Molecular biomarker identification for esophageal adenocarcinoma using endoscopic brushing and magnified endoscopy.

BACKGROUND: Barrett's esophagus (BE) is a predisposing factor for esophageal adenocarcinoma (EAC); however, the precise mechanism underlying this association remains unclear. The identification of biomarkers that are associated with an increased risk of BE progression to EAC would facilitate diagnosis and early treatment. Toward this goal, we aimed to identify biomarkers associated with BE and EAC in patients. METHODS: In conjunction with high-resolution magnified endoscopy with narrow-band imaging (ME-NBI), we obtained brushing samples from the long-segment BE (LSBE) or short-segment BE (SSBE) of patients with EAC or without EAC (control). To identify candidate biomarker genes, microarray analysis was performed for a training set of 28 American samples. To confirm the microarray results, expression levels of the 16 candidate biomarkers were evaluated by real-time polymerase chain reaction analysis, using samples collected from an additional 53 American patients. In addition, we also performed a functional analysis for these genes using Gene Ontology (GO) enrichment analysis. RESULTS: Among the 16 genes identified as differentially expressed by microarray analysis, the GO analysis indicated matrix metalloproteinase (MMP) family associated with 'collagen metabolic process' and 'multicellular organismal macromolecule metabolic process' as the two top biological processes. Brushing samples of patients with EAC showed up-regulated expression of decay-accelerating factors (DAF and CD55) and topoisomerase type Iiα (TOP2A), and down-regulated expression of the sodium channel epithelial 1 beta subunit (SCNN1B). CONCLUSIONS: The up-regulation of CD55 and TOP2A, and the down-regulation of SCNN1B were common to the brushing samples and might serve as molecular biomarkers for identifying EAC in patients with SSBE. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) (000004004).

New ultrasonographic screening method for oropharyngeal dysphagia: tissue Doppler imaging.

Ultrasound tissue Doppler imaging (US-TDI) has been used to diagnose regional wall motion (WM) abnormalities in coronary artery disease but has not been applied to oropharyngeal diseases. This study aimed first to validate an US-TDI method to assess cervical esophageal (CE) WM and secondly to use the method to evaluate CE WM in patients with oropharyngeal dysphagia (OD). First, we enrolled 22 healthy men (mean age: 59.7 yr) who all underwent both US-TDI and videofluoroscopy (VF) and then esophageal high-resolution manometry (HRM) in the same week. We evaluated the reproducibility of the US-TDI and the relationship between US-TDI and other modalities (VF and HRM). Second, we enrolled 56 mild OD patients (mean age: 58.0 yr) and age- and sex-matched healthy controls. Difference in CE WM between these groups was evaluated by US-TDI. All healthy subjects underwent US-TDI, VF, and HRM successfully, with a sufficiently high reproducibility coefficient for this method, and significant correlation between US-TDI and VF/HRM parameters. US-TDI showed mean time to open CE wall and mean velocity of CE wall opening significantly differed between patients and healthy controls ( P < 0.01). In conclusion, we have developed a US-TDI method for easily assessing CE WM in daily practice and also found significant differences in CE WM between mild OD patients and healthy controls. NEW & NOTEWORTHY A new ultrasonographic screening method using tissue Doppler imaging for oropharyngeal dysphagia was found to be a reliable, reproducible, and well-tolerated method. There is a significant correlation between this new method and conventional methods. This method revealed that patients having mild symptoms of oropharyngeal dysphagia had already significantly delayed cervical esophageal wall opening.

Hypergastrinemia in Long-Term Use of Proton Pump Inhibitors.

