Ryota Niikura

Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling

Within the gastrointestinal stem cell niche, nerves help to regulate both normal and neoplastic stem cell dynamics. Here, we reveal the mechanisms underlying the cancer-nerve partnership. We find that Dclk1+ tuft cells and nerves are the main sources of acetylcholine (ACh) within the gastric mucosa. Cholinergic stimulation of the gastric epithelium induced nerve growth factor (NGF) expression, and in turn NGF overexpression within gastric epithelium expanded enteric nerves and promoted carcinogenesis. Ablation of Dclk1+ cells or blockade of NGF/Trk signaling inhibited epithelial proliferation and tumorigenesis in an ACh muscarinic receptor-3 (M3R)-dependent manner, in part through suppression of yes-associated protein (YAP) function. This feedforward ACh-NGF axis activates the gastric cancer niche and offers a compelling target for tumor treatment and prevention.

Visceral abdominal fat measured by computed tomography is associated with an increased risk of colorectal adenoma

We investigated whether visceral adipose tissue (VAT) measured by computed tomography (CT) is a risk factor for colorectal adenoma. For a total of 1,328 patients (857 without adenoma, 471 with colorectal adenoma) undergoing colonoscopy and CT, associations between colorectal adenoma and body mass index (BMI), VAT area and subcutaneous adipose tissue (SAT) were assessed using odds ratios (ORs) with 95% confidence intervals (CIs) adjusted for age, sex, family history, smoking, alcohol intake, diabetes mellitus, aspirin use and nonsteroidal anti‐inflammatory drug use. Multivariate analysis showed that colorectal adenoma was marginally associated (p = 0.06) with BMI, but not with SAT, while it was significantly associated with VAT and the VAT to SAT ratio (VAT/SAT) for both categorical data and trend (p < 0.05). When the obesity indices were considered simultaneously, colorectal adenoma remained significantly associated with VAT and VAT/SAT (p < 0.05), but not BMI and SAT. In patients with colorectal adenoma, the adjusted OR for the highest quartiles of VAT and VAT/SAT was 1.90 (95% CI 1.16–3.13) and 2.25 (95% CI 1.49–3.41), respectively, compared to the lowest quartiles. Only VAT area was significantly associated with colorectal adenoma in both men and women (p < 0.05). Proximal, multiple and advanced adenomas had significantly higher VAT areas (p < 0.05) than distal, solitary and nonadvanced adenomas. Our findings implicate abdominal VAT in the development and progression of colorectal adenoma, and it was better obesity index for colorectal adenoma than BMI in both sexes.

Histologic intestinal metaplasia and endoscopic atrophy are predictors of gastric cancer development after Helicobacter pylori eradication

BACKGROUND AND AIMS Helicobacter pylori eradication therapy is effective at reducing the incidence of gastric cancer; however, gastric cancer still develops after eradication. We conducted a cohort study to elucidate the risk factors for gastric cancer development after successful H pylori eradication therapy. METHODS From June 1998 to December 2012 we assessed histologic and endoscopic findings of gastritis and performed H pylori eradication therapy in 748 patients without a history of gastric cancer. Patients were classified according to the distribution of intestinal metaplasia (IM) as follows: no IM (IM group A), IM in the antrum only (IM group B), and IM in the corpus (IM group C). We assessed atrophy endoscopically according to the Kimura-Takemoto classification system. Gastric cancer incidence was assessed. RESULTS A total of 573 patients underwent follow-up endoscopy; the mean duration of follow-up was 6.2 ± 4.8 years. Gastric cancer developed in 21 (20 intestinal type). The cumulative 5-year incidences of gastric cancer were 3.2% overall; 1.5%, 5.3%, and 9.8% in IM groups A, B, and C; and 0.7%, 1.9%, and 10% in the none/mild, moderate, and severe endoscopic atrophy groups, respectively. Compared with IM group A, the hazard ratio for IM group B was 3.6 (95% confidence interval [CI], 1.2-11), and that for IM group C was 3.7 (95% CI, 1.1-12). Compared with the none/mild endoscopic atrophy group, the hazard ratio for severe atrophy was 9.3 (95% CI, 1.7-174). CONCLUSIONS Patients with histologic IM or severe endoscopic atrophy were at increased risk of gastric cancer development after H pylori eradication.

