A pragmatic randomised controlled trial of the effectiveness and cost-effectiveness of Well Parent Japan in routine care in Japan: The training and nurturing support for mothers (TRANSFORM) study.

BACKGROUND: Well Parent Japan (WPJ) is a new hybrid group parent training programme combining sessions to improve mothers' psychological well-being with a culturally adapted version of the New Forest Parenting Programme (NFPP). This study investigates the effectiveness and cost-effectiveness of WPJ against treatment as usual (TAU) within Japanese child mental health services. METHODS: TRANSFORM was a pragmatic multi-site randomised controlled trial (RCT) with two parallel arms. Altogether 124 mothers of 6-12-year-old children with DSM-5 ADHD were randomised to WPJ (n = 65) or TAU (n = 59). Participants were assessed at baseline, post-treatment and three-month follow-up. The primary outcome was parent-domain stress following intervention. Secondary outcomes included maternal reports of child-domain stress, parenting practices, parenting efficacy, mood, family strain, child behaviour and impairment. Objective measures of the parent-child relationship were collected at baseline and post-treatment. Data analysis was intention to treat (ITT) with treatment effects quantified through analysis of covariance (ANCOVA) via multilevel modelling. An incremental cost-effectiveness ratio (ICER) assessed WPJ's cost-effectiveness. RESULTS: WPJ was superior to TAU in reducing parent-domain stress post-treatment (adjusted mean difference = 5.05, 95% CI 0.33 to 9.81, p = .036) and at follow-up (adjusted mean difference 4.82, 95% CI 0.09 to 9.55, p = .046). Significant WPJ intervention effects were also observed for parenting practices, parenting efficacy and family strain. WPJ and TAU were not significantly different post-intervention or at follow-up for the other secondary outcomes. The incremental cost of WPJ was 34,202 JPY (315.81 USD). The probability that WPJ is cost-effective is 74% at 10,000 JPY (USD 108.30) per one-point improvement in parenting stress, 92% at 20,000 JPY (216.60 USD). The programme was delivered with high fidelity and excellent retention. CONCLUSIONS: WPJ can be delivered in routine clinical care at modest cost with positive effects on self-reported well-being of the mothers, parenting practices and family coping. WPJ is a promising addition to psychosocial interventions for ADHD in Japan.

Red Dichromatic Imaging Improves the Recognition of Bleeding Points During Endoscopic Submucosal Dissection.

BACKGROUND: Previous studies have indicated that red dichromatic imaging (RDI) improved the visibility of gastrointestinal bleeding. AIMS: To investigate the recognition of bleeding points during endoscopic submucosal dissection (ESD) under RDI compared with that under white light imaging (WLI). METHODS: Consecutive patients scheduled to undergo esophageal or gastric ESD at a single center were enrolled. Paired videos of active bleeding during ESD under WLI and RDI were created. Six endoscopists identified the virtual hemostasis point on still images after random video viewing. The distance between virtual hemostasis and actual bleeding points was scored in four levels (0-3 points), and the association with the color value was analyzed in both WLI and RDI. RESULTS: We evaluated 116 videos for 58 bleeding points. The median visibility score and recognition rate were significantly higher for RDI than for WLI (2.17 vs. 1.42, p < 0.001 and 62.1% vs 27.6%, p < 0.001). Additionally, the recognition rate of trainees in RDI was higher than that of experts in WLI (60.3% vs. 43.1%, p = 0.067). The median color difference of RDI was significantly higher than that of WLI (8.97 vs. 3.69, p < 0.001). Furthermore, the correlation coefficient between the visibility score and color difference was 0.712 (strong correlation). CONCLUSION: RDI can provide better recognition of bleeding points than WLI during ESD. Therefore, further studies are warranted to investigate whether RDI improves ESD outcomes.

The Paris System for reporting urinary cytology improves the negative predictive value of high-grade urothelial carcinoma.

