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.

Team dynamics and clinician's experience influence decision-making during Upper-GI multidisciplinary team meetings: A multiple case study.

Background: The probability of undergoing treatment with curative intent for esophagogastric cancer has been shown to vary considerately between hospitals of diagnosis. Little is known about the factors that attribute to this variation. Since clinical decision making (CDM) partially takes place during an MDTM, the aim of this qualitative study was to assess clinician's perspectives regarding facilitators and barriers associated with CDM during MDTM, and second, to identify factors associated with CDM during an MDTM that may potentially explain differences in hospital practice. Methods: A multiple case study design was conducted. The thematic content analysis of this qualitative study, focused on 16 MDTM observations, 30 semi-structured interviews with clinicians and seven focus groups with clinicians to complement the collected data. Interviews were transcribed ad verbatim and coded. Results: Factors regarding team dynamics that were raised as aspects attributing to CDM were clinician's personal characteristics such as ambition and the intention to be innovative. Clinician's convictions regarding a certain treatment and its outcomes and previous experiences with treatment outcomes, and team dynamics within the MDTM influenced CDM. In addition, a continuum was illustrated. At one end of the continuum, teams tended to be more conservative, following the guidelines more strictly, versus the opposite in which hospitals tended towards a more invasive approach maximizing the probability of curation. Conclusion: This study contributes to the awareness that variation in team dynamics influences CDM during an MDTM.

Eliminating exogenous insulin therapy in patients with type 2 diabetes by duodenal ablation and GLP-1RA decreases risk scores for cardiovascular events.

INTRODUCTION: Duodenal Mucosal Resurfacing (DMR) is an endoscopic ablation technique aimed at improving glycaemia and metabolic health in patients with type 2 diabetes mellitus (T2DM). DMR has an insulin sensitizing effect in patients with T2DM. Reducing hyperinsulinemia can improve cardiovascular health. In the INSPIRE trial, we combined a single DMR with a glucagon-like-peptide-1 receptor agonist (GLP-1RA) and demonstrated elimination of insulin treatment in 69% of patients at 6 months and 53% of patients at 18 months while improving glycaemic control and metabolic health. We hypothesized that this treatment approach is associated with improved cardiovascular health, by reducing hyperinsulinemia. METHODS: Before and 6 months after starting the combination treatment to replace insulin, the following assessments were performed to evaluate cardiovascular health: magnetic resonance imaging (MRI) to measure abdominal visceral adipose tissue volume, ambulatory 24 h blood pressure (ABPM) analysis, postprandial insulin and triglycerides, fasting lipid panel and urine microalbumin. The Atherosclerotic Cardiovascular Disease (ASCVD) score was calculated to estimate 10-year risk of cardiovascular disease or stroke and the diabetes lifetime-perspective prediction (DIAL) score was calculated to estimate years free of cardiovascular disease. RESULTS: Six months after replacing exogenous insulin by DMR and GLP-1RA, visceral adipose tissue decreased significantly by 24%. Postprandial triglyceride and insulin concentrations decreased significantly (p < 0.001), as did total cholesterol (from median 3.64 (IQR 3.34-4.89) to 3.48 (3.18-3.97) mmol/l, p = 0.008), LDL (from median 1.92 (IQR 1.49-2.30) to 1.79 (1.49-2.08 mmol/l, p = 0.044), and urine microalbumin (from median 7 (IQR 3-27) to 4 (3-8) mg/l, p = 0.018). All daytime blood pressure values decreased significantly. The ASCVD 10-year risk score decreased (from median 13.6 (IQR 5.7-26.0) to 11.5 (4.2-22.5) %, p = 0.030)) and the DIAL score increased (from median 82 (IQR 81-83) to 83 (81-84) years, (p = 0.039)). DISCUSSION: The combination of DMR and GLP-1RA to replace insulin therapy in patients with T2DM is associated with a positive effect on multiple parameters of cardiovascular health. Taken together, they show a pattern of overall improvement in cardiovascular health, as evidenced by decreased risk scores for cardiovascular complications. However, it is not yet clear whether these improvements will translate into a true reduction in cardiovascular events.

FOXO transcriptional activity is associated with response to chemoradiation in EAC.

In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies.

Safety and efficacy of hydrothermal duodenal mucosal resurfacing in patients with type 2 diabetes: the randomised, double-blind, sham-controlled, multicentre REVITA-2 feasibility trial.

