Probe-guided endoscopic system for 5-aminolevulinic acid-based photodynamic diagnosis in cholangiocarcinoma.

BACKGROUND AND AIM: The diagnostic accuracy for cholangiocarcinoma (CCA) is inadequate, necessitating the exploration of novel diagnostic approaches. Protoporphyrin IX (Pp IX), a metabolic product of 5-aminolevulinic acid (5-ALA), emits red fluorescence upon blue light exposure. Because it accumulates selectively in cancer cells, photodynamic diagnosis using 5-ALA (5-ALA-PDD) has been integrated into clinical practice for diverse cancer types. Nevertheless, there is currently no device capable of capturing Pp IX-derived fluorescence for real-time 5-ALA-PDD within the biliary tract, largely due to challenges in device miniaturization. METHODS: To investigate the feasibility of real-time 5ALA-PDD in CCA, we developed two essential components of the cholangioscopy system: a small-diameter flexible camera and a light guide for emitting blue light. We evaluated the detectability of Pp IX fluorescence using these devices in experimental gels and animal models. RESULTS: Our camera and light guide were smoothly inserted into the lumen of existing cholangioscopes. Incorporating a long-pass filter at the camera tip enabled efficient detection of red fluorescence without significantly impacting white-light observation. The integration of these devices facilitated clear visualization of red fluorescence from gels containing Pp IX at concentrations of 5 µM or higher. Additionally, when observing subcutaneous human CCA tumor models in nude mice treated with 5-ALA, we successfully demonstrated distinct red fluorescence from Pp IX accumulation in tumors compared to peritumoral subcutaneous areas. CONCLUSION: The integration of our device combination holds promise for real-time 5-ALA-PDD in human CCA, potentially enhancing the diagnostic accuracy for this complex condition.

Metabolic Factors Associated with Endoscopic Atrophy, Intestinal Metaplasia, and Gastric Neoplasms in Helicobacter pylori-Positive Patients.

BACKGROUND: Previous studies demonstrate an association between metabolic factors and Helicobacter pylori-related gastric cancer. However, the association of gastric atrophy or intestinal metaplasia (IM) with these factors remains unknown. METHODS: Data on 1603 Helicobacter pylori-positive patients who underwent esophagogastroduodenoscopy between 2001 and 2021 were evaluated. The outcome measures were endoscopic atrophy, IM grade, and the incidence of endoscopically diagnosed and pathologically confirmed gastric neoplasms. Clinical factors associated with these findings were also determined. RESULTS: Advanced age; successful Helicobacter pylori eradication; and comorbidities including diabetes mellitus (DM), hypertension, dyslipidemia, and fib4 index were significantly associated with endoscopic gastric atrophy grade. Male sex; advanced age; and comorbidities including DM, hypertension, dyslipidemia, hyperuricemia, fatty liver, aortic calcification, and fib4 index were also significantly associated with endoscopic IM grade, whereas advanced age, successful Helicobacter pylori eradication, DM, fatty liver, and fib4 index were significantly associated with the incidence of gastric neoplasms. CONCLUSION: Several metabolic disorders, including DM, hypertension, dyslipidemia, hyperuricemia, and fatty liver disease, are risk factors for advanced-grade gastric atrophy, intestinal metaplasia, and gastric neoplasms. Risk stratification according to these factors, particularly those with metabolic disorders, would affect EGD surveillance for Helicobacter pylori-positive patients.

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.

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.

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.

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.

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.

Clinicopathological Features of Gastric Cancer with Autoimmune Gastritis.