BACKGROUND: The Paris System (TPS) for reporting urinary cytology differs from conventional systems (CS) in that it focuses on the diagnosis of high-grade urothelial carcinoma (HGUC). This study investigated the impact of TPS implementation on the diagnostic accuracy of HGUC by comparing it with our institutional CS. METHODS: A total of 649 patients who underwent transurethral resection of bladder tumor (TURBT) between January 2009 and December 2020 were included in this study. Our institution adopted TPS to report urinary cytology in February 2020. The diagnostic accuracy of HGUC in preoperative urinary cytology was compared with the presence or absence of HGUC in resected specimens of TURBT before and after TPS implementation. RESULTS: After implementing TPS in urinary cytology, 89 patients were reviewed and compared with 560 patients whose urinary cytology was diagnosed by CS. TPS and CS for detecting HGUC had 56.0% and 58.2% sensitivity, 97.8% and 91.2% specificity, and 93.3% and 87.9% positive predictive values, respectively. There were no significant differences between TPS and CS in terms of sensitivity, specificity, and positive predictive value for HGUC (P = 0.83, 0.21, 1.00). On the other hand, the negative predictive value for HGUC using TPS was 80.0%, which was significantly higher than that of CS (66.4%, P = 0.04) The multivariate logistic regression analysis indicated that not using TPS was one of the independent predictive factors associated with false-negative results for HGUC (odds ratio, 2.26; 95% confidence interval, 1.08-4.77; P = 0.03). CONCLUSION: In instances where urinary cytology is reported as negative for HGUC by TPS, there is a low probability of HGUC, indicating that TPS has a potential diagnostic benefit.

Incidental Bladder Cancer Found on Cystoscopy during Prostate Biopsy: Prevalence, Pathological Findings, and Oncological Outcome.

INTRODUCTION: We examined the prevalence, pathological findings, and oncological outcomes of incidental bladder cancer found on cystoscopy among patients eligible for prostate biopsy (PB). METHODS: We retrospectively reviewed 803 patients who underwent cystoscopy prior to PB between January 2010 and September 2020. In cases of bladder tumor-like findings on cystoscopy, biopsy or transurethral resection of the bladder tumor was performed. The primary and secondary outcomes were the prevalence of incidental bladder cancer and pathological and oncological outcomes of incidental bladder cancer, respectively. RESULTS: Incidental findings were observed in 31/803 patients (3.9%). Bladder tumor-like findings were found in 24/803 patients (3%), while 9/803 patients (1.1%) were pathologically diagnosed with urothelial carcinoma. The stage and grade of incidental bladder cancer were pTa in 8/9 patients and pT1 in 1/9 and low grade in 8/9 and high in 1/9, respectively. The median tumor size of the papillary pedunculated type was 0.5 cm. At 26-month median follow-up, no recurrence was observed. CONCLUSION: Cystoscopy during PB may yield incidental bladder cancer findings, although the prevalence is very low. Incidental bladder cancer was of low stage and grade, which seemed unrelated to survival. Moreover, performing routine cystoscopy in conjunction with PB is not recommended as it may lead to overdiagnosis of low-risk bladder cancer.

Outcomes of endoscopic submucosal dissection for gastroesophageal reflux disease (ESD-G) for medication-refractory gastroesophageal reflux disease: 35 cases underwent ESD-G including 15 cases followed more than 5 years.

BACKGROUND: Although some kinds of endoluminal surgery for patients with proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) have been reported, there are few reports on their long-term outcomes. In 2014, we reported the effectiveness of endoscopic surgery for PPI-refractory GERD, which we invented and named endoscopic submucosal dissection for GERD (ESD-G) in 2008. Thereafter, we accumulated more cases and monitored the patients' condition postoperatively and describe the outcomes herein. PATIENTS AND METHODS: This single-center, single-arm trial was conducted at the Osaka Medical and Pharmaceutical University Hospital. We compared outcomes between before and 3-6 months after ESD-G. Additionally, we investigated the outcomes of patients 5 or more years after ESD-G. RESULTS: We performed 42 ESD-G procedures in 35 patients between 2008 and 2020. In seven patients, ESD-G was performed twice for various reasons. The frequency scale for the symptoms of GERD score was significantly improved 3-6 months after ESD-G (22 → 10, p < 0.0001); the Los Angeles classification for reflux esophagitis was clearly improved after ESD-G (p = 0.0423). The number of reflux episodes was not decreased by ESD-G. There was a significant difference in the potency unit of gastric acid secretion suppressants for controlling GERD-related symptoms between baseline and 3-6 months after ESD-G (p = 0.0009). In patients without a history of distal gastrectomy who underwent ESD-G, the potency unit of gastric acid secretion suppressants significantly decreased 5 or more years after ESD-G (p = 0.0121). CONCLUSION: ESD-G may be effective in patients with refractory GERD-related symptoms without a history of distal gastrectomy.