OBJECTIVE: Hydrothermal duodenal mucosal resurfacing (DMR) is a safe, outpatient endoscopic procedure. REVITA-2, a double-blind, superiority randomised controlled trial, investigates safety and efficacy of DMR using the single catheter Revita system (Revita DMR (catheter and system)), on glycaemic control and liver fat content in type 2 diabetes (T2D). DESIGN: Eligible patients (haemoglobin A1c (HbA1c) 59-86 mmol/mol, body mass index≥24 and ≤40 kg/m2, fasting insulin >48.6 pmol/L, ≥1 oral antidiabetic medication) enrolled in Europe and Brazil. Primary endpoints were safety, change from baseline in HbA1c at 24 weeks, and liver MRI proton-density fat fraction (MRI-PDFF) at 12 weeks. RESULTS: Overall mITT (DMR n=56; sham n=52), 24 weeks post DMR, median (IQR) HbA1c change was -10.4 (18.6) mmol/mol in DMR group versus -7.1 (16.4) mmol/mol in sham group (p=0.147). In patients with baseline liver MRI-PDFF >5% (DMR n=48; sham n=43), 12-week post-DMR liver-fat change was -5.4 (5.6)% in DMR group versus -2.9 (6.2)% in sham group (p=0.096). Results from prespecified interaction testing and clinical parameter assessment showed heterogeneity between European (DMR n=39; sham n=37) and Brazilian (DMR n=17; sham n=16) populations (p=0.063); therefore, results were stratified by region. In European mITT, 24 weeks post DMR, median (IQR) HbA1c change was -6.6 mmol/mol (17.5 mmol/mol) versus -3.3 mmol/mol (10.9 mmol/mol) post-sham (p=0.033); 12-week post-DMR liver-fat change was -5.4% (6.1%) versus -2.2% (4.3%) post-sham (p=0.035). Brazilian mITT results trended towards DMR benefit in HbA1c, but not liver fat, in context of a large sham effect. In overall PP, patients with high baseline fasting plasma glucose ((FPG)≥10 mmol/L) had significantly greater reductions in HbA1c post-DMR versus sham (p=0.002). Most adverse events were mild and transient. CONCLUSIONS: DMR is safe and exerts beneficial disease-modifying metabolic effects in T2D with or without non-alcoholic liver disease, particularly in patients with high FPG. TRIAL REGISTRATION NUMBER: NCT02879383.

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.

Standalone performance of artificial intelligence for upper GI neoplasia: a meta-analysis.

OBJECTIVE: Artificial intelligence (AI) may reduce underdiagnosed or overlooked upper GI (UGI) neoplastic and preneoplastic conditions, due to subtle appearance and low disease prevalence. Only disease-specific AI performances have been reported, generating uncertainty on its clinical value. DESIGN: We searched PubMed, Embase and Scopus until July 2020, for studies on the diagnostic performance of AI in detection and characterisation of UGI lesions. Primary outcomes were pooled diagnostic accuracy, sensitivity and specificity of AI. Secondary outcomes were pooled positive (PPV) and negative (NPV) predictive values. We calculated pooled proportion rates (%), designed summary receiving operating characteristic curves with respective area under the curves (AUCs) and performed metaregression and sensitivity analysis. RESULTS: Overall, 19 studies on detection of oesophageal squamous cell neoplasia (ESCN) or Barrett's esophagus-related neoplasia (BERN) or gastric adenocarcinoma (GCA) were included with 218, 445, 453 patients and 7976, 2340, 13 562 images, respectively. AI-sensitivity/specificity/PPV/NPV/positive likelihood ratio/negative likelihood ratio for UGI neoplasia detection were 90% (CI 85% to 94%)/89% (CI 85% to 92%)/87% (CI 83% to 91%)/91% (CI 87% to 94%)/8.2 (CI 5.7 to 11.7)/0.111 (CI 0.071 to 0.175), respectively, with an overall AUC of 0.95 (CI 0.93 to 0.97). No difference in AI performance across ESCN, BERN and GCA was found, AUC being 0.94 (CI 0.52 to 0.99), 0.96 (CI 0.95 to 0.98), 0.93 (CI 0.83 to 0.99), respectively. Overall, study quality was low, with high risk of selection bias. No significant publication bias was found. CONCLUSION: We found a high overall AI accuracy for the diagnosis of any neoplastic lesion of the UGI tract that was independent of the underlying condition. This may be expected to substantially reduce the miss rate of precancerous lesions and early cancer when implemented in clinical practice.

Multicenter study on the diagnostic performance of multiframe volumetric laser endomicroscopy targets for Barrett's esophagus neoplasia with histopathology correlation.

