Safety and Feasibility of Robot-Assisted Minimally Invasive Esophagectomy (RAMIE) with Three-Field Lymphadenectomy and Neoadjuvant Chemoradiotherapy in Patients with Resectable Esophageal Cancer and Cervical Lymph Node Metastasis.

BACKGROUND: In the West, patients with cervical lymph node metastasis of resectable esophageal cancer at diagnosis are generally precluded from curative treatment. This study prospectively explored the safety and feasibility of neoadjuvant chemoradiotherapy followed by robot-assisted minimally invasive esophagectomy (RAMIE) with three-field lymphadenectomy for these patients. METHODS: Between 2015 and 2021, patients with resectable thoracic esophageal cancer and cervical lymph node metastasis were recruited nationwide in the Netherlands. Patients without interval metastasis following neoadjuvant chemoradiotherapy and good physical condition underwent RAMIE with bilateral three-field lymphadenectomy. Safety was predefined as ≤50% Clavien-Dindo grade ≥3b postoperative complications. RESULTS: Neoadjuvant chemoradiotherapy was administered to 29 patients (19 (66%) adenocarcinoma and 10 (34%) squamous cell carcinoma). After restaging, nine (31%) patients were excluded (interval metastasis, clinical deterioration, or withdrawn consent). RAMIE was performed in 20 patients (R0-rate 95%). A median of 42 [range 21-71] lymph nodes were resected of which 13 [range 2-35] were cervical. Only 1 (5%) patient had an unexpected contralateral cervical lymph node metastasis. Complications grade ≥3b occurred in 50%. Most frequent complications of any grade were recurrent laryngeal nerve palsy (45%) and pneumonia (40%). Overall survival at 1 year was 85% and quality of life at 6 months was comparable to esophageal cancer patients treated with curative intent. CONCLUSIONS: RAMIE with three-field lymphadenectomy following neoadjuvant chemoradiotherapy for patients with resectable esophageal cancer presenting with cervical lymph node metastasis is feasible in a Western population. Because contralateral cervical metastasis is rare, a unilateral neck dissection would suffice in the majority of cases. CLINICAL TRIAL: gov Identifier: NCT02426879. Dutch trial register Identifier: NTR 4552.

Long-term oncological outcomes of endoscopic full-thickness resection after previous incomplete resection of low-risk T1 CRC (LOCAL-study): study protocol of a national prospective cohort study.

BACKGROUND: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization. METHODS/DESIGN: In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate. DISCUSSION: Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Trial registration Nederlands Trial Register, NL 7879, 16 July 2019 ( https://trialregister.nl/trial/7879 ).

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.

Single-Step Treatment with Limited Endoscopic Resection and Cryoballoon Ablation Is Feasible and Safe in an Esophageal Porcine Model.

BACKGROUND: Treatment of Barrett's neoplasia consists of two steps: endoscopic resection of visible lesions with subsequent ablation of remaining Barrett's epithelium. However, extensive resection might hamper subsequent ablation due to stenosis. Combining both modalities in one session therefore offers potential advantages. Single-step treatment with radiofrequency ablation and resection appeared to be unsafe. AIMS: To evaluate feasibility and safety of single-step treatment with cryoballoon ablation and endoscopic resection. METHODS: Two single-step treatment regimens (15 treatment areas per regimen) were evaluated: (1) CRYO-EMR: four side-by-side focal ablations of 10 seconds followed by resection in the treated area; (2) EMR-CRYO: resection followed by 10-s ablation targeted on the resection wound. Primary outcome for both regimens was safety (perforations, clinically relevant strictures) and for CRYO-EMR also feasibility of resection and histopathological evaluation. Secondly, all CRYO-EMR and esophageal resection specimens were histopathologically evaluated. RESULTS: Six female pigs were treated (five treatment areas per animal). During 28 days of follow-up, no perforations or clinically relevant stenosis occurred. All resections were technically successful. For all CRYO-EMR specimens, histopathological evaluation was feasible with ablation effects present throughout all layers, while the architecture requisite for histopathological analysis remained intact. After 28 days, histopathological evaluation of the esophagi was performed. For EMR-CRYO, post-treatment fibrosis was present throughout the submucosa. The muscularis propria was the deepest layer involved for CRYO-EMR. CONCLUSIONS: Single-step treatment with limited endoscopic resection and cryoballoon ablation is feasible and safe in a porcine model and justifies further evaluation in a clinical trial.

