Frederike G. Van Vilsteren

Radiofrequency Ablation vs Endoscopic Surveillance for Patients With Barrett Esophagus and Low-Grade Dysplasia: A Randomized Clinical Trial

IMPORTANCE Barrett esophagus containing low-grade dysplasia is associated with an increased risk of developing esophageal adenocarcinoma, a cancer with a rapidly increasing incidence in the western world. OBJECTIVE To investigate whether endoscopic radiofrequency ablation could decrease the rate of neoplastic progression. DESIGN, SETTING, AND PARTICIPANTS Multicenter randomized clinical trial that enrolled 136 patients with a confirmed diagnosis of Barrett esophagus containing low-grade dysplasia at 9 European sites between June 2007 and June 2011. Patient follow-up ended May 2013. INTERVENTIONS Eligible patients were randomly assigned in a 1:1 ratio to either endoscopic treatment with radiofrequency ablation (ablation) or endoscopic surveillance (control). Ablation was performed with the balloon device for circumferential ablation of the esophagus or the focal device for targeted ablation, with a maximum of 5 sessions allowed. MAIN OUTCOMES AND MEASURES The primary outcome was neoplastic progression to high-grade dysplasia or adenocarcinoma during a 3-year follow-up since randomization. Secondary outcomes were complete eradication of dysplasia and intestinal metaplasia and adverse events. RESULTS Sixty-eight patients were randomized to receive ablation and 68 to receive control. Ablation reduced the risk of progression to high-grade dysplasia or adenocarcinoma by 25.0% (1.5% for ablation vs 26.5% for control; 95% CI, 14.1%-35.9%; P < .001) and the risk of progression to adenocarcinoma by 7.4% (1.5% for ablation vs 8.8% for control; 95% CI, 0%-14.7%; P = .03). Among patients in the ablation group, complete eradication occurred in 92.6% for dysplasia and 88.2% for intestinal metaplasia compared with 27.9% for dysplasia and 0.0% for intestinal metaplasia among patients in the control group (P < .001). Treatment-related adverse events occurred in 19.1% of patients receiving ablation (P < .001). The most common adverse event was stricture, occurring in 8 patients receiving ablation (11.8%), all resolved by endoscopic dilation (median, 1 session). The data and safety monitoring board recommended early termination of the trial due to superiority of ablation for the primary outcome and the potential for patient safety issues if the trial continued. CONCLUSIONS AND RELEVANCE In this randomized trial of patients with Barrett esophagus and a confirmed diagnosis of low-grade dysplasia, radiofrequency ablation resulted in a reduced risk of neoplastic progression over 3 years of follow-up. TRIAL REGISTRATION trialregister.nl Identifier: NTR1198.

Stepwise radical endoscopic resection versus radiofrequency ablation for Barrett's oesophagus with high-grade dysplasia or early cancer: a multicentre randomised trial

Objective After focal endoscopic resection (ER) of high-grade dysplasia (HGD) or early cancer (EC) in Barretts oesophagus (BO), eradication of all remaining BO reduces the recurrence risk. The aim of this study was to compare the safety of stepwise radical ER (SRER) versus focal ER followed by radiofrequency ablation (RFA) for complete eradication of BO containing HGD/EC. Methods A multicentre randomised clinical trial was carried out in three tertiary centres. Patients with BO ≤5 cm containing HGD/EC were randomised to SRER or ER/RFA. Patients in the SRER group underwent piecemeal ER of 50% of BO followed by serial ER. Patients in the ER/RFA group underwent focal ER for visible lesions followed by serial RFA. Follow-up endoscopy with biopsies (four-quadrant/2 cm BO) was performed at 6 and 12 months and then annually. The main outcome measures were: stenosis rate; complications; complete histological response for neoplasia (CR-neoplasia); and complete histological response for intestinal metaplasia (CR-IM). Results CR-neoplasia was achieved in 25/25 (100%) SRER and in 21/22 (96%) ER/RFA patients. CR-IM was achieved in 23 (92%) SRER and 21 (96%) ER/RFA patients. The stenosis rate was significantly higher in SRER (88%) versus ER/RFA (14%; p<0.001), resulting in more therapeutic sessions in SRER (6 vs 3; p<0.001) due to dilations. After median 24 months follow-up, one SRER patient had recurrence of EC, requiring ER. Conclusions In patients with BO ≤5 cm containing HGD/EC, SRER and ER/RFA achieved comparably high rates of CR-IM and CR-neoplasia. However, SRER was associated with a higher number of complications and therapeutic sessions. For these patients, a combined endoscopic approach of focal ER followed by RFA may thus be preferred over SRER. Clinical trial number NTR1337.