Volumetric laser endomicroscopy (VLE) has been shown to improve detection of early neoplasia in Barrett's esophagus (BE). However, diagnostic performance using histopathology-correlated VLE regions of interest (ROIs) has not been adequately studied. We evaluated the diagnostic accuracy of VLE assessors for identification of early BE neoplasia in histopathology-correlated VLE ROIs. In total, 191 ROIs (120 nondysplastic and 71 neoplastic) from 50 BE patients were evaluated in a random order using a web-based module. All ROIs contained histopathology correlations enabled by VLE laser marking. Assessors were blinded to endoscopic BE images and histology. ROIs were first scored as nondysplastic or neoplastic. Level of confidence was assigned to the predicted diagnosis. Outcome measures were: (i) diagnostic performance of VLE assessors for identification of BE neoplasia in all VLE ROIs, defined as accuracy, sensitivity, and specificity; (ii) diagnostic performance of VLE assessors for only high level of confidence predictions; and (iii) interobserver agreement. Accuracy, sensitivity, and specificity for BE neoplasia identification were 79% (confidence interval [CI], 75-83), 75% (CI, 71-79), and 81% (CI, 76-86), respectively. When neoplasia was identified with a high level of confidence, accuracy, sensitivity, and specificity were 88%, 83%, and 90%, respectively. The overall strength of interobserver agreement was fair (k = 0.29). VLE assessors can identify BE neoplasia with reasonable diagnostic accuracy in histopathology-correlated VLE ROIs, and accuracy is enhanced when BE neoplasia is identified with high level of confidence. Future work should focus on renewed VLE image reviewing criteria and real-time automatic assessment of VLE scans.

Improved Barrett's neoplasia detection using computer-assisted multiframe analysis of volumetric laser endomicroscopy.

Volumetric laser endomicroscopy (VLE) is a balloon-based technique, which provides a circumferential near-microscopic scan of the esophageal wall layers, and has potential to improve Barrett's neoplasia detection. Interpretation of VLE imagery in Barrett's esophagus (BE) however is time-consuming and complex, due to a large amount of visual information and numerous subtle gray-shaded VLE images. Computer-aided detection (CAD), analyzing multiple neighboring VLE frames, might improve BE neoplasia detection compared to automated single-frame analyses. This study is to evaluate feasibility of automatic data extraction followed by CAD using a multiframe approach for detection of BE neoplasia. Prospectively collected ex-vivo VLE images from 29 BE-patients with and without early neoplasia were retrospectively analyzed. Sixty histopathology-correlated regions of interest (30 nondysplastic vs. 30 neoplastic) were assessed using different CAD systems. Multiple neighboring VLE frames, corresponding to 1.25 millimeter proximal and distal to each region of interest, were evaluated. In total, 3060 VLE frames were analyzed via the CAD multiframe analysis. Multiframe analysis resulted in a significantly higher median AUC (median level = 0.91) compared to single-frame (median level = 0.83) with a median difference of 0.08 (95% CI, 0.06-0.10), P < 0.001. A maximum AUC of 0.94 was reached when including 22 frames on each side using a multiframe approach. In total, 3060 VLE frames were automatically extracted and analyzed by CAD in 3.9 seconds. Multiframe VLE image analysis shows improved BE neoplasia detection compared to single-frame analysis. CAD with multiframe analysis allows for fast and accurate VLE interpretation, thereby showing feasibility of automatic full scan assessment in a real-time setting during endoscopy.

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.

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.

Endoscopic management of dysplasia and early oesophageal cancer.

In the past decade there have been technological advances in Endoscopic Eradication Therapy (EET) for the management of patients with oesophageal neoplasia and early cancer. Multiple endoscopic techniques now exist for both squamous and Barrett's oesophagus associated neoplasia or early cancer. A fundamental aspect of endotherapy is removal of the target lesion by endoscopic mucosal resection, or endosopic submucosal dissection. Residual tissue is subsequently ablated to remove the risk of recurrence. The most validated technique for Barrett's oesophagus is radiofrequency ablation, but other techniques such as hybrid-APC and cryotherapy also show good results. This chapter will discuss the evolution of EET, and which patients are most likely to benefit. It will also explore the evidence behind the success of different techniques and provide practical advice on how to carry out the endoscopic techniques with a focus on radiofrequency ablation and endoscopic mucosal resection in particular.

Preoperative image-guided identification of response to neoadjuvant chemoradiotherapy in esophageal cancer (PRIDE): a multicenter observational study.

