output heart failure associated with lactic acidosis.