Volumetric laser endomicroscopy and its application to Barrett's esophagus: results from a 1,000 patient registry.

Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) for real-time, microscopic cross-sectional imaging. A US-based multi-center registry was constructed to prospectively collect data on patients undergoing upper endoscopy during which a VLE scan was performed. The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to Barrett's esophagus (BE) management. All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern. Following the VLE procedure, investigators were asked to answer six key questions regarding how VLE impacted each case. Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed. One thousand patients were enrolled across 18 US trial sites from August 2014 through April 2016. In patients with previously diagnosed or suspected BE (894/1000), investigators used VLE and identified areas of concern not seen on white light endoscopy (WLE) in 59% of the procedures. VLE imaging also guided tissue acquisition and treatment in 71% and 54% of procedures, respectively. VLE as an adjunct modality improved the neoplasia diagnostic yield by 55% beyond the standard of care practice. In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700%. Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool. The ability of VLE to image large segments of the esophagus with microscopic cross-sectional detail may provide additional benefits including higher yield biopsies and more efficient tissue acquisition. Clinicaltrials.gov NCT02215291

Endoscopic Assessment and Treatment of Barrett’s Oesophagus

Oesophageal cancer worldwide is the eighth commonest cancer and carries a poor prognosis. Barrett’s oesophagus is the only known risk factor for oesophageal adenocarcinoma. Cancer progresses along a metaplasia-dysplasia pathway. Dysplastic changes may be seen on endoscopic assessment. This thesis presents evidence that i-Scan virtual chromoendoscopy together with acetic acid chromoendoscopy can improve dysplasia detection using a simple classification system. Superficial lesions, without deeper invasion (low and high grade dysplasia, early cancers) have a low risk of distant metastasis. Endoscopic resection and ablation techniques have been demonstrated to have an excellent efficacy and safety profile. The current standard of care for early Barrett’s neoplasia is endoscopic management rather than surgical intervention. Surgery for oesophageal cancer is centred in specialist units due to improved outcomes in high volume centres. The UK radiofrequency ablation registry collects outcomes for patients undergoing endoscopic therapy for Barrett’s neoplasia. This thesis demonstrates that there is no difference in dysplasia or intestinal metaplasia resolution rates or dysplasia recurrence between low and high volume centres. Learning curve analysis suggests that there is a change point at 18 cases, when the observed successful treatment rate of the centre becomes better than the expected rate. Centres should complete 20 cases before competency can be achieved. Treatment of Barrett’s neoplasia involves endoscopic resection of visible lesions. Due to the high risk of metachronous lesions, the remaining Barrett’s epithelium undergoes field ablation, commonly with radiofrequency ablation. Following successful treatment the risk of dysplasia recurrence is 6%. The risk increases with increasing length of the initial Barrett segment and with increasing age. The risk of untreated islands of Barrett’s IM is unknown but this thesis demonstrates that it does not seem to confer an increased risk of recurrence and may not require further ablation if unresponsive to treatment

Screening and Surveillance of the Gastrointestinal Tract

This thesis aims to optimise prevention programmes for gastric- and colorectal cancer. The first part consists of studies on surveillance of premalignant gastric lesions. Prospectively, we evaluated current guidelines on the proper identification of patients with premalignant gastric lesions that deserve further follow up. After one extra gastro endoscopy – were guidelines would advise to stop further surveillance - it appeared that a considerable part would have an indication for further surveillance after all. We investigated several possibilities for the improvement of surveillance programmes. To name; the use of a new endoscopy technique, evaluating risk factors within patients (such as smoking and a family history of gastric cancer), and the new possibility of detecting the most important risk factor for the occurrence of gastric cancer – Helicobacter Pylori bacterium – in the fecal test used in colorectal cancer screening. The second part of this thesis consist of studies on colorectal cancer screening. First, the video capsule was used to determine prevalence rates of several abnormalities (benign or malignant) in a general population. Further, a comprehensive retrospective study in 20 European countries was performed on the incidence of colorectal cancer over time within different age groups. This showed that the incidence is increasing mostly at younger ages. Lastly, literature studies were performed in order to further improve and innovate the current colorectal cancer screening programme. We showed that the use of anticoagulants do not affect the fecal blood test used in screening. Also, the video capsule appeared to be a good alternative beside colonoscopy.<br/

