Hannah T. Künzli

Treatment of Barrett's esophagus with a novel focal cryoablation device : a safety and feasibility study

BACKGROUND AND AIMS Currently, eradication of Barretts epithelium is preferably achieved using radiofrequency ablation (RFA) or spray cryoablation (SCA). However, both modalities suffer from drawbacks such as the need for sizing, multiple deployment steps, large controller units (RFA), imprecise dosing and need for gas-venting (SCA). The new Cryoballoon Focal Ablation System (CbFAS) may address these limitations. This study assessed the safety, feasibility, and dose response of the CbFAS in patients with flat Barretts epithelium with or without dysplasia. PATIENTS AND METHODS In this multicenter, prospective non-randomized trial, 39 patients were each treated with one or two ablations of 6, 8, or 10 seconds. Symptoms were assessed immediately and 2 days post-cryoablation. Follow-up endoscopy was performed 6-8 weeks post-procedure to assess response. Outcome parameters were incidence of adverse events, pain, esophageal stricture formation, and ablation response by cryogen dose. RESULTS Of 62 ablations, 56 (10 with 6 seconds, 28 with 8 seconds, 18 with 10 seconds) were successfully performed. Six ablations failed because of device malfunction (n=3) and procedural or anatomic issues (n=3). Median procedure time was 7 minutes (interquartile range [IQR] 4-10). No major adverse events occurred; six patients experienced a minor mucosal laceration requiring no intervention. Mild pain was reported by 27% of patients immediately after cryoablation and by 14% after 2 days. No strictures were evident at follow-up.  Full squamous regeneration was seen in 47 treated areas (6 [60%] of the 6-second areas; 23 [82%] of the 8-second areas; 18 [100%] of 10-second areas). CONCLUSIONS Focal cryoablation of Barretts epithelium with the CbFAS is feasible and safe, resulting in squamous regeneration in the majority of patients.

Efficacy of the CryoBalloon Focal Ablation System for the eradication of dysplastic Barrett’s esophagus islands

Background and study aim Cryoablation can be used for the treatment of Barretts esophagus (BE). A recent dosimetry study, using the CryoBalloon Focal Ablation System (CryoBalloon), demonstrated that 10-second ablations result in complete eradication of BE. However, the efficacy of 10-second ablation in a larger cohort of patients has not been investigated, nor has the potential of precise targeting of specific areas. The aim of the study was to assess the efficacy and performance (i. e. targeting of BE islands) of a 10-second cryoablation using the CryoBalloon. Results A total of 30 patients were enrolled (worst pathology: low grade dysplasia in 14 [47 %], high grade dysplasia in 7 [23 %], early adenocarcinoma in 9 [30 %]). Of the 47 BE islands, 44 (94 %) were adequately targeted. Complete eradication of intestinal metaplasia and dysplasia was observed in 100 % of the completely ablated areas. No stenoses were observed. Conclusion Cryoablation of BE islands using the CryoBalloon is effective. BE islands were effectively targeted.

Erratum to: Management of patients with T1b esophageal adenocarcinoma: a retrospective cohort study on patient management and risk of metastatic disease.

Background Esophagectomy for submucosal (T1b) esophageal adenocarcinoma (EAC) is performed in order to optimize patient outcomes given the risk of concurrent lymph node metastases (LNM). However, not seldom, comorbidity precludes these patients from surgery. Therefore, the aim of our study was to assess the course of follow-up after treatment in submucosal EAC patients undergoing surgery versus conservative therapy and to evaluate the incidence of metastatic disease.

