Diagnostic workup for esophageal cancer patients can be improved with checklists and clearer protocols; a comparative study between two tertiary centers in Europe.

BACKGROUND: Rapid and complete workup of newly diagnosed esophageal cancer is vital for a timely, individual and high-quality treatment strategy. The aim of this study was to uncover potential delay, inefficiencies and non-contributing investigations in the diagnostic process in two tertiary referral centers. METHODS: This retrospective cohort study included all newly diagnosed esophageal cancer patients referred to or diagnosed in the Amsterdam UMC and Karolinska University Hospital between July 2020 and July 2021. Radiology, pathological assessment and multidisciplinary team meeting reports were reviewed. To assess time interval from diagnosis to treatment, dates of diagnosis, admittance to referral hospital, MDT meeting and start of treatment were collected. RESULTS: In total, 252 esophageal cancer patients were included, 187 were treated with curative intent. Curatively treated patients had a mean age of 66 years, were predominantly male (74.9 %) with an adenocarcinoma (71.1 %). Curatively treated patients had a median time from diagnosis to referral of seven days (IQR:0-11) and of 35 days (IQR:28-45) between diagnosis and start of treatment. Main reasons for the significant (P < 0.001) differences in time between diagnosis and treatment between centers, Amsterdam UMC (39 days) vs Karolinska (27 days), were need for additional diagnostics (47.8 %) and differences in referral routine. Gastroscopy was repeated in 32.2 % of patients, mainly for further anatomical mapping. CONCLUSION: Significant time differences between centers in the path from diagnosis to start treatment can be explained by differences in workup approach, referral routines and MDT meeting regulations. Repeat of gastroscopy can be prevented with clearer endoscopy guidelines.

A deep learning system for detection of early Barrett's neoplasia: a model development and validation study.

BACKGROUND: Computer-aided detection (CADe) systems could assist endoscopists in detecting early neoplasia in Barrett's oesophagus, which could be difficult to detect in endoscopic images. The aim of this study was to develop, test, and benchmark a CADe system for early neoplasia in Barrett's oesophagus. METHODS: The CADe system was first pretrained with ImageNet followed by domain-specific pretraining with GastroNet. We trained the CADe system on a dataset of 14 046 images (2506 patients) of confirmed Barrett's oesophagus neoplasia and non-dysplastic Barrett's oesophagus from 15 centres. Neoplasia was delineated by 14 Barrett's oesophagus experts for all datasets. We tested the performance of the CADe system on two independent test sets. The all-comers test set comprised 327 (73 patients) non-dysplastic Barrett's oesophagus images, 82 (46 patients) neoplastic images, 180 (66 of the same patients) non-dysplastic Barrett's oesophagus videos, and 71 (45 of the same patients) neoplastic videos. The benchmarking test set comprised 100 (50 patients) neoplastic images, 300 (125 patients) non-dysplastic images, 47 (47 of the same patients) neoplastic videos, and 141 (82 of the same patients) non-dysplastic videos, and was enriched with subtle neoplasia cases. The benchmarking test set was evaluated by 112 endoscopists from six countries (first without CADe and, after 6 weeks, with CADe) and by 28 external international Barrett's oesophagus experts. The primary outcome was the sensitivity of Barrett's neoplasia detection by general endoscopists without CADe assistance versus with CADe assistance on the benchmarking test set. We compared sensitivity using a mixed-effects logistic regression model with conditional odds ratios (ORs; likelihood profile 95% CIs). FINDINGS: Sensitivity for neoplasia detection among endoscopists increased from 74% to 88% with CADe assistance (OR 2·04; 95% CI 1·73-2·42; p<0·0001 for images and from 67% to 79% [2·35; 1·90-2·94; p<0·0001] for video) without compromising specificity (from 89% to 90% [1·07; 0·96-1·19; p=0·20] for images and from 96% to 94% [0·94; 0·79-1·11; ] for video; p=0·46). In the all-comers test set, CADe detected neoplastic lesions in 95% (88-98) of images and 97% (90-99) of videos. In the benchmarking test set, the CADe system was superior to endoscopists in detecting neoplasia (90% vs 74% [OR 3·75; 95% CI 1·93-8·05; p=0·0002] for images and 91% vs 67% [11·68; 3·85-47·53; p<0·0001] for video) and non-inferior to Barrett's oesophagus experts (90% vs 87% [OR 1·74; 95% CI 0·83-3·65] for images and 91% vs 86% [2·94; 0·99-11·40] for video). INTERPRETATION: CADe outperformed endoscopists in detecting Barrett's oesophagus neoplasia and, when used as an assistive tool, it improved their detection rate. CADe detected virtually all neoplasia in a test set of consecutive cases. FUNDING: Olympus.

