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Navaneethan U, Lourdusamy D. Advanced Endoscopic Imaging to Predict Clinical Outcomes in Inflammatory Bowel Disease. Gastrointest Endosc Clin N Am 2025; 35:195-212. [PMID: 39510688 DOI: 10.1016/j.giec.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2024]
Abstract
Advanced endoscopic imaging including high-definition endoscopy, confocal laser endomicroscopy (CLE) and endocytoscopy (EC) serve as an adjunct to predict clinical outcomes in inflammatory bowel disease (IBD). CLE can identify gut barrier dysfunction which correlates with disease behavior and long-term disease outcome. EC allows the assessment of histologic activity. Future controlled studies are warranted to define a definite role of these novel technologies in the management of patients with IBD.
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Affiliation(s)
- Udayakumar Navaneethan
- Center for Inflammatory Bowel Disease and Interventional Inflammatory Bowel Disease, Orlando Health, Orlando Health Digestive Health Institute, 22 West Underwood Street, Orlando, FL 32806, USA.
| | - Dennisdhilak Lourdusamy
- Department of Internal Medicine, Texas Health Presbyterian, 3000 I-35, Denton, TX 76201, USA
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2
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Cicala M, Gori M, Balestrieri P, Altomare A, Tullio A, Di Cola S, Dejongh S, Graziani MG, Pagnini C, Carotti S, Perrone G, Ribolsi M, Fiorani M, Guarino MPL, Farré R. Colonic Epithelial Permeability to Ions Is Restored after Vedolizumab Treatment and May Predict Clinical Response in Inflammatory Bowel Disease Patients. Int J Mol Sci 2024; 25:5817. [PMID: 38892004 PMCID: PMC11172326 DOI: 10.3390/ijms25115817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/22/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
Vedolizumab (VDZ) is used for treating inflammatory bowel disease (IBD) patients. A study investigating colonic epithelial barrier function ex vivo following VDZ is lacking. This work aims to evaluate ex vivo the colonic epithelial barrier function in IBD patients at baseline and during VDZ treatment, and to investigate the relationships between barrier function and clinical parameters. Colonic specimens were obtained from 23 IBD patients before, and at 24 and 52 weeks after VDZ treatment, and from 26 healthy volunteers (HV). Transepithelial electrical resistance (TEER, permeability to ions) and paracellular permeability were measured in Ussing chambers. IBD patients showed increased epithelial permeability to ions (TEER, 13.80 ± 1.04 Ω × cm2 vs. HV 20.70 ± 1.52 Ω × cm2, p < 0.001) without changes in paracellular permeability of a 4 kDa probe. VDZ increased TEER (18.09 ± 1.44 Ω × cm2, p < 0.001) after 52 weeks. A clinical response was observed in 58% and 25% of patients at week 24, and in 62% and 50% at week 52, in ulcerative colitis and Crohn's disease, respectively. Clinical and endoscopic scores were strongly associated with TEER. TEER < 14.65 Ω × cm2 predicted response to VDZ (OR 11; CI 2-59). VDZ reduces the increased permeability to ions observed in the colonic epithelium of IBD patients before treatment, in parallel to a clinical, histological (inflammatory infiltrate), and endoscopic improvement. A low TEER predicts clinical response to VDZ therapy.
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Affiliation(s)
- Michele Cicala
- Gastroenterology Unit, Fondazione Policlinico Universitario Campus Bio-Medico and Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (M.C.); (P.B.); (A.A.); (A.T.); (S.D.C.); (M.R.); (M.F.); (M.P.L.G.)
| | - Manuele Gori
- Gastroenterology Unit, Fondazione Policlinico Universitario Campus Bio-Medico and Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (M.C.); (P.B.); (A.A.); (A.T.); (S.D.C.); (M.R.); (M.F.); (M.P.L.G.)
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), International Campus “A. Buzzati-Traverso”, Via E. Ramarini 32, Monterotondo Scalo, 00015 Rome, Italy
| | - Paola Balestrieri
- Gastroenterology Unit, Fondazione Policlinico Universitario Campus Bio-Medico and Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (M.C.); (P.B.); (A.A.); (A.T.); (S.D.C.); (M.R.); (M.F.); (M.P.L.G.)
| | - Annamaria Altomare
- Gastroenterology Unit, Fondazione Policlinico Universitario Campus Bio-Medico and Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (M.C.); (P.B.); (A.A.); (A.T.); (S.D.C.); (M.R.); (M.F.); (M.P.L.G.)
| | - Alessandro Tullio
- Gastroenterology Unit, Fondazione Policlinico Universitario Campus Bio-Medico and Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (M.C.); (P.B.); (A.A.); (A.T.); (S.D.C.); (M.R.); (M.F.); (M.P.L.G.)
| | - Simone Di Cola
- Gastroenterology Unit, Fondazione Policlinico Universitario Campus Bio-Medico and Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (M.C.); (P.B.); (A.A.); (A.T.); (S.D.C.); (M.R.); (M.F.); (M.P.L.G.)
| | - Sander Dejongh
- Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, 3000 Leuven, Belgium; (S.D.); (R.F.)
- Laboratory of Nephrology and Renal Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Maria Giovanna Graziani
- Department of Gastroenterology and Digestive Endoscopy, S. Giovanni Addolorata Hospital, 00184 Rome, Italy; (M.G.G.); (C.P.)
| | - Cristiano Pagnini
- Department of Gastroenterology and Digestive Endoscopy, S. Giovanni Addolorata Hospital, 00184 Rome, Italy; (M.G.G.); (C.P.)
| | - Simone Carotti
- Microscopic and Ultrastructural Anatomy Research Unit Medicine and Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy;
- Predictive Molecular Diagnostics, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | - Giuseppe Perrone
- Anatomical Pathology Operative Research Unit, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy;
| | - Mentore Ribolsi
- Gastroenterology Unit, Fondazione Policlinico Universitario Campus Bio-Medico and Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (M.C.); (P.B.); (A.A.); (A.T.); (S.D.C.); (M.R.); (M.F.); (M.P.L.G.)
| | - Marcello Fiorani
- Gastroenterology Unit, Fondazione Policlinico Universitario Campus Bio-Medico and Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (M.C.); (P.B.); (A.A.); (A.T.); (S.D.C.); (M.R.); (M.F.); (M.P.L.G.)
| | - Michele P. L. Guarino
- Gastroenterology Unit, Fondazione Policlinico Universitario Campus Bio-Medico and Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (M.C.); (P.B.); (A.A.); (A.T.); (S.D.C.); (M.R.); (M.F.); (M.P.L.G.)
| | - Ricard Farré
- Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, 3000 Leuven, Belgium; (S.D.); (R.F.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
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3
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Pal P, Ramchandani M, Patel R, Banerjee R, Kanaganti S, Gupta R, Tandan M, Reddy DN. Role of ultra-high definition endoscopy (endomicroscopy and endocytoscopy) and real-time histologic examination in inflammatory bowel disease: Scoping review. Dig Endosc 2024; 36:274-289. [PMID: 37573562 DOI: 10.1111/den.14659] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 08/06/2023] [Indexed: 08/15/2023]
Abstract
OBJECTIVES Confocal laser endomicroscopy (CLE) and endocytoscopy (EC) are ultra-high definition (HD) imaging modalities that enable real-time histological assessment. Although existent for nearly two decades, their role in current clinical decision making in inflammatory bowel disease management is not well defined. METHODS We searched PubMed using keywords ("confocal" OR "CLE" OR "endocytoscopy") AND ("IBD" OR "inflammatory bowel" OR "Crohn*" OR "Crohn's" OR "colitis ulcerosa" OR "ulcerative colitis") between 2005 and March 2023. We identified 52 studies for detailed review. RESULTS Confocal laser endomicroscopy was useful in real-time assessment of histologic inflammation and dysplasia characterization in both ulcerative colitis (UC) and Crohn's disease. Although CLE was associated with higher per-biopsy yield for UC-associated neoplasia (UCAN), the benefit was offset by higher procedure time, frequent equipment failure, and conflicting results on incremental yield over chromoendoscopy. Assessment of barrier dysfunction by CLE did not correlate with disease/endoscopic activity but could predict major adverse outcomes. The implications of residual CLE abnormalities in endoscopic remission remain uncertain. Ex vivo binding of labeled biologics can help in predicting biologic response in UC. EC can discriminate mucosal inflammatory cells by morphology and allows assessment of histologic activity. EC combined with pit pattern was better than pit pattern alone for UCAN. Artificial intelligence-assisted EC in UCAN needs further study. CONCLUSION Ultra-HD imaging in inflammatory bowel disease can be useful in assessment of UCAN, barrier dysfunction, predicting histologic remission, and biologic response. Future controlled studies are warranted to define the role of these novel technologies in clinical decision making.