BACKGROUND: Nearly one third of patients undergoing neoadjuvant chemoradiotherapy (nCRT) for locally advanced esophageal cancer have a pathologic complete response (pCR) of the primary tumor upon histopathological evaluation of the resection specimen. The primary aim of this study is to develop a model that predicts the probability of pCR to nCRT in esophageal cancer, based on diffusion-weighted magnetic resonance imaging (DW-MRI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET-CT). Accurate response prediction could lead to a patient-tailored approach with omission of surgery in the future in case of predicted pCR or additional neoadjuvant treatment in case of non-pCR. METHODS: The PRIDE study is a prospective, single arm, observational multicenter study designed to develop a multimodal prediction model for histopathological response to nCRT for esophageal cancer. A total of 200 patients with locally advanced esophageal cancer - of which at least 130 patients with adenocarcinoma and at least 61 patients with squamous cell carcinoma - scheduled to receive nCRT followed by esophagectomy will be included. The primary modalities to be incorporated in the prediction model are quantitative parameters derived from MRI and 18F-FDG PET-CT scans, which will be acquired at fixed intervals before, during and after nCRT. Secondary modalities include blood samples for analysis of the presence of circulating tumor DNA (ctDNA) at 3 time-points (before, during and after nCRT), and an endoscopy with (random) bite-on-bite biopsies of the primary tumor site and other suspected lesions in the esophagus as well as an endoscopic ultrasonography (EUS) with fine needle aspiration of suspected lymph nodes after finishing nCRT. The main study endpoint is the performance of the model for pCR prediction. Secondary endpoints include progression-free and overall survival. DISCUSSION: If the multimodal PRIDE concept provides high predictive performance for pCR, the results of this study will play an important role in accurate identification of esophageal cancer patients with a pCR to nCRT. These patients might benefit from a patient-tailored approach with omission of surgery in the future. Vice versa, patients with non-pCR might benefit from additional neoadjuvant treatment, or ineffective therapy could be stopped. TRIAL REGISTRATION: The article reports on a health care intervention on human participants and was prospectively registered on March 22, 2018 under ClinicalTrials.gov Identifier: NCT03474341 .

Validation of a biomarker panel in Barrett's esophagus to predict progression to esophageal adenocarcinoma.

In a prior study, baseline mutational load (ML) predicted progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) in Barrett's esophagus (BE) with an area under the curve (AUC) of 0.95. We aimed to validate the test characteristics of this predictive biomarker panel using crude DNA lysates in a larger well-characterized cohort. We performed a nested case-control study of BE patients from three tertiary referral centers in the Netherlands. Cases had baseline nondysplastic BE (NDBE) and developed HGD/EAC ≥ 2 years later. Controls were matched 2:1, had baseline NDBE, and no progression. Polymerase chain reaction (PCR)-based mutational analysis was performed on crude lysates from formalin-fixed, paraffin-embedded tissue. ML was calculated from loss of heterozygosity (LOH) and microsatellite instability (MSI) at 10 genomic loci. Receiver operator characteristic (ROC) curves were created to assess the diagnostic utility of various cutoffs of ML for progression. Of 159 subjects, 58 were progressors and 101 were nonprogressors, there was no difference in mean ML in preprogression tissue in progressors and nonprogressors (ML = 0.73 ± 0.69 vs. ML = 0.74 ± 0.61, P = 0.93). ROC curves showed poor discrimination of ML in predicting progression with AUC of 0.50 at ML ≥ 1. AUC did not vary with different ML cut-points. The utility of the ML to stratify BE patients for risk of progression was not confirmed in this study. The etiology for discrepancies between this and prior studies showing high predictiveness is likely due to the use of crude lysates in this study, but requires further investigation.

Balloon-based esophageal cryoablation with a novel focal ablation device: dose-finding and safety in porcine and human models.

The new Cryoballoon Focal Ablation System (CbFAS), a through-the-scope catheter with battery-powered handle that delivers cryogenic fluid into an inflated balloon, differs from current cryotherapy methods used for treatment of Barrett's epithelium. In this dose-finding study, short- and long-term histopathological effects and safety of the CbFAS were evaluated. Cryoablations with (supra)therapeutic durations (4-24 seconds) were performed in pigs that survived for 12 or 48 hours or 4 or 28 days. Next, cryoablations (durations based on animal data) were performed in normal mucosa of esophageal cancer patients scheduled to undergo esophagectomy. The outcome parameters, the occurrence of any bleeding or perforation, the histological presence of edema, inflammation, and necrosis throughout the esophageal wall layers, were evaluated. A total of 60 cryoablations were performed in 11 pigs. 48 hour cryoablations with therapeutic durations (4-10 seconds) resulted in edema/inflammation as deep as the serosa and necrosis ranging from submucosa to serosa with a median depth of 3.2 mm. In 4 day cryoablations this was in the serosa, and muscularis tunica to serosa at a median depth of 4.5 mm, respectively. No necrosis or inflammation remained after 28 days, not even after supratherapeutic cryoablation (12-24 seconds). No acute or delayed bleeding or perforation was observed. Next, eight 6-second cryoablations were performed in four patients. Direct postablation mucosal necrosis was observed; after 4 days necrosis and inflammation was limited to the submucosa. CbFAS cryoablation penetrates deeply into the esophageal wall layers resulting in severe early ablation. After 4 weeks, little injury and no fibrosis remain, even after supratherapeutic durations of administration, suggesting that CbFAS combines deep ablation with a potentially favorable safety profile.