Endoscopically placed fiducial markers for image-guided radiotherapy in preoperative gastric cancer: Technical feasibility and potential benefit.

Background and study aims Fiducial markers have demonstrated clinical value in radiotherapy in several organs, but little is known about markers in the stomach. Here, we assess the technical feasibility of endoscopic placement of markers in gastric cancer patients and their potential benefit for image-guided radiotherapy (IGRT). Patients and methods In this prospective feasibility study, 14 gastric cancer patients underwent endoscopy-guided gold (all patients) and liquid (7 patients) marker placements distributed throughout the stomach. Technical feasibility, procedure duration, and potential complications were evaluated. Assessed benefit for IGRT comprised marker visibility on acquired imaging (3-4 computed tomography [CT] scans and 19-25 cone-beam CTs [CBCTs] per patient) and lack of migration. Marker visibility was compared per marker type and location (gastroesophageal junction (i.e., junction/cardia), corpus (corpus/antrum/fundus), and pylorus). Results Of the 93 marker implantation attempts, 59 were successful, i.e., marker in stomach wall and present during entire 5-week radiotherapy course (2-6 successfully placed markers per patient), with no significant difference (Fisher's exact test; P >0.05) in success rate between gold (39/66=59%) and liquid (20/27=74%). Average procedure duration was 24.4 min (range 16-38). No procedure-related complications were reported. All successfully placed markers were visible on all CTs, with 81% visible on ≥95% of CBCTs. Five markers were poorly visible (on <75% of CBCTs), possibly due to small marker volume and peristaltic motion since all five were liquid markers located in the corpus. No migration was observed. Conclusions Endoscopic placement of fiducial markers in the stomach is technically feasible and safe. Being well visible and positionally stable, markers provide a potential benefit for IGRT.

Pre-treatment tumor-infiltrating T cells influence response to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a disease with dismal treatment outcomes. Response to neoadjuvant chemoradiation (CRT) varies greatly. Although the underlying mechanisms of CRT resistance are not identified, accumulating evidence indicates an important role for local antitumor immunity. To explore the immune microenvironment in relation to response to CRT we performed an in-depth analysis using multiplex immunohistochemistry, flow cytometry and mRNA expression analysis (NanoString) to generate a detailed map of the immunological landscape of pretreatment biopsies as well as peripheral blood mononuclear cells (PBMCs) of EAC patients. Response to CRT was assessed by Mandard's tumor regression grade (TRG), disease-free- and overall survival. Tumors with a complete pathological response (TRG 1) to neoadjuvant CRT had significantly higher tumor-infiltrating T cell levels compared to all other response groups (TRG 2-5). These T cells were also in closer proximity to tumor cells in complete responders compared to other response groups. Notably, immune profiles of near-complete responders (TRG 2) showed more resemblance to non-responders (TRG 3-5) than to complete responders. A high CD8:CD163 ratio in the tumor was associated with an improved disease-free survival. Gene expression analyses revealed that T cells in non-responders were Th2-skewed, while complete responders were enriched in cytotoxic immune cells. Finally, complete responders were enriched in circulating memory T cells. preexisting immune activation enhances the chance for a complete pathological response to neoadjuvant CRT. This information can potentially be used for future patient selection, but also fuels the development of immunomodulatory strategies to enhance CRT efficacy.

Significant variation in histopathological assessment of endoscopic resections for Barrett's neoplasia suggests need for consensus reporting: propositions for improvement.