Small Intestinal Lesions in Patients with Anemia on Hemodialysis: A Two-Center, Cross-Sectional Study.

AIM: The number of patients on chronic dialysis in Japan is increasing every year, and the average age of these patients is also increasing annually. Iron deficiency is an important cause of anemia in patients on hemodialysis (HD). However, it has not been clarified whether these patients might have small intestinal mucosal lesions causing iron deficiency anemia. METHODS: We conducted a cross-sectional study in -asymptomatic patients on HD between April 2014 and -December 2015. We performed small bowel capsule endoscopy (SBCE) and analyzed the relationship between small intestinal endoscopic findings and anemia. RESULTS: SBCE was successfully completed in 39 eligible patients. Univariate analysis revealed that there was a significant difference in blood hemoglobin levels between the morbid SBCE-finding group (median 7.7 g/dL; range 6.7-9.2 g/dL) and the non-morbid SBCE-finding group (median 10.65 g/dL; range 6.4-13.1 g/dL; p = 0.0006, Mann-Whitney U test). On multivariate analysis, the blood hemoglobin level was an independent predictor of morbid SBCE findings (p = 0.0033). The cutoff value of blood hemoglobin level for the morbid SBCE finding was determined as 9.2 g/dL using receiver operating characteristic curve analysis. CONCLUSIONS: Patients on HD with anemia are at a high risk of small intestinal lesions. Since the control of small intestinal lesion may improve the anemia, these outcomes are significant factors for managing patients on HD.

Endoscopic Evaluation of Neoadjuvant Chemotherapeutic Efficacy in Gastric Cancer before Gastrectomy Might be as Useful as Histological Assessment after Gastrectomy.

BACKGROUND: Neoadjuvant chemotherapy for advanced gastric cancer is expected to improve prognoses. However, as there is no method to evaluate neoadjuvant chemotherapeutic efficacy before gastrectomy, some patients at high risk for a poor prognosis undergo gastrectomy. The aim of the present study was to investigate whether endoscopy could be useful for assessing the efficacy of neoadjuvant chemotherapy. METHODS: In this retrospective study, we analyzed the data of 41 patients who received neoadjuvant chemotherapy followed by gastrectomy at our institution to investigate whether responsiveness to neoadjuvant chemotherapy, as assessed with endoscopy, can serve as a surrogate marker for histological grades 1b or higher in the Japanese Classification of Gastric Carcinoma (JCGC) scheme. RESULTS: There were 32 (78.0%) responders and 9 (22.0%) nonresponders to neoadjuvant chemotherapy, as observed in endoscopic evaluations. Among the endoscopic responders, 24 (75.0%) had cancer of histological grade 1b or higher, and 15 (46.9%) had cancer of grade 2 or higher. Among the endoscopic nonresponders, 1 (11.1%) patient had histological grade 1b cancer. Compared with endoscopic nonresponders, endoscopic responders were more likely to show a histological response (chi-square test: p = 0.0005 for JCGC grade 1b or higher; p = 0.0099 for JCGC grade 2 or higher). CONCLUSIONS: Most endoscopic responders showed JCGC histological responses. Evaluation of neoadjuvant chemotherapeutic efficacy by endoscopy in gastric cancer may be useful before gastrectomy. As this was a retrospective study, further investigations are required. The protocol was approved by the ethics review committee at Osaka Medical College (No. 2422) and was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN000033088).

Induction of brain-derived neurotrophic factor in enteric glial cells stimulated by interleukin-1ß via a c-Jun N-terminal kinase pathway.