Image enhanced endoscopy and molecular biomarkers vs Seattle protocol to diagnose dysplasia in Barrett's esophagus

BACKGROUND: Dysplasia in Barrett's esophagus (BE) is often invisible on high-resolution white-light endoscopy (HRWLE). We compared the diagnostic accuracy for inconspicuous dysplasia of the combination of autofluorescence (AFI)-guided probe-based confocal laser endomicroscopy (pCLE) and molecular biomarkers versus HRWLE with Seattle protocol biopsies. METHODS: BE patients with no dysplastic lesions were block randomized to standard endoscopy (HRWLE with Seattle protocol) or AFI-guided pCLE with targeted biopsies for molecular biomarkers (p53 and cyclin A by immunohistochemistry; aneuploidy by image cytometry), with crossover to the other arm after 6-12 weeks. Histological endpoint was diagnosis from all study biopsies (trial histology). Sensitivity analysis was performed for overall histology, which included diagnoses within 12 months from first study endoscopy. Endoscopists were blinded to the referral endoscopy and histology results. Primary outcome was diagnostic accuracy for dysplasia by real-time pCLE versus HRWLE biopsies. RESULTS: Of 154 patients recruited, 134 completed both arms. In the primary outcome analysis (trial histology analysis), AFI-guided pCLE had similar sensitivity for dysplasia compared to standard endoscopy [74.3% (95%CI, 56.7-87.5) vs 80.0% (95%CI 63.1-91.6), p=0.48]. Multivariate logistic regression showed pCLE optical dysplasia, aberrant p53 and aneuploidy had strongest correlation with dysplasia (secondary outcome). This 3-biomarker panel had higher sensitivity for any grade of dysplasia than Seattle protocol (81.5% vs 51.9%, p<0.001) in the overall histology analysis, but not in the trial histology analysis (91.4% vs 80.0%; p=0.16) with an area under receiver operating curve of 0.83. CONCLUSIONS: Seattle protocol biopsies miss dysplasia in approximately half of patients with inconspicuous neoplasia. AFI-guided pCLE has similar accuracy to the current gold standard. Addition of molecular biomarkers could improve diagnostic accuracy

Long-term outcomes after endoscopic treatment for Barrett's neoplasia with radiofrequency ablation +/- endoscopic resection:results from the national Dutch database in a 10-year period

OBJECTIVE: Radiofrequency ablation (RFA)±endoscopic resection (ER) is the preferred treatment for early neoplasia in Barrett’s oesophagus (BE). We aimed to report short-term and long-term outcomes for all 1384 patients treated in the Netherlands (NL) from 2008 to 2018, with uniform treatment and follow-up (FU) in a centralised setting. DESIGN: Endoscopic therapy for early BE neoplasia in NL is centralised in nine expert centres with specifically trained endoscopists and pathologists that adhere to a joint protocol. Prospectively collected data are registered in a uniform database. Patients with low/high-grade dysplasia or low-risk cancer, were treated by ER of visible lesions followed by trimonthly RFA sessions of any residual BE until complete eradication of BE (CE-BE). Patients with ER alone were not included. RESULTS: After ER (62% of cases; 43% low-risk cancers) and median 1 circumferential and 2 focal RFA (p25-p75 0–1; 1–2) per patient, CE-BE was achieved in 94% (1270/1348). Adverse events occurred in 21% (268/1386), most commonly oesophageal stenosis (15%), all were managed endoscopically. A total of 1154 patients with CE-BE were analysed for long-term outcomes. During median 43 months (22–69) and 4 endoscopies (1–5), 38 patients developed dysplastic recurrence (3%, annual recurrence risk 1%), all were detected as endoscopically visible abnormalities. Random biopsies from a normal appearing cardia showed intestinal metaplasia (IM) in 14% and neoplasia in 0%. A finding of IM in the cardia was reproduced during further FU in only 33%, none progressed to neoplasia. Frequent FU visits in the first year of FU were not associated with recurrence risk. CONCLUSION: In a setting of centralised care, RFA±ER is effective for eradication of Barrett’s related neoplasia and has remarkably low rates of dysplastic recurrence. Our data support more lenient FU intervals, with emphasis on careful endoscopic inspection. Random biopsies from neosquamous epithelium and cardia are of questionable value. NETHERLANDS TRIAL REGISTER NUMBER: NL7039