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Affiliation(s)
- Partha Pal
- Asian Institute of Gastroenterology, Hyderabad, India
| | | | | | - Rupa Banerjee
- Asian Institute of Gastroenterology, Hyderabad, India
| | | | - Rajesh Gupta
- Asian Institute of Gastroenterology, Hyderabad, India
| | - Manu Tandan
- Asian Institute of Gastroenterology, Hyderabad, India
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Chiriac S, Sfarti CV, Minea H, Stanciu C, Cojocariu C, Singeap AM, Girleanu I, Cuciureanu T, Petrea O, Huiban L, Muzica CM, Zenovia S, Nastasa R, Stafie R, Rotaru A, Stratina E, Trifan A. Impaired Intestinal Permeability Assessed by Confocal Laser Endomicroscopy-A New Potential Therapeutic Target in Inflammatory Bowel Disease. Diagnostics (Basel) 2023; 13:1230. [PMID: 37046447 PMCID: PMC10093200 DOI: 10.3390/diagnostics13071230] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/19/2023] [Accepted: 03/22/2023] [Indexed: 04/14/2023] Open
Abstract
Inflammatory bowel diseases (IBD) represent a global phenomenon, with a continuously rising prevalence. The strategies concerning IBD management are progressing from clinical monitorization to a targeted approach, and current therapies strive to reduce microscopic mucosal inflammation and stimulate repair of the epithelial barrier function. Intestinal permeability has recently been receiving increased attention, as evidence suggests that it could be related to disease activity in IBD. However, most investigations do not successfully provide adequate information regarding the morphological integrity of the intestinal barrier. In this review, we discuss the advantages of confocal laser endomicroscopy (CLE), which allows in vivo visualization of histological abnormalities and targeted optical biopsies in the setting of IBD. Additionally, CLE has been used to assess vascular permeability and epithelial barrier function that could correlate with prolonged clinical remission, increased resection-free survival, and lower hospitalization rates. Moreover, the dynamic evaluation of the functional characteristics of the intestinal barrier presents an advantage over the endoscopic examination as it has the potential to select patients at risk of relapses. Along with mucosal healing, histological or transmural remission, the recovery of the intestinal barrier function emerges as a possible target that could be included in the future therapeutic strategies for IBD.
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Affiliation(s)
- Stefan Chiriac
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Catalin Victor Sfarti
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Horia Minea
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Carol Stanciu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Camelia Cojocariu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Ana-Maria Singeap
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Irina Girleanu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Tudor Cuciureanu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Oana Petrea
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Laura Huiban
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Cristina Maria Muzica
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Sebastian Zenovia
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Robert Nastasa
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Remus Stafie
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Adrian Rotaru
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Ermina Stratina
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Anca Trifan
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
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Ngo PA, Neurath MF, López-Posadas R. Impact of Epithelial Cell Shedding on Intestinal Homeostasis. Int J Mol Sci 2022; 23:ijms23084160. [PMID: 35456978 PMCID: PMC9027054 DOI: 10.3390/ijms23084160] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
The gut barrier acts as a first line of defense in the body, and plays a vital role in nutrition and immunoregulation. A layer of epithelial cells bound together via intercellular junction proteins maintains intestinal barrier integrity. Based on a tight equilibrium between cell extrusion and cell restitution, the renewal of the epithelium (epithelial turnover) permits the preservation of cell numbers. As the last step within the epithelial turnover, cell shedding occurs due to the pressure of cell division and migration from the base of the crypt. During this process, redistribution of tight junction proteins enables the sealing of the epithelial gap left by the extruded cell, and thereby maintains barrier function. Disturbance in cell shedding can create transient gaps (leaky gut) or cell accumulation in the epithelial layer. In fact, numerous studies have described the association between dysregulated cell shedding and infection, inflammation, and cancer; thus epithelial cell extrusion is considered a key defense mechanism. In the gastrointestinal tract, altered cell shedding has been observed in mouse models of intestinal inflammation and appears as a potential cause of barrier loss in human inflammatory bowel disease (IBD). Despite the relevance of this process, there are many unanswered questions regarding cell shedding. The investigation of those mechanisms controlling cell extrusion in the gut will definitely contribute to our understanding of intestinal homeostasis. In this review, we summarized the current knowledge about intestinal cell shedding under both physiological and pathological circumstances.
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Affiliation(s)
- Phuong A. Ngo
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (P.A.N.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (P.A.N.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
| | - Rocío López-Posadas
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (P.A.N.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Correspondence:
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Beauséjour M, Boutin A, Vachon PH. Anoikis and the Human Gut Epithelium in Health and Disease. ANOIKIS 2021:95-126. [DOI: 10.1007/978-3-030-73856-3_5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Muehler A, Slizgi JR, Kohlhof H, Groeppel M, Peelen E, Vitt D. Clinical relevance of intestinal barrier dysfunction in common gastrointestinal diseases. World J Gastrointest Pathophysiol 2020; 11:114-130. [PMID: 33362939 PMCID: PMC7739114 DOI: 10.4291/wjgp.v11.i6.114] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 10/07/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023] Open
Abstract
The intestinal barrier is a complex and well-controlled physiological construct designed to separate luminal contents from the bowel wall. In this review, we focus on the intestinal barrier’s relationship with the host’s immune system interaction and the external environment, specifically the microbiome. The bowel allows the host to obtain nutrients vital to survival while protecting itself from harmful pathogens, luminal antigens, or other pro-inflammatory factors. Control over barrier function and the luminal milieu is maintained at the biochemical, cellular, and immunological level. However, disruption to this highly regulated environment can cause disease. Recent advances to the field have progressed the mechanistic understanding of compromised intestinal barrier function in the context of gastrointestinal pathology. There are numerous examples where bowel barrier dysfunction and the resulting interaction between the microbiome and the immune system has disease-triggering consequences. The purpose of this review is to summarize the clinical relevance of intestinal barrier dysfunction in common gastrointestinal and related diseases. This may help highlight the importance of restoring barrier function as a therapeutic mechanism of action in gastrointestinal pathology.
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Chu F, Esworthy RS, Shen B, Doroshow JH. Role of the microbiota in ileitis of a mouse model of inflammatory bowel disease-Glutathione peroxide isoenzymes 1 and 2-double knockout mice on a C57BL background. Microbiologyopen 2020; 9:e1107. [PMID: 32810389 PMCID: PMC7568258 DOI: 10.1002/mbo3.1107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 07/19/2020] [Accepted: 07/25/2020] [Indexed: 12/13/2022] Open
Abstract
C57Bl6 (B6) mice devoid of glutathione peroxidases 1 and 2 (Gpx1/2-DKO) develop ileitis after weaning. We previously showed germ-free Gpx1/2-DKO mice of mixed B6.129 background did not develop ileocolitis. Here, we examine the composition of the ileitis provoking microbiota in B6 Gpx1/2-DKO mice. DNA was isolated from the ileum fecal stream and subjected to high-throughput sequencing of the V3 and V4 regions of the 16S rRNA gene to determine the abundance of operational taxonomic units (OTUs). We analyzed the role of bacteria by comparing the microbiomes of the DKO and pathology-free non-DKO mice. Mice were treated with metronidazole, streptomycin, and vancomycin to alter pathology and correlate the OTU abundances with pathology levels. Principal component analysis based on Jaccard distance of abundance showed 3 distinct outcomes relative to the source Gpx1/2-DKO microbiome. Association analyses of pathology and abundance of OTUs served to rule out 7-11 of 24 OTUs for involvement in the ileitis. Collections of OTUs were identified that appeared to be linked to ileitis in this animal model and would be classified as commensals. In Gpx1/2-DKO mice, host oxidant generation from NOX1 and DUOX2 in response to commensals may compromise the ileum epithelial barrier, a role generally ascribed to oxidants generated from mitochondria, NOX2 and endoplasmic reticulum stress in response to presumptive pathogens in IBD. Elevated oxidant levels may contribute to epithelial cell shedding, which is strongly associated with progress toward inflammation in Gpx1/2-DKO mice and predictive of relapse in IBD by allowing leakage of microbial components into the submucosa.