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.

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 .

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.

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.

Circumferential cryoablation in a strictured esophagus: a feasibility and dose-finding study in a porcine model after inducing stenosis by endoscopic mucosal resection.

In the treatment of early esophageal Barrett's neoplasia, radiofrequency ablation may be hindered by stenosis due to prior endoscopic resection (ER). The flexible balloon-based circumferential CryoBalloon Ablation System (CBAS) may overcome this problem by the conformability of the compliant balloon which might enable circumferential cryoablation in a stenosis. The aim of the current study was to evaluate the feasibility of the CBAS as well as the dose-response effect of cryoablation in a strictured esophagus model. In six pigs, a stenosis was induced by ER (3 cm in length, 75% of circumference) in the proximal, mid, and distal esophagus. After 28 days, cryoablation with the CBAS was performed, with the length of ablation time (6, 8, or 10 seconds) randomly assigned per stricture location within the esophagus. Four days post-ablation, the esophagi were harvested for histopathological assessment of the percentage of the total circumference affected by cryoablation and the maximum depth of necrosis. At 28 days, all 18 ER areas had transformed into strictures with ±50% of its original diameter remaining. In 9 of 18 strictures, more than one attempt for cryoablation was necessary due to displacement of the balloon. Histopathological evaluation showed a wide range in circumferential uniformity (0-100%) and maximum necrosis depth (epithelium to external proper muscle layer) of cryoablation, both independent of ablation times. Deepest ablation effects were seen at the center of the resection-induced scar. This first generation CryoBalloon Focal Ablation System was not feasible for ablation within severe stenoses, since it results in inconsistent circumferential uniformity of cryoablation with subsequent differences in depth of ablation. Further research with a next generation CBAS in a more realistic stricture model is warranted.

Incidental colonic focal FDG uptake on PET/CT: can the maximum standardized uptake value (SUVmax) guide us in the timing of colonoscopy?

PURPOSE: In patients undergoing (18)F-FDG PET/CT, incidental colonic focal lesions can be indicative of inflammatory, premalignant or malignant lesions. The maximum standardized uptake value (SUVmax) of these lesions, representing the FDG uptake intensity, might be helpful in differentiating malignant from benign lesions, and thereby be helpful in determining the urgency of colonoscopy. The aim of our study was to assess the incidence and underlying pathology of incidental PET-positive colonic lesions in a large cohort of patients, and to determine the usefulness of the SUVmax in differentiating benign from malignant pathology. METHODS: The electronic records of all patients who underwent FDG PET/CT from January 2010 to March 2013 in our hospital were retrospectively reviewed. The main indications for PET/CT were: characterization of an indeterminate mass on radiological imaging, suspicion or staging of malignancy, and suspicion of inflammation. In patients with incidental focal FDG uptake in the large bowel, data regarding subsequent colonoscopy were retrieved, if performed within 120 days. The final diagnosis was defined using colonoscopy findings, combined with additional histopathological assessment of the lesion, if applicable. RESULTS: Of 7,318 patients analysed, 359 (5 %) had 404 foci of unexpected colonic FDG uptake. In 242 of these 404 lesions (60 %), colonoscopy follow-up data were available. Final diagnoses were: adenocarcinoma in 25 (10 %), adenoma in 90 (37 %), and benign in 127 (53 %). The median [IQR] SUVmax was significantly higher in adenocarcinoma (16.6 [12 - 20.8]) than in benign lesions (8.2 [5.9 - 10.1]; p < 0.0001), non-advanced adenoma (8.3 [6.1 - 10.5]; p < 0.0001) and advanced adenoma (9.7 [7.2 - 12.6]; p < 0.001). The receiver operating characteristic curve of SUVmax for malignant versus nonmalignant lesions had an area under the curve of 0.868 (SD ± 0.038), the optimal cut-off value being 11.4 (sensitivity 80 %, specificity 82 %, positive predictive value 34 %, negative predictive value 98 %). CONCLUSION: In these patients with incidental colonic focal activity undergoing PET/CT (the largest series published to date), malignancies had significantly higher SUVmax values than all other types of lesions. However, SUVmax could not distinguish between benign lesions and adenomas. In conclusion, all incidental findings in the colon should be further evaluated and lesions with SUVmax ≥11.4 should be evaluated without delay.

