title: Autofluorescence-Directed Confocal Endomicroscopy in Combination With a Three-Biomarker Panel Can Inform Management Decisions in Barrett's Esophagus.
abstract: OBJECTIVE
  Barrett's esophagus (BE) surveillance with white-light endoscopy and quadrantic biopsies (Seattle protocol) is resource intensive and limited by sampling error. Previous work suggests that autofluorescence imaging (AFI) in combination with a molecular panel might reduce the number of biopsies, but this was not sufficiently sensitive for low-grade dysplasia, now a point for endoscopic intervention. Here we used AFI to direct narrow-field imaging tools for real-time optical assessment of dysplasia and biopsies for a biomarker panel. We compared the new diagnostic algorithm with the current standard.
  
  
  METHODS
  A total of 55 patients with BE were recruited at a single tertiary referral center. Patients underwent high-resolution endoscopy followed by AFI. AFI-targeted areas (n=194) were examined in turn by narrow-band imaging with magnification (NBIz) and probe-based confocal laser endomicroscopy (pCLE). Biopsies were taken from AFI-targeted areas and tested using an established molecular panel comprising aneuploidy plus cyclin A and p53 immunohistochemistry.
  
  
  RESULTS
  In the per-patient analysis the overall sensitivity and specificity of AFI-targeted pCLE were 100% and 53.6% for high-grade dysplasia/intramucosal cancer and 96.4% and 74.1% for any grade of dysplasia, respectively. NBIz had equal specificity for dysplasia detection (74.1%), but significantly lower sensitivity (57.1%) than pCLE. The time required to perform AFI-targeted pCLE was shorter that that taken by the Seattle protocol (P=0.0004). We found enrichment of molecular abnormalities in areas with optical dysplasia by pCLE (P<0.001), regardless of histologic dysplasia. The addition of the 3-biomarker panel reduced the false positive rate of pCLE by 50%, leading to sensitivity and specificity for any grade of dysplasia of 89.2% and 88.9%, respectively.
  
  
  CONCLUSIONS
  The combination of pCLE on AFI-targeted areas and a 3-biomarker panel identifies patients with dysplasia.
authors.affiliation: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: di Pietro
authors.affiliation: MRC Cancer Unit, University of Cambridge, Cambridge, UK.|Translational Gastroenterology Unit, Experimental Medicine Division, John Radcliffe Hospital, Oxford, UK.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Bird-Lieberman
authors.affiliation: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors.forename: Xinxue
authors.initials: X
authors.lastname: Liu
authors.affiliation: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors.forename: Tara
authors.initials: T
authors.lastname: Nuckcheddy-Grant
authors.affiliation: Department of Digestive Endoscopy, Nuovo Ospedale Civile S. Agostino, Modena, Italy.
authors.forename: Helga
authors.initials: H
authors.lastname: Bertani
authors.affiliation: Department of Histopathology, Cambridge University Hospitals, Cambridge, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: O'Donovan
authors.affiliation: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fitzgerald
mesh_terms: D000368:Aged; D000465:Algorithms; D000782:Aneuploidy; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D019925:Cyclin A / Q000032:analysis; D018450:Disease Progression; D004945:Esophagoscopy; D004947:Esophagus / Q000473:pathology; D005189:False Positive Reactions; D005260:Female; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D008875:Middle Aged; D062048:Narrow Band Imaging; D061848:Optical Imaging; D011230:Precancerous Conditions / Q000737:chemistry* / Q000235:genetics / Q000473:pathology*; D012680:Sensitivity and Specificity; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D057832:Watchful Waiting / Q000379:methods*
chemical_list: D015415:Biomarkers; D019925:Cyclin A; D016159:Tumor Suppressor Protein p53