Brain-derived neurotrophic factor exhibits neurotropic and neuroprotective functions and is increased in the colonic mucosa of patients with irritable bowel syndrome in correlation with the severity and frequency of abdominal pain. However, there are no reports of brain-derived neurotrophic factor expression in enteric glial cells. We evaluated the mRNA and protein expressions of brain-derived neurotrophic factor in enteric glial cells and culture medium and levels of mitogen-activated protein kinase after stimulation with interleukin-1ß. Brain-derived neurotrophic factor mRNA expression was increased by interleukin-1ß (3.125-75 ng/ml) and time-dependently increased 3-fold (24 h) and 4-fold (48 h) by interleukin-1ß (50 ng/ml). Pro- and mature brain-derived neurotrophic factor proteins were both significantly increased at 48 h by interleukin-1ß. However, the mature form was predominant in the cultured medium. Interleukin-1ß increased phosphorylated-p38 mitogen-activated protein kinase expressions 2-fold higher at 5 and 15 min, and also phosphorylated-c-Jun N-terminal kinase expression 5-fold at 5 min and 10-fold at 15 min. Prior treatment with phosphorylated-c-Jun N-terminal kinase inhibitors decreased interleukin-1ß-induced brain-derived neurotrophic factor by 50%. Thus, brain-derived neurotrophic factor expression was induced by interleukin-1ß in enteric glial cells via a phosphorylated-c-Jun N-terminal kinase pathway, which might affect the enteric nervous system during stress.

Fluoropyrimidine-induced intestinal mucosal injury is associated with the severity of chemotherapy-related diarrhea.

BACKGROUND AND AIM: Although the fluoropyrimidines are effective chemotherapeutic agents for malignant gastrointestinal tumors, they sometimes cause enteritis with diarrhea. Severe treatment-related diarrhea may result in chemotherapy discontinuation. We investigated the relationship between diarrhea severity and fluoropyrimidine-induced small intestinal mucosal injury. METHODS: We performed small bowel capsule endoscopy in patients undergoing chemotherapy including fluoropyrimidine for a malignant tumor between May 2017 and June 2018 and analyzed the relationship between the endoscopic findings and diarrhea severity. We also performed a cross-sectional analysis of patient factors and routes of chemotherapy to identify risk factors of fluoropyrimidine-induced small intestinal injury. RESULTS: Small bowel capsule endoscopy was successfully completed in 16 eligible patients. The diarrhea grade (per the Common Terminology Criteria for Adverse Events, version 4.0) was significantly correlated with the percentage of patients with a small intestinal mucosal break (grade 0, 16.7%; grade 1, 57.1%; grade 2, 100%; p = .016, Cochran-Armitage trend test). Compared to patients receiving intravenous therapy, those receiving an orally administered fluoropyrimidine had a significantly greater number of small intestinal mucosal breaks (median number of breaks [range]; intravenous 5-fluorouracil, 0 [0-13]; oral fluoropyrimidine, 6.5 [1-20]; p = .0162, Mann-Whitney U test). CONCLUSIONS: Many patients with diarrhea caused by chemotherapy including fluoropyrimidine had small intestinal mucosal breaks. Additionally, small intestinal mucosal breaks were more severe in patients receiving a regimen of oral treatment than in those receiving a regimen of intravenous therapy. These outcomes have important implications for investigations of new strategies for preventing anti-cancer drug-induced diarrhea.

Preventive effect of ecabet sodium on low-dose aspirin-induced small intestinal mucosal injury: a randomized, double-blind, pilot study.

BACKGROUND: We aimed to investigate how high-dose ecabet sodium affects low-dose aspirin-induced small intestinal mucosal injury in healthy volunteers. METHODS: Healthy volunteers were enrolled randomly into one of two groups with the following drug regimens for 2 weeks: group A, low-dose aspirin once per day and group B, low-dose aspirin and 4.0 g of ecabet sodium. Small bowel capsule endoscopy was performed before and 2 weeks after low-dose aspirin administration. RESULTS: A significant difference was found in the median number [range] of small intestinal lesions between baseline and two weeks after low-dose aspirin administration in group A (baseline: 1 [0-5], after: 5 [1-11]; p = 0.0059) but not in group B (baseline: 0.5 [0-9], after: 3 [0-23]; p = 0.0586). In group B, although the median number [range] of lesions in the first tertile of the small intestine did not increase two weeks after low-dose aspirin administration (baseline: 0 [0-4], after: 1.5 [0-8]; p = 0.2969), the number of lesions in the second and third tertiles of the small intestine increased significantly (baseline: 0 [0-5], after: 2 [0-15]; p = 0.0469). CONCLUSIONS: Ecabet sodium had a preventive effect on low-dose aspirin-induced small intestinal mucosal injury in the upper part of the small intestine. TRIAL REGISTRATION: ISRCTN 99322160 , 01/10/2018.