Endoscopic resection (ER) is an important diagnostic step in management of patients with early Barrett's esophagus (BE) neoplasia. Based on ER specimens, an accurate histological diagnosis can be made, which guides further treatment. Based on depth of tumor invasion, differentiation grade, lymphovascular invasion, and margin status, the risk of lymph node metastases and local recurrence is judged to be low enough to justify endoscopic management, or high enough to warrant invasive surgical esophagectomy. Adequate assessment of these histological risk factors is therefore of the utmost importance. Aim of this study was to assess pathologist concordance on these histological features on ER specimens and evaluate causes of discrepancy. Of 62 challenging ER cases, one representative H&E slide and matching desmin and endothelial marker were digitalized and independently assessed by 13 dedicated GI pathologists from 8 Dutch BE expert centers, using an online assessment module. For each histological feature, concordance and discordance were calculated. Clinically relevant discordances were observed for all criteria. Grouping depth of invasion categories according to expanded endoscopic treatment criteria (T1a and T1sm1 vs. T1sm2/3), ≥1 pathologist was discrepant in 21% of cases, increasing to 45% when grouping diagnoses according to the traditional T1a versus T1b classification. For differentiation grade, lymphovascular invasion, and margin status, discordances were substantial with 27%, 42%, and 32% of cases having ≥1 discrepant pathologist, respectively. In conclusion, histological assessment of ER specimens of early BE cancer by dedicated GI pathologists shows significant discordances for all relevant histological features. We present propositions to improve definitions of diagnostic criteria.

The SpaTemp cohort: 168 nondysplastic Barrett's esophagus surveillance patients with and without progression to early neoplasia to evaluate the distribution of biomarkers over space and time.

The ReBus cohort is a matched nested case-control cohort of patients with nondysplastic (ND) Barrett's esophagus (BE) at baseline who progressed (progressors) or did not progress (nonprogressors) to high-grade dysplasia (HGD) or cancer. This cohort is constructed using the most stringent inclusion criteria to optimize explorative studies on biomarkers predicting malignant progression in NDBE. These explorative studies may benefit from expanding the number of cases and by incorporating samples that allow assessment of the biomarker over space (spatial variability) and over time (temporal variability). To (i) update the ReBus cohort by identifying new progressors and (ii) identify progressors and nonprogressors within the updated ReBus cohort containing spatial and temporal information. The ReBus cohort was updated by identifying Barrett's patients referred for endoscopic work-up of neoplasia at 4 tertiary referral centers. Progressors and nonprogressors with a multilevel (spatial) endoscopy and additional prior (temporal) endoscopies were identified to evaluate biomarkers over space and over time. The original ReBus cohort consisted of 165 progressors and 723 nonprogressors. We identified 65 new progressors meeting the same strict selection criteria, resulting in a total number of 230 progressors and 723 matched nonprogressors in the updated ReBus cohort. Within the updated cohort, 61 progressors and 107 nonprogressors (mean age 61 ± 10 years) with a spatial endoscopy (median level 3 [2-4]) were identified. 33/61 progressors and 50/107 nonprogressors had a median of 3 (2-4) additional temporal endoscopies. Our updated ReBus cohort consists of 230 progressors and 723 matched nonprogressors using the most strict selection criteria. In a subgroup of 168 Barrett's patients (the SpaTemp cohort), multiple levels have been sampled at baseline and during follow-up providing a unique platform to study spatial and temporal distribution of biomarkers in BE.

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.

Adherence to pre-set benchmark quality criteria to qualify as expert assessor of dysplasia in Barrett's esophagus biopsies - towards digital review of Barrett's esophagus.

