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.

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.

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.

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.

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.

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.

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.

Burden of spousal caregivers of stage II and III esophageal cancer survivors 3 years after treatment with curative intent.

OBJECTIVES: The aim of this study is to examine caregiver burden of spousal caregivers of patients with esophageal cancer after curative treatment with neoadjuvant chemoradiation followed by resection and to assess factors associated with caregiver burden. METHODS: In this exploratory, cross-sectional study, spousal caregivers and patients were eligible if the caregiver was the patient's spouse and the patient had been treated with chemoradiation followed by surgery after esophageal carcinoma diagnosis. Forty-seven couples were included. Spousal caregivers completed a questionnaire, examining caregivers' burden (Self-Perceived Pressure from Informal Care (SPPIC, Dutch)), caregiver unmet needs (SCNS-P&S), anxiety and depression (Hospital Anxiety and Depression Scale (HADS)), and marital satisfaction (Maudsley Marital Questionnaire (MMQ)). Patients completed the latter two questionnaires and a cancer specific quality of life questionnaire (EORTC-QLQ C30 and OES18 (oesophageal module). Logistic regression analysis was performed to identify correlates for caregiver burden. RESULTS: The median time after esophagectomy was 38 months. Thirty-four percent of the spousal caregivers reported moderate or high burden. Spousal caregivers most frequently reported unmet needs were managing concerns about the cancer coming back (43%), dealing with others not acknowledging the impact on your life of caring for a person with cancer (38%), and balancing the needs of the person with cancer and one's own needs. A comparable proportion of spousal caregivers and patients showed symptoms of anxiety (23 vs 17%) and depression (17 vs 17%). Spousal caregivers reported significantly more dissatisfaction than patients on the marital scale (p < 0.01). Factors independently associated with higher caregiver burden were fatigue of the patient (OR = 1.66, 95% CI 1.12-2.47) and depression of the spousal caregiver (OR = 1.44, 95% CI 1.11-1.86). CONCLUSIONS: More than a third of the spousal caregivers of patients with esophageal cancer treated with curative intent report moderate or high burden 3 years after treatment. Fatigue of the patient and depression of the spousal caregiver are associated with caregiver burden. To improve clinical care, identification of spousal caregivers at risk for experiencing higher caregiver burden and implementation of specific interventions is needed.

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.

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.

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.

Endoscopic TriModal imaging and biomarkers for neoplasia conjoined: a feasibility study in Barrett's esophagus.

In Barrett's esophagus (BE), the normal squamous lining of the esophagus is replaced by specialized columnar epithelium. Endoscopic surveillance with autofluorescence imaging (AFI) and molecular biomarkers have been studied separately to detect early neoplasia (EN) in BE. The combination of advanced-imaging modalities and biomarkers has not been investigated; AFI may help detecting biomarkers as a risk-stratification tool. We retrospectively evaluated a cohort of patients undergoing endoscopy for EN in BE with AFI and correlated five biomarkers (HPP1, RUNX3, p16, cyclin A, and p53) in tissue samples with AFI and dysplasia status. Fifty-eight samples from a previous prospective study were selected: 15 true-positive (TP: AFI-positive, EN), 21 false-positive (FP: AFI-positive, no EN), 12 true-negative (TN1; AFI-negative, no EN in sample), 10 true-negative (TN2: AFI-negative, no EN in esophagus). Methylation-specific RT-PCR was performed for HPP1, RUNX3, p16, and immunohistochemistry for cyclin A, p53. P < 0.05 was considered statistically significant. Bonferroni correction was used for multiple comparisons. P16, cyclin A, p53 correlated with dysplasia (P < 0.01, P = 0.003, P < 0.001, respectively). Increased p16 methylation was observed between TP versus TN2 (P = 0.003) and TN1 versus TN2 (P = 0.04) subgroups, suggesting a field defect. Only p53 correlated with AFI-status (P = 0.003). After exclusion of EN samples, significance was lost. Although correlation with dysplasia status was confirmed for p16, cyclin A and p53, underlining the importance of these biomarkers as an early event in neoplastic progression, none of the investigated biomarkers correlated with AFI status. A larger prospective study is needed to assess the combination of AFI and a larger panel of biomarkers to improve risk stratification in BE.