Therapy of gastroesophageal reflux disease and functional dyspepsia overlaps with symptoms after usual-dose proton pump inhibitor: Acotiamide plus usual-dose proton pump inhibitor versus double-dose proton pump inhibitor.

BACKGROUND AND AIM: Gastroesophageal reflux disease (GERD) and functional dyspepsia (FD) often coexist or overlap. In this study, the efficacy of acotiamide in combination with a standard dose of rabeprazole for GERD and FD was compared with that of a double dose of rabeprazole. METHODS: Patients with overlap between GERD and FD experiencing heartburn and epigastric fullness symptoms after standard-dose proton pump inhibitor (PPI) for ≥ 8 weeks were randomized into two groups and received either acotiamide 300 mg/day + rabeprazole 10 mg/day or rabeprazole 20 mg/day for 4 weeks. Efficacy was assessed by reductions in symptom scores using the Izumo scale questionnaire and modified F-scale questionnaire. RESULTS: As the primary endpoint, three upper gastrointestinal symptoms (heartburn, epigastralgia, and epigastric fullness) were reduced by ≥ 50% in 40.8% and 46.9% of patients in the combination and PPI double-dose groups, respectively, with no significant difference between the two groups. Essentially similar results were obtained for the modified F-scale questionnaire. No serious adverse events were noted. CONCLUSIONS: Acotiamide 300 mg/day in combination with rabeprazole 10 mg/day or rabeprazole 20 mg/day relieved symptoms in patients with overlap between GERD and FD experiencing heartburn and epigastric fullness symptoms after standard-dose PPI for ≥ 8 weeks, and the efficacies did not differ between the two treatments. The combination therapy may be an alternative option for persistent symptoms in these patients.

Vonoprazan, a Novel Potassium-Competitive Acid Blocker, Should Be Used for the Helicobacter pylori Eradication Therapy as First Choice: A Large Sample Study of Vonoprazan in Real World Compared with Our Randomized Control Trial Using Second-Generation Proton Pump Inhibitors for Helicobacter pylori Eradication Therapy.

BACKGROUND/AIMS: Phase III study demonstrated that vonoprazan-based Helicobacter pylori eradication therapy achieved higher eradication rate compared with lansoprazole. However, there is no study that evaluated the efficacy of vonoprazan in a large sample in real world. We investigated the eradication rate and safety of vonoprazan-based eradication therapy compared with our randomized control trial using second-generation proton pump inhibitor (PPIs). METHODS: (First study) A total of 147 patients who have H. pylori infection were randomly assigned to receive either, esomeprazole (EPZ) group and rabeprazole (RPZ) group. (Second study) 1,688 patients who have H. pylori infection underwent primary eradication with triple therapy involving vonoprazan. In both studies, triple therapy with amoxicillin, clarithromycin, and PPI or vonoprazan was performed, and eradication effect was assessed by an urea breath test. RESULTS: (First study) Eradication rate was 77.5% in the EPZ group and 68.4% in the RPZ group; no significant difference was observed between the 2 groups. (Second study) The successful primary eradication rate was 90.8%. There was no severe adverse effect. CONCLUSIONS: The eradication rate of vonoprazan-based triple therapy was remarkably higher compared with second-generation PPIs-based triple therapy in real world. Vonoprazan is very likely to become the first option for future eradication therapy.

Comparison of the Effects of Vonoprazan and Lansoprazole for Treating Endoscopic Submucosal Dissection-Induced Artificial Ulcers.

