BACKGROUND & AIMS Radiofrequency ablation (RFA) is an established treatment for dysplastic Barrett’s esophagus (BE). Although short-term endpoints of ablation have been ascertained, there have been concerns about recurrence of intestinal metaplasia (IM) after ablation. We aimed to estimate the incidence and identify factors that predicted the recurrence of IM after successful RFA. METHODS We analyzed data from 592 patients with BE treated with RFA from 2003 through 2011 at 3 tertiary referral centers. Complete remission of intestinal metaplasia (CRIM) was defined as eradication of IM (in esophageal and gastro esophageal junction biopsies), documented by 2 consecutive endoscopies. Recurrence was defined as presence of IM or dysplasia after CRIM in surveillance biopsies. Two experienced gastrointestinal pathologists confirmed pathology findings. RESULTS Based on histology analysis, before RFA, 71% of patients had high-grade dysplasia or esophageal adenocarcinoma, 15% had low-grade dysplasia, and 14% had non-dysplastic BE. Of patients treated, 448 (76%) were assessed following RFA. 55% of patients underwent endoscopic mucosal resection before RFA. The median time to CRIM was 22 months, with 56% of patients in CRIM by 24 months. Increasing age and length of BE segment were associated with a longer times to CRIM. Twenty-four months after CRIM, the incidence of recurrence was 33%; 22% of all recurrences observed were dysplastic BE. There were no demographic or endoscopic factors associated with recurrence. Complications developed in 6.5% of subjects treated with RFA; strictures were the most common complication. CONCLUSION Of patients with BE treated by RFA, 56% are in complete remission after 24 months. However, 33% of these patients have disease recurrence within the next 2 years. Most recurrences were non-dysplastic and endoscopically manageable, but continued surveillance after RFA is essential.

Millions of patients suffer from Major Depressive Disorder (MDD), but many do not respond to selective serotonin reuptake inhibitor (SSRI) therapy. We used a pharmacometabolomics-informed pharmacogenomics research strategy to identify genes associated with metabolites that were related to SSRI response. Specifically, 306 MDD patients were treated with citalopram or escitalopram and blood was drawn at baseline, four and eight weeks for blood drug levels, genome-wide single nucleotide polymorphism (SNP) genotyping and metabolomic analyses. SSRI treatment decreased plasma serotonin concentrations (p<0.0001). Baseline and plasma serotonin concentration changes were associated with clinical outcomes (p<0.05). Therefore, baseline and serotonin concentration changes were used as phenotypes for genome wide association studies (GWAS). GWAS for baseline plasma serotonin concentrations revealed a genome-wide significant (p=7.84E-09) SNP clusters on chromosome four 5’ of TSPAN5 and a cluster across ERICH3 on chromosome one (p=9.28E-08) that were also observed during GWAS for change in serotonin at four (p=5.6E-08 and p=7.54E-07, respectively) and eight weeks (p=1.25E-06 and p=3.99E-07, respectively). The SNPs on chromosome four were eQTLs for TSPAN5. Knockdown (KD) and over expression (OE) of TSPAN5 in a neuroblastoma cell line significantly altered expression of serotonin pathway genes (TPH1, TPH2, DDC and MAOA). Chromosome one SNPs included two ERICH3 nonsynonymous SNPs that resulted in accelerated proteasome-mediated degradation. In addition, ERICH3 and TSPAN5 KD and OE altered media serotonin concentrations. Application of a pharmacometabolomics-informed pharmacogenomic research strategy, followed by functional validation, indicated that TSPAN5 and ERICH3 are associated with plasma serotonin concentrations and may play a role in SSRI treatment outcomes.

Background: Gastroparesis, defined by delayed gastric emptying in the absence of mechanical outlet obstruction, is a frequent neuropathic complication of diabetes mellitus, and effective treatments are lacking. Prucalopride is a pan-gut prokinetic with selective agonist effects on serotonin 5-HT4 receptors in the gut. This study aimed to assess the effect of prucalopride 4 mg daily on Gastroparesis Cardinal Symptom Index (GCSI), meal-related symptom score (MRSS), and gastric emptying rate in diabetic or connective tissue disease (CTD)-related gastroparesis patients. Methods: This was a double-blind crossover trial of four-week treatment periods with prucalopride or placebo divided by two weeks of washout. GSCI, MRSS, gastric emptying scintigraphy, PAGI-SYM, and PAGI-QoL were assessed at baseline and the end of each treatment period. Daily bowel movement (BM) frequency and gastrointestinal symptoms were recorded in each period. Key Results: Fifteen gastroparesis patients (13 diabetic, 2 CTD) were enrolled. GCSI scores were lower than baseline but not different between treatment arms. MRSS scores over time or cumulative score were not significantly different between groups. Gastric emptying was more rapid in the prucalopride treatment period, with mean four-hour meal retention of 22 ± 6% in PRU period vs 40 ± 9% in the placebo period (P = 0.05). Weekly BM frequency was significantly higher in prucalopride than placebo periods (10.5 ± 1.8 vs 7.5 ± 0.8, P < 0.0001). Perception of weight loss was higher in patients on prucalopride. Analysis of diabetic gastroparesis (n = 13) population did not change the conclusions. Conclusion and Inference: Prucalopride at 4 mg accelerates gastric emptying and bowel movement frequency but does not appear to ameliorate gastroparesis or meal-related symptoms in this study.

Background Esophagogastric junction outflow obstruction (EGJOO) is a manometric diagnosis based on the Chicago Classification defined by inadequate relaxation of the gastroesophageal junction (GEJ) with swallowing, but with sufficient peristalsis such that the criteria for achalasia are not met. Possible causes include anatomical and functional etiologies. Further investigations, including computed tomography (CT) of the chest and endoscopic ultrasound (EUS), to help elucidate the etiology of EGJOO have been suggested, but the utility of this approach has not been proven. Methods All new diagnoses of EGJOO made in the calendar years 2015‐2016 were included. A review was performed for each patient to assess clinical outcomes, diagnostic, and therapeutic interventions after the EGJOO diagnosis. Key Results 107 EGJOO patients were included. Their primary complaints were dysphagia (68%), chest pain (12%), reflux (8%), pre‐operative assessment (6%), regurgitation (3%), and cough (3%). The mean IRP was 21.8 mm Hg. After a mean follow‐up period of 463 days, the etiology of EGJOO remained undetermined in 67% of patients. 48% of patients were investigated with cross‐sectional imaging (and 10% with EUS to rule out external compression or malignancy as a cause of EGJOO; none of these tests provided any further useful information). In only two cases did the EGJOO progress to achalasia. Conclusions & Inferences EGJOO is a manometric diagnosis with unclear clinical significance and outcome. CT and EUS of the GEJ were unhelpful at determining the cause of this entity. In this series, very few appear to progress to achalasia, none were due to malignancy, and many resolved spontaneously.