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Affiliation(s)
- Fong‐Fong Chu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital and College of Clinical Medicine of HenanUniversity of Science and TechnologyLuoyangChina
| | - R. Steven Esworthy
- Department of Cancer Genetics and EpigeneticsBeckman Research InstituteCity of HopeDuarteCAUSA
| | - Binghui Shen
- Department of Cancer Genetics and EpigeneticsBeckman Research InstituteCity of HopeDuarteCAUSA
| | - James H. Doroshow
- Center for Cancer Research and Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMDUSA
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Osterman MT, Gordon IO, Davis EM, Ciorba M, Glover SC, Abraham B, Khan F, Guo X, Yee EU, Allard FD, Claggett B, Shen B, Liu JJ. Mucosal Biomarker of Innate Immune Activation Predicts Response to Vedolizumab in Crohn's Disease. Inflamm Bowel Dis 2020; 26:1554-1561. [PMID: 31553433 DOI: 10.1093/ibd/izz222] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Mucosal barrier dysfunction plays a crucial role in intestinal inflammation in Crohn's disease (CD). Intestinal epithelial cell (IEC) death resulting from innate immune activation, termed pyroptosis, was recently found to be a cause of this barrier defect. The aim of this study was to determine the predictive value of pretreatment ileal biopsy pyroptosis as a biomarker for clinical response to vedolizumab in CD. DESIGN Crohn's disease patients ranging 18 to 80 years old from 5 IBD centers with pre-vedolizumab ileal biopsies during colonoscopy were enrolled. Biopsies were stained for activated caspases, and levels of ileal IEC pyroptosis levels were quantified. The primary outcome was clinical response 6 months after therapy, defined as a reduction of Harvey-Bradshaw Index (HBI) of ≥5 points from baseline. Secondary outcomes included clinical remission, defined as HBI <5, and endoscopic improvement, as measured by the Simple Endoscopic Score for Crohn's Disease (SES-CD). RESULTS One hundred CD patients (45 male, 55 female), median age 47 (19, 78) years, were included; clinical response rate was 60%, and clinical remission was 36%. The response rate in patients with ileal pyroptosis <14 positive cells per 1000 IECs was significantly higher than those above the threshold: 89% (25 of 28) vs 49% (35 of 72), odds ratio (OR) 8.8 (95% CI, 2.3-48.6; P < 0.001). Corresponding remission rates were 54% (15 of 28) vs 29% (21 of 72; OR 2.8 [1.03-7.59; P = 0.036]). For endoscopic improvement, ileal pyroptosis of 22 positive cells per 1000 IECs was the optimal threshold that determines the magnitude SES-CD change. CONCLUSIONS Ileal biopsy IEC pyroptosis was predictive of clinical response and endoscopic improvement to vedolizmab in CD patients.
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Affiliation(s)
- Mark T Osterman
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Ilyssa O Gordon
- Department of Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Elisabeth M Davis
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Matthew Ciorba
- Division of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, MO, USA
| | - Sarah C Glover
- Division of Gastroenterology and Hepatology, University of Florida, Gainesville, FL, USA
| | - Bincy Abraham
- Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, TX, USA
| | - Freeha Khan
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Xueyan Guo
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Eric U Yee
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Felicia D Allard
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Brian Claggett
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Bo Shen
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Julia J Liu
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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10
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Buchner AM. Confocal Laser Endomicroscopy in the Evaluation of Inflammatory Bowel Disease. Inflamm Bowel Dis 2019; 25:1302-1312. [PMID: 30877772 DOI: 10.1093/ibd/izz021] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, can be effectively monitored with the use of endoscopy. The additional application of small field imaging technology such as confocal laser endomicroscopy CLE during ongoing endoscopic evaluation has led to real-time visualization of mucosal abnormalities and thus in vivo histology. The endomicroscopy (CLE) can improve IBD endoscopic evaluation by identifying seemingly normal-appearing mucosa, assessing the function of the intestinal barrier of the epithelium and vascular permeability, and by characterizing any mucosal lesions, including dysplastic lesions. CLE used during conventional endoscopy could especially facilitate the evaluation of mucosal healing in IBD. In addition, future developments in molecular imaging in IBD may optimize therapeutic approaches by identifying mucosal targets for therapy and determining the reasons for lack of response to specific therapy or subsequent loss of the response.
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Affiliation(s)
- Anna M Buchner
- Division of Gastroenterology at University of Pennsylvania, Philadelphia, Pennsylvania
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11
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Auzoux J, Boschetti G, Anon B, Aubourg A, Caulet M, Poisson L, Besson P, Lecomte T, Roger S, Picon L, Nancey S, Moussata D, Flourie B. Usefulness of confocal laser endomicroscopy for predicting postoperative recurrence in patients with Crohn's disease: a pilot study. Gastrointest Endosc 2019; 90:151-157. [PMID: 30849396 DOI: 10.1016/j.gie.2019.02.030] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 02/23/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Confocal laser endomicroscopy (CLE) has been shown to predict relapse in inflammatory bowel disease, but its value in the detection of postoperative recurrence in Crohn's disease (CD) is unknown. The aims of this pilot study performed in patients with CD after ileocolonic resection were to compare the macroscopic appearance of the neoterminal ileum, according to the endoscopic Rutgeerts score, with the microscopic findings provided by CLE 6 to 12 months after surgery and to assess the predictive values of CLE-generated parameters for predicting further recurrence in patients with postoperative endoscopic remission. METHODS In 25 consecutive patients with CD within 6 to 12 months of surgery, the neoterminal ileum was examined by standard white-light endoscopy (Rutgeerts scale) followed by CLE (Watson grade). Only patients without endoscopic recurrence (Rutgeerts i0 and i1) were then followed endoscopically and clinically (median follow-up 38 months). RESULTS At the time of the first postoperative colonoscopy, 18 patients (72%) were in endoscopic remission, and 7 (28%) experienced an endoscopic recurrence (Rutgeerts ≥i2). The Rutgeerts score was significantly correlated with the Watson score (ρ = 0 .73; P < .0001). The Watson scores at baseline were significantly higher in patients with further endoscopic recurrence (median 2.0; interquartile range [IQR] 1.5-2.0) than in those with endoscopic remission (median 1.0; IQR 1.0-1.0; P = .032) and were significantly higher in patients with clinical relapse (medium 2.0, IQR 2.0-2.0) compared with those in clinical remission (median 1.0; IQR 1.0-1.0; P = .036). CONCLUSIONS CLE could be useful in monitoring patients with CD after intestinal resection. Further studies with a larger population are necessary to confirm these preliminary results.
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Affiliation(s)
- Julie Auzoux
- Department of Hepato-Gastroenterology and Oncology, CHRU Trousseau Tours, France
| | - Gilles Boschetti
- Department of Hepato-Gastroenterology, Lyon-Sud Hospital, Hospices Civils of Lyon, Pierre-Bénite and University Claude Bernard Lyon 1, Lyon, France
| | - Benjamin Anon
- Department of Hepato-Gastroenterology and Oncology, CHRU Trousseau Tours, France
| | - Alexandre Aubourg
- Department of Hepato-Gastroenterology and Oncology, CHRU Trousseau Tours, France
| | - Morgane Caulet
- Department of Hepato-Gastroenterology and Oncology, CHRU Trousseau Tours, France
| | | | | | - Thierry Lecomte
- Department of Hepato-Gastroenterology and Oncology, CHRU Trousseau Tours, France
| | | | - Laurence Picon
- Department of Hepato-Gastroenterology and Oncology, CHRU Trousseau Tours, France
| | - Stephane Nancey
- Department of Hepato-Gastroenterology, Lyon-Sud Hospital, Hospices Civils of Lyon, Pierre-Bénite and University Claude Bernard Lyon 1, Lyon, France
| | - Driffa Moussata
- Department of Hepato-Gastroenterology and Oncology, CHRU Trousseau Tours, France; INSERM Unit 1069, Tours University, Tours, France
| | - Bernard Flourie
- Department of Hepato-Gastroenterology, Lyon-Sud Hospital, Hospices Civils of Lyon, Pierre-Bénite and University Claude Bernard Lyon 1, Lyon, France
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12
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Liu JJ, Rosson TB, Xie JJ, Harris ZP, McBride RG, Siegel E, Hagedorn C. Personalized Inflammatory Bowel Disease Care Reduced Hospitalizations. Dig Dis Sci 2019; 64:1809-1814. [PMID: 30746632 DOI: 10.1007/s10620-019-05485-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 01/22/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND AIMS IBD patients with inadequately treated disease often relapse and require hospitalizations for further management. The purpose of this practice review was to determine whether personalized IBD care improved patient outcomes as measured by IBD-related hospitalizations. METHODS A dedicated IBD clinic was created for personalized patient care in a tertiary veterans health care center in 2014. In the first year, the care program consisted of patient-centered medical home (PCMH). In the second year, personalized biologic therapy was incorporated into the program, based on the severity of mucosal barrier dysfunction measured by probe-based confocal laser endomicroscopy (pCLE) analysis of the terminal ileum during colonoscopy. IBD-related hospitalizations during these 2 years were compared to the year before the care program. RESULTS The IBD-related admissions at baseline, year 1 and 2 of the program were: total number of admissions of 25, 24, 8 (P = 0.03) per year, total number of hospital days of 177, 144, 31 days per year (P < 0.01), median length of stay 7, 4, and 2 days per visit (P = 0.013), respectively. Patients had significant increases in serum hemoglobin (11.5 ± 2.7, 11.9 ± 2.6, 14.0 ± 1.4 g/dl; P = 0.035), albumin (2.7 ± 0.7, 3.0 ± 0.6 g/dl 3.7 ± 0.8 g/dl; P = 0.031) and body mass index (26.6 ± 2.9, 28.1 ± 5.9; 34.0 ± 10.8; P = 0.047). CONCLUSIONS Personalized IBD care incorporating a PCMH model and tailored biologic therapy based on pCLE findings of mucosal barrier dysfunction significantly reduced IBD-related hospitalizations.
