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Fluorescence Endoscopy of Cathepsin Activity Discriminates Dysplasia from Colitis

Gounaris, Elias PhD*; Martin, John MD*; Ishihara, Yasushige MS; Khan, Mohammad Wasim DVM*; Lee, Goo MD*; Sinh, Preetika MD*; Chen, Eric Zongming MD; Angarone, Michael MD§; Weissleder, Ralph MD; Khazaie, Khasharyasha PhD*; Barrett, Terrence A. MD*

doi: 10.1097/MIB.0b013e318281f3f8
Original Basic Science Article

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.

Article first published online 15 April 2013Supplemental Digital Content is Available in the Text.

*Division of Gastroenterology, Feinberg School of Medicine, Northwestern University, Northwestern Memorial Hospital, Chicago, Illinois;

Molecular Diagnostic Technology Group, Advanced Core Technology Department, Research and Development Division, Olympus Tokyo, Tokyo, Japan;

Department of Pathology, Division of Surgical Pathology, and

§Department of Medicine, Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Reprints: Terrence A. Barrett, MD, Division of Gastroenterology, Feinberg School of Medicine, Northwestern University, 676 N. St. Clair Street, Suite 1400, Chicago, IL 60611 (e-mail:

The authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Supported by Northwestern Memorial Hospital, Excellence in Academic Medicine (EAM) 222 (T.A.B., E.G.) and by NIH Grant RO1 2R01DK095662-06A1 (T.A.B.).

Received November 07, 2012

Accepted November 25, 2012

© Crohn's & Colitis Foundation of America, Inc.
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