Efficacy and safety of a novel submucosal lifting gel used for endoscopic submucosal dissection: a study in a porcine model.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is technically demanding. A viscous gel for submucosal lifting might induce mechanical submucosal dissection facilitating easier and safer ESD. METHODS: In 12 female pigs (median 64 kg), ESDs of simulated lesions were performed at the posterior wall and greater curvature in the gastric body (one ESD per location) with randomly assigned injection fluids: gel or control fluid (0.9% saline with hydroxypropyl methylcellulose 3 mg/ml [7:1] and indigo carmine droplets). Additionally, 10 cc gel was injected into the submucosa at the anterior wall without ESD to assess effects of inappropriate injection. Pigs were euthanized at day 0, 3 or 28. In four additional pigs (euthanized day 3 or 28) 10 cc gel was injected into the muscularis propria (MP) after four endoscopic mucosal resections in the gastric body. RESULTS: Both fluid groups showed equal ESD-procedure times (28 [gel] vs. 26 min [control]) and complications. Gel-ESDs required less accessory interchanges (3.5 vs. 5.5; p = 0.01). Mechanical dissection after circumferential incision was achieved in 25% of gel-ESDs; none in control-ESDs. The severity of inflammation and fibrosis was equal in both fluid groups. Normal architecture and vital mucosa were found after inappropriate submucosal injection. MP-injections resulted in one transmural hematoma (day 3), and intramuscular encapsulation in 25% of the sites (day 28). LIMITATIONS: A pig's stomach differs from the human stomach. CONCLUSIONS: The mechanical dissection properties of the gel may reduce the need for submucosal dissection during ESD. The gel is safe when advertently injected in the submucosa and MP. The porcine model appeared suboptimal to evaluate the true mechanical dissection properties of the gel.

Effects of Lugol staining on stenosis formation induced by radiofrequency ablation of esophageal squamous epithelium: a study in a porcine model.

Preliminary data show higher stricture rates after radiofrequency ablation (RFA) for early esophageal squamous neoplasia compared with Barrett's esophagus. We studied the effects of Lugol stain (LS) directly prior to RFA on stricture formation in squamous epithelium. Of 16 pigs, the distal half of the esophagus was LS, followed by circumferential RFA (single application 12 J/cm(2) ) in the unstained and stained esophagus. Pigs were euthanized at day 0 (n = 4), 3 (n = 4), or 28 (n = 8). Histology was evaluated in four areas: blank-control (no RFA, no LS), blank-RFA (no LS), LS+RFA, and LS-control (no RFA). Stenosis severity in LS+RFA and blank-RFA at 28 days was assessed by the ratio of the mucosal diameter at the RFA area to the diameter 2 cm proximal of this zone. Histology showed submucosal edema in 50% of LS+RFA versus 0% in blank-RFA. Severity and depth of inflammation (day 3) was equal in LS+RFA and blank-RFA. Severity and depth of fibrosis (day 28) appeared more severe in LS+RFA. Consequently, stenosis was present in 100% (LS+RFA) versus 12.5% (blank-RFA). The stenosis-severity ratio was 0.40 (interquartile range 0.29-0.45) in LS+RFA versus 0.73 (interquartile range 0.64-0.78) in blank-RFA (P = 0.012). Limitations of this study were the difference in uptake of LS between pigs and humans, the difference in esophageal anatomy between pigs and humans, and between the proximal and distal esophagus within pigs. In conclusion, in the porcine squamous esophagus, stenosis rate and severity after RFA increased when preceded by LS. LS may be contributing in the altered response of squamous epithelium to RFA as compared with Barrett's esophagus.

