Robert A. Ganz

Circumferential ablation of Barrett's esophagus that contains high-grade dysplasia: a U.S. multicenter registry

BACKGROUND The management strategies for Barretts esophagus (BE) that contains high-grade dysplasia (HGD) include intensive endoscopic surveillance, photodynamic therapy, thermal ablation, EMR, and esophagectomy. OBJECTIVE To assess the safety and effectiveness of endoscopic circumferential balloon-based ablation by using radiofrequency energy for treating BE HGD. DESIGN Multicenter U.S. registry. SETTING Sixteen academic and community centers; treatment period from September 2004 to March 2007. PATIENTS Patients with histologic evidence of intestinal metaplasia (IM) that contained HGD confirmed by at least 2 expert pathologists. A prior EMR was permitted, provided that residual HGD remained in the BE region for ablation. INTERVENTION Endoscopic circumferential ablation with follow-up esophageal biopsies to assess the histologic response to treatment. OUTCOMES Histologic complete response (CR) end points: (1) all biopsy specimen fragments obtained at the last biopsy session were negative for HGD (CR-HGD), (2) all biopsy specimens were negative for any dysplasia (CR-D), and (3) all biopsy specimens were negative for IM (CR-IM). RESULTS A total of 142 patients (median age 66 years, interquartile range [IQR] 59-75 years) who had BE HGD (median length 6 cm, IQR 3-8 cm) underwent circumferential ablation (median 1 session, IQR 1-2). No serious adverse events were reported. There was 1 asymptomatic stricture and no buried glands. Ninety-two patients had at least 1 follow-up biopsy session (median follow-up 12 months, IQR 8-15 months). A CR-HGD was achieved in 90.2% of patients, CR-D in 80.4%, and CR-IM in 54.3%. LIMITATIONS A nonrandomized study design, without a control arm, a lack of centralized pathology review, ablation and biopsy technique not standardized, and a relatively short-term follow-up. CONCLUSIONS Endoscopic circumferential ablation is a promising modality for the treatment of BE that contains HGD. In this multicenter registry, the intervention safely achieved a CR for HGD in 90.2% of patients at a median of 12 months of follow-up.

Complete ablation of esophageal epithelium with a balloon-based bipolar electrode: a phased evaluation in the porcine and in the human esophagus

BACKGROUND The aim of this study was to evaluate the endoscopic and the histologic effects of a balloon-based bipolar radiofrequency electrode for ablation of porcine and human esophageal epithelium. METHODS All procedures were performed with a balloon-based, bipolar radiofrequency system that creates a circumferential, thin-layer epithelial ablation zone within the esophagus. In Phase I, multiple ablations were created in 10 farm swine, followed by acute euthanasia and histologic assessment for completeness of epithelial removal and ablation depth. In Phase II, multiple ablations were created in 19 farm swine, with varying power and energy density, followed by endoscopy at 2 and 4 weeks to assess stricture formation. In Phase III, 3 ablations were created in 12 farm swine, with varying energy density (5, 8, 10, 12, 15, or 20 J/cm 2 ) at 350 W. Animals were euthanized at 48 hours. Histologic examination determined the percentage of epithelium removed and the ablation depth. In Phase IV, 3 patients underwent esophageal epithelial ablation before esophagectomy, creating separate lesions proximal to the tumor. Completeness of epithelial ablation and ablation depth was quantified histologically. RESULTS In Phase I, complete removal of esophageal epithelium was achieved at energy density settings of 9.7 to 29.5 J/cm 2 . In Phase II, 9.7 and 10.6 J/cm 2 produced no stricture, whereas more than 20 J/cm 2 produced a stricture in every case. In Phase III, 8-20 J/cm 2 resulted in 100% epithelial ablation. Five and 8 J/cm 2 spared the muscularis mucosae, whereas 10 J/cm 2 caused injury to the muscularis mucosae but preserved the submucosa. In Phase IV, histologic examination demonstrated full-thickness epithelial removal in areas of electrode contact. Ablation extended only to the muscularis mucosae, without injury to submucosa. CONCLUSIONS In the porcine and the human esophagus, circumferential, full-thickness ablation of epithelium without direct injury to the submucosa is possible and was well tolerated. In all cases, depth of ablation was linearly related to energy density of treatment.

Esophageal sphincter device for gastroesophageal reflux disease.