Endoscopic trimodal imaging versus standard video endoscopy for detection of early Barrett's neoplasia: a multicenter, randomized, crossover study in general practice

BACKGROUND Endoscopic trimodal imaging (ETMI) may improve detection of early neoplasia in Barretts esophagus (BE). Studies with ETMI so far have been performed in tertiary referral settings only. OBJECTIVE To compare ETMI with standard video endoscopy (SVE) for the detection of neoplasia in BE patients with an intermediate-risk profile. DESIGN Multicenter, randomized, crossover study. SETTING Community practice. PATIENTS AND METHODS BE patients with confirmed low-grade intraepithelial neoplasia (LGIN) underwent both ETMI and SVE in random order (interval 6-16 weeks). During ETMI, BE was inspected with high-resolution endoscopy followed by autofluorescence imaging (AFI). All visible lesions were then inspected with narrow-band imaging. During ETMI and SVE, visible lesions were sampled followed by 4-quadrant random biopsies every 2 cm. MAIN OUTCOME MEASUREMENTS Overall histological yield of ETMI and SVE and targeted histological yield of ETMI and SVE. RESULTS A total of 99 patients (79 men, 63±10 years) underwent both procedures. ETMI had a significantly higher targeted histological yield because of additional detection of 22 lesions with LGIN/high-grade intraepithelial neoplasia (HGIN)/carcinoma (Ca) by AFI. There was no significant difference in the overall histological yield (targeted+random) between ETMI and SVE. HGIN/Ca was diagnosed only by random biopsies in 6 of 24 patients and 7 of 24 patients, with ETMI and SVE, respectively. LIMITATIONS Inspection, with high-resolution endoscopy and AFI, was performed sequentially. CONCLUSION ETMI performed in a community-based setting did not improve the overall detection of dysplasia compared with SVE. The diagnosis of dysplasia is still being made in a significant number of patients by random biopsies. Patients with a confirmed diagnosis of LGIN have a significant risk of HGIN/Ca. ( CLINICAL TRIAL REGISTRATION NUMBER ISRCTN91816824; NTR867.).

Randomized trial on endoscopic resection-cap versus multiband mucosectomy for piecemeal endoscopic resection of early Barrett's neoplasia

BACKGROUND Endoscopic resection (ER) is an important treatment for high-grade intraepithelial neoplasia and early cancer in Barretts esophagus. ER-cap requires submucosal lifting and positioning of a snare in the cap, making it technically demanding and laborious. Multiband mucosectomy (MBM) uses a modified variceal band ligator and requires no submucosal lifting or positioning of a snare. OBJECTIVE To compare ER-cap and MBM for piecemeal ER of early Barretts neoplasia. DESIGN Randomized, controlled trial. SETTING Tertiary-care and community-care centers. PATIENTS This study involved 84 patients (64 men; median age 70 years) undergoing piecemeal ER of Barretts neoplasia. INTERVENTION Piecemeal ER was performed by using ER-cap (n = 42) or MBM (n = 42). MAIN OUTCOME MEASUREMENTS Safety, efficacy, procedure time, costs. RESULTS Procedure time (34 vs 50 minutes; P = .02) and costs (€240 vs €322; P < .01) were significantly less with MBM compared with ER-cap. MBM resulted in smaller resection specimens than ER-cap (18 ×13 mm vs 20 × 15 mm; P < .01). Maximum thicknesses of specimens and resected submucosa were not significantly different. There were no clinically relevant bleeding episodes. Four perforations occurred, 3 with ER-cap, 1 with MBM (P = not significant). LIMITATIONS Potential bias because of different levels of experience among participating endoscopists. CONCLUSION Piecemeal ER with MBM is faster and cheaper than with ER-cap. Despite the lack of submucosal lifting, MBM appears not to be associated with more perforations. Although MBM results in slightly smaller specimens, the clinical relevance of this may be limited because depth of resections does not differ between both techniques. MBM may thus be preferred for piecemeal ER of early Barretts neoplasia. ( CLINICAL TRIAL REGISTRATION NUMBER NTR1435.).