Simultaneous use of endoscopic resection and radiofrequency ablation is not safe in an esophageal porcine model.

Radiofrequency ablation (RFA) is safe and effective for eradication of Barrett's esophagus after endoscopic resection (ER) of neoplasia. Widespread ER, however, is likely to induce stenosis, hampering subsequent circumferential RFA. A 'single step' procedure with ER and circumferential RFA in the same session may avoid this problem. Two variants are possible: circumferential RFA of Barrett's esophagus including the lesion followed by ER of the ablated lesion ('RFA→ER'), or ER of the lesion directly followed by circumferential RFA of remaining Barrett's esophagus including the resection wound ('ER→RFA'). First aim was to evaluate perforation risk of 'ER→RFA' using increasing RFA energies. Second aim was to compare stenosis rate after 'ER→RFA' versus 'RFA→ER'. In Experiment 1, 24 areas in six pigs underwent widespread ER directly followed by circumferential RFA with increasing energies (2 x 10, 2 x 12-6 x 12 J/cm(2)) in the esophagus. In Experiment 2, eight pigs each had four treatment areas randomized: 'ER→RFA', RFA alone, ER alone, and 'RFA→ER'. No acute perforations occurred when ablating ER wounds. Two delayed perforations occurred: one in experiment 1, another in experiment n2 at the 'ER→RFA' area. The remaining seven pigs in experiment 2 showed stenosis in all 'ER→RFA' and 'RFA→ER' areas versus 5/7 RFA alone areas, and 0/7 ER alone areas. In conclusion, the 'single step' variant 'ER→RFA' is not safe in this porcine model and seems therefore not ethical to evaluate in humans at this stage. Given the high rate of stenosis after 'RFA→ER' and RFA alone, one might question the validity of the porcine model for this type of experiments.

The predictive value of proteinuria in acute pancreatitis.

BACKGROUND/OBJECTIVES: Acute pancreatitis has a highly variable clinical course. Early and reliable predictors for the severity of acute pancreatitis are lacking. Proteinuria appears to be a useful predictor of disease severity and outcome in a variety of clinical conditions. This study aims to investigate the predictive value of proteinuria on admission for the severity of acute pancreatitis compared with other commonly used predictors; the APACHE II score, Modified Glasgow score and C-reactive protein (CRP). METHODS: This is a post-hoc analysis of 64 patients admitted with acute pancreatitis treated in one teaching hospital, who participated in a previous randomized trial. Proteinuria was defined as a Protein/Creatinine (P/C) ratio >23 mg/mmol. The primary endpoint was severe acute pancreatitis. Secondary endpoints included infectious complications, need for invasive intervention, ICU stay and in-hospital mortality. RESULTS: Proteinuria was present in 30/64 patients (47%). Eleven patients (17%) had severe acute pancreatitis. There was no difference in incidence of severe acute pancreatitis between patients with and without proteinuria: 6/30 patients (20%) versus 5/34 patients (15%) respectively (p = 0.58). Likewise, the occurrence of infectious complications, need for intervention and ICU stay and mortality did not differ significantly (p = 0.58, p = 0.99, p = 0.33 and p = 0.60 respectively). The diagnostic performance of the P/C ratio for the prediction of severe pancreatitis was inferior to the Modified Glasgow score (p = 0.04) and CRP (p = 0.03). CONCLUSION: Proteinuria on admission does not seem to be a reliable predictor for disease severity in acute pancreatitis. The diagnostic performance of the P/C ratio is inferior to the Modified Glasgow score and CRP.