BACKGROUND: Vonoprazan exhibits a more potent, rapid, and longer-lasting inhibitory effect on gastric acid secretion than proton pump inhibitors; however, whether it is more effective than PPI for treating endoscopic submucosal dissection (ESD)-induced artificial ulcers remains controversial. AIM: This study aimed to assess and compare the effects of vonoprazan and lansoprazole for treating ESD-induced artificial ulcers. METHODS: This prospective, randomized controlled trial enrolled 149 patients who underwent ESD for the treatment of early gastric neoplasms from April 2015 to May 2017. They were randomly treated with either 20 mg/day vonoprazan (V group) or 30 mg/day lansoprazole (L group) orally. The primary end points were the area and shrinkage ratio of the ulcers at 4 and 8 weeks post-ESD. RESULTS: Data from 127 patients were analyzed, which showed that the 4- and 8-week healing ratios were not significantly different between the V and L groups (4 weeks, 16.3 vs. 25.8%; 8 weeks, 86.9 vs. 90.9%, respectively). Similarly, the shrinkage ratio, categorized as less than 90%, 90% or more but less than 100%, or 100% at 4 weeks and as less than 100% or 100% at 8 weeks were not statistically different between the V and L groups (4 weeks: 12, 41, 8 vs. 13, 41, 12, p = 0.7246; 8 weeks: 9, 52 vs. 9, 57, p = 0.8568). Delayed bleeding was also not significantly different between both the groups (5.4 vs. 5.3%; p = 0.9844). CONCLUSIONS: Vonoprazan is as effective as lansoprazole in treating ESD-induced ulcers.

Dual antiplatelet therapy does not affect the incidence of low-dose aspirin-induced small intestinal mucosal injury in patients after percutaneous coronary intervention for coronary stenosis: a multicenter cross-sectional study.

Although low-dose aspirin (LDA) is known to induce small intestinal mucosal injury, the effect of dual antiplatelet therapy (DAPT; LDA + clopidogrel) on small intestinal mucosa in patients after percutaneous coronary intervention (PCI) for coronary stenosis is unknown. Fifty-one patients with a history of PCI and LDA use were enrolled, and 45 eligible patients were analyzed. Patients were grouped based on DAPT (DAPT: n = 10 and non-DAPT: n = 35) and proton pump inhibitor (PPI) use (PPI user: n = 22 and PPI-free patients: n = 23) to compare small intestinal endoscopic findings. The relationship between LDA-use period and small intestinal endoscopic findings was also examined. Multivariate analysis was performed to identify risk factors for LDA-induced mucosal injury using age, sex, DAPT, PPI, gastric mucoprotective drug, and LDA-use period. The rate of small intestinal mucosal injury incidence did not significantly differ between DAPT and non-DAPT patients (50% vs 51.1%, respectively; p = 0.94), or PPI users and PPI-free patients (50% vs 52.2%, respectively; p = 0.88). Additionally, LDA-use period of ≤24 months (n = 15) yielded a significantly higher rate of small intestinal mucosal injury incidence than LDA-use period >24 months (n = 30) (80% vs 36.7%, respectively; p = 0.006). Multivariate analysis revealed that a LDA-use period of ≤24 months was a significant risk factor for small intestinal mucosal injury (odds ratio: 19.5, 95% confidence interval: 2.48-154.00, p = 0.005). Following PCI for coronary stenosis, neither DAPT nor PPI affected LDA-induced small intestinal mucosal injury. Moreover, patients who used LDA within the last 24 months were at a greater risk of small intestinal mucosal injury.

Effect of egualen sodium hydrate on small-intestinal mucosal damage induced by low-dose aspirin: a prospective randomized clinical trial.

Low-dose aspirin, which is widely used to reduce the risk of cardio- and cerebrovascular thrombosis, often induces gastroenteropathy by increasing the permeability of the mucosa. However, therapeutic strategies for patients with low-dose aspirin-induced small intestinal injury have not been determined. We evaluated the preventative effect of egualen sodium hydrate, a gastro-protective agent that suppresses indomethacin-induced small-intestinal damage in rats, against small-intestinal mucosal damage induced by low-dose aspirin in healthy adult male volunteers. Participants were randomly allocated to receive aspirin 100 mg/kg daily (control group, n = 10) or aspirin 100 mg/kg plus egualen sodium 30 mg daily (egualen sodium group, n = 10). Small intestinal mucosal injury was evaluated by capsule endoscopy two weeks after initiation of drug administration. Fecal analyses (occult blood test, immunochemical test, transferrin measurement and calprotectin measurement) were carried out before and after treatment. Egualen sodium significantly suppressed the total number of small intestinal injuries detected by capsule endoscopy and the positive ratio for the fecal occult blood test. Daily use of 30 mg of egualen sodium showed a preventative effect on low-dose aspirin-induced small intestinal injury. Since acid suppression therapy was reported to exacerbate NSAIDs-induced enteropathy via dysbiosis, egualen sodium may be useful for patients treated with low-dose aspirin.