Background: Dysplasia assessment of Barrett's esophagus biopsies is associated with low observer agreement; guidelines advise expert review. We have developed a web-based review panel for dysplastic Barrett's esophagus biopsies. Objective: The purpose of this study was to test if 10 gastrointestinal pathologists working at Dutch Barrett's esophagus expert centres met pre-set benchmark scores for quality criteria. Methods: Ten gastrointestinal pathologists twice assessed 60 digitalized Barrett's esophagus cases, enriched for dysplasia; then randomised (7520 assessments). We tested predefined benchmark quality criteria: (a) percentage of 'indefinite for dysplasia' diagnoses, benchmark score ≤14% for all cases, ≤16% for dysplastic subset, (b) intra-observer agreement; benchmark score ≥0.66/≥0.39, (c) percentage agreement with 'gold standard diagnosis'; benchmark score ≥82%/≥73%, (d) proportion of cases with high-grade dysplasia underdiagnosed as non-dysplastic Barrett's esophagus; benchmark score ≤1/78 (≤1.28%) assessments for dysplastic subset. Results: Gastrointestinal pathologists had seven years' Barrett's esophagus-experience, handling seven Barrett's esophagus-cases weekly. Three met stringent benchmark scores; all cases and dysplastic subset, three met extended benchmark scores. Four pathologists lacked one quality criterion to meet benchmark scores. Conclusion: Predefined benchmark scores for expert assessment of Barrett's esophagus dysplasia biopsies are stringent and met by some gastrointestinal pathologists. The majority of assessors however, only showed limited deviation from benchmark scores. We expect further training with group discussions will lead to adherence of all participating gastrointestinal pathologists to quality criteria, and therefore eligible to join the review panel.

Results of a two-phased clinical study evaluating a new multiband mucosectomy device for early Barrett's neoplasia: a randomized pre-esophagectomy trial and a pilot therapeutic pilot study.

BACKGROUND: Multiband mucosectomy (MBM) is the preferred technique for piecemeal resection of early neoplastic lesions in Barrett's esophagus (BE). The currently most widely used device for MBM is the Duette device. Recently, the Captivator EMR device has come available which might have practical advantages over the Duette device. METHODS: Phase I was a randomized pre-esophagectomy trial with a non-inferiority design aiming to compare EMR specimens obtained with the Captivator and the Duette device. PRIMARY OUTCOME: max diameter of the EMR specimens, secondary outcomes: min diameter, max thickness of the EMR specimens and resected submucosal stroma. Phase II were clinical pilot cases aiming to evaluate the feasibility of EMR using the Captivator device. Primary outcome was the successful EMR rate and secondary outcomes included procedure time and adverse events. RESULTS: Phase I: 24 EMR specimens (12 pairs) were obtained from six patients. The median max diameter of EMR specimens obtained with the Captivator device was 16 mm [IQR 12-21] versus 18 mm [IQR 13-23] for the Duette device. Non-inferiority of the max diameter of the Captivator specimens could not be demonstrated (median difference 1 mm, 95% CI - 3.26 to + 5.26). However, when using paired analysis, no significant difference was found (p 0.573). In addition, no statistically significant differences were found in the min diameter, max thickness of EMR specimens, and max thickness of resected submucosal stroma. Phase II: 5 BE patients with early neoplastic lesions were included. Successful EMR was achieved in 100%. Median procedure time was 33 min (IQR 25-39). One patient developed transient dysphagia, without signs of stenosis on endoscopy. CONCLUSIONS: EMR of early Barrett's neoplasia using the Captivator device is comparable to Duette EMR when looking at size of resected specimens. In the first patients, EMR using the Captivator was feasible, resulting in successful resection without acute adverse events.

A biomarker panel predicts progression of Barrett's esophagus to esophageal adenocarcinoma.

Progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is uncommon but the consequences are serious. Predictors of progression are essential to optimize resource utilization. This study assessed the utility of a promising panel of biomarkers applicable to routine paraffin embedded biopsies (FFPE) to predict progression of BE to EAC in a large population-based, nested case-control study.We utilized the Amsterdam-based ReBus nested case-control cohort. BE patients who progressed to high-grade dysplasia (HGD)/EAC (n = 130) and BE patients who never progressed (n = 130) were matched on age, sex, length of the BE segment, and duration of endoscopic surveillance. All progressors had minimum 2 years of endoscopic surveillance without HGD/EAC to exclude prevalent neoplasia. We assessed abnormal DNA content, p53, Cyclin A, and Aspergillus oryzae lectin (AOL) in FFPE sections. We performed conditional logistic regression analysis to estimate odds ratio (OR) of progression based on biomarker status.Expert LGD (OR, 8.3; 95% CI, 1.7-41.0), AOL (3 vs. 0 epithelial compartments abnormal; OR, 3.6; 95% CI, 1.2-10.6) and p53 (OR, 2.3; 95% CI, 1.2-4.6) were independently associated with neoplastic progression. Cyclin A did not predict progression and DNA ploidy analysis by image cytometry was unsuccessful in the majority of cases, both were excluded from the multivariate analysis. The multivariable biomarker model had an area under the receiver operating characteristic curve of 0.73.Expert LGD, AOL, and p53 independently predict neoplastic progression in BE patients and are applicable to routine practice. These biomarkers can aid in selecting patients for endoscopic ablation or more intensive surveillance.