Third-generation autofluorescence endoscopy for the detection of early neoplasia in Barrett's esophagus: a pilot study.

In Barrett's esophagus (BE), second-generation autofluorescence imaging (AFI-II) improves targeted detection of high-grade intra-epithelial neoplasia (HGIN) and early cancer (EC), yet suffers from high false-positive (FP) rates. The newest generation AFI (AFI-III) specifically targets fluorescence in malignant cells and may therefore improve detection of early neoplasia and reduce FP rate. The aim was to compare AFI-III with AFI-II for endoscopic detection of early neoplasia in BE. BE patients with endoscopically inconspicuous neoplasia underwent two diagnostic endoscopies (AFI-II/AFI-III) in a single session. End-points: number of patients and lesions with HGIN/EC detected with AFI-II and AFI-III after white-light endoscopy (WLE) and the value of reinspection of AFI-positive areas with WLE and narrow-band imaging. Forty-five patients were included (38 males, age 65 years). Nineteen patients showed HGIN/EC. AFI-II inspection after WLE increased detection of HGIN/EC from 9 to 15 patients (47 to 79%); AFI-III increased detection from 9 to 17 patients (47 to 89%). WLE plus random biopsies diagnosed 13/19 (68%) HGIN/EC patients. One hundred and four abnormal AFI areas were inspected; 23 (22%) showed HGIN/EC. AFI-II increased detection of HGIN/EC from 10 to 18 lesions (43 to 78%). AFI-III increased detection from 10 to 20 lesions (43-87%). FP rate was 86% for AFI-II and AFI-III. Reinspection with WLE or narrow-band imaging reduced FP rate to 21% and 22%, respectively, but misclassified HGIN/EC lesions as unsuspicious in 54% and 31%, respectively. This first feasibility study on third-generation AFI again showed improved targeted detection of HGIN/EC in BE. However, the results do not suggest AFI-III performs significantly better than conventional AFI-II.

Prospective feasibility study on the use of multiband mucosectomy for endoscopic resection of early squamous neoplasia in the esophagus.

BACKGROUND AND STUDY AIMS: Endoscopic resection for esophageal squamous high-grade intraepithelial neoplasia (HGIN) or intramucosal cancer (esophageal squamous cell carcinoma [ESCC]) with the endoscopic resection cap technique is technically difficult, and requires submucosal lifting and multiple snares for piecemeal resections. Multiband mucosectomy (MBM) is an easy-to-use endoscopic resection technique and may be the modality of choice in China, where ESCC is extremely prevalent. The aim of the current study was to prospectively evaluate MBM for piecemeal endoscopic resection of squamous neoplasia of the esophagus. METHODS: Patients with HGIN/ESCC and no signs of submucosal invasion or metastatic disease were included in the study. Lesions were delineated using electrocoagulation and resected using the MBM technique. Endpoints were procedure time, endoscopic radicality, complications, histology of the endoscopic resection specimens, and absence of HGIN/ESCC at the endoscopic resection scar during follow-up. RESULTS: A total of 41 patients (26 male; mean age 61 years) underwent MBM; all lesions were visible with white light endoscopy (median length 5 cm, interquartile range [IQR] 4 - 6 cm; median circumferential extent 42 %, IQR 25 - 50 %). Median procedure time was 12 minutes (IQR 8 - 24 minutes). Median number of resections was 5 (IQR 3 - 6). Endoscopic complete resection was achieved in all lesions. There was one perforation, which was treated by application of clips. No other complications were observed. The worst histology was ESCC (n = 19), HGIN (n = 17), middle grade intraepithelial neoplasia (n = 4), and normal squamous epithelium (n = 1). Endoscopic follow-up at 3 months showed HGIN at the endoscopic resection scar in two patients, which was effectively treated endoscopically, and showed normal squamous epithelium in all patients at final follow-up (median 15 months, IQR 12 - 24 months). CONCLUSION: This first prospective study on MBM for piecemeal endoscopic resection of early esophageal squamous neoplasia showed that MBM was effective for the complete removal of lesions with short procedure time, few complications, effective histological assessment of resected specimens, and durable treatment effect.