A Social Program for the Early Detection of Pancreatic Cancer: The Kishiwada Katsuragi Project.

OBJECTIVES: The early-stage pancreatic cancer (e-PC; stage I/II) detection rate is quite low at approximately 25%. The aim of this study was to evaluate the feasibility of a social program (the Kishiwada Katsuragi project) wherein our hospital, which specializes in PC, and primary care medical offices (PMOs) used clinical findings to detect e-PC. METHODS: Patients with a score of ≥2 points on clinical findings were enrolled: symptoms of abdominal pain/back pain (1 point), new-onset diabetes (1 point), high amylase (AMY) and/or pancreaitc AMY (P-AMY) (1 point), high carbohydrate antigen 19-9 (1 point), and ultrasonography (US) findings including direct (e.g., a solid pancreatic tumor) and/or indirect findings (e.g., dilatation of a pancreatic diameter of ≥2.5 mm and/or cystic lesions) (2 points) were evaluated using the protocol for social programs. RESULTS: Between November 2014 and December 2016, 244 patients were enrolled by 41 PMOs as cooperative facilities, and 15 e-PC cases (53.6%) of the 28 PC patients were detected. The mean clinical finding score of the e-PC group (3.13 ± 1.9) was significantly higher than that of the overall non-PC group (2.1 ± 0.4) (p < 0.05). "High AMY/P-AMY" and "symptoms" were significantly more frequent in the e-PC group than in the non-PC group (p < 0.05). Although the sensitivity of direct findings by US was 40.0%, that of indirect-findings was 93.3% in the e-PC group. Nine and 6 of the 15 patients with e-PC were enrolled via general internal medicine offices (GIMs) and other PMOs without GIMs (general surgery, n = 3; urology, n = 2; otolaryngology, n = 1). CONCLUSION: This social program with collaborations between medical centers that specialize in PC and PMOs used clinical findings, suggesting that not only GIMs but also other PMOs and indirect findings by US may play an important role in improving the e-PC detection rate.

Exploratory Research on Latent Esophageal Motility Disorders in Dysphagia Patients.

BACKGROUND/AIMS: High-resolution manometry (HRM) has been applied to assess esophageal motility disorders. However, the frequency and types of motility disorders in patients with dysphagia, which are frequently seen in clinical practice, are not clear. We evaluated latent esophageal motility disorders associated with dysphagia. METHODS: The study included patients without erosive esophageal mucosal damage and with dysphagia symptoms refractory to at least 8 weeks of standard-dose proton pump inhibitors. After enrolment, HRM was used to evaluate for esophageal motility disorder based on the Chicago classification. RESULTS: Esophageal motility disorder was found in 58 of 100 patients and was classified based on the causes: achalasia (13%), esophagogastric junction outflow obstruction (16%), distal esophageal spasms (3%), weak peristalsis (14%), frequently failed peristalsis (5%), and hypertensive peristalsis (7%). CONCLUSION: Primary esophageal motility disorder was found in approximately 50% of cases in dysphagia patients. Therefore, esophageal motility disorder is not an uncommon condition and should be sought for in order to elucidate precisely the cause of dysphagia.

Determination of the adequate dosage of rebamipide, a gastric mucoprotective drug, to prevent low-dose aspirin-induced gastrointestinal mucosal injury.