Digital microscopy as valid alternative to conventional microscopy for histological evaluation of Barrett's esophagus biopsies.

Management of Barrett's esophagus (BE) relies heavily on histopathological assessment of biopsies, associated with significant intra- and interobserver variability. Guidelines recommend biopsy review by an expert in case of dysplasia. Conventional review of biopsies, however, is impractical and does not allow for teleconferencing or annotations. An expert digital review platform might overcome these limitations. We compared diagnostic agreement of digital and conventional microscopy for diagnosing BE ± dysplasia. Sixty BE biopsy glass slides (non-dysplastic BE (NDBE); n = 25, low-grade dysplasia (LGD); n = 20; high-grade dysplasia (HGD); n = 15) were scanned at ×20 magnification. The slides were assessed four times by five expert BE pathologists, all practicing histopathologists (range: 5-30 years), in 2 alternating rounds of digital and conventional microscopy, each in randomized order and sequence of slides. Intraobserver and pairwise interobserver agreement were calculated, using custom weighted Cohen's kappa, adjusted for the maximum possible kappa scores. Split into three categories (NDBE, IND, LGD+HGD), the mean intraobserver agreement was 0.75 and 0.84 for digital and conventional assessment, respectively (p = 0.35). Mean pairwise interobserver agreement was 0.80 for digital and 0.85 for conventional microscopy (p = 0.17). In 47/60 (78%) of digital microscopy reviews a majority vote of ≥3 pathologists was reached before consensus meeting. After group discussion, a majority vote was achieved in all cases (60/60). Diagnostic agreement of digital microscopy is comparable to that of conventional microscopy. These outcomes justify the use of digital slides in a nationwide, web-based BE revision platform in the Netherlands. This will overcome the practical issues associated with conventional histologic review by multiple pathologists.

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 adenocarcinoma's 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.

Treatment strategies in recurrent esophageal or junctional cancer.

Little evidence is available about survival rates in patients with recurrent disease after potentially curative surgery for esophageal or junctional cancer. Only in limited occasions, potentially curative salvage strategies are available. The aim of this study is to analyze survival rates and patterns of dissemination, and to identify independent prognostic factors in a consecutive series of patients who develop recurrent esophageal or junctional cancer. Between 1994 and 2015, patients who developed disease recurrence after neoadjuvant chemo(radio)therapy followed by radical esophagectomy for esophageal or junctional cancer were retrospectively analyzed. The Kaplan-Meier estimates were performed to calculate and compare overall survival between patients with different patterns of dissemination and to compare between different treatment strategies. Furthermore, univariate and multivariate Cox-regression analyses were performed to identify independent prognostic factors for post recurrence survival. In this study, we included 219 patients. The median overall survival of all included patients was 3.2 months (range: 0.0-101.1 months). The median overall survival in patients with exclusively locoregional recurrence (n = 23, 10.8%) was 4.9 months (range: 0.1- 55.6) and 2.9 months (range: 0.0-101.1) in patients who had distant metastases (n = 189, 89.2%), P = 0.003. Patients who received treatment aimed at complete tumor eradication (n = 28, 13.7%) had a median overall survival of 13.6 months (range: 1.1-101.1) and palliative treated patients (n = 94, 46.1%) of 4.7 months (range: 0.3-25.6), P < 0.001. In a selected group of patients survival of more than 20 months was achieved. Univariate and multivariate Cox-regression analysis showed that a higher age at the diagnosis of recurrent disease (hazard ratio: 1.087, P ≤ 0.001), an irradical resection of the primary tumor (hazard ratio: 3.355, P = < 0.001), the number of positive lymph nodes after neoadjuvant therapy (hazard ratios: ypN2 = 1.724 (P = 0.024) and ypN3 = 2.082 (P = 0.028) and the presence of a single hematogenous distant metastases (hazard ratio: 2.281, P = 0.003) or more than one hematogenous distant metastasis (hazard ratio: 2.385, P = 0.005) were associated with a shorter postrecurrence survival. The prognosis of patients who develop recurrent esophageal or junctional cancer is poor. In a selected group of patients however relatively long survival can be achieved. This offers new perspectives to improve treatment strategies and survival rates.