BACKGROUND/AIM: The use of proton pump inhibitors (PPIs) is known to lead to hypergastrinemia; however, the data in patients with atrophic gastritis is still lacking. The aim of this study was to investigate the effects of long-term PPIs use on the gastrin levels in patients with atrophic gastritis and to determine factors affecting hypergastrinemia in long-term users of PPIs. METHODS: Serum Helicobacter pylori IgG, gastrin and pepsinogen levels were measured. Atrophic gastritis was assessed by upper gastrointestinal endoscopies based on the Kimura-Takemoto classification and pepsinogen levels. CYP2C19 polymorphisms were assessed using DNA extracted from peripheral blood. RESULTS: A total number of 382 patients (275 men and 107 women) were enrolled. Median serum gastrin levels were higher in PPI users than in non- users (234 vs. 113 pg/mL, p < 0.001) and in women than in men (252 vs. 155 pg/mL, p = 0.006). Gastrin levels were significantly associated with corpus atrophy only in the subgroup of non-users of PPIs. Multivariate analysis revealed that hypergastrinemia (over 150 pg/mL) was significantly associated with PPI use (OR 5.30; 95% CI 3.32-8.47), women (OR 2.22; 95% CI 1.33-3.72) and corpus atrophy (OR 1.82; 95% CI 1.14-2.90). CONCLUSION: PPI use, women and corpus atrophy were risk factors for hypergastrinemia. Gender, but not corpus atrophy, affected the gastrin levels in long-term users of PPIs.

Differences in the clinical course of 516 Japanese patients with upper gastrointestinal bleeding between weekday and weekend admissions.

BACKGROUND AND AIMS: Patients suspected of having upper gastrointestinal bleeding (UGIB) admitted during the weekend tend to have a poor outcome in western countries. However, no Japanese studies have been reported on this matter. We aimed to evaluate differences in the clinical course of patients with UGIB between weekday and weekend admissions in Japan. METHODS: Medical records of patients who had undergone emergency endoscopy for UGIB were retrospectively reviewed. The severity of UGIB was evaluated using the Glasgow-Blatchford (GB) and AIMS65 score. Patients in whom UGIB was stopped and showed improved iron deficiency anemia after admission were considered as having a good clinical course. RESULTS: We reviewed 516 consecutive patients and divided them into two groups: Group A (daytime admission on a weekday: 234 patients) and Group B (nighttime or weekend admission: 282 patients). There was no significant difference in GB and AIM65 scores between the Groups. The proportions of patients with good clinical course were not significantly different between groups (A, 67.5% and B, 67.0%; p = .90). However, patients in Group B underwent hemostatic treatments more frequently compared with those in Group A (58.5% vs 47.4%, p = .012). Multivariate analysis showed that taking acid suppressants, no need for blood transfusions, use of hemostatic treatments, and GB score <12 were associated with a good clinical course. CONCLUSIONS: There were no significant differences in the clinical outcomes of patients with UGIB admitted during daytime on weekdays and those admitted at nighttime or weekends partly owing to the sufficient performance of endoscopic hemostatic treatments.

Effects of Capsaicin on Older Patients with Oropharyngeal Dysphagia: A Double-Blind, Placebo-Controlled, Crossover Study.

BACKGROUND/AIMS: The standard of care for older patients with oropharyngeal dysphagia (OD) is poor. Stimulation of transient receptor potential vanilloid 1 might become a pharmacological strategy for these patients. This study aimed to compare the therapeutic effect of film food containing 0.75 µg of capsaicin in these patients. METHODS: In a crossover, randomized trial, 49 patients with OD were provided capsaicin or identical placebo at least 7 days apart. Patients' reported symptoms during repeated swallowing, the volume, pH and substance P (SP) concentrations in saliva, and cervical esophageal wall motion evaluated by ultrasonographic tissue Doppler imaging were obtained before and after capsaicin or placebo administration. RESULTS: Significantly more patients with OD who took capsaicin experienced improvement in symptoms than those who took placebo. Salivary SP levels were significantly increased after capsaicin administration compared with placebo in the effective group. The duration of cervical esophageal wall opening was significantly shorter in capsaicin administration in the effective group. Furthermore, a significant negative correlation was found between the duration of cervical esophageal wall opening and salivary SP levels. CONCLUSION: Elevated salivary SP concentrations stimulated by capsaicin greatly improve the safety and efficacy of swallowing, and shorten the swallow response in older patients with OD.

Age-Related Differences in Clinical Characteristics and Esophageal Motility in Patients with Dysphagia.