Simplified protocol for focal radiofrequency ablation using the HALO90 device: short-term efficacy and safety in patients with dysplastic Barrett’s esophagus

BACKGROUND AND STUDY AIMS The standard protocol for focal radiofrequency ablation (RFA) of Barretts esophagus comprises two applications of radiofrequency energy, cleaning of the ablated areas and catheter, and two further applications (2 × 15 J/cm(2) - cleaning - 2 × 15 J/cm(2)). A simplified protocol (3 × 15 J/cm(2), no cleaning) proved noninferior to standard protocol for individual islands of Barretts esophagus, but may be associated with higher stenosis rates when applied circumferentially and sequentially over time. We evaluated the efficacy and safety of the above mentioned simplified protocol. PATIENTS AND METHODS Barretts esophagus patients undergoing focal RFA using the simplified protocol in four tertiary referral centers were retrospectively included. During each focal ablation, the gastroesophageal junction (GEJ) was ablated circumferentially in addition to Barretts esophagus islands or tongues. Sessions continued at 8 to 12-week intervals until complete resolution of Barretts esophagus. Primary outcome parameters comprised complete remission of dysplasia and of intestinal metaplasia, and stenosis requiring dilation. RESULTS 83 patients with dysplastic Barretts esophagus (median Prague classification C1M3) were enrolled; 66/83 (80 %) had endoscopic resection of a visible lesion before RFA. Intention-to-treat analysis showed complete remission of dysplasia in 78/83 (94 %) and of intestinal metaplasia in 72/83 (87 %). Stenosis requiring dilation developed in 9/83 (11 %), necessitating a median 2 dilation sessions (range 1 - 9), with ≥ 8 sessions in three patients. CONCLUSION A treatment algorithm incorporating the simplified protocol of 3 × 15 J/cm(2), with no cleaning, for all focal RFA sessions, appears effective. The associated number and severity of stenoses, however, raises safety concerns.

Nitrous oxide cryotherapy for treatment of esophageal squamous cell neoplasia: initial multicenter international experience with a novel portable cryoballoon ablation system (with video)

BACKGROUND AND AIMS Early esophageal squamous cell neoplasia (ESCN) can be successfully treated by EMR, endoscopic submucosal dissection (ESD), or radiofrequency ablation. A new portable, battery-powered cryotherapy system using nitrous oxide (cryoballoon focal ablation system [CbFAS]) has been used for Barretts esophagus. It consists of a small hand-held device containing liquid nitrous oxide, which converts to gas within a low-pressure-compliant through-the-scope balloon and freezes targeted mucosa in contact with the balloon. This study evaluated the feasibility of endoscopic eradication of early ESCN with the CbFAS. METHODS Patients with early ESCN (defined as low-grade intraepithelial neoplasia [LGIN], high-grade intraepithelial neoplasia [HGIN], or early T1 squamous mucosal cancer) were treated with the CbFAS. After chromoendoscopy, all Lugols unstained lesions (USLs) were targeted with 8, 10, or 12 seconds of ice per site, and treatment was repeated until biopsy samples demonstrated eradication of ESCN. Postprocedure adverse events were recorded. RESULTS Ten patients (4 men; median age, 69.5 years) with LGIN (n=2), HGIN (n=7), or esophageal squamous cell carcinoma (ESCC; n=1, after EMR) in 24 USLs were treated. The median maximum diameter of the largest USL was 1.5 cm (interquartile range, 1-2 cm), and median total length of all neoplastic USLs was 2 cm (range, 1-10 cm). Patients with focal disease received a median of 2 cryoablations, whereas 4 patients with large and/or multifocal circumferential neoplasia had 6 to 12 ablations per procedure. The median procedure time was 34 minutes (range, 18-57 minutes). Treatment was completed in all patients. No major adverse events occurred. Four patients developed mild self-limited chest pain requiring narcotic analgesics immediately after the procedure. Two patients who received circumferential ablation developed a stricture responding to dilation, with no recurrence. Complete endoscopic and pathologic response was achieved in all patients at 3 months. One year follow-up biopsy specimens in 7 patients showed no USL or ESCN. All patients were disease free at last visit, with a median follow-up time of 10.7 months (interquartile range, 4-14 months). CONCLUSIONS We report the first application of nitrous cryoballoon ablation for curative treatment of early primary or recurrent ESCN. Our initial experience suggests that efficacy is high and the safety profile is reasonable. Prospective trials are needed to optimize cryogen dosimetry and assess safety and efficacy.

