Optimal timing of simethicone administration prior to upper endoscopy: A multicenter, single-blind, randomized controlled trial.

Background and study aims Simethicone is useful as premedication for upper endoscopy because of its antifoaming effects. We aimed to evaluate the effect of timing of simethicone administration on mucosal visibility. Patients and methods In this multicenter, randomized, endoscopist-blinded study, patients scheduled for upper endoscopy were randomized to receive 40 mg simethicone at the following time points prior to the procedure: 20 to 30 minutes (early group), 0 to 10 minutes (late group) or 20 mg simethicone at both time points (split-dose group). Images were taken from nine predefined locations in the esophagus, stomach, and duodenum before endoscopic flushing. Each image was scored on mucosal visibility by three independent endoscopists on a 4-point scale (lower scores indicating better visibility), with adequate mucosal visibility defined as a score ≤ 2. Primary outcome was the percentage of patients with adequate total mucosal visibility (TMV), reached if all median subscores for each location were ≤ 2. Results A total of 386 patients were included (early group: 132; late group: 128; split-dose group: 126). Percentages of adequate TMV were 55%, 42%, and 61% in the early, late, and split-dose group, respectively ( P < 0.01). Adequate TMV was significantly higher in the split-dose group compared to the late group ( P < 0.01), but not compared to the early group ( P = 0.29). Differences between groups were largest in the stomach, where percentages of adequate mucosal visibility were higher in the early (68% vs 53%, P = 0.03) and split-dose group (69% vs 53%, P = 0.02) compared to the late group. Conclusions Mucosal visibility can be optimized with early simethicone administration, either as a single administration or in a split-dose regimen.

Endoscopic Resection Without Subsequent Ablation Therapy for Early Barrett's Neoplasia: Endoscopic Findings and Long-Term Mortality.

INTRODUCTION: After endoscopic resection (ER) of neoplasia in Barrett's esophagus (BE), it is recommended to ablate the remaining BE to minimize the risk for metachronous disease. However, we report long-term outcomes for a nationwide cohort of all patients who did not undergo ablation of the remaining BE after ER for early BE neoplasia, due to clinical reasons or performance status. METHODS: Endoscopic therapy for BE neoplasia in the Netherlands is centralized in 8 expert centers with specifically trained endoscopists and pathologists. Uniformity is ensured by a joint protocol and regular group meetings. We report all patients who underwent ER for a neoplastic lesion between 2008 and 2018, without further ablation therapy. Outcomes include progression during endoscopic FU and all-cause mortality. RESULTS: Ninety-four patients were included with mean age 74 (± 10) years. ER was performed for low-grade dysplasia (LGD) (10%), high-grade dysplasia (HGD) (25%), or low-risk esophageal adenocarcinoma (EAC) (65%). No additional ablation was performed for several reasons; in 73 patients (78%), the main argument was expected limited life expectancy. Median C2M5 BE persisted after ER, and during median 21 months (IQR 11-51) with 4 endoscopies per patient, no patient progressed to advanced cancer. Seventeen patients (18%) developed HGD/EAC: all were curatively treated endoscopically. In total, 29/73 patients (40%) with expected limited life expectancy died due to unrelated causes during FU, none of EAC. CONCLUSION: In selected patients, ER monotherapy with endoscopic surveillance of the residual BE is a valid alternative to eradication therapy with ablation.

Impact of nationwide enhanced implementation of best practices in pancreatic cancer care (PACAP-1): a multicenter stepped-wedge cluster randomized controlled trial.

BACKGROUND: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. METHODS/DESIGN: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. DISCUSSION: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018.

Treatment of refractory post-esophagectomy anastomotic esophageal strictures using temporary fully covered esophageal metal stenting compared to repeated bougie dilation: results of a randomized controlled trial.

