title: Fluorescence endoscopy of cathepsin activity discriminates dysplasia from colitis.
abstract: BACKGROUND
  Surveillance colonoscopy using random biopsies to detect colitis-associated cancer (CAC) suffers from poor sensitivity. Although chromoendoscopy improves detection, acceptance in the community has been slow. Here, we examine the usefulness of near infrared fluorescence (NIRF) endoscopy to image molecular probes for cathepsin activity in colitis-induced dysplasia.
  
  
  METHODS
  In patient samples, cathepsin activity was correlated with colitis and dysplasia. In mice, cathepsin activity was detected as fluorescent hydrolysis product of substrate-based probes after injection into Il10(-/-) colitic mice. Fluorescence colonoscopy and colonic whole-mount imaging were performed before complete sectioning and pathology review of resected colons.
  
  
  RESULTS
  Cathepsin activity was 5-fold and 8-fold higher in dysplasia and CAC, respectively, compared with areas of mild colitis in patient tissue sections. The signal-to-noise ratios for dysplastic lesions seen by endoscopy in Il10(-/-) mice were 5.2 ± 1.3 (P = 0.0001). Lesions with increased NIRF emissions were classified as raised or flat dysplasia, lymphoid tissue, and ulcers. Using images collected by endoscopy, a receiver operating characteristic curve for correctly diagnosing dysplasia was calculated. The area under the curve was 0.927. At a cutoff of 1000 mean fluorescence intensity, the sensitivity and specificity for detecting dysplasia were 100% and 83%, respectively. Analysis revealed that focally enhanced NIRF emissions derived from increased numbers of infiltrating myeloid-derived suppressor cells and macrophages with equivalent cathepsin activity.
  
  
  CONCLUSIONS
  These studies indicate that cathepsin substrate-based probe imaging correctly identifies dysplastic foci within chronically inflamed colons. Combined white light and NIRF endoscopy presents unique advantages that may increase sensitivity and specificity of surveillance colonoscopy in patients with CAC.
authors.affiliation: Division of Gastroenterology, Feinberg School of Medicine, Northwestern University, Northwestern Memorial Hospital, Chicago, Illinois 60611, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Gounaris
authors.forename: John
authors.initials: J
authors.lastname: Martin
authors.forename: Yasushige
authors.initials: Y
authors.lastname: Ishihara
authors.forename: Mohammad Wasim
authors.initials: MW
authors.lastname: Khan
authors.forename: Goo
authors.initials: G
authors.lastname: Lee
authors.forename: Preetika
authors.initials: P
authors.lastname: Sinh
authors.forename: Eric Zongming
authors.initials: EZ
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Angarone
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Khasharyasha
authors.initials: K
authors.lastname: Khazaie
authors.forename: Terrence A
authors.initials: TA
authors.lastname: Barrett
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002403:Cathepsins / Q000378:metabolism*; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D004724:Endoscopy; D005453:Fluorescence; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D059629:Signal-To-Noise Ratio
chemical_list: C556062:IL10 protein, mouse; D016753:Interleukin-10; D002403:Cathepsins