Dysphagia in elderly patients has a major effect on nutrition and quality of life (QOL). Although several studies have shown that aging itself is associated with changes in esophageal motility, the impact of these changes on dysphagia symptoms and QOL is unknown. This study assessed the manometric diagnoses of elderly patients with dysphagia compared with diagnoses in younger counterparts. Participants included 116 consecutive patients examined for dysphagia from 2007 to 2014. We divided patients into three groups by age: Group A, 66 years and older (24 men, 23 women); Group B, 45-65 years (18 men, 24 women); and Group C, 44 years and younger (15 men, 12 women). The three groups were compared in regard to symptoms, esophageal motility, and health-related QOL (HRQOL). All patients underwent esophageal manometry examination and completed a self-administered questionnaire concerning their symptoms; HRQOL assessment was based on results of the Short Form-8 General Health Survey. Symptoms rated ≥4 points on the Likert scale were defined as significant. Although all patients had dysphagia as a major symptom, more elderly patients reported globus sensation, whereas more young patients reported heartburn as the primary symptom. Manometric diagnoses were generally similar across the three groups. Ineffective esophageal motility was more prevalent in Groups A and C than in Group B, although the difference was not statistically significant. No significant differences in manometric parameters or HRQOL were detected among the three groups. Despite differences in symptom patterns, broad manometric diagnoses and impairment of HRQOL in elderly patients with dysphagia are similar to those in younger counterparts.

Molecular Detection of H. pylori Using Adherent Gastric Mucous to Biopsy Forceps.

BACKGROUND AND AIM: We assessed whether adherent gastric mucous to biopsy forceps instead of biopsy samples was suitable for the diagnosis of H. pylori infection. We confirmed the PCR methods to improve the diagnosis of H. pylori infection and clarithromycin (CAM) susceptibility. METHODS: Gastric mucous was obtained by gently scraping gastric mucosa using biopsy forceps in patients undergoing upper gastrointestinal (GI) endoscopy for PCR and rapid urease test (RUT). DNA was extracted from gastric mucous present within the gel of RUT. H. pylori status and CAM susceptibility were evaluated using H. pylori-specific PCR amplification for 23S rRNA using 4 different primer sets and 16S rRNA. H. pylori positive was defined as two of the three tests (serum antibody, histology, and RUT or PCR) were positive. CAM susceptibility was evaluated by point mutations (A 2142G and A 2143G of 23S rRNA). RESULTS: Samples taken from 494 subjects were evaluated: 300 H. pylori-positive patients and 194 negative patients. The results of PCR using DNA extracted from gastric mucous present within the RUT gel were consistent with those within water. The accuracy of 23S rRNA PCR for H. pylori detection using RUT samples was superior to the other tests. The frequency of CAM resistance was 38.9%, and eradication rate was 91.3% in the patients with wild-type and 47.0% in the patients with the mutant strains. CONCLUSION: Adherent gastric mucous to biopsy forceps in RUT gel can be used for molecular testing to confirm the diagnosis of H. pylori infection and for CAM susceptibility.

Helicobacter pylori Eradication with Proton Pump Inhibitors or Potassium-Competitive Acid Blockers: The Effect of Clarithromycin Resistance.

BACKGROUND: Vonoprazan is a novel potassium-competitive acid blocker (P-CAB) recently approved for Helicobacter pylori eradication therapy in Japan. AIMS: To compare PPI- and P-CAP-containing triple therapy and vonoprazan-based triple therapy. METHODS: Two hundred ninety-five initial subjects received a PPI-containing triple therapy; the next 125 subjects received vonoprazan-containing triple therapy. Two sequential groups received 7-day eradication regimens consisting of amoxicillin 750 mg, clarithromycin 200 mg both twice a day with standard dose PPI or vonoprazan (20 mg) each twice daily. H. pylori eradication was confirmed by a 13C-UBT. Clarithromycin susceptibility was evaluated by 23S rRNA PCR. RESULTS: Population cure rates with clarithromycin susceptible strains were 89.6 versus 100 % for PPI and vonoprazan therapies, respectively. Cure rates with resistant strains were 40.2 % with PPI therapy versus 76.1 % with vonoprazan triple therapy. There was no difference in side effects. CONCLUSIONS: Although 7-day P-CAB triple therapy was superior to 7-day PPI triple therapy, neither was highly effective, or can be recommended, in the presence of clarithromycin-resistant infections.

Safety of gastrointestinal endoscopic biopsy in patients taking antithrombotics.