Small intestinal mucosal injury caused by low-dose aspirin is a common cause of obscure gastrointestinal bleeding. We aimed to investigate the protective effects and optimal dose of rebamipide for low-dose aspirin-induced gastrointestinal mucosal injury. In this prospective randomized trial, 45 healthy volunteers (aged 20-65 years) were included and divided into three groups. The groups received enteric-coated aspirin 100 mg (low-dose aspirin) plus omeprazole 10 mg (Group A: proton pump inhibitor group), low-dose aspirin plus rebamipide 300 mg (Group B: standard-dose group), or low-dose aspirin plus rebamipide 900 mg (Group C: high-dose group). Esophagogastroduodenoscopy and video capsule endoscopy were performed, and the fecal occult blood reaction and fecal calprotectin levels were measured before and two weeks after drug administration. Although the fecal calprotectin levels increased significantly in Group A, they did not increase in Groups B and C. The esophagogastroduodenoscopic and video capsule endoscopic findings and the fecal occult blood test findings did not differ significantly among the three groups. In conclusion, standard-dose rebamipide is sufficient for preventing mucosal injury of the small intestine induced by low-dose aspirin, indicating that high-dose rebamipide is not necessary.

Autophagy Deficiency Diminishes Indomethacin-Induced Intestinal Epithelial Cell Damage through Activation of the ERK/Nrf2/HO-1 Pathway.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause epithelial cell damage in the stomach, intestine, and colon. NSAIDs are reported to induce autophagy and apoptosis in intestinal epithelial cells; however, their role in cell damage is poorly understood. To examine the role of autophagy in cell damage, we used autophagy-related gene Atg5-conditional knockout mice, in which the Atg5 gene is only knocked out in intestinal epithelial cells. In an indomethacin (IM)-induced gastrointestinal ulcer mouse model, intestinal epithelium damage was reduced in Atg5-conditional knockout mice compared with wild-type mice. IM-induced damage in IEC6 rat intestinal epithelial cells was reduced when Atg5 was silenced (IEC6shAtg5 cells). Western blot analyses indicated that IM-induced apoptosis decreased, and the potent, oxidative stress-related extracellular signal-regulated kinase (ERK)/nuclear factor-erythroid2-like2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway was upregulated in IEC6shAtg5 cells. An experiment using a reactive oxygen species (ROS)-sensitive fluorescent dye in IEC6shAtg5 cells revealed that the amount of ROS at the baseline and the rate of increase after IM treatment were lower than in intact IEC6 cells. The mitochondrial membrane potential at the baseline and the reduction rate in IM-treated IEC6shAtg5 cells were lower than in intact IEC6 cells, indicating that autophagy deficiency increased ROS production caused by mitochondrial disturbance. Furthermore, MnTMPyP, a manganese-superoxide dismutase mimetic, significantly inhibited IM-induced autophagy and subsequent apoptosis as well as activation of the ERK/Nrf2/HO-1 pathway. These data suggest that autophagy deficiency and subsequent activation of the ERK/Nrf2/HO-1 pathway diminished IM-induced, apoptosis-mediated intestinal epithelial cell damage, and genetic analyses of single nucleotide polymorphisms in autophagy-related genes could predict NSAID-induced intestinal injury.

Current Topics of Strategy of NSAID-Induced Small Intestinal Lesions.

Small intestinal mucosal injuries have been recently recognized as common complications associated with non-steroidal anti-inflammatory drugs (NSAIDs) because video capsule endoscopy and balloon enteroscopy are now available for the detection of small intestinal lesions. Small intestinal injury occurs not in an acid-dependent mechanism but by various factors such as enteric bacteria, bile acids, prostaglandin (PG) deficiency and topical factors (abnormal intestinal mucosal permeability, mitochondrial dysfunction, reactive oxygen species, endoplasmic reticulum stress and so on), and there is no well-established prophylactic approach. Several experimental and clinical studies found the effectiveness of some of the mucoprotective drugs, PG analogs, but not that of acid suppressants. Considering the effect of proton pump inhibitors (PPIs) for upper gastrointestinal (GI) disease and in the small intestine, the following 2 kinds of strategies against NSAID-induced GI injuries may be recommended. In patients with a high risk of upper GI disease (peptic ulcer etc.), simultaneous administration of a PPI (for upper GI disease) and a mucoprotective drug (for small intestine) is needed to prevent NSAID-induced GI injury. In other cases, an effective mucoprotective drug is enough for the protection of the entire digestive tract, that is, starting from the esophagus to the small intestine. These strategies may fulfill both economical and curative effects.