Alcohol and smoking affect risk of uncomplicated colonic diverticulosis in Japan.

Colonic diverticula are located predominantly on the right side in Asia and on the left side in Europe and the United States. Factors associated with uncomplicated colonic diverticulosis and its distribution pattern have been unknown. Our aims are to investigate the prevalence and risk factors for uncomplicated colonic diverticulosis. We conducted a prospective cross-sectional study in adults who underwent colonoscopy. Alcohol, alcohol related flushing, smoking, medications, and comorbidities were assessed by interview on the colonoscopy day. Alcohol consumption was categorized as nondrinker, light (1–180 g/week), moderate (181–360 g/week), and heavy (≥361 g/week). Smoking index was defined as the number of cigarettes per day multiplied by the number of smoking years and categorized as nonsmoker, <400, 400–799, and ≥800. A total of 2,164 consecutive patients were enrolled. Overall, 542 patients (25.1%) had uncomplicated colonic diverticulosis located on the right side (50%), bilaterally (29%), and on the left side (21%). Univariate analysis revealed age, male, smoking index, alcohol consumption, aspirin use, anticoagulants use, corticosteroid use, hypertension, and atherosclerotic disease as factors significantly associated with diverticulosis. Alcohol related flushing was not associated with the disease. Multivariate analysis showed increasing age (P<0.01), increasing alcohol consumption (P<0.01) and smoking (P<0.01), and atherosclerotic disease (P<0.01) as significantly associated factors. Alcohol and smoking were associated with right-sided and bilateral diverticula. In conclusion, one in four Japanese adults have colonic diverticulosis (50% right-sided). Age, alcohol consumption, and smoking were found to be significant risk factors for uncomplicated colonic diverticulosis, particularly right-sided and bilateral.

Hypertension and concomitant arteriosclerotic diseases are risk factors for colonic diverticular bleeding: a case-control study.

PurposeColonic diverticular bleeding is a major cause of lower gastrointestinal bleeding. However, a limited number of studies have been reported on the risk factors for diverticular bleeding. Our aim was to identify risk factors for diverticular bleeding.MethodsOur study design is a case (diverticular bleeding)–control (diverticulosis) study. We prospectively collected information of habits, comorbidities, history of medications and symptoms by a questionnaire, and diagnosed diverticular bleeding and diverticulosis by colonoscopy. Logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI).ResultsA total of 254 patients (diverticular bleeding, 45; diverculosis, 209) were selected for analysis. Cluster (≥10 diverticula) type (OR, 4.0; 95% CI, 1.8–8.9), hypertension (OR, 2.2; 95% CI, 1.0–4.6), ischemic heart disease (OR, 2.4; 95% CI, 1.1–5.4), and chronic renal failure (OR, 6.4; 95% CI, 1.3–32) were independent risk factors for diverticular bleeding.ConclusionsLarge number of diverticula, hypertension, and concomitant arteriosclerotic diseases including ischemic heart disease and chronic renal failure are risk factors for diverticular bleeding. This study identifies new information on the risk factors for diverticular bleeding.

Distribution of intestinal metaplasia as a predictor of gastric cancer development

Helicobacter pylori, gastritis, and intestinal metaplasia (IM) are known risk factors for gastric cancer. In the present study, we conducted a cohort study to evaluate the predictive value of the distribution of IM for gastric cancer development.

Colonic diverticular hemorrhage associated with the use of nonsteroidal anti-inflammatory drugs, low-dose aspirin, antiplatelet drugs, and dual therapy.

The effects of various medications on lower gastrointestinal tract remains unknown. Here, we investigated the effects of nonsteroidal anti‐inflammatory drugs (NSAIDs), low‐dose aspirin, and antiplatelet drugs associated with diverticular bleeding.

Predictors for identification of stigmata of recent hemorrhage on colonic diverticula in lower gastrointestinal bleeding.