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Affiliation(s)
- Julia J Liu
- Department of Medicine, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA. .,Division of Gastroenterology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
| | - Thomas Brent Rosson
- Department of Medicine, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
| | - Jesse J Xie
- Department of Medicine, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.,Division of Gastroenterology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Zachary P Harris
- Department of Medicine, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.,Division of Gastroenterology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Regina G McBride
- Department of Nursing, Central Arkansas Veterans Healthcare Systems, Little Rock, AR, USA
| | - Eric Siegel
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Curt Hagedorn
- Department of Medicine, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.,Division of Gastroenterology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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13
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Vejzovic V. Professionals' experiences with paediatric colonoscopy: an interview study. BMC Nurs 2019; 18:7. [PMID: 30911284 PMCID: PMC6416969 DOI: 10.1186/s12912-019-0331-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 02/25/2019] [Indexed: 12/31/2022] Open
Abstract
Background Colonoscopy plays a crucial role in the diagnosis of paediatric inflammatory bowel disease (IBD), adolescents comprise 25% of all cases of IBD. Several studies have found that a safe, informative, and effective colonoscopy, performed in a child-friendly atmosphere with minimal distress to the child, is difficult to achieve. The aim of this study was to describe nurse’s experiences of the pre-colonoscopy procedure prior in children. Methods A qualitative design with a thematic content analysis approach was used. Fifteen nurses at a children’s hospital participated in interviews regarding their experiences of the bowel cleansing procedure with PEG in children. Results Four key themes were extracted from the nurses’ experiences; lack of knowledge, challenges surrounding information, responsibility without control and assembly line- like procedure.. Conclusions This study shows that nurses feel that they need more time and education opportunities before involved in paediatric colonoscopies.
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Affiliation(s)
- Vedrana Vejzovic
- Department of Care Science, Malmö University, Faculty of Health and Society, SE-205 06 Malmö, Sweden
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14
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Stefanson AL, Bakovic M. Falcarinol Is a Potent Inducer of Heme Oxygenase-1 and Was More Effective than Sulforaphane in Attenuating Intestinal Inflammation at Diet-Achievable Doses. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:3153527. [PMID: 30420908 PMCID: PMC6215554 DOI: 10.1155/2018/3153527] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/20/2018] [Accepted: 09/02/2018] [Indexed: 02/08/2023]
Abstract
Nuclear factor- (erythroid-derived 2) like 2 (Nrf2) is a transcription factor that regulates the expression of a battery of antioxidant, anti-inflammatory, and cytoprotective enzymes including heme oxygenase-1 (Hmox1, Ho-1) and NADPH:quinone oxidoreductase-1 (Nqo1). The isothiocyanate sulforaphane (SF) is widely understood to be the most effective natural activator of the Nrf2 pathway. Falcarinol (FA) is a lesser studied natural compound abundant in medicinal plants as well as dietary plants from the Apiaceae family such as carrot. We evaluated the protective effects of FA and SF (5 mg/kg twice per day in CB57BL/6 mice) pretreatment for one week against acute intestinal and systemic inflammation. The phytochemical pretreatment effectively reduced the magnitude of intestinal proinflammatory gene expression (IL-6, Tnfα/Tnfαr, Infγ, STAT3, and IL-10/IL-10r) with FA showing more potency than SF. FA was also more effective in upregulating Ho-1 at mRNA and protein levels in both the mouse liver and the intestine. FA but not SF attenuated plasma chemokine eotaxin and white blood cell growth factor GM-CSF, which are involved in the recruitment and stabilization of first-responder immune cells. Phytochemicals generally did not attenuate plasma proinflammatory cytokines. Plasma and intestinal lipid peroxidation was also not significantly changed 4 h after LPS injection; however, FA did reduce basal lipid peroxidation in the mesentery. Both phytochemical pretreatments protected against LPS-induced reduction in intestinal barrier integrity, but FA additionally reduced inflammatory cell infiltration even below negative control.
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Affiliation(s)
- Amanda L. Stefanson
- Department of Human Health and Nutritional Sciences, 50 Stone Rd E, University of Guelph, Guelph, ON, Canada N1G 2W1
| | - Marica Bakovic
- Department of Human Health and Nutritional Sciences, 50 Stone Rd E, University of Guelph, Guelph, ON, Canada N1G 2W1
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15
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Sivanathan V, Tontini GE, Möhler M, Galle PR, Neumann H. Advanced endoscopic imaging for diagnosis of inflammatory bowel diseases: Present and future perspectives. Dig Endosc 2018; 30:441-448. [PMID: 29360261 DOI: 10.1111/den.13023] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 01/17/2018] [Indexed: 02/06/2023]
Abstract
Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD) causing severe damage of the luminal gastrointestinal tract. Differential diagnosis between both disease entities is sometimes awkward requiring a multifactorial pathway, including clinical and laboratory data, radiological findings, histopathology and endoscopy. Apart from disease diagnosis, endoscopy in IBD plays a major role in prediction of disease severity and extent (i.e. mucosal healing) for tailored patient management and for screening of colitis-associated cancer and its precursor lesions. In this state-of-the-art review, we focus on current applications of endoscopy for diagnosis and surveillance of IBD. Moreover, we will discuss the latest guidelines on surveillance and provide an overview of the most recent developments in the field of endoscopic imaging and IBD.
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Affiliation(s)
- Visvakanth Sivanathan
- Department of Interdisciplinary Endoscopy, I. Medizinische Klinik und Poliklinik, University Hospital, Mainz, Germany
| | - Gian Eugenio Tontini
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, Milan, Italy
| | - Markus Möhler
- Department of Interdisciplinary Endoscopy, I. Medizinische Klinik und Poliklinik, University Hospital, Mainz, Germany
| | - Peter R Galle
- Department of Interdisciplinary Endoscopy, I. Medizinische Klinik und Poliklinik, University Hospital, Mainz, Germany
| | - Helmut Neumann
- Department of Interdisciplinary Endoscopy, I. Medizinische Klinik und Poliklinik, University Hospital, Mainz, Germany
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16
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Tontini GE, Mudter J, Vieth M, Günther C, Milani V, Atreya R, Rath T, Nägel A, Hatem G, Sturniolo GC, Vecchi M, Neurath MF, Galle PR, Buda A, Neumann H. Prediction of clinical outcomes in Crohn's disease by using confocal laser endomicroscopy: results from a prospective multicenter study. Gastrointest Endosc 2018; 87:1505-1514.e3. [PMID: 29108979 DOI: 10.1016/j.gie.2017.10.033] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 10/19/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Assessment of prognostic factors in patients with Crohn's disease (CD) is of pivotal importance for early intervention and "treat-to-target" strategies. Confocal laser endomicroscopy (CLE) enables on-demand in vivo characterization of mucosal inflammatory and architectural changes during endoscopy. We prospectively assessed the value of CLE for prediction of clinical outcome parameters in CD. METHODS Consecutive patients with CD undergoing colonoscopy were included in a multicenter study. Confocal imaging focused on 2 highly reproducible histologic hallmarks of active colonic inflammation: focal cryptitis and crypt architectural abnormality. We evaluated whether CLE, CD endoscopic index of severity (CDEIS), serum C-reactive protein (CRP), and CD activity index (CDAI) were associated with the risk of medical treatment escalation, transmural adverse events, and CD-related hospitalization or surgery during a 4-year follow-up. RESULTS Among 49 patients (53% men, median age, 39 years), baseline CRP was ≥5 mg/L in 47%, CDEIS ≥3 in 75%, and CDAI >150 in 51%. Focal cryptitis and crypt architectural abnormality were observed in 63% (CLE+ group). CLE+ patients showed an increased incidence of medical treatment escalation (P < .001; relative risk [RR] = 3.27) and transmural lesions (P = .025; RR = 1.70), whereas patients with CRP ≥5 mg/L had increased CD-related hospitalization and surgery (P = .020, RR = 2.71) at 1-year follow-up. No further association with prognostic clinical outcomes was found over the 1-year follow-up as well as for CDEIS and CDAI at any time. CONCLUSIONS CLE reveals CD-related features of mucosal inflammation and allows for early prediction of relevant clinical outcomes. Further studies should now address whether this promising prognostic tool could refine the timing of treatment strategies in patients with CD.