A single-step sizing and radiofrequency ablation catheter for circumferential ablation of Barrett's esophagus: Results of a pilot study.

BACKGROUND: The 360 Express balloon catheter (360 Express) has the ability to self-adjust to the esophageal lumen, ensuring optimal tissue contact. OBJECTIVE: The objective of this article is to evaluate the efficacy and safety of the 360 Express for radiofrequency ablation (RFA) treatment of Barrett's esophagus (BE). METHODS: BE patients with low-grade dysplasia (LGD), high-grade dysplasia (HGD) or early cancer (EC) were included. Visible lesions were removed by endoscopic resection (ER) prior to RFA. RFA was performed with the 360 Express using the standard ablation regimen (12J/cm2-clean-12J/cm2). Primary outcome: BE regression percentage at three months. Secondary outcomes: procedure time, adverse events, complete eradication of dysplasia (CE-D) and intestinal metaplasia (CE-IM). RESULTS: Thirty patients (median BE C4M6) were included. Eight patients underwent ER prior to RFA. Median BE regression: 90%. Median procedure time: 31 minutes. Adverse events (13%): laceration (n = 1); atrial fibrillation (n = 1); vomiting and dysphagia (n = 1); dysregulated diabetes (n = 1). After subsequent treatment CE-D and CE-IM was achieved in 97% and 87%, respectively. In 10% a stenosis developed during additional treatment requiring a median of one dilation. CONCLUSION: This study shows that circumferential RFA using the 360 Express may shorten procedure time, while maintaining efficacy compared to standard circumferential RFA.

Endoscopic management and follow-up of patients with a submucosal esophageal adenocarcinoma.

INTRODUCTION: The risk of lymph node metastases (LNM) in submucosal esophageal adenocarcinoma (EAC) patients is subject to debate. These patients might be treated endoscopically if the risk of LNM appears to be low. OBJECTIVE: The objective of this article is to evaluate the outcome of patients who underwent an endoscopic resection (ER) and subsequent endoscopic follow-up for a submucosal EAC. METHODS: All patients who underwent ER for submucosal EAC between January 2012 and August 2016 and were subsequently managed with endoscopic follow-up were retrospectively identified. Primary outcome was the number of patients diagnosed with LNM; secondary outcomes included intraluminal recurrences. RESULTS: Thirty-five patients (median age 68 years) were included: 17 low-risk (submucosal invasion <500 microns, G1-G2, no lymphovascular invasion (LVI)), and 18 high-risk (submucosal invasion >500 microns, and/or G3-G4, and/or LVI, and/or a tumor-positive deep resection margin (R1)) EACs. After a median follow-up of 23 (IQR 15-43) months, in which patients underwent a median of six (IQR 4-8) endoscopies and a median of four (IQR 2-8) endoscopic ultrasound procedures, none of the included patients were diagnosed with LNM. Five (14%) patients developed a local intraluminal recurrence a median of 18 (IQR 11-21) months after baseline ER that were treated endoscopically. CONCLUSIONS: In 35 patients with a submucosal EAC, no LNM were found during a median follow-up of 23 months. Endoscopic therapy may be an alternative for surgery in selected patients with a submucosal EAC.

Development of benchmark quality criteria for assessing whole-endoscopy Barrett's esophagus biopsy cases.