Background and study aims Fully covered self-expanding metal stents (FCSEMS) provide an alternative to bougie dilation (BD) for refractory benign esophageal strictures. Controlled studies comparing temporary placement of FCSES to repeated BD are not available. Patients and methods Patients with refractory anastomotic esophageal strictures, dysphagia scores ≥ 2, and two to five prior BD were randomized to 8 weeks of FCSEMS or to repeated BD. The primary endpoint was the number of BD during the 12 months after baseline treatment. Results Eighteen patients were included (male 67 %, median age 66.5; 9 received metal stents, 9 received BD). Technical success rate of stent placement and stent removal was 100 %. Recurrent dysphagia occurred in 13 patients (72 %) during follow-up. No significant difference was found between the stent and BD groups for mean number of BD during follow-up (5.4 vs. 2.4, P  = 0.159), time to recurrent dysphagia (median 36 days vs. 33 days, Kaplan-Meier: P  = 0.576) and frequency of reinterventions per month (median 0.3 vs. 0.2, P  = 0.283). Improvement in quality of life score was greater in the stent group compared to the BD group at month 12 (median 26 % vs. 4 %, P  = 0.011). Conclusions The current data did not provide evidence for a statistically significant difference between the two groups in the number of BD during the 12 months after initial treatment. Metal stenting offers greater improvement in quality of life from baseline at 12 months compared to repeated BD for patients with refractory anastomotic esophageal strictures.

Rapid on-site evaluation during endoscopic ultrasound-guided fine-needle aspiration of lymph nodes does not increase diagnostic yield: A randomized, multicenter trial.

OBJECTIVES: Studies on the impact of rapid on-site evaluation (ROSE) during endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of lymph nodes are retrospective and have shown conflicting results. We aimed to compare the diagnostic yield of EUS-FNA of lymph nodes with ROSE (ROSE+) and without ROSE (ROSE-). METHODS: This was a multicenter, randomized controlled trial. Consecutive patients who were scheduled to undergo EUS-FNA of mediastinal or abdominal lymph nodes were randomized to ROSE+ or ROSE-. In the ROSE+ group, the number of passes was dictated by the on-site cytotechnician. In the ROSE- group, five passes were performed without interference from the cytotechnician. All samples were reviewed by a single-expert cytopathologist, blinded to group allocation. Primary endpoint was diagnostic yield with and without ROSE. RESULTS: After inclusion of 90 patients, interim analysis showed futility of study continuation since diagnostic yield of ROSE+ and ROSE- were comparable. A total of 91 patients were randomized to ROSE+ (N = 45) or ROSE- (N = 46). Diagnostic yield of ROSE+ and ROSE- and diagnostic accuracy were comparable: 93.3% vs. 95.7% (P = 0.68) and 97.6% vs. 93.2% (P = 0.62), respectively. Two major complications (one per group) occurred (p = 0.99). ROSE- patients more often reported self-limiting post-procedural pain (p < 0.001). Median procedure time for ROSE+ (20 min) and ROSE- (23 min) was comparable (P = 0.06). Median time to review slides in the ROSE- group (12:47 min) was longer than with ROSE+ (7:52 min) (P < 0.001). Mean costs of ROSE- and ROSE+ were comparable: €938.29 (±172.70) vs. €945.98 (±223.38) (P = 0.91), respectively. CONCLUSIONS: Diagnostic yield and accuracy of EUS-FNA of mediastinal and abdominal lymph nodes with and without ROSE are comparable. Time needed to review slides was shorter and post-procedural pain was less often reported in the ROSE+ group. Based on the primary outcome, the implementation of ROSE during EUS-FNA of mediastinal and abdominal lymph nodes cannot be advised. (Dutch Trial Register: NTR4876).

Management of eosinophilic esophagitis in daily clinical practice.

In recent years, new guidelines and recommendations have been published regarding the diagnostic criteria and therapeutic management of eosinophilic esophagitis (EoE). The aim of this study is to assess the diagnostic and therapeutic management of patients diagnosed with EoE in daily clinical practice and whether this was performed according to current guidelines and recommendations. A population-based, multicenter retrospective cohort study was conducted using data from the national pathology registry (PALGA), medical records, and telephone interviews of patients diagnosed with EoE in two academic and two nonacademic hospitals in the period 2004 to 2014. The study was approved by all involved ethical committees. Data regarding demographics, clinical manifestations, endoscopic results, histologic samples, and therapeutic strategies were collected. Standard statistical analyses were performed to summarize patient characteristics. We included 119 patients diagnosed with EoE in this study. The median age at onset of symptoms was 29 years (IQR: 15-42) and the median age at diagnosis was 38 years (IQR: 23-51 years), leading to a median diagnostic patients' delay of 6.5 years (IQR: 2-14 years). The median physicians' delay in diagnosis between first contact in the hospital and diagnosis was 1.0 year (IQR: 1-7 years). The incidence of newly diagnosed patients with EoE increased steadily over a period of 11 years. Criteria for the microscopic diagnosis of EoE varied between pathologists in each hospital. Initial treatment included topical corticosteroids (TCS) (30.3%), proton pump inhibitors (PPI) (29.4%), or a combination (10.1%). A follow-up endoscopy was performed in 40.3% of patients. During follow-up, treatment included PPIs (76.0%), TCS (59.6%), a combination of PPIs and TCS (45.4%), and endoscopic dilations (6.7%). Diagnostic and therapeutic discrepancies between daily clinical practice and recommendations from current and past guidelines were observed. Apart from developing guidelines, efforts should be undertaken to implement these in daily clinical practice.

