Fluorescence endoscopy of cathepsin activity discriminates dysplasia from colitis

Elias Gounaris, John Martin, Yasushige Ishihara, Mohammad Wasim Khan, Goo Lee, Preetika Sinh, Eric Zongming Chen, Michael Angarone, Ralph Weissleder, Khashayarsha Khazaie, Terrence A. Barrett

Research output: Contribution to journalReview article

27 Citations (Scopus)

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 6 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.

Original languageEnglish (US)
Pages (from-to)1339-1345
Number of pages7
JournalInflammatory Bowel Diseases
Volume19
Issue number7
DOIs
StatePublished - Jun 2013
Externally publishedYes

Fingerprint

Cathepsins
Colitis
Endoscopy
Fluorescence
Colonoscopy
Interleukin-10
Colon
Molecular Probes
Sensitivity and Specificity
Neoplasms
Signal-To-Noise Ratio
Lymphoid Tissue
ROC Curve
Ulcer
Area Under Curve
Hydrolysis
Macrophages
Pathology
Biopsy
Light

Keywords

  • Cathepsin activity
  • Colitis
  • Dysplasia
  • Fluorescence endoscopy
  • Macrophages

ASJC Scopus subject areas

  • Gastroenterology
  • Immunology and Allergy

Cite this

Gounaris, E., Martin, J., Ishihara, Y., Khan, M. W., Lee, G., Sinh, P., ... Barrett, T. A. (2013). Fluorescence endoscopy of cathepsin activity discriminates dysplasia from colitis. Inflammatory Bowel Diseases, 19(7), 1339-1345. https://doi.org/10.1097/MIB.0b013e318281f3f8

Fluorescence endoscopy of cathepsin activity discriminates dysplasia from colitis. / Gounaris, Elias; Martin, John; Ishihara, Yasushige; Khan, Mohammad Wasim; Lee, Goo; Sinh, Preetika; Chen, Eric Zongming; Angarone, Michael; Weissleder, Ralph; Khazaie, Khashayarsha; Barrett, Terrence A.

In: Inflammatory Bowel Diseases, Vol. 19, No. 7, 06.2013, p. 1339-1345.

Research output: Contribution to journalReview article

Gounaris, E, Martin, J, Ishihara, Y, Khan, MW, Lee, G, Sinh, P, Chen, EZ, Angarone, M, Weissleder, R, Khazaie, K & Barrett, TA 2013, 'Fluorescence endoscopy of cathepsin activity discriminates dysplasia from colitis', Inflammatory Bowel Diseases, vol. 19, no. 7, pp. 1339-1345. https://doi.org/10.1097/MIB.0b013e318281f3f8
Gounaris, Elias ; Martin, John ; Ishihara, Yasushige ; Khan, Mohammad Wasim ; Lee, Goo ; Sinh, Preetika ; Chen, Eric Zongming ; Angarone, Michael ; Weissleder, Ralph ; Khazaie, Khashayarsha ; Barrett, Terrence A. / Fluorescence endoscopy of cathepsin activity discriminates dysplasia from colitis. In: Inflammatory Bowel Diseases. 2013 ; Vol. 19, No. 7. pp. 1339-1345.
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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 6 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.",
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T1 - Fluorescence endoscopy of cathepsin activity discriminates dysplasia from colitis

AU - Gounaris, Elias

AU - Martin, John

AU - Ishihara, Yasushige

AU - Khan, Mohammad Wasim

AU - Lee, Goo

AU - Sinh, Preetika

AU - Chen, Eric Zongming

AU - Angarone, Michael

AU - Weissleder, Ralph

AU - Khazaie, Khashayarsha

AU - Barrett, Terrence A.

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N2 - 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 6 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.

AB - 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 6 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.

KW - Cathepsin activity

KW - Colitis

KW - Dysplasia

KW - Fluorescence endoscopy

KW - Macrophages

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