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Affiliation(s)
- Gian Eugenio Tontini
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany; Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | - Jonas Mudter
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Claudia Günther
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany
| | | | - Raja Atreya
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Timo Rath
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Andreas Nägel
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Giorgia Hatem
- Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Giacomo Carlo Sturniolo
- Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Maurizio Vecchi
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Markus F Neurath
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Peter R Galle
- First Medical Department, University Medical Center Mainz, Mainz, Germany
| | - Andrea Buda
- Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padua, Padua, Italy; Gastroenterology and Digestive Endoscopy Unit, Ospedale di Feltre, Feltre, Italy
| | - Helmut Neumann
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany; First Medical Department, University Medical Center Mainz, Mainz, Germany
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17
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Waldner MJ, Rath T, Schürmann S, Bojarski C, Atreya R. Imaging of Mucosal Inflammation: Current Technological Developments, Clinical Implications, and Future Perspectives. Front Immunol 2017; 8:1256. [PMID: 29075256 PMCID: PMC5641553 DOI: 10.3389/fimmu.2017.01256] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Accepted: 09/21/2017] [Indexed: 12/12/2022] Open
Abstract
In recent years, various technological developments markedly improved imaging of mucosal inflammation in patients with inflammatory bowel diseases. Although technological developments such as high-definition-, chromo-, and autofluorescence-endoscopy led to a more precise and detailed assessment of mucosal inflammation during wide-field endoscopy, probe-based and stationary confocal laser microscopy enabled in vivo real-time microscopic imaging of mucosal surfaces within the gastrointestinal tract. Through the use of fluorochromes with specificity against a defined molecular target combined with endoscopic techniques that allow ultrastructural resolution, molecular imaging enables in vivo visualization of single molecules or receptors during endoscopy. Molecular imaging has therefore greatly expanded the clinical utility and applications of modern innovative endoscopy, which include the diagnosis, surveillance, and treatment of disease as well as the prediction of the therapeutic response of individual patients. Furthermore, non-invasive imaging techniques such as computed tomography, magnetic resonance imaging, scintigraphy, and ultrasound provide helpful information as supplement to invasive endoscopic procedures. In this review, we provide an overview on the current status of advanced imaging technologies for the clinical non-invasive and endoscopic evaluation of mucosal inflammation. Furthermore, the value of novel methods such as multiphoton microscopy, optoacoustics, and optical coherence tomography and their possible future implementation into clinical diagnosis and evaluation of mucosal inflammation will be discussed.
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Affiliation(s)
- Maximilian J. Waldner
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Timo Rath
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sebastian Schürmann
- Institute of Medical Biotechnology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Bojarski
- Department of Gastroenterology, Infectiology and Rheumatology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Raja Atreya
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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18
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Kim ES. Role of Advanced Endoscopic Imaging Techniques in the Management of Inflammatory Bowel Disease. Clin Endosc 2017; 50:424-428. [PMID: 29017290 PMCID: PMC5642067 DOI: 10.5946/ce.2017.143] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 09/24/2017] [Accepted: 09/24/2017] [Indexed: 12/19/2022] Open
Abstract
Endoscopy plays a crucial role in the management of inflammatory bowel disease (IBD) in terms of diagnosis, monitoring of mucosal status, and surveillance of colitis-associated neoplasia. Mucosal healing evaluated by endoscopy has been recognized as the target of treatment in the era of powerful biologics therapy. The optimal modality for identifying dysplasia in IBD has yet to be well defined. Increasing progress has recently been made in endoscopic technologies to more accurately assess mucosal inflammation and more effectively detect dysplasia. Here we review the data of advanced endoscopic imaging techniques such as chromoendoscopy, virtual chromoendoscopy, endocytoscopy, and confocal laser endomicroscopy in the management of IBD.
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Affiliation(s)
- Eun Soo Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
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19
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Kiesslich R, Neurath MF. Advanced endoscopy imaging in inflammatory bowel diseases. Gastrointest Endosc 2017; 85:496-508. [PMID: 27816496 DOI: 10.1016/j.gie.2016.10.034] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 10/24/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Rapid assessment of mucosal inflammation is of crucial importance for the initial diagnosis and the assessment of mucosal healing in inflammatory bowel disease (IBD). Moreover, the identification of intraepithelial neoplasias in IBD is of key relevance for clinical management. Here, we systematically analyzed the utility of advanced endoscopic imaging techniques for optimized diagnosis in IBD. METHODS PubMed/Medline, Web of Knowledge, and Cochrane library were searched twice for diagnostic studies on advanced endoscopic imaging in IBD. Clinical and technical information was retrieved and subsequently analyzed. Main outcome parameters consisted of the quality of the results, adverse events, and diagnostic yield. RESULTS Fifty-six clinical studies with a total of 3296 patients were selected for final analysis. Filter technologies permitted a more detailed analysis of mucosal inflammation in IBD. In spite of substantial heterogeneity across studies, dye-based chromoendoscopy with targeted biopsy sampling yielded higher detection rates of intraepithelial neoplasias in ulcerative colitis as compared with white-light endoscopy with random biopsy sampling. Moreover, endocytoscopy and endomicroscopy allowed subsurface imaging of inflamed or neoplastic mucosa in IBD at subcellular resolution. Finally, endomicroscopy-aided molecular imaging enabled the identification of membrane-bound tumor necrosis factor on mucosal cells as a potential driver of disease activity in Crohn's disease. No relevant adverse events were reported. CONCLUSIONS Advanced endoscopic imaging technologies are feasible, safe, and partially effective tools for detailed diagnosis of mucosal inflammation and detection of neoplasias in IBD. Results obtained from these advanced techniques may provide a rational basis for individualized, optimized therapy for IBD patients.
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Affiliation(s)
- Ralf Kiesslich
- Department of Medicine II, HELIOS Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
| | - Markus F Neurath
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nürnberg, Nürnberg, Germany; Ludwig Demling Endoscopy Center of Excellence, Erlangen, Germany
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20
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Tontini GE, Pastorelli L, Ishaq S, Neumann H. Advances in endoscopic imaging in ulcerative colitis. Expert Rev Gastroenterol Hepatol 2016; 9:1393-405. [PMID: 26365308 DOI: 10.1586/17474124.2015.1087848] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Modern strategies for the treatment of ulcerative colitis require more accurate tools for gastrointestinal imaging to better assess mucosal disease activity and long-term prognostic clinical outcomes. Recent advances in gastrointestinal luminal endoscopy are radically changing the role of endoscopy in every-day clinical practice and research trials. Advanced endoscopic imaging techniques including high-definition endoscopes, optical magnification endoscopy, and various chromoendoscopy techniques have remarkably improved endoscopic assessment of ulcerative colitis. More recently, optical biopsy techniques with either endocytoscopy or confocal laser endomicroscopy have shown great potential in predicting several histological changes in real time during ongoing endoscopy. Here, we review current applications of advanced endoscopic imaging techniques in ulcerative colitis and present the most promising upcoming headways in this field.
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Affiliation(s)
- Gian Eugenio Tontini
- a 1 Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Luca Pastorelli
- a 1 Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy.,b 2 Department of Biomedical Sciences for Health, University of Milan, Milano, Italy
| | - Sauid Ishaq
- c 3 Department of Gastroenterology, Dudley Group Hospitals, Birmingham City University, Birmingham, UK.,d 4 Department of Medicine, St. George's University, Grenada, West Indies
| | - Helmut Neumann
- e 5 Department of Medicine I, University of Erlangen-Nuremberg, Erlangen, Germany
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21
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Karstensen JG, Săftoiu A, Brynskov J, Hendel J, Ciocalteu A, Klausen P, Klausen TW, Riis LB, Vilmann P. Confocal laser endomicroscopy in ulcerative colitis: a longitudinal study of endomicroscopic changes and response to medical therapy (with videos). Gastrointest Endosc 2016; 84:279-286.e1. [PMID: 26945556 DOI: 10.1016/j.gie.2016.01.069] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 01/13/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Confocal laser endomicroscopy enables real-time in vivo microscopy during endoscopy and can predict relapse in patients with inflammatory bowel disease in remission. However, little is known about how endomicroscopic features change with time. The aim of this longitudinal study was to correlate colonic confocal laser endomicroscopy (CLE) in ulcerative colitis with histopathology and macroscopic appearance before and after intensification of medical treatment. METHODS Twenty-two patients with ulcerative colitis in clinical relapse and 7 control subjects referred for colonoscopy were enrolled. The colonic mucosa was examined with high-definition colonoscopy, histopathology, and CLE at 4 colonic sites. Subsequently, patients requiring medical treatment escalation were referred for repeat endoscopy with CLE after 6 to 8 weeks. RESULTS The baseline frequency of fluorescein leakage (P < .001), microerosions (P < .001), tortuosity of the crypts (P = .001), distortion of the crypts openings (P = .001), presence of inflammatory infiltrates (P < .001), and decreased crypt density (P < .001) were significantly higher in active ulcerative colitis compared with inactive ulcerative colitis and control subjects. A decrease in histopathologic score after medical treatment escalation was correlated with improvement in crypt tortuosity (rs = .35, P = .016), distortion of crypt openings (rs = .30, P = .045), and decreased crypt density (rs = .33, P = .026) but not in other features. CONCLUSIONS CLE is an emerging endoscopic technique that reproducibly identifies mucosal changes in ulcerative colitis. With the exception of crypt changes, endomicroscopic features appear to improve slowly with time after medical treatment. ( CLINICAL TRIAL REGISTRATION NUMBER NCT01684514.).