Assessment of bolus transit with intraluminal impedance measurement in patients with esophageal motility disorders.

BACKGROUND: The clinical management of patients with non-obstructive dysphagia is notoriously difficult. Esophageal impedance measurement can be used to measure esophageal bolus transit without the use of radiation exposure to patients. However, validation of measurement of bolus transit with impedance monitoring has only been performed in healthy subjects with normal motility and not in patients with dysphagia and esophageal motility disorders. The aim was, therefore, to investigate the relationship between transit of swallowed liquid boluses in healthy controls and in patients with dysphagia. METHODS: Twenty healthy volunteers and 20 patients with dysphagia underwent concurrent impedance measurement and videofluoroscopy. Each subject swallowed five liquid barium boluses. The ability of detecting complete or incomplete bolus transit by means of impedance measurement was assessed, using radiographic bolus transit as the gold standard. KEY RESULTS: Impedance monitoring recognized stasis and transit in 80.5% of the events correctly, with 83.9% of bolus transit being recognized and 77.2% of stasis being recognized correctly. In controls 79.8% of all swallows were scored correctly, whereas in patients 81.3% of all swallows were scored correctly. Depending on the contractility pattern, between 77.0% and 94.3% of the swallows were scored correctly. CONCLUSIONS & INFERENCES: Impedance measurement can be used to assess bolus clearance patterns in healthy subjects, but can also be used to reliably assess bolus transit in patients with dysphagia and motility disorders.

Electrical stimulation therapy of the lower oesophageal sphincter for refractory gastro-oesophageal reflux disease - interim results of an international multicentre trial.

BACKGROUND: A previous single-centre study showed that lower oesophageal sphincter electrical stimulation therapy (LES-EST) in gastro-oesophageal reflux disease (GERD) patients improves reflux symptoms and decreases oesophageal acid exposure. AIM: To evaluate safety and efficacy of LES-EST in GERD patients with incomplete response to proton pump inhibitors (PPIs) in a prospective, international, multicentre, open-label study. METHODS: GERD patients, partially responsive to PPIs, received LES-EST. GERD health-related quality of life (GERD-HRQL), daily symptom diaries, quality of life scores, oesophageal acid exposure, and LES resting and residual pressure were measured before and after initiation of LES-EST. Stimulation sessions were optimised based on residual symptoms and oesophageal acid exposure. RESULTS: Forty-four patients were enrolled and 6-month data from 41 patients are available. Hiatal repair was performed in 16 patients. One device-related, one procedure-related and one unrelated severe adverse event were reported. GERD-HRQL improved from 31.0 (IQR 26.2-36.8) off-PPI and 16.5 (IQR 9.0-22.8) on-PPI to 4 (IQR 1-8) at 3-month and 5 (IQR 3-9) at 6-month follow-up (P < 0.0001 vs. on- and off-PPI). Oesophageal acid exposure (pH < 4.0) improved from 10.0% (IQR 7.5-12.9) to 3.8% (IQR 1.9-12.3) at 3 months (P = 0.0027) and 4.4% (IQR 2.2-7.2) at 6 months (P < 0.0001). CONCLUSIONS: These interim results show an acceptable safety record of LES-EST to date, combined with good short-term efficacy in GERD patients who are partially responsive to PPI therapy. A remarkable reduction in regurgitation symptoms, without the risk of intervention-requiring dysphagia may prove to be an advantage compared with other anti-reflux procedures. ClinicalTrials.gov Identifier: NCT01574339.

Inter-observer agreement for diagnostic classification of esophageal motility disorders defined in high-resolution manometry.