Validation of the Prague C&M classification of Barrett’s esophagus in clinical practice

BACKGROUND AND STUDY AIMS The Prague C&M classification for Barretts esophagus has found widespread acceptance but has only been validated by Barretts experts scoring video sequences. To date, validation has been lacking for its application in routine practice during real-time endoscopy. The aim of this study was to evaluate agreement between Barretts experts and community hospital endoscopists when using this classification to describe Barretts esophagus and hiatal hernia length during real-time endoscopy. PATIENTS AND METHODS Patients underwent two consecutive endoscopies performed by different endoscopists. The study was performed in two cohorts: one cohort was seen by Barretts experts and the other cohort by community hospital endoscopists. Landmarks were recorded according to the Prague classification. Outcomes were interobserver agreement (assessed with intraclass correlation coefficient [ICC]), absolute agreement, and relative agreement. RESULTS A total of 187 patients were included, with median extent of C3M5 (IQR C1 - 7 M4 - 9) for Barretts esophagus and 3 cm (IQR 2-5) for hiatal hernia length. ICC was 0.91 (95 % confidence interval [CI] 0.88-0.93) for maximum length, 0.92 (95% CI 0.90-0.94) for circumferential extent, and 0.59 (95% CI 0.49-0.68) for hiatal hernia length. Absolute agreement within ≤ 1 cm was 74% (95% CI 68-80) for circumference, 68% (95% CI 62-75) for length, and 63% (95% CI 56 - 70) for hiatal hernia length. Relative agreement was 91% for Barretts esophagus and 80 % for hiatal hernia length. Barretts experts and community hospital endoscopists showed no differences in agreement. Shorter Barretts segments (≤ 5 cm) had lower agreement compared with longer segments (> 5 cm). CONCLUSIONS Agreement was good for Barretts esophagus and reasonable for hiatal hernia length. These findings strengthen the value of the Prague C&M classification to describe Barretts esophagus and hiatal hernia length. Although absolute agreement during real-time endoscopy was high, one should anticipate that Barretts values may vary by 1 - 2 cm between two endoscopies.

Endoscopic Therapy Using Radiofrequency Ablation for Esophageal Dysplasia and Carcinoma in Barrett's Esophagus

Radiofrequency ablation (RFA) is a novel and promising treatment modality for treatment of Barretts esophagus (BE) with high-grade dysplasia or early carcinoma. RFA can be used as a single-modality therapy for flat-type mucosa or as a supplementary therapy after endoscopic resection of visible abnormalities. The treatment protocol consists of initial circumferential ablation using a balloon-based electrode, followed by focal ablation of residual Barretts epithelium. RFA is less frequently associated with stenosis and buried glandular mucosa as are other ablation techniques and has shown to be safe and effective in the treatment of patients with BE and early neoplasia. In this article, the technical background, current clinical experience, and future prospects of RFA are evaluated.

Circumferential Balloon-based Radiofrequency Ablation of Barrett's Esophagus With Dysplasia Can Be Simplified, yet Efficacy Maintained, by Omitting the Cleaning Phase

BACKGROUND & AIMS The current procedure for circumferential balloon-based radiofrequency ablation (c-RFA) for the removal of dysplastic Barretts esophagus (BE) is labor intensive, comprising 2 ablation passes with a cleaning step to remove debris from the ablation zone and electrode. We compared the safety and efficacy of 3 different c-RFA ablation regimens. METHODS We performed a prospective trial of consecutive patients with flat-type BE with high-grade dysplasia. Fifty-seven patients (45 men; age, 64 ± 15 y; 28 with prior endoscopic resection) were assigned randomly to groups that underwent c-RFA with a double application of RFA (12 J/cm(2)). The standard group received c-RFA, with device removal and cleaning, followed by c-RFA; the simple-with-cleaning group underwent c-RFA, with device cleaning without removal, followed by c-RFA; and the simple-no-cleaning group received 2 applications of c-RFA, and the device was not removed or cleaned. The primary outcome was surface regression of BE 3 months later, graded by 2 blinded expert endoscopists. Calculated sample size was 57 patients, based on a noninferiority design. RESULTS Median BE surface regression at 3 months was 83% in the standard group, 78% in the simple-with-cleaning group, and 88% in the simple-no-cleaning group (P = .14). RF ablation time was 20 minutes (interquartile range [IQR], 18-25 min) for the standard group, 13 minutes (IQR, 11-15 min) for the simple-with-cleaning group, and 5 minutes (IQR, 5-9 min) for the simple-no-cleaning group (P < .01). The median number of introductions (RFA devices/endoscope) for the standard group was 7, vs 4 for the simple groups (P < .01). CONCLUSIONS This randomized, prospective study suggests that c-RFA is easier and faster, but equally safe and effective, when the cleaning phase between ablations is omitted or simplified. Trialregister.nl, NTR 2495.