BACKGROUND: Dysplasia in Barrett's esophagus (BE) biopsies is associated with low observer agreement among general pathologists. Therefore, expert review is advised. We are developing a web-based, national expert review panel for histological review of BE biopsies. OBJECTIVE: The aim of this study was to create benchmark quality criteria for future members. METHODS: Five expert BE pathologists, with 10-30 years of BE experience, weekly handling 5-10 cases (25% dysplastic), assessed a case set of 60 digitalized cases, enriched for dysplasia. Each case contained all slides from one endoscopy (non-dysplastic BE (NDBE), n = 21; low-grade dysplasia (LGD), n = 20; high-grade dysplasia (HGD), n = 19). All cases were randomized and assessed twice followed by group discussions to create a consensus diagnosis. Outcome measures: percentage of 'indefinite for dysplasia' (IND) diagnoses, intra-observer agreement, and agreement with the consensus 'gold standard' diagnosis. RESULTS: Mean percentage of IND diagnoses was 8% (3-14%) and mean intra-observer agreement was 0.84 (0.66-1.02). Mean agreement with the consensus diagnosis was 90% (95% prediction interval (PI) 82-98%). CONCLUSION: Expert pathology review of BE requires the scoring of a limited number of IND cases, consistency of assessment and a high agreement with a consensus gold standard diagnosis. These benchmark quality criteria will be used to assess the performance of other pathologists joining our panel.

In vitro assessment of the performance of a new multiband mucosectomy device for endoscopic resection of early upper gastrointestinal neoplasia.

BACKGROUND AND STUDY AIMS: Multiband mucosectomy (MBM) is widely used for the endoscopic resection of early neoplasia in the upper gastrointestinal tract. A new MBM-device may have advantages over the current MBM-device with improved visualization, easier passage of accessories, and higher suction power due to different trip wire and cap. METHODS: Rubber bands were released one by one for both MBM-devices while endoscopic images were collected. First, free endoscopic view was assessed by computer-assisted measurements (quantitative) and by ranking the images by a panel of 11 endoscopists (qualitative). Second, using a visual analog scale, three 'blinded' endoscopists assessed introduction and advancement of three types of endoscopic devices through the working channel of a diagnostic endoscope with the MBM-devices assembled. Third, suction power was evaluated by a manometer attached to the cap of the assembled MBM-devices in four endoscopes. Negative pressures were measured after 5 and 10 s of suction and repeated five times. The passage and suction experiments were performed with dry trip wires and repeated after soaking with bloody, mucous fluids. RESULTS: With all bands present, endoscopic views were 90 and 40% in the new and current MBM-device, respectively. With the release of more bands, differences slowly disappeared. The panel scored a better endoscopic view in the new MBM-device (p = 0.03). Passage of all accessories was considered significantly easier in the new MBM-device. With the associated snare in the working channel, suction power was significantly better with the new MBM-device. CONCLUSION: Compared to the currently available MBM-device, the new MBM-device provides improved endoscopic visibility, smoother passage of accessories, and higher suction power.

Predictive factors for initial treatment response after circumferential radiofrequency ablation for Barrett's esophagus with early neoplasia: a prospective multicenter study.

BACKGROUND AND STUDY AIMS: Radiofrequency ablation (RFA) is safe and effective for the eradication of neoplastic Barrett's esophagus; however, occasionally there is minimal regression after initial circumferential balloon-based RFA (c-RFA). This study aimed to identify predictive factors for a poor response 3 months after c-RFA, and to relate the percentage regression at 3 months to the final treatment outcome. METHODS: We included consecutive patients from 14 centers who underwent c-RFA for high grade dysplasia at worst. Patient and treatment characteristics were registered prospectively. "Poor initial response" was defined as < 50 % regression of the Barrett's esophagus 3 months after c-RFA, graded by two expert endoscopists using endoscopic images. Predictors of initial response were identified through logistic regression analysis. RESULTS: There were 278 patients included (median Barrett's segment C4M6). In poor initial responders (n = 36; 13 %), complete response for neoplasia (CR-neoplasia) was ultimately achieved in 86 % (vs. 98 % in good responders; P < 0.01) and complete response for intestinal metaplasia (CR-IM) in 66 % (vs. 95 %; P < 0.01). Poor responders required 13 months treatment (vs. 7 months; P < 0.01) for a median of four RFA sessions (vs. three; P < 0.01). We identified four independent baseline predictors of poor response: active reflux esophagitis (odds ratio [OR] 37.4; 95 % confidence interval [CI] 3.2 - 433.2); endoscopic resection scar regeneration with Barrett's epithelium (OR 4.7; 95 %CI 1.1 - 20.0); esophageal narrowing pre-RFA (OR 3.9; 95 %CI 1.0 - 15.1); and years of neoplasia pre-RFA (OR 1.2; 95 %CI 1.0 - 1.4). CONCLUSIONS: Patients with a poor initial response to c-RFA have a lower ultimate success rate for CR-neoplasia/CR-IM, require more treatment sessions, and a longer treatment period. A poor initial response to c-RFA occurs more frequently in patients who regenerate their endoscopic resection scar with Barrett's epithelium, and those with ongoing reflux esophagitis, neoplasia in Barrett's esophagus for a longer time, or a narrow esophagus.