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.

Optimal timing of simethicone administration prior to upper endoscopy: A multicenter, single-blind, randomized controlled trial.

Background and study aims Simethicone is useful as premedication for upper endoscopy because of its antifoaming effects. We aimed to evaluate the effect of timing of simethicone administration on mucosal visibility. Patients and methods In this multicenter, randomized, endoscopist-blinded study, patients scheduled for upper endoscopy were randomized to receive 40 mg simethicone at the following time points prior to the procedure: 20 to 30 minutes (early group), 0 to 10 minutes (late group) or 20 mg simethicone at both time points (split-dose group). Images were taken from nine predefined locations in the esophagus, stomach, and duodenum before endoscopic flushing. Each image was scored on mucosal visibility by three independent endoscopists on a 4-point scale (lower scores indicating better visibility), with adequate mucosal visibility defined as a score ≤ 2. Primary outcome was the percentage of patients with adequate total mucosal visibility (TMV), reached if all median subscores for each location were ≤ 2. Results A total of 386 patients were included (early group: 132; late group: 128; split-dose group: 126). Percentages of adequate TMV were 55%, 42%, and 61% in the early, late, and split-dose group, respectively ( P < 0.01). Adequate TMV was significantly higher in the split-dose group compared to the late group ( P < 0.01), but not compared to the early group ( P = 0.29). Differences between groups were largest in the stomach, where percentages of adequate mucosal visibility were higher in the early (68% vs 53%, P = 0.03) and split-dose group (69% vs 53%, P = 0.02) compared to the late group. Conclusions Mucosal visibility can be optimized with early simethicone administration, either as a single administration or in a split-dose regimen.

Adherence to guideline recommendations for Barrett's esophagus (BE) surveillance endoscopies: Effects of dedicated BE endoscopy lists.

Background and study aims For non-dysplastic Barrett's Esophagus (BE) patients, guidelines recommend endoscopic surveillance every 3 to 5 years with four-quadrant random biopsies every 2 cm of BE length. Adherence to these guidelines is low in clinical practice. Pooling BE surveillance endoscopies on dedicated endoscopy lists performed by dedicated endoscopists could possibly enhance guideline adherence, detection of visible lesions, and dysplasia detection rates (DDRs). Patients and methods Data were used from the ACID-study (Netherlands Trial Registry NL8214), a prospective trial of BE surveillance in the Netherlands. BE patients with known or previously treated dysplasia were excluded. Guideline adherence, detection of visible lesions, and DDRs were compared for patients on dedicated and general endoscopy lists. Results A total of 1,244 patients were included, 318 on dedicated lists and 926 on general lists. Endoscopies on dedicated lists showed significantly higher adherence to the random biopsy protocol (85% vs. 66%, P <0.01) and recommended surveillance intervals (60% vs. 47%, P <0.01) compared to general lists. Detection of visible lesions (8.8% vs. 8.1%, P =0.79) and DDRs were not significantly different (6.9% and 6.6%, P =0.94). None (0.0%) of the patients scheduled on dedicated lists and 10 (1.1%) on general lists were diagnosed with esophageal adenocarcinoma ( P =0.07). In multivariable analysis, dedicated lists were significantly associated with biopsy protocol adherence and adherence to surveillance interval recommendations with odds ratios of 4.45 (95% confidence interval [CI] 2.07-9.57) and 1.64 (95% CI 1.03-2.61), respectively. Conclusions Dedicated endoscopy lists are associated with better adherence to the random biopsy protocol and surveillance interval recommendations.