High-resolution esophageal manometry (HRM) is a recent development used in the evaluation of esophageal function. Our aim was to assess the inter-observer agreement for diagnosis of esophageal motility disorders using this technology. Practitioners registered on the HRM Working Group website were invited to review and classify (i) 147 individual water swallows and (ii) 40 diagnostic studies comprising 10 swallows using a drop-down menu that followed the Chicago Classification system. Data were presented using a standardized format with pressure contours without a summary of HRM metrics. The sequence of swallows was fixed for each user but randomized between users to avoid sequence bias. Participants were blinded to other entries. (i) Individual swallows were assessed by 18 practitioners (13 institutions). Consensus agreement (≤ 2/18 dissenters) was present for most cases of normal peristalsis and achalasia but not for cases of peristaltic dysmotility. (ii) Diagnostic studies were assessed by 36 practitioners (28 institutions). Overall inter-observer agreement was 'moderate' (kappa 0.51) being 'substantial' (kappa > 0.7) for achalasia type I/II and no lower than 'fair-moderate' (kappa >0.34) for any diagnosis. Overall agreement was somewhat higher among those that had performed >400 studies (n = 9; kappa 0.55) and 'substantial' among experts involved in development of the Chicago Classification system (n = 4; kappa 0.66). This prospective, randomized, and blinded study reports an acceptable level of inter-observer agreement for HRM diagnoses across the full spectrum of esophageal motility disorders for a large group of clinicians working in a range of medical institutions. Suboptimal agreement for diagnosis of peristaltic motility disorders highlights contribution of objective HRM metrics.

Sensation of stasis is poorly correlated with impaired esophageal bolus transport.

BACKGROUND: It is common belief that symptoms of patients with non-obstructive dysphagia are the result of impaired bolus clearance in the esophagus, usually caused by esophageal motility disorders. We therefore investigated the relationship between transit of swallowed boluses and the symptom dysphagia. METHODS: Twenty healthy volunteers and 20 patients with dysphagia underwent videofluoroscopy. Success of bolus transport was graded on a 7-point scale. Each subject swallowed five liquid and five solid barium boluses. KEY RESULTS: For liquids, patients reported dysphagia during 1 [0-3] of the five swallows, while controls reported no dysphagia (median 0 [0-0]; p = 0.003). For solids, patients reported dysphagia during 3 [2-4] of five swallows, while controls reported dysphagia in 0.5 [0-2] of five swallows (p = 0.001). When correlating dysphagia to ineffective clearance (score ≥ 3), in 3 [2-4] of five liquids, the subjects perception of clearance was related to the clearance result on fluoroscopy in patients and also 3 [1-5] were correctly perceived in controls (p = 0.6). For solids, in 4 [3-5] of five swallows, the subjects perception of clearance was related to the clearance result on fluoroscopy in patients, but only 2 [1-3] of five swallows were correctly perceived by controls, the difference being statistically significant. CONCLUSIONS & INFERENCES: Patients very frequently report dysphagia when bolus clearance is successful. Therefore, the major underlying problem in patients with non-obstructive dysphagia is disordered perception and increased sensitivity to physiological bolus stasis. Treatment should therefore be directed at reducing increased sensitivity rather than at improving motility.

Normal values for esophageal high-resolution manometry.

BACKGROUND: Esophageal high-resolution manometry (HRM) is a novel method to assess esophageal motility. Several software and hardware systems are currently available. A set of normal values for HRM parameters was established in the US, using proprietary tactile-sensing catheter technology (Given Imaging). We wished to determine normal values for HRM performed with another type of catheter (Unisensor). METHODS: Fifty-two healthy volunteers underwent supine HRM. Each subject swallowed 10 liquid water boluses. Esophageal contraction parameters were evaluated and normal values were calculated (defined as 5th and 95th percentile of values). KEY RESULTS: The normal range for the following parameters was calculated; distal contractile integral (mean 1319.44, with a 5-95th percentile range [185.65-3407.60]), contractile front velocity (mean 3.98, 5-95th percentile range [2.40-6.50]), Intrabolus pressure (mean 9.68, range [1.00-19.00]), contraction amplitude measured 5 cm above the esophagogastric junction (EGJ; mean 78.76, range [23.00-146.00]), contraction amplitude 15 cm above the EGJ (mean 43.66, range [3.60-96.00]), transition zone (TZ) length (mean 1.34, range [0.00-5.63]), upper esophageal sphincter (UES) pressure (mean 81.63, range [19.50-165.10]), EGJ length (mean 2.97, range [2.17-4.00]), EGJ resting pressure (mean 29.35, range [8.95-51.40]), EGJ relaxation pressure (mean 16.79, range [1.00-39.35]), IRPs4 (mean 13.42, range [2.59-28.28]), and gastric pressure (mean 5.06, range [0.00-9.46]). CONCLUSIONS & INFERENCES: Overall, the normal values of esophageal HRM parameters obtained with the Unisensor catheter resemble those of the previously published series. Marked differences in upper limits of normal were found for parameters related to the esophageal sphincters and TZ length. Users of HRM should be aware of these differences and define pathology based on comparison to appropriate normal values.