Reproducibility of protein identification of selected cell types in Barrett's esophagus analyzed by combining laser-capture microdissection and mass spectrometry.

Barretts esophagus (BE) is associated with increased risk of esophageal adenocarcinoma (EAC) and characterized by replacement of normal esophageal squamous epithelium by columnar epithelium. These alterations are also reflected in changes in the protein-expression profiles of the cell types involved. To separately investigate the proteomes of selected cell-types we combined laser-capture microdissection (LCM) and liquid chromatography-mass spectrometry (LC-MS). Aims were to determine the sensitivity, specificity, and technical reproducibility of the sampling method, and the biological variability within and between biopsies and patients. Frozen biopsies were cryo-sectioned, samples of around 2000 epithelial or stroma cells microdissected, digested and measured by Orbitrap LC-MS. Proteins were then identified by MS/MS database search and quantified by label-free analysis. An average of 366 protein-groups were identified per sample, and more protein-groups were found in epithelial samples than in stromal samples (442 vs 301, p < 0.0001). Altogether, 1254 distinct protein-groups were found, 289 and 88 of them significantly more often in epithelial and stroma samples, respectively. We assessed five different types of reproducibilities (run-to-run, intrabiopsy, biopsy-to-biopsy, experiment-to-experiment, and patient-to-patient) for protein identification and protein quantification. Reproducibility of protein identification ranged from 78 to 57%, and standard deviation of protein quantification was on patient-to-patient level four times higher than for run-to-run. We conclude that sampling around 2000 cells requires groups of 32 samples to detect significant, over 10-fold differences in protein abundances and thus creates a successful compromise between throughput and quality of results. We therefore believe that this method is suitable for investigating protein-expression profiles during carcinogenesis.

1004 Radiofrequency Ablation in Barrett's Esophagus With Confirmed Low-Grade Dysplasia: Interim Results of a European Multicenter Randomized Controlled Trial (SURF)

(EMR) prior to RFA, we stratified results by those treated with EMR/RFA versus RFA alone and performed comparative statistics using parametric tests. Results: Among 204 patients with IMC who were treated with RFA, 152 (75%) had one or more preceding EMRs. There were no deaths, perforations, or post-procedural bleeding after RFA; 11 patients (5.4%) experienced a treatment-related complication during 594 treatment sessions (1.8% of procedures), including 8 strictures (3.9%; 4.6% with EMR/RFA, 1.9% with RFA alone) and 3 hospitalizations (1.5%; all of whom underwent EMR/RFA). Rates of stricture, bleeding, and hospitalization were not clinically or statistically different (p.0.05) between patients treated with EMR/RFA and RFA alone. CEIM was achieved in 73% (72% EMR/RFA, 81% RFA alone) and CED was achieved in 89% (90% EMR/RFA, 85% RFA alone) over a mean of 2.6 ± 1.3 treatment sessions (see table 1). Efficacy rates were similar among those treated with EMR/RFA versus RFA alone (p.0.05) although fewer RFA treatment sessions were necessary if EMR was performed first (p=0.02). Six subjects required esophagectomy despite therapy. There was a trend toward higher rates of CEIM at academic centers (78%) as compared to community-based practices (61%) (p=0.05). Conclusions: In the largest reported series of patients with IMC, IM and dysplasia were eradicated in 73% and 89% of patients, respectively. Complications occurred in 5.4% of patients, with the majority being benign stricture (3.9%). Efficacy and safety rates were similar for EMR/RFA and RFA alone. RFA, with preceding EMR for nodular disease, is effective and safe treatment of intramucosal carcinoma; however close follow-up is required, since a small number of patients will require surgery for definitive therapy.

981 A Pilot Trial of Endoscopic Radiofrequency Ablation for the Eradication of Esophageal Squamous Intraepithelial Neoplasia and Early Squamous Cell Carcinoma Limited to the Mucosa

We present the case of a 71-year-old female with a five month history of dysphagia, weight loss and heartburn. Preoperative investigation with barium swallow and upper endoscopy demonstrated a large lower esophageal pulsion divertictulum. A laparoscopic transhiatal resection of the esophageal diverticulum was performed with Heller myotomy and crural repair. Intraoperative endoscopy helps to identify the diverticulum in the mediastinum, to ensure complete resection of the diverticulum, to ensure an adequate esophageal myotomy, and to perform an air leak test. A Heller myotomy is performed to treat the esophageal dysmotility. A fundoplication is not performed due to poor esophageal motility.