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Affiliation(s)
- John Gásdal Karstensen
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Adrian Săftoiu
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark; Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy, Craiova, Romania
| | - Jørn Brynskov
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Jakob Hendel
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Adriana Ciocalteu
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark; Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy, Craiova, Romania
| | - Pia Klausen
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
| | | | - Lene Buhl Riis
- Department of Pathology, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Peter Vilmann
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
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22
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Liu JJ, Kay TM, Davis EM, Lou Y, Kao D, Claggett B, Fedorak RN, Irvin RT. Epithelial Cell Extrusion Zones Observed on Confocal Laser Endomicroscopy Correlates with Immunohistochemical Staining of Mucosal Biopsy Samples. Dig Dis Sci 2016; 61:1895-902. [PMID: 27098414 PMCID: PMC5896752 DOI: 10.1007/s10620-016-4154-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 03/31/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The density of epithelial cell extrusion zones in the intestinal lining, also known as gap density (number of gaps/1000 epithelial cells counted), can be quantitated using probe-based confocal laser endomicroscopy (pCLE). Gap density has been reported to be higher than normal in both inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) patients. Epithelial cells destined for extrusion from the intestinal surface would stain positive for either activated caspase-1 or caspase-3 on mucosal biopsy samples. The aim of this study was to determine whether epithelial gap density on pCLE correlates with quantitative analysis of activated caspase staining of mucosal biopsy samples from patients. METHODS We obtained pCLE images and biopsy samples of the terminal ileum during colonoscopies of healthy controls and patients with either IBD or IBS. The pCLE images and biopsy samples were blindly analyzed for gap density and for cells staining positive for activated caspases, respectively. The degree of correlation was determined using nonparametric statistical tests. RESULTS The median results were 10 gaps/1000 cells counted for controls versus 33 gaps/1000 cells counted for chronic intestinal disorder patients (p = 0.02). Activated caspase staining showed 13 positive cells/1000 epithelial cells counted versus 26 positive cells/1000 epithelial cells counted, respectively (p = 0.02), thus showing a strong correlation with a Spearman's coefficient ρ of 0.61 (strong correlation for ρ = 0.4-0.75, p = 0.01). CONCLUSIONS Intestinal epithelial gap density via pCLE correlated strongly with quantitative analysis of immunohistochemical staining of mucosal biopsy samples.
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Affiliation(s)
- Julia J Liu
- Division of Gastroenterology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Shorey S8/62, Little Rock, AR, 72205, USA.
| | - Theresa M Kay
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Elisabeth M Davis
- Division of Gastroenterology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
| | - Yuefei Lou
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Dina Kao
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Brian Claggett
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Richard N Fedorak
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Randall T Irvin
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
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23
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A Pilot Study of Confocal Laser Endomicroscopy to Predict Barrier Dysfunction and Relapse in Pediatric Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2016; 62:873-8. [PMID: 26513619 PMCID: PMC5854472 DOI: 10.1097/mpg.0000000000001022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Probe-based confocal laser endomicroscopy (pCLE) is a novel imaging modality that enables virtual optical biopsy in vivo. Loss of barrier function of the small bowel observed via pCLE as increased density of epithelial gaps (extrusion zones left in the intestinal lining after cells are shed) is predictive of relapse in adult patients with inflammatory bowel disease (IBD). This study aims to determine whether such observations on pCLE are similarly predictive of disease relapse in pediatric patients with IBD. METHODS Pediatric patients with biopsy-proven IBD underwent pCLE during colonoscopy and subsequent clinical follow-up every 6 months. Relapse was defined as moderate to severe flare with endoscopic evidence of inflammation during the follow-up period. The relations between epithelial gap density, disease relapse, and imaging parameters were determined using Cox models. RESULTS Twenty-four patients with IBD (13 with Crohn disease, 11 with ulcerative colitis) with a median age of 14 years (range 10-21) were studied for a median of 13 (4-33) months. The median duration of disease was 2.9 years (range 0-9). Increased epithelial gap density in the terminal ileum on pCLE of normal endoscopic appearing terminal ileum mucosa (N = 19) was predictive of disease relapse when 3 or more areas were imaged (N = 6, log-rank P = 0.02, C-statistic = 0.94). CONCLUSIONS In pediatric patients with IBD, barrier dysfunction observed on pCLE imaging of the small bowel was predictive of disease relapse.
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24
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Fugazza A, Gaiani F, Carra MC, Brunetti F, Lévy M, Sobhani I, Azoulay D, Catena F, de'Angelis GL, de'Angelis N. Confocal Laser Endomicroscopy in Gastrointestinal and Pancreatobiliary Diseases: A Systematic Review and Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2016; 2016:4638683. [PMID: 26989684 PMCID: PMC4773527 DOI: 10.1155/2016/4638683] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Accepted: 12/31/2015] [Indexed: 12/15/2022]
Abstract
Confocal laser endomicroscopy (CLE) is an endoscopic-assisted technique developed to obtain histopathological diagnoses of gastrointestinal and pancreatobiliary diseases in real time. The objective of this systematic review is to analyze the current literature on CLE and to evaluate the applicability and diagnostic yield of CLE in patients with gastrointestinal and pancreatobiliary diseases. A literature search was performed on MEDLINE, EMBASE, Scopus, and Cochrane Oral Health Group Specialized Register, using pertinent keywords without time limitations. Both prospective and retrospective clinical studies that evaluated the sensitivity, specificity, or accuracy of CLE were eligible for inclusion. Of 662 articles identified, 102 studies were included in the systematic review. The studies were conducted between 2004 and 2015 in 16 different countries. CLE demonstrated high sensitivity and specificity in the detection of dysplasia in Barrett's esophagus, gastric neoplasms and polyps, colorectal cancers in inflammatory bowel disease, malignant pancreatobiliary strictures, and pancreatic cysts. Although CLE has several promising applications, its use has been limited by its low availability, high cost, and need of specific operator training. Further clinical trials with a particular focus on cost-effectiveness and medicoeconomic analyses, as well as standardized institutional training, are advocated to implement CLE in routine clinical practice.
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Affiliation(s)
- Alessandro Fugazza
- Unit of Gastroenterology and Digestive Endoscopy, University of Parma, 43100 Parma, Italy
| | - Federica Gaiani
- Unit of Gastroenterology and Digestive Endoscopy, University of Parma, 43100 Parma, Italy
| | | | - Francesco Brunetti
- Unit of Digestive, Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Henri Mondor Hospital, AP-HP, 94010 Créteil, France
| | - Michaël Lévy
- Department of Gastroenterology and Digestive Endoscopy, Henri Mondor Hospital, AP-HP, 94010 Créteil, France
| | - Iradj Sobhani
- Department of Gastroenterology and Digestive Endoscopy, Henri Mondor Hospital, AP-HP, 94010 Créteil, France
- Cancer Research Lab. EC2M3, Université Paris-Est, Val de Marne UPEC, 94010 Créteil, France
| | - Daniel Azoulay
- Unit of Digestive, Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Henri Mondor Hospital, AP-HP, 94010 Créteil, France
| | - Fausto Catena
- Emergency Surgery Department, University of Parma, 43100 Parma, Italy
| | - Gian Luigi de'Angelis
- Unit of Gastroenterology and Digestive Endoscopy, University of Parma, 43100 Parma, Italy
| | - Nicola de'Angelis
- Unit of Digestive, Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Henri Mondor Hospital, AP-HP, 94010 Créteil, France
- Cancer Research Lab. EC2M3, Université Paris-Est, Val de Marne UPEC, 94010 Créteil, France
- Department of Advanced Biomedical Sciences, University Federico II of Naples, 80138 Naples, Italy
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25
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Tontini GE, Rath T, Neumann H. Advanced gastrointestinal endoscopic imaging for inflammatory bowel diseases. World J Gastroenterol 2016; 22:1246-1259. [PMID: 26811662 PMCID: PMC4716035 DOI: 10.3748/wjg.v22.i3.1246] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 10/15/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal luminal endoscopy is of paramount importance for diagnosis, monitoring and dysplasia surveillance in patients with both, Crohn's disease and ulcerative colitis. Moreover, with the recent recognition that mucosal healing is directly linked to the clinical outcome of patients with inflammatory bowel disorders, a growing demand exists for the precise, timely and detailed endoscopic assessment of superficial mucosal layer. Further, the novel field of molecular imaging has tremendously expanded the clinical utility and applications of modern endoscopy, now encompassing not only diagnosis, surveillance, and treatment but also the prediction of individual therapeutic responses. Within this review, we describe how novel endoscopic approaches and advanced endoscopic imaging methods such as high definition and high magnification endoscopy, dye-based and dye-less chromoendoscopy, confocal laser endomicroscopy, endocytoscopy and molecular imaging now allow for the precise and ultrastructural assessment of mucosal inflammation and describe the potential of these techniques for dysplasia detection.