Pilot-study on the feasibility of sentinel node navigation surgery in combination with thoracolaparoscopic lymphadenectomy without esophagectomy in early esophageal adenocarcinoma patients

High-risk submucosal esophageal adenocarcinomas might be treated curatively by means of radical endoscopic resection, followed by thoracolaparoscopic lymphadenectomy without concomitant esophagectomy. A preclinical study has shown the feasibility and safety of this approach; however, no studies are performed in a clinical setting. In addition, sentinel node navigation surgery could be valuable in tailoring the extent of the lymphadenectomy. This study aimed to evaluate the feasibility and safety of thoracolaparoscopic lymphadenectomy without esophagectomy (phase I) and sentinel node navigation surgery (phase II) in patients with early esophageal adenocarcinoma. Patients with T1N0M0 early esophageal adenocarcinoma scheduled for esophagectomy without neoadjuvant therapy were included. Phase I: Two-field, esophagus preserving, thoracolaparoscopic lymphadenectomy was performed, followed by esophagectomy in the same session. Primary outcome parameters were the number of lymph nodes resected, and number of retained lymph nodes in the esophagectomy specimen. Phase II: A radioactive tracer was injected endoscopically the day before surgery. Static imaging was performed 15 and 120 minutes after injection. The day of surgery, sentinel node navigation surgery followed by esophagectomy was performed. Primary outcome parameters were the percentage of patients with a detectable sentinel node, and the concordance between static imaging and probe-based detection of sentinel node. Phase I: Five patients were included, and a median of 30 (IQR: 25-46) lymph nodes was resected. A median of 6 (IQR: 2-9) retained lymph nodes was found in the esophagectomy specimen. No acute adverse events occurred, but near the end of lymphadenectomy esophageal discoloration was observed, possibly indicating ischemia. Phase II: In all five included patients sentinel nodes could be visualized and resected, at a median of 3 (IQR: 2-5) locations. There was a high concordance between imaging and probe-based detection of sentinel nodes. In conclusion, sentinel node navigation surgery followed by lymphadenectomy without concomitant esophagectomy seems feasible in patients with high-risk submucosal early esophageal adenocarcinoma. More evidence is however needed before applying this technique in clinical practice.

Endoscopic resection of early esophageal neoplasia in patients with esophageal varices: how to succeed while preventing the bleed.

Endoscopic resection is an accepted treatment modality for early esophageal neoplasia [1–3]. In patients with esophageal varices, however, endotherapy is contraindicated, although those patients are also precluded from esophagectomy. In patient 1 (a 66-year-old man), upper endoscopy showed esophageal varices (grade II– III) and a long Barrett’s segment containing a polypoid lesion (Paris 0-Ip) [4]. Endoscopic ultrasound (EUS) revealed varices directly beneath the stalk. We decided to snare the lesion with the Duette MBM device (Cook Endoscopy, Limerick, Ireland) mounted on the endoscope as a precautionary measure that would enable direct variceal ligation in case of bleeding. The resection was uneventful, and histolopathological examination showed an intramucosal adenocarcinoma. At 2 months, a recurrent neoplastic lesion was observed (Paris 0-IIa) at the exact location of the previous resection. This lesion was captured by means of one rubber band by which not only the lesion but also the underlying varix was ligated; however snaring was omitted since this would have led to a massive variceal bleed. During 4.5 years of follow-up, no recurrence was detected. Patient 2 (a 50-year-old man) had shortsegment Barrett esophagus, a Paris 0-IIa+

Simplified versus standard regimen for focal radiofrequency ablation of dysplastic Barrett's oesophagus: a multicentre randomised controlled trial