Radiofrequency ablation and endoscopic resection in a single session for Barrett's esophagus containing early neoplasia: a feasibility study.

BACKGROUND AND STUDY AIM: Endoscopic resection with radiofrequency ablation (RFA) 6 weeks later safely and effectively eradicates Barrett's esophagus with high grade dysplasia (HGD) and early cancer. After widespread endoscopic resection, related scarring may hamper balloon-based circumferential RFA (c-RFA). However c-RFA immediately followed by endoscopic resection in the same session might avoid the impact of scarring and reduce laceration and stenosis risk. We aimed to assess the feasibility of such an approach. PATIENTS AND METHODS: Patients with Barrett's esophagus ≥ 3 cm and ≥ 1 visible lesion (HGD/early cancer) were included. Visible lesions were marked with cautery, and c-RFA (12 J/cm2) was delivered using two applications and a cleaning step, followed by resection of the delineated area. Outcome measures were surface regression of Barrett's esophagus at 3 months, need for subsequent c-RFA, complications, and quality of resection specimens. RESULTS: 24 patients (20 men, 4 women; mean age 68 years, standard deviation [SD] 12; Barrett's esophagus median length C6M8) underwent single-session c-RFA + endoscopic resection, providing a median of 4 (interquartile range [IQR] 2 - 6) resection specimens (early cancer 18 patients; HGD 6). Complications included 1 perforation, 4 bleedings, and 5 stenoses; all were managed endoscopically. Specimens allowed assessment of neoplasia depth, differentiation, and lymphatic/vascular invasion. Median Barrett's esophagus surface regression at 3 months was 95 %. No patient required a second c-RFA procedure and 40 % required repeat endoscopic resection for visible lesions. Complete response for neoplasia was achieved in 100 % and complete response for intestinal metaplasia (CR-IM) in 95 %. CONCLUSIONS: c-RFA followed by endoscopic resection in the same session is feasible, but technically demanding and associated with a substantial rate of complications and repeat endoscopic resection. This approach should be reserved for selected cases in expert centers, with endoscopic resection and RFA 6 - 8 weeks later remaining the standard combined approach.

Learning to perform endoscopic resection of esophageal neoplasia is associated with significant complications even within a structured training program.

BACKGROUND AND STUDY AIMS: Endoscopic resection is the cornerstone of endoscopic treatment of esophageal high grade dysplasia or early cancer. Endoscopic resection is, however, a technically demanding procedure, which requires training and expertise. The aim of the current study was to prospectively evaluate efficacy and safety of the first 120 endoscopic resection procedures of early esophageal neoplasia performed by six endoscopists (20 endoscopic resections each) who were participating in an endoscopic resection training program. PATIENTS AND METHODS: The program consisted of four tri-monthly 1-day courses with lectures, live-demonstrations, hands-on training on anesthetized pigs, and one-on-one hands-on training days. Gastroenterologists from centers with multidisciplinary expertise in upper gastrointestinal oncology participated, together with an endoscopy nurse and a pathologist. Outcome measures were complete endoscopic removal of the target area and acute complications. RESULTS: A total of 120 consecutive esophageal endoscopic resection procedures (85 ER-cap, 35 multiband mucosectomy [MBM]) were performed by six endoscopists: 109 in Barrett's esophagus, 11 for squamous neoplasia; 85 piecemeal endoscopic resections (median 3 specimens, interquartile range 2 - 4 specimens). Complete endoscopic removal was achieved in 111 /120 cases (92.5 %). Six perforations occurred (5.0 %): five were effectively treated endoscopically (clips, covered stent), and one patient underwent esophagectomy. There were 11 acute mild bleedings (9.2 %), which were managed endoscopically. Perforations occurred in ER-cap procedures performed by four participants (7.1 % ER-cap vs. 0 % MBM; P = 0.18), and in 1.7 % of the first 10 endoscopic resections and 8.3 % of the second 10 endoscopic resections per endoscopist (P = 0.26). CONCLUSION: In this intense, structured training program, the first 120 esophageal endoscopic resections performed by six participants were associated with a 5.0 % perforation rate. Although perforations were adequately managed, performing 20 endoscopic resections may not be sufficient to reach the peak of the learning curve in endoscopic resection.