BACKGROUND Patients with gastroesophageal reflux disease who have a partial response to proton-pump inhibitors often seek alternative therapy. We evaluated the safety and effectiveness of a new magnetic device to augment the lower esophageal sphincter. METHODS We prospectively assessed 100 patients with gastroesophageal reflux disease before and after sphincter augmentation. The study did not include a concurrent control group. The primary outcome measure was normalization of esophageal acid exposure or a 50% or greater reduction in exposure at 1 year. Secondary outcomes were 50% or greater improvement in quality of life related to gastroesophageal reflux disease and a 50% or greater reduction in the use of proton-pump inhibitors at 1 year. For each outcome, the prespecified definition of successful treatment was achievement of the outcome in at least 60% of the patients. The 3-year results of a 5-year study are reported. RESULTS The primary outcome was achieved in 64% of patients (95% confidence interval [CI], 54 to 73). For the secondary outcomes, a reduction of 50% or more in the use of proton-pump inhibitors occurred in 93% of patients, and there was improvement of 50% or more in quality-of-life scores in 92%, as compared with scores for patients assessed at baseline while they were not taking proton-pump inhibitors. The most frequent adverse event was dysphagia (in 68% of patients postoperatively, in 11% at 1 year, and in 4% at 3 years). Serious adverse events occurred in six patients, and in six patients the device was removed. CONCLUSIONS In this single-group evaluation of 100 patients before and after sphincter augmentation with a magnetic device, exposure to esophageal acid decreased, reflux symptoms improved, and use of proton-pump inhibitors decreased. Follow-up studies are needed to assess long-term safety. (Funded by Torax Medical; ClinicalTrials.gov number, NCT00776997.).

Endoscopic implantation of enteryx for treatment of GERD: 12-month results of a prospective, multicenter trial

OBJECTIVES:This study aimed to assess the efficacy and safety of endoscopically implanting a nonresorbable biocompatible polymer (Enteryx) in the distal esophagus and proximal gastric cardia for the treatment of gastroesophageal reflux disease (GERD).METHODS:In a prospective, multicenter, international trial, 85 well-controlled GERD patients who were receiving chronic proton pump inhibitor (PPI) therapy underwent Enteryx implantation under fluoroscopic visualization, without general anesthesia. After the procedure, patients were discharged within approximately 2–4 h. Patients were judged to be treatment responders if after implantation they reduced PPI dosage by ≥50%. Follow-up evaluations were conducted at 1, 3, 6, and 12 months and included medication usage, symptoms, quality of life, endoscopy, pH monitoring, manometry, and documentation of adverse events.RESULTS:At 12 months, 80.3% (95% CI = 69.9%–88.3%) of 81 evaluable patients were treatment responders. Of the responders, 87.7% completely discontinued PPIs, and 12.3% reduced PPI dosage by ≥50%. Treatment response was more likely in patients with residual implant volume of ≥5 mL (p = 0.027). Other patient and treatment variables were not predictive. Both GERD heartburn and regurgitation symptom scores significantly improved at 12 months compared with baseline (p < 0.001). There were significant reductions in median supine, upright, and total percent time of esophageal exposure to pH <4. Endoscopically assessed esophagitis grades were unchanged. No serious adverse events were encountered. Transient retrosternal chest pain was experienced by 91.8% of patients. This pain was seldom severe and was typically successfully managed with prescription pain medication.CONCLUSION:Enteryx implantation allows most patients to discontinue PPI therapy, improves their symptoms, and reduces esophageal acid exposure. The effects of implantation are long-lasting, and morbidity is transient and minimal. The procedure requires basic endoscopic skills and seems to provide a useful option in the effective clinical management of GERD.

Helicobacter pylori Accumulates Photoactive Porphyrins and Is Killed by Visible Light

ABSTRACT Helicobacter pylori colonizes the mucus layer of the human stomach and duodenum, causes chronic gastritis, gastric ulcer, and is a risk factor for gastric adenocarcinoma. There is a 20% failure rate in antibiotic therapy, which is increasingly due to antibiotic resistance and necessitates the search for alternative antimicrobial methods. We have discovered that H. pylori when cultured in liquid medium, accumulates significant quantities of coproporphyrin and protoporphyrin IX, both in the cells and secreted into the medium. These photoactive porphyrins lead to cell death (up to 5 logs) by photodynamic action upon illumination with low doses of visible light, with blue/violet light being most efficient. The degree of killing increases with the age of the culture and is greater than that found with Propionibacterium acnes (another bacterium known to be photosensitive due to porphyrin accumulation). Both virulent and drug-resistant strains are killed. The data suggest that phototherapy might be used to treat H. pylori infection in the human stomach.

Endoscopic, deep mural implantation of Enteryx for the treatment of GERD: 6-month follow-up of a multicenter trial.