BACKGROUND For focal radiofrequency ablation of Barretts oesophagus, a simplified regimen (3 × 15 J/cm2, without cleaning) has proven to be as effective as the standard regimen (2 × 15 J/cm2, followed by cleaning, followed by 2 × 15 J/cm2). However, this simplified regimen seemed to be associated with a higher stenosis rate. Therefore, we lowered the radiofrequency energy and hypothesised that this new simplified regimen would be as effective and safe as the standard regimen. METHODS This randomised non-inferiority trial included patients with dysplastic Barretts oesophagus or residual Barretts oesophagus after endoscopic resection or circumferential radiofrequency ablation, in five European tertiary referral centres. Patients were randomly assigned (1:1) to the new simplified regimen (3 × 12 J/cm2, without cleaning) or the standard regimen, with variable block sizes of four, six, and eight patients, stratified by participating hospital. Focal radiofrequency ablation was done every 3 months, up to a maximum of three treatments, until all Barretts oesophagus was eradicated. The primary outcome was complete endoscopic and histological regression of dysplasia and intestinal metaplasia after two focal radiofrequency ablation treatments, assessed in the intention-to-treat population. Non-inferiority was assessed on the basis of the difference between groups in the median percentage of Barretts oesophagus surface regression, with a non-inferiority margin of -15%. This study is registered with www.trialregister.nl, number NTR4994, and is completed. FINDINGS Between March 25, 2015, and July 25, 2016, 84 patients were randomly assigned to treatment: 44 to receive the simplified regimen and 40 to receive the standard regimen. One patient assigned to the simplified regimen and four assigned to the standard regimen were excluded because they weree found not to be eligible; therefore the final intention-to-treat population consisted of 43 patients in the simplified ablation group and 36 in the standard ablation group. Complete endoscopic and histological regression of dysplasia and intestinal metaplasia after two focal radiofrequency ablation treatments was achieved in 32 (74%, 95% CI 59-87) patients treated with the simplified protocol, versus 30 (83%, 95% CI 67-94) patients treated with the standard protocol (p=0·34). Median Barretts oesophagus surface regression after two focal radiofrequency ablation sessions was 98% (IQR 95-100) in the simplified regimen group and 100% (97-100) in the standard regimen group. The difference between medians was 2% (95% CI -0·562 to 3·162); thus the simplified regimen was deemed non-inferior to the standard regimen. Stenoses requiring dilatation were observed in four (9%) of 43 patients in the simplified regimen group and four (11%) of 36 in the standard regimen group. Post-procedural bleeding requiring repeat endoscopy occurred in one (2%) patient in the simplified ablation group and three (8%) patients in the standard ablation group. One patient (2%) in the simplified treatment group died 36 days after the second radiofrequency ablation procedure, due to an unknown cause. INTERPRETATION Based on the results of this study, we conclude that the simplified regimen is the preferred regimen for focal radiofrequency ablation of Barretts oesophagus. FUNDING None.

Thoracolaparoscopic dissection of esophageal lymph nodes without esophagectomy is feasible in human cadavers and safe in a porcine survival study

High-risk early esophageal adenocarcinoma (i.e. submucosal invasion >500 nm, poor differentiation, and/or presence of lymphovascular invasion) is currently treated with esophagectomy with lymph node (LN) dissection given the high rates of LN metastases. However, esophagectomy is associated with substantial morbidity and mortality. Endoscopic radical resection followed by thoracolaparoscopic LN dissection without concomitant esophagectomy could be an alternative. The study aim was to evaluate the feasibility and safety of thoracolaparoscopic dissection of esophageal LNs in a preclinical setting. (i) In human cadavers, thoracolaparoscopic dissection of LNs involved in drainage of the esophagus was performed. Subsequently, esophagectomy was performed to be able to detect retained LNs. Outcome parameters included the number of dissected LNs, the number of retained LNs in the esophagectomy specimen (ES), and technical success. (ii) In swine, thoracolaparoscopic LN dissection was also performed. After the procedure, the swine survived for 28 days. Thereafter, the swine were sacrificed and esophagectomy was performed. Outcome parameters included the presence of ischemia and/or stenosis in the ES and other complications. (i) In five human cadavers, a median of 26 LNs (interquartile range 22-46) were dissected. In two ES, one retained LN was found: one high paraesophageal, one low paraesophageal. Technical success rate was 100%. (ii) None of the seven porcine ES showed signs of ischemia or stenosis. One swine died because of ventricular fibrillation during surgery; during follow up no complications were observed. Thoracolaparoscopic dissection of LNs involved in the drainage of the esophagus is feasible in human cadavers and swine. The porcine survival study suggests that the esophageal vascularity is not severely compromised by the procedure. As anatomy differs between swine and humans, safety of the procedure will have to be investigated thoroughly before applying this new technique as the treatment of choice.