Relationship between esophageal contraction patterns and clearance of swallowed liquid and solid boluses in healthy controls and patients with dysphagia.

BACKGROUND: Non-obstructive dysphagia patients prove to be a difficult category for clinical management. Esophageal high-resolution manometry (HRM) is a novel method, used to analyze dysphagia. However, it is not yet clear how findings on HRM relate to bolus transport through the esophagus. METHODS: Twenty healthy volunteers and 20 patients with dysphagia underwent HRM and videofluoroscopy in a supine position. Each subject swallowed five liquid and five solid barium boluses. Esophageal contraction parameters and bolus transport were evaluated with HRM and concurrent videofluoroscopy. KEY RESULTS: Stasis of liquid and solid barium boluses occurred in patients and in healthy volunteers in 64% and 41% and in 84% and 82% of the swallows, respectively. Overall, 70% of the liquid and 72% of the solid bolus swallows were followed by a peristaltic contraction, the difference not being statistically significant. Statistically significant associations were found for transition zone length of liquid and solid boluses, and for DCI and distal contraction amplitudes for liquid stasis. No correlation was found between the degree of stasis and other manometric parameters. CONCLUSIONS & INFERENCES: Stasis of both liquid and solid boluses occurs frequently in patients and in controls and can be regarded as physiological. Motility patterns can predict the effectiveness of bolus transit and level of stasis to some degree but the relationship between esophageal motility and transit is complex and far from perfect. Esophageal manometry is therefore currently deemed unfit to be used for the prediction of bolus transit, and should rather be used for the identification of treatable esophageal motility disorders.

Reproducibility of esophageal high-resolution manometry.

BACKGROUND: Esophageal high-resolution manometry (HRM) is a novel method for esophageal function testing that has prompted the development of new parameters for quantitative analysis of esophageal function. Until now, the reproducibility of these parameters has not been investigated. METHODS: Twenty healthy volunteers underwent HRM on two separate days. Standard HRM parameters were measured. In addition, in conventional (virtual) line tracings, lower esophageal sphincter (LES) resting pressure, relaxation pressure, and relative relaxation pressure were measured. Firstly, for each variable, the mean percentage of covariation (100×SD/mean: %COV) was derived as a measure of inter- and intra-individual variation. Secondly, Kendall's coefficients of concordance (W values) were calculated. Thirdly, Bland-Altman plots were used to express concordance graphically. KEY RESULTS: Statistically significant concordance values were found for upper esophageal sphincter (UES) pressure (W=0.90, P=0.02), transition zone length (W=0.92, P=0.01), LES length (W=0.81, P=0.04), LES pressure (W=0.75, P=0.05), LES relaxation pressure (W=0.75, P=0.03), relative LES relaxation pressure (W=0.78, P=0.05), gastric pressure (W=0.81, P=0.04), and contraction amplitude 5cm above the LES (W=0.86, P=0.03). In conventional setting, only LES resting pressure (W=0.835, P=0.03) proved significant. In HRM tracings, concordance values for contraction wave parameters, and in conventional line tracings, LES relaxation pressure and relative relaxation pressure did not reach levels of statistical significance. CONCLUSIONS & INFERENCES: Esophageal HRM yields reproducible results. Parameters that represent anatomic structures show better reproducibility than contraction wave parameters. The reproducibility of LES resting and relaxation pressure assessed with HRM is better than with conventional manometry and further supports the clinical use of HRM.