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26
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López-Posadas R, Becker C, Günther C, Tenzer S, Amann K, Billmeier U, Atreya R, Fiorino G, Vetrano S, Danese S, Ekici AB, Wirtz S, Thonn V, Watson AJM, Brakebusch C, Bergö M, Neurath MF, Atreya I. Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation. J Clin Invest 2016; 126:611-26. [PMID: 26752649 DOI: 10.1172/jci80997] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 11/18/2015] [Indexed: 01/08/2023] Open
Abstract
Although defects in intestinal barrier function are a key pathogenic factor in patients with inflammatory bowel diseases (IBDs), the molecular pathways driving disease-specific alterations of intestinal epithelial cells (IECs) are largely unknown. Here, we addressed this issue by characterizing the transcriptome of IECs from IBD patients using a genome-wide approach. We observed disease-specific alterations in IECs with markedly impaired Rho-A signaling in active IBD patients. Localization of epithelial Rho-A was shifted to the cytosol in IBDs, and inflammation was associated with suppressed Rho-A activation due to reduced expression of the Rho-A prenylation enzyme geranylgeranyltransferase-I (GGTase-I). Functionally, we found that mice with conditional loss of Rhoa or the gene encoding GGTase-I, Pggt1b, in IECs exhibit spontaneous chronic intestinal inflammation with accumulation of granulocytes and CD4+ T cells. This phenotype was associated with cytoskeleton rearrangement and aberrant cell shedding, ultimately leading to loss of epithelial integrity and subsequent inflammation. These findings uncover deficient prenylation of Rho-A as a key player in the pathogenesis of IBDs. As therapeutic triggering of Rho-A signaling suppressed intestinal inflammation in mice with GGTase-I-deficient IECs, our findings suggest new avenues for treatment of epithelial injury and mucosal inflammation in IBD patients.
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27
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Atkinson CD, Singh SK. Luminal Confocal Laser Endomicroscopy. ENDOSCOPIC IMAGING TECHNIQUES AND TOOLS 2016:83-114. [DOI: 10.1007/978-3-319-30053-5_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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28
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Rasmussen DN, Karstensen JG, Riis LB, Brynskov J, Vilmann P. Confocal Laser Endomicroscopy in Inflammatory Bowel Disease--A Systematic Review. J Crohns Colitis 2015. [PMID: 26209861 DOI: 10.1093/ecco-jcc/jjv131] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Confocal laser endomicroscopy is an endoscopic method that provides in vivo real-time imaging of the mucosa at a cellular level, elucidating mucosal changes that are undetectable by white light endoscopy. This paper systematically reviews current indications and perspectives of confocal laser endomicroscopy for inflammatory bowel disease. METHODS Available literature was searched systematically for studies applying confocal laser endomicroscopy in Crohn's disease or ulcerative colitis. Relevant literature was reviewed and only studies reporting original clinical data were included. Next, eligible studies were analysed with respect to several parameters, such as technique and clinical aim and definitions of outcomes. RESULTS Confocal laser endomicroscopy has been used for a wide range of purposes in inflammatory bowel disease, covering assessment of inflammatory severity, prediction of therapeutic response and relapse and adenoma surveillance in patients with ulcerative colitis. Methods for measurement of the histological changes ranged from subjective grading to objective quantification analysed by computer-aided models. The studies derived their conclusions from assessment of histological features such as colonic crypts, epithelial gaps and epithelial leakiness to fluorescein. CONCLUSIONS Confocal laser endomicroscopy remains an experimental but emerging tool for assessment of inflammatory bowel disease. It is the only method that enables in vivo functional assessment of intestinal barrier function. There is great heterogeneity in the literature and no single approach has been validated and reproduced to the level of general acceptance.
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Affiliation(s)
- Ditlev Nytoft Rasmussen
- Department of Gastroenterology and Gastrointestinal Surgery, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark
| | - John Gásdal Karstensen
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Copenhagen, Denmark
| | - Lene Buhl Riis
- Department of Pathology, Copenhagen University Hospital Herlev, Copenhagen, Denmark
| | - Jørn Brynskov
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Copenhagen, Denmark
| | - Peter Vilmann
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Copenhagen, Denmark
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29
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Rath T, Tontini GE, Neurath MF, Neumann H. From the surface to the single cell: Novel endoscopic approaches in inflammatory bowel disease. World J Gastroenterol 2015; 21:11260-11272. [PMID: 26523101 PMCID: PMC4616203 DOI: 10.3748/wjg.v21.i40.11260] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 07/31/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) comprise the two major entities Crohn's disease and ulcerative colitis and endoscopic imaging of the gastrointestinal tract has always been an integral and central part in the management of IBD patients. Within the recent years, mucosal healing emerged as a key treatment goal in IBD that substantially decides about the clinical outcome of IBD patients, thereby demanding for a precise, timely and detailed endoscopic assessment of the mucosal inflammation associated with IBD. Further, molecular imaging has tremendously expanded the clinical utility and applications of modern endoscopy, now encompassing not only diagnosis, surveillance, and treatment but also the prediction of individual therapy response. Within this review we describe novel endoscopic approaches and advanced endoscopic imaging methods for the diagnosis, treatment and surveillance of IBD patients. We begin by providing an overview over novel and advanced imaging techniques such as magnification endoscopy and dye-based and dye-less chromoendoscopy, endomicroscopy and endocytoscopy. We then describe how these techniques can be utilized for the precise and ultrastructural assessment of mucosal inflammation and dysplasia development associated with IBD and outline how they have enabled the endoscopist to gain insight onto the cellular level in real-time. Finally, we provide an outlook on how molecular imaging has rapidly evolved in the recent past and can be used to make individual predictions about the therapeutic response towards biological treatment.
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30
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Wang KK, Carr-Locke DL, Singh SK, Neumann H, Bertani H, Galmiche JP, Arsenescu RI, Caillol F, Chang KJ, Chaussade S, Coron E, Costamagna G, Dlugosz A, Ian Gan S, Giovannini M, Gress FG, Haluszka O, Ho KY, Kahaleh M, Konda VJ, Prat F, Shah RJ, Sharma P, Slivka A, Wolfsen HC, Zfass A. Use of probe-based confocal laser endomicroscopy (pCLE) in gastrointestinal applications. A consensus report based on clinical evidence. United European Gastroenterol J 2015; 3:230-254. [PMID: 26137298 PMCID: PMC4480534 DOI: 10.1177/2050640614566066] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 11/17/2014] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Probe-based confocal laser endomicroscopy (pCLE) provides microscopic imaging during an endoscopic procedure. Its introduction as a standard modality in gastroenterology has brought significant progress in management strategies, affecting many aspects of clinical care and requiring standardisation of practice and training. OBJECTIVE This study aimed to provide guidance on the standardisation of its practice and training in Barrett's oesophagus, biliary strictures, colorectal lesions and inflammatory bowel diseases. METHODS Initial statements were developed by five group leaders, based on the available clinical evidence. These statements were then voted and edited by the 26 participants, using a modified Delphi approach. After two rounds of votes, statements were validated if the threshold of agreement was higher than 75%. RESULTS Twenty-six experts participated and, among a total of 77 statements, 61 were adopted (79%) and 16 were rejected (21%). The adoption of each statement was justified by the grade of evidence. CONCLUSION pCLE should be used to enhance the diagnostic arsenal in the evaluation of these indications, by providing microscopic information which improves the diagnostic performance of the physician. In order actually to implement this technology in the clinical routine, and to ensure good practice, standardised initial and continuing institutional training programmes should be established.