BACKGROUND AND AIM: Current Japanese gastrointestinal (GI) endoscopic guidelines permit endoscopic biopsy without cessation of antiplatelet agents and warfarin in patients with a therapeutic range of prothrombin time-international normalized ratio (PT-INR) levels, although the evidence levels are low. We evaluated the safety of endoscopic biopsy in patients currently taking antithrombotics. METHODS: Consecutive patients receiving antithrombotics who underwent GI endoscopy from August 2012 to August 2013 were enrolled. Adverse events and endoscopic hemostasis after biopsy were evaluated. PT-INR level was measured in patients taking warfarin the day before endoscopy. RESULTS: Among 7939 patients undergoing endoscopy, 1034 patients (13.0%, 706 men and 328 women, average age 72.8 years) were receiving antithrombotics. Antithrombotics included aspirin (44.8%), warfarin (34.7%), thienopyridine (16.1%), cilostazol (10.3%), dabigatran (4.8%) etc. PT-INR levels in patients taking warfarin were >3.0 in 13 patients (4.3%), between 2.5 and 3.0 in 18 patients (6.0%), <2.5 in 269 patients (89.7%). Two hundred and six patients received endoscopic biopsy while taking aspirin (51.2%), warfarin (22.8%), and thienopyridine (13.6%). Endoscopic hemostasis was required in three patients after endoscopic biopsy (spraying thrombin in two patients, spraying thrombin and clipping in one patient). There were no major complications. The incidence of endoscopic hemostasis after biopsy in patients without antithrombotic cessation was not significantly different than in the controls not taking antithrombotics (1.5% vs 0.98%, P = 0.51). CONCLUSION: Endoscopic biopsy did not increase the bleeding risk despite not stopping antithrombotics prior to biopsy even among patients taking warfarin whose PT-INR was within the therapeutic range.

Diagnosis and treatments for oropharyngeal dysphagia: effects of capsaicin evaluated by newly developed ultrasonographic method.

Oropharyngeal dysphagia (OD) is a common symptom in the older people, and may cause fatal complications such as aspiration pneumonia. However, there is no established treatment for OD. The relationship between the transient receptor potential vanilloid 1 (TRPV1) and substance P released by activated TRPV1 was recently demonstrated. Further, there are several reports showing that capsaicin, a specific agonist of TRPV1, can improve OD. Currently, the evaluation of swallowing is mainly performed by videofluoroscopic examination. However, there are no reports on the clinical application of ultrasonography using tissue Doppler imaging. In this review, we describe the pathophysiology and treatments for OD, introduce our novel US method to evaluate cervical esophageal motility, and then outline our clinical study examining the effects of capsaicin, a specific TRPV1 agonist, in older patients with OD.

Colonic endoscopic mucosal resection in patients taking anticoagulants: Is heparin bridging therapy necessary?

OBJECTIVE: Heparin bridging therapy (HBT) reportedly increases the risk of post-procedural bleeding, and its safety during endoscopic interventions remains unclear. We aimed to evaluate the effects of peri-procedural HBT in patients taking anticoagulants who underwent colonic endoscopic mucosal resection (EMR) for polyps. METHODS: Patients who underwent colonic EMR while taking a single anticoagulant agent were enrolled in this study. Anticoagulants were temporarily ceased in all patients either without (the non-HBT group, prospectively enrolled) or with HBT (the HBT group, retrospectively enrolled). The incidences of post-procedural bleeding and anemia exacerbation and their length of hospitalization were evaluated and compared. RESULTS: There were altogether 43 consecutive adult patients (30 men; mean age 72.2 ± 7.4 years) in the non-HBT group and 41 sex- and age-matched adults (32 men; mean age 72.9 ± 8.3 years) in the HBT group. There were no significant differences in the location, number or size of resected polyps between the two groups. The percentage of patients with post-procedural bleeding within 2 weeks after colonic EMR in the non-HBT group was lower than that in the HBT group (2.3% vs 9.8%, P = 0.15), although the frequency of anemia exacerbation was not significantly different between the two groups. The total hospitalization length was shorter in the non-HBT compared with the HBT group (4.5 days vs 6.0 days, P < 0.001). CONCLUSIONS: No patient in either group developed embolism during hospitalization. Colonic EMR with the temporary cessation of anticoagulants without HBT may be acceptable and beneficial for patients taking anticoagulants.