Most gastric cancers develop in patients with chronic gastritis. Chronic gastritis can be classified into two major subtypes: Helicobacter pylori (H. pylori)-induced gastritis and autoimmune gastritis (AIG). Whereas H. pylori-related gastric cancers are more common and have been extensively investigated, the clinicopathological features of gastric cancer with autoimmune gastritis are unclear. Patients diagnosed with gastric cancer and hospitalized in the University Tokyo Hospital from 1998 to 2017 were enrolled. Diagnosis of autoimmune gastritis was based on positivity for serum anti-parietal cell antibody (APCA). We evaluated mucin expression and immune cell infiltration by immunohistochemical staining for MUC5AC, MUC6, PD-L1, CD3, CD11, Foxp3, and PD1. We also examined the presence of bacterial taxa that are reportedly enriched in AIG. Survival analyses of recurrence and 5-year mortality were also performed. In total, 261 patients (76 APCA-positive and 185 APCA-negative) were analyzed. Immunohistochemical staining in the matched cohort showed that AIG-related gastric cancer had higher MUC5AC expression (p = 0.0007) and MUC6 expression (p = 0.0007). Greater infiltration of CD3-positive (p = 0.001), Foxp3-positive (p < 0.001), and PD1-positive cells (p = 0.001); lesser infiltration of CD11b-positive (p = 0.005) cells; and a higher prevalence of Bacillus cereus (p = 0.006) were found in AIG-related gastric cancer patients. The cumulative incidences of gastric cancer recurrence were 2.99% at 2 years, 15.68% at 6 years, and 18.81% at 10 years in APCA-positive patients; they were 12.79% at 2 years, 21.35% at 6 years, and 31.85% at 10 years in APCA-negative patients. The cumulative incidences of mortality were 0% at 3 years and 0% at 5 years in APCA-positive patients; they were 1.52% at 3 years and 2.56% at 5 years in APCA-negative patients. We identified molecular differences between AIG and non-AIG gastric cancer. Differences in T-cell populations and the gastric microbiota may contribute to the pathogenesis of gastric cancers and potentially affect the response to immunotherapy.

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.

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.

Nonsteroidal anti-inflammatory drugs prevent gastric cancer associated with the use of proton pump inhibitors after Helicobacter pylori eradication.

BACKGROUND AND AIM: Proton pump inhibitors (PPIs) are a potential cause of gastric carcinogenesis after Helicobacter pylori eradication. Thus, appropriate management including chemoprevention is required. The aim of this study was to evaluate the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and the incidence of post-eradication gastric cancer in PPI users. METHODS: A multicenter retrospective cohort study was conducted. Patients who used a PPI (≥30 days) after H. pylori eradication between 2014 and 2019 were analyzed in nine hospital databases. Gastric cancer incidence was a primary outcome, and their association with NSAIDs use and clinical factors was evaluated. Hazard ratios were adjusted by age, sex, smoking, and Charlson Comorbidity Index. RESULTS: During the mean follow-up period of 2.38 years, 1.13% (31/2431) of all patients developed gastric cancer. The cumulative incidence of gastric cancer in PPI users was 0.25% at 1 year, 0.51% at 3 years, and 1.09% at 5 years in the NSAID users and 0.89% at 1 year, 2.32% at 3 years, and 3.61% at 5 years in nonusers. NSAIDs were associated with a lower gastric cancer risk (adjusted hazard ratio = 0.28, P = 0.005). No gastric cancer was observed in the cyclooxygenase-2 inhibitor users (n = 256). NSAID use with high dose and long duration was significantly associated with a lower incidence of gastric cancer. CONCLUSION: NSAIDs were associated with a 60% decrease in the gastric cancer incidence in H. pylori-eradicated PPI users, with dose and duration response effects. NSAIDs may be effective for chemoprevention against PPI-related gastric cancer.

Use of Antibiotics and Probiotics Reduces the Risk of Metachronous Gastric Cancer after Endoscopic Resection.

Metachronous gastric cancer often occurs after endoscopic resection. Appropriate management, including chemoprevention, is required after the procedure. This study was performed to evaluate the association between medication use and the incidence of metachronous gastric cancer after endoscopic resection. This multicenter retrospective cohort study was conducted with data from nine hospital databases on patients who underwent endoscopic resection for gastric cancer between 2014 and 2019. The primary outcome was the incidence of metachronous gastric cancer. We evaluated the associations of metachronous gastric cancer occurrence with medication use and clinical factors. Hazard ratios were adjusted by age and Charlson comorbidity index scores, with and without consideration of sex, smoking status, and receipt of Helicobacter pylori eradication therapy during the study period. During a mean follow-up period of 2.55 years, 10.39% (140/1347) of all patients developed metachronous gastric cancer. The use of antibiotics other than those used for H. pylori eradication was associated with a lower incidence of metachronous gastric cancer than was non-use (adjusted hazard ratio (aHR) 0.56, 95% confidence interval (CI) 0.38-0.85, p = 0.006). Probiotic drug use was also associated with a lower incidence of metachronous gastric cancer compared with non-use (aHR 0.29, 95% CI 0.091-0.91, p = 0.034). In conclusion, the use of antibiotics and probiotic drugs was associated with a decreased risk of metachronous gastric cancer. These findings suggest that the gut microbiome is associated with metachronous gastric cancer development.