Goals: The aim of this study was to identify predictors for the identification of stigmata of recent hemorrhage (SRH) on colonic diverticula. Background: Several factors influence the identification of SRH in the diagnosis of colonic diverticular bleeding. Study: A total of 396 patients hospitalized for lower gastrointestinal bleeding were analyzed. Comorbidities, medications, timing of colonoscopy [<24 h (h); urgent, 24 to 48 h, >48 h], preparation, expert colonoscopist, use of a cap, use of a water-jet scope, total colonoscopy, and procedure time (over 60 min) were assessed. A multivariable logistic regression model was used to estimate odds ratio (OR) and 95% confidence interval (CI). Results: Two hundred fifteen patients were diagnosed with colonic diverticular bleeding and 37 (17%) were identified with SRH. Urgent colonoscopy (OR, 8.4; 95% CI, 2.3-30; P<0.01), expert colonoscopist (OR, 3.0; 95% CI, 1.2-7.3; P=0.02), use of a cap (OR, 3.4; 95% CI, 1.4-8.0; P=0.01), and use of water-jet scope (OR, 5.8; 95% CI, 2.3-15; P<0.01) were found to be independent predictive factors for SRH. The accuracy of these factors in combination was 0.90 (95% CI, 0.85-0.96) as measured by area under the receiver operating characteristic curve (ROC-AUC). SRH identification rate was higher in the urgent (22%) than in the 24 to 48 hours (2.9%, P<0.01) and >48 hours groups (1.0%, P<0.01), showing a tendency to decrease with time (P<0.01 for trend). Conclusions: Factors of urgent colonoscopy, expert colonoscopist, use of a cap, and use of water-jet scope are useful for identifying SRH diverticula.

Predictive findings for Helicobacter pylori-uninfected, -infected and -eradicated gastric mucosa: Validation study

AIM To validate the usefulness of screening endoscopy findings for predicting Helicobacter pylori (H. pylori) infection status. METHODS H. pylori infection status was determined by histology, serology, and the urea breast test in 77 consecutive patients who underwent upper endoscopy. Based on the findings, patients were categorized as H. pylori-uninfected, -infected, or -eradicated cases. Using six photos of certain sites in the stomach per case, we determined the presence or absence of the following endoscopic findings: regular arrangement of collecting venules (RAC), linear erythema, hemorrhage, fundic gland polyp (FGP), atrophic change, rugal hyperplasia, edema, spotty erythema, exudate, xanthoma, and mottled patchy erythema (MPE). The diagnostic odds ratio (DOR) and inter-observer agreement (Kappa value) for these 11 endoscopic findings used in the determination of H. pylori infection status were calculated. RESULTS Of the 77 patients [32 men and 45 women; mean age (SD), 39.7 (13.4) years] assessed, 28 were H. pylori uninfected, 28 were infected, and 21 were eradicated. DOR values were significantly high (< 0.05) for the following H. pylori cases: uninfected cases with RAC (11.5), linear erythema (24.5), hemorrhage (4.1), and FGP (34.5); for infected cases with atrophic change (8.67), rugal hyperplasia (15.8), edema (14.2), spotty erythema (11.5), and exudate (3.52); and for eradicated cases with atrophic change (32.4) and MPE (103.0). Kappa values were excellent for FGP (0.93), good for RAC (0.63), hemorrhage (0.79), atrophic change (0.74), and MPE (0.75), moderate for linear erythema (0.51), rugal hyperplasia (0.49), edema (0.58), spotty erythema (0.47), and exudate (0.46), and poor for xanthoma (0.19). CONCLUSION The endoscopic findings of RAC, hemorrhage, FGP, atrophic change, and MPE will be useful for predicting H. pylori infection status.

Vonoprazan versus conventional proton pump inhibitor-based triple therapy as first-line treatment against Helicobacter pylori: A multicenter retrospective study in clinical practice.

Vonoprazan is a potassium‐competitive acid blocker, a new type of acid‐suppressing drug, and has recently become available for peptic ulcers, gastroesophageal reflux disease, and Helicobacter pylori (H. pylori) eradication. Its efficacy for H. pylori eradication has been reported. However, the evidence for its efficacy and feasibility remains limited. We aimed to compare the feasibility, effectiveness and safety of vonoprazan‐based triple therapy with conventional proton pump inhibitor (PPI)‐based triple therapy in multicenter clinical practice.