OBJECTIVES:This prospective, multicenter, single-arm study evaluated the safety and efficacy of the endoscopic implantation of Enteryx, a biocompatible, non-biodegradable liquid polymer for the treatment of GERD.METHODS:Eighty-five patients with heartburn symptoms responsive to proton pump inhibitor (PPI) use were enrolled. Inclusion requirements were HRQL score ≤ 11 on PPI and ≥ 20 off PPI, and 24-hour PH probe with ≥ 5% total time at PH ≤ 4. Patients with a hiatus hernia > 3 cm, grade 3 or 4 esophagitis, or esophageal motility disorder were excluded. Using a 4-mm needle tipped catheter during standard endoscopy, implants were made in 3–4 quadrants deep into the wall of the cardia. Use of PPI medications, pH-metry, manometry, GERD symptoms, and patient quality of life were assessed over a 6-month follow-up period.RESULTS:At 6 months, PPI use was eliminated in 74% and reduced by > 50% in 10% of patients. The median HRQL score improved from 24.0 pre-implant (baseline off PPIs) to 4.0 at 6 months (p < 0.001). Mean total esophageal acid exposure time was 9.5% pretherapy and 6.7% at 6 months (p < 0.001). Mean LES length increased from 2.0 cm at baseline to 3.0 cm posttherapy (p = 0.003). There were no clinically serious adverse events. Transient mild-to-moderate chest pain commonly occurred after implantation.CONCLUSIONS:The endoscopic implantation of Enteryx is a safe and effective therapy for eliminating or decreasing the need for PPI medications, improving GERD symptoms and patient quality of life, and decreasing esophageal acid exposure among patients suffering from GERD.

Laparoscopic sphincter augmentation device eliminates reflux symptoms and normalizes esophageal acid exposure: one- and 2-year results of a feasibility trial.

Objectives:One- and 2-year evaluation of a feasibility trial (clinicaltrials.gov registration numbers NCT01057992, NCT01058070, and 01058564) to assess the safety and efficacy of a laparoscopically implanted sphincter augmentation device for the treatment of gastroesophageal reflux disease (GERD). Methods:A sphincter augmentation device (LINX Reflux Management System; Torax Medical, Shoreview, MN), designed to prevent reflux due to abnormal opening of the lower esophageal sphincter (LES), was laparoscopically implanted at the gastroesophageal junction in 44 patients. At baseline, all patients had abnormal esophageal acid exposure on 24-hour pH monitoring and improved, but persistent, typical GERD symptoms while on acid suppression therapy with proton pump inhibitors (PPIs). The device comprises a miniature string of interlinked titanium beads, with magnetic cores, placed around the gastroesophageal junction. The magnetic bond between adjacent beads augments sphincter competence. The beads temporarily separate to accommodate a swallowed bolus, allow belching or vomiting, and reapproximate to augment the LES in the closed position. Patients were evaluated after surgery by GERD Health-Related Quality of Life symptom score, PPI usage, endoscopy, esophageal manometry, and 24-hour esophageal pH monitoring. Results:The total mean GERD Health-Related Quality of Life symptom scores improved from a mean baseline value of 25.7 to 3.8 and 2.4 at 1- and 2-year follow-up, representing an 85% and 90% reduction, respectively (P < 0.0001). Complete cessation of PPI use was reported by 90% of patients at 1 year and by 86% of patients at 2 years. Early dysphagia occurred in 43% of the patients and self-resolved by 90 days. One device was laparoscopically explanted for persistent dysphagia without disruption of the anatomy or function of the cardia. There were no device migrations, erosions, or induced mucosal injuries. At 1 and 2 years, 77% and 90% of patients had a normal esophageal acid exposure. The mean percentage time pH was less than 4 decreased from a baseline of 11.9% to 3.1% (P < 0.0001) at 1 year and to 2.4% (P < 0.0001) at 2 years. Patient satisfaction was 87% at 1 year and 86% at 2 years. Conclusions:The new laparoscopically implanted sphincter augmentation device eliminates GERD symptoms without creating undue side effects and is effective at 1 and 2 years of follow-up.

Safety analysis of first 1000 patients treated with magnetic sphincter augmentation for gastroesophageal reflux disease.