Radiofrequency ablation for the endoscopic eradication of esophageal squamous high grade intraepithelial neoplasia and mucosal squamous cell carcinoma.

BACKGROUND AND STUDY AIMS: Radiofrequency ablation (RFA) with or without prior endoscopic resection safely and effectively removes early neoplasia in Barrett's esophagus. We speculated that this approach might also be suited for early squamous neoplasia of the esophagus. The aim of the study was to assess our initial experiences with RFA for high grade intraepithelial neoplasia (HGIN) and esophageal squamous cell cancer (ESCC) limited to the mucosa. PATIENTS AND METHODS: This was a prospective case series study in two tertiary centers. Patients with at least one unstained lesion (USL) of the esophagus using Lugol's chromoendoscopy and squamous HGIN/ESCC upon biopsy were included. In the case of nonflat USLs, endoscopic resection was performed for staging and to render the mucosa flat. After endoscopic resection and subsequent circumferential RFA, chromoendoscopy was repeated every 3 months with focal RFA of residual USLs. Follow-up chromoendoscopy was repeated at 6 months and annually thereafter. The main outcome measure was complete histological response for any squamous intraepithelial neoplasia or ESCC. RESULTS: A total of 13 patients (10 HGIN, three ESCC) were included. Following endoscopic resection in nine patients, the median extent of USLs was 4 cm and 50 % of circumference. All 13 patients achieved a complete response after a median of 2 RFA sessions (IQR 1 - 3 sessions). RFA-related complications included two mucosal lacerations (at the endoscopic resection scar) and one intramural hematoma, none requiring therapy. Endoscopic resection-/RFA-related complications were three stenoses. Dilation resulted in perforation in one patient (managed with a covered stent). There were no recurrences (median follow-up 17 months [IQR 11 - 22 months]). CONCLUSIONS: This study suggests that RFA with or without prior endoscopic resection for esophageal squamous HGIN and mucosal ESCC is feasible and effective.

Safety and efficacy of multiband mucosectomy in 1060 resections in Barrett's esophagus.

INTRODUCTION: Multiband mucosectomy (MBM) is a relatively new technique for endoscopic resection in Barrett's esophagus. This ligate-cut technique uses a modified variceal band ligator allowing for six consecutive resections without prior submucosal lifting. The aim was to evaluate the safety of MBM and its efficacy for complete endoscopic removal of delineated target areas in Barrett's esophagus. METHODS: Prospective registration of all MBM procedures in Barrett's esophagus was carried out between November 2004 and October 2009 in two hospitals. Prior to MBM, the target area was delineated with coagulation markings, followed by endoscopic resection until the delineated area was completely resected. Primary end points were acute (during procedure) plus early complications (<30 days) and the rate of complete endoscopic resection of the delineated target area. RESULTS: A total of 243 MBM procedures, with 1060 resections, were performed in 170 patients. MBM was performed for focal lesions (n=113), for Barrett's esophagus removal as part of a (stepwise) radical endoscopic resection protocol (n=117), and as escape treatment after radiofrequency ablation (n=13). The only acute complication was bleeding (in 3%, endoscopically managed); no perforations occurred despite absence of submucosal lifting. Early complications consisted of delayed bleeding (in 2%, endoscopically managed) and stenosis, which occurred in 48% of patients treated in a (stepwise) radical resection protocol; patients treated for focal lesions or in escape treatment showed no stenosis. Complete endoscopic resection was achieved in 91% of the focal lesions, in 86% of cases treated under the (stepwise) radical endoscopic resection protocol, and 100% for escape treatment after radiofrequency ablation. CONCLUSION: MBM is a safe and effective technique for the removal of delineated target areas in Barrett's esophagus.