Antireflux surgery with a magnetic sphincter augmentation device (MSAD) restores the competency of the lower esophageal sphincter with a device rather than a tissue fundoplication. As a regulated device, safety information from the published clinical literature can be supplemented by tracking under the Safe Medical Devices Act. The aim of this study was to examine the safety profile of the MSAD in the first 1000 implanted patients. We compiled safety data from all available sources as of July 1, 2013. The analysis included intra/perioperative complications, hospital readmissions, procedure-related interventions, reoperations, and device malfunctions leading to injury or inability to complete the procedure. Over 1000 patients worldwide have been implanted with the MSAD at 82 institutions with median implant duration of 274 days. Event rates were 0.1% intra/perioperative complications, 1.3% hospital readmissions, 5.6% endoscopic dilations, and 3.4% reoperations. All reoperations were performed non-emergently for device removal, with no complications or conversion to laparotomy. The primary reason for device removal was dysphagia. No device migrations or malfunctions were reported. Erosion of the device occurred in one patient (0.1%). The safety analysis of the first 1000 patients treated with MSAD for gastroesophageal reflux disease confirms the safety of this device and the implantation technique. The overall event rates were low based on data from 82 institutions. The MSAD is a safe therapeutic option for patients with chronic, uncomplicated gastroesophageal reflux disease.

Enteryx implantation for GERD: expanded multicenter trial results and interim postapproval follow-up to 24 months

BACKGROUND Enteryx implantation in the esophagus is an alternative therapy for patients with proton pump inhibitor (PPI) dependent GERD. Although this treatment resulted in highly significant improvement at 6 and 12 months, longer follow-up is needed to more fully assess the durability of these positive effects. METHODS An open-label, international clinical trial was conducted in 144 PPI-dependent patients with GERD with follow-up at 6 and 12 months. In addition, the durability and the safety of the treatment were assessed for 24 months in 64 patients enrolled in a postapproval study. The primary study outcome measure was usage of PPI. Secondary outcomes in the multicenter trial were GERD health-related quality of life (GERD-HRQL) symptom score and esophageal acid exposure. RESULTS At 12 months, PPI use was reduced > or =50% in 84%: 95% confidence interval (CI) [76%, 90%] and was eliminated in 73%: 95% CI[64%, 81%] of evaluable patients (intent-to-treat analysis 78%: 95% CI[70%, 84%] and 68%: 95% CI[60%, 76%], respectively). A GERD-HRQL < or =11 was attained in 78%: 95% CI[69%, 85%] of evaluable patients. Esophageal acid exposure (total time pH <4) was reduced by 31%: 95% CI[17%, 43%]. At 24 months, a > or =50% or greater reduction in PPI use was achieved in 72%: 95% CI[59%, 82%] and PPI use was eliminated in 67%: 95% CI[54%, 78%] of patients. CONCLUSIONS This investigation provides evidence for sustained effectiveness and safety of implantation of Enteryx in the esophagus in PPI-dependent patients with GERD.

Long-term Outcomes of Patients Receiving a Magnetic Sphincter Augmentation Device for Gastroesophageal Reflux

BACKGROUND & AIMS Based on results from year 2 of a 5-year trial, in 2012 the US Food and Drug Administration approved the use of a magnetic device to augment lower esophageal sphincter function in patients with gastroesophageal reflux disease (GERD). We report the final results of 5 years of follow-up evaluation of patients who received this device. METHODS We performed a prospective study of the safety and efficacy of a magnetic device in 100 adults with GERD for 6 months or more, who were partially responsive to daily proton pump inhibitors (PPIs) and had evidence of pathologic esophageal acid exposure, at 14 centers in the United States and The Netherlands. The magnetic device was placed using standard laparoscopic tools and techniques. Eighty-five subjects were followed up for 5 years to evaluate quality of life, reflux control, use of PPIs, and side effects. The GERD-health-related quality of life (GERD-HRQL) questionnaire was administered at baseline to patients on and off PPIs, and after placement of the device; patients served as their own controls. A partial response to PPIs was defined as a GERD-HRQL score of 10 or less on PPIs and a score of 15 or higher off PPIs, or a 6-point or more improvement when scores on vs off PPI were compared. RESULTS Over the follow-up period, no device erosions, migrations, or malfunctions occurred. At baseline, the median GERD-HRQL scores were 27 in patients not taking PPIs and 11 in patients on PPIs; 5 years after device placement this score decreased to 4. All patients used PPIs at baseline; this value decreased to 15.3% at 5 years. Moderate or severe regurgitation occurred in 57% of subjects at baseline, but only 1.2% at 5 years. All patients reported the ability to belch and vomit if needed. Bothersome dysphagia was present in 5% at baseline and in 6% at 5 years. Bothersome gas-bloat was present in 52% at baseline and decreased to 8.3% at 5 years. CONCLUSIONS Augmentation of the lower esophageal sphincter with a magnetic device provides significant and sustained control of reflux, with minimal side effects or complications. No new safety risks emerged over a 5-year follow-up period. These findings validate the long-term safety and efficacy of the magnetic sphincter augmentation device for patients with GERD. ClinicalTrials.gov no: NCT00776997.