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Affiliation(s)
- Kenneth K Wang
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - David L Carr-Locke
- Division of Digestive Diseases, Beth Israel Medical Center, New York City, NY, USA
| | - Satish K Singh
- Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Helmut Neumann
- The Ludwig Demling Endoscopy Center of Excellence, Erlangen, Germany
| | - Helga Bertani
- Endoscopy Unit, Nuovo Ospedale Civile S. Agostino Estense, Modena, Italy
| | | | | | - Fabrice Caillol
- Endoscopy Unit, Paoli-Calmettes Institute, Marseille, France
| | - Kenneth J Chang
- H.H. Chao Comprehensive Digestive Disease Center, University of California, Irvine, CA, USA
| | - Stanislas Chaussade
- Division of Gastroenterology, Hopital Cochin and Paris-Descartes University, Paris, France
| | - Emmanuel Coron
- Division of Gastroenterology and Hepatology, Nantes CHU, Rouen, France
| | | | - Aldona Dlugosz
- Karolinska Institutet, Department of Medicine, Division of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden
| | - S Ian Gan
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, USA
| | - Marc Giovannini
- Endoscopy Unit, Paoli-Calmettes Institute, Marseille, France
| | - Frank G Gress
- Division of Digestive and Liver disease, Columbia University Medical Center, New York City, NY, USA
| | - Oleh Haluszka
- Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA
| | - Khek Y Ho
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Michel Kahaleh
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York City, NY, USA
| | - Vani J Konda
- Center for Endoscopic Research and Therapeutics, Department of Medicine, University of Chicago Medicine, Chicago, IL, USA
| | - Frederic Prat
- Division of Gastroenterology, Hopital Cochin and Paris-Descartes University, Paris, France
| | - Raj J Shah
- University of Colorado School of Medicine, Aurora, CO, USA
| | - Prateek Sharma
- Department of Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MI, USA
- Department of Gastroenterology and Hepatology, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Adam Slivka
- Division of Gastroenterology & Hepatology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | | | - Alvin Zfass
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University Medical Center, Richmond, VA, USA
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31
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Wei ZZ, Li N. Application of confocal laser endomicroscopy in ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2015; 23:1924-1929. [DOI: 10.11569/wcjd.v23.i12.1924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The etiology of ulcerative colitis (UC) is not very clear. Most scholars believe that intestinal inflammation caused by immune system abnormalities plays an important role in the pathogenesis of UC. The clinical course of UC is characterized by episodes of exacerbation and remission alternately. Traditional electronic endoscopy with random biopsy plays an important role in the diagnosis, treatment and prognosis evaluation of UC. However, this method has some deficiencies, such as poor sensitivity, cumbersome procedures, bleeding caused by multiple biopsies and other complications. The advent of high resolution confocal laser endomicroscopy (CLE) can allow real-time, noninvasive histopathological examination in vivo, to achieve the goal of "virtual biopsy". This paper reviews the application of CLE in UC.
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32
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Vejzovic V, Bramhagen AC, Idvall E, Wennick A. Parents' experiences when their child is undergoing an elective colonoscopy. J SPEC PEDIATR NURS 2015; 20:123-30. [PMID: 25845734 DOI: 10.1111/jspn.12109] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 02/26/2015] [Accepted: 02/26/2015] [Indexed: 11/30/2022]
Abstract
PURPOSE The purpose was to illuminate parents' experiences when their children are undergoing an elective colonoscopy performed using polyethylene glycol-based regimes for bowel preparation. DESIGN AND METHODS Individual interviews with 12 parents were performed and analysed using content analysis. RESULTS The parents' experiences were structured into one theme: "Charged with conflicting emotions" with three categories: "Being forced to force," "Losing one's sense of being a parent" and "Standing without guidance." PRACTICE IMPLICATIONS Understanding parents' experiences can help healthcare staff guide parents in helping their children undergo a colonoscopy.
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Affiliation(s)
- Vedrana Vejzovic
- Department of Care Science, Faculty of Health and Society, Malmö University, Malmö, Sweden
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33
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The current and future role of endomicroscopy in the management of inflammatory bowel disease. Ann Gastroenterol 2015; 28:331-336. [PMID: 26130373 PMCID: PMC4480169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 12/24/2014] [Indexed: 11/12/2022] Open
Abstract
Confocal laser-induced endomicroscopy (CLE), first introduced in 2003, allows the capture of images of "virtual histology" of the gastrointestinal mucosa during endoscopy, providing the opportunity to retrieve real-time visualization of the pathology of the mucosal epithelium with its cellular and subcellular structures. This new endoscopic imaging technique serves as an adjunctive diagnostic tool to the traditional ileocolonoscopy in the management of inflammatory bowel disease (IBD) patients. In multiple clinical trials, CLE has been shown to improve detection of dysplasia, assess disease activity, predict future clinical relapses, and assess potential responsiveness to anti-tumor necrosis factor therapy. This review explores in depth the current and future role of CLE in the management of IBD patients.
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Abstract
PURPOSE OF REVIEW Low-grade inflammation can persist in many patients with inflammatory bowel disease (IBD) who have otherwise obtained clinical remission. This review will summarize the prognostic implications of this finding for patients. RECENT FINDINGS At least 40% of patients with IBD in clinical remission have ongoing histological evidence of inflammation, despite continued use of maintenance therapy. Follow-up endoscopy and biopsy is the current gold standard for identifying these patients. Recent studies have suggested that an elevated C-reactive protein is associated with underlying histological abnormalities in this setting. Patients with histological inflammation at baseline are at increased risk of clinical relapse, hospitalization, surgery, and colon cancer in observational longitudinal studies. Even when endoscopic healing has been achieved, the presence of underlying architectural changes on biopsies can identify patients at a higher risk of complications. Prospective studies to determine if 'histological healing' provides additional outcome benefits beyond endoscopic or clinical remission alone have not been performed to date, but warrant inclusion in future trials. SUMMARY Chronic low-grade inflammation is common in patients with IBD in clinical remission. Clinicians should actively try to identify these patients and consider a lower threshold for intervention to reduce their higher risk of adverse outcomes over time.
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35
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Tontini GE, Vecchi M, Neurath MF, Neumann H. Advanced endoscopic imaging techniques in Crohn's disease. J Crohns Colitis 2014; 8:261-9. [PMID: 24080247 DOI: 10.1016/j.crohns.2013.09.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2013] [Revised: 09/05/2013] [Accepted: 09/05/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Endoscopy is of pivotal importance in Crohn's disease (CD) patients for diagnosis, surveillance and assessment of disease activity and extent. Device-assisted enteroscopy (DAE) and small-bowel capsule endoscopy (SBCE) have recently changed our endoscopic approach to small-bowel imaging. Furthermore, new advanced endoscopic imaging techniques have been implemented into clinical practice to improve both characterization of mucosal inflammation and detection of dysplastic lesions. AIM To provide readers with a review about the concept of advanced endoscopic imaging for the diagnosis and characterization of CD. METHODS A literature search on the use of advanced endoscopy techniques in IBD patients was performed. RESULTS DAE and SBCE allow for deep enteroscopy with high diagnostic yields and low complication's rate but their collocation in the diagnostic algorithm is still not clearly defined. Dye-based chromoendoscopy (DBC) and magnification chromoendoscopy improved dysplasia's detection in long standing colitis and prediction of inflammatory activity and extent. Dye-less chromoendoscopy (DLC) might offer the potential to replace conventional DBC for surveillance. However, both narrow band imaging and i-scan have already shown to significantly improve activity and extent assessment in comparison to white-light endoscopy. Confocal laser endomicroscopy (CLE) can detect more dysplastic lesions in surveillance colonoscopy and predict neoplastic and inflammatory changes with high accuracy compared to histology. Moreover, CLE-based molecular imaging may anticipate the therapeutic responses to biological therapy. Endocytoscopy can identify in vivo inflammatory mucosal cells harboring a new method to assess the mucosal activity. CONCLUSIONS Recent progresses in small-bowel enteroscopy offer several potential benefits to improve both diagnosis and characterization of CD. New advanced endoscopic imaging techniques can improve detection of dysplasia and refine mucosal healing assessment, even looking beyond the morphological parameters revealed by conventional endoscopic imaging.
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Affiliation(s)
- Gian Eugenio Tontini
- Department of Medicine I, University of Erlangen-Nuremberg, Germany; Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy.
| | - Maurizio Vecchi
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy; Department of Medical Science for Health, University of Milan, Italy
| | - Markus F Neurath
- Department of Medicine I, University of Erlangen-Nuremberg, Germany
| | - Helmut Neumann
- Department of Medicine I, University of Erlangen-Nuremberg, Germany.
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36
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Liu J, Dlugosz A, Neumann H. Beyond white light endoscopy: The role of optical biopsy in inflammatory bowel disease. World J Gastroenterol 2013; 19:7544-7551. [PMID: 24282344 PMCID: PMC3837252 DOI: 10.3748/wjg.v19.i43.7544] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 10/08/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023] Open
Abstract
In this review, we will discuss the use of two optical biopsy modalities in inflammatory bowel disease (IBD). The two techniques reviewed here are confocal laser endomicroscopy and endocytoscopy. We will describe the technical performance of the procedure, discuss the clinical indications for optical biopsy in IBD, and highlight active research areas with respect to the pathogenesis of IBD. Clinical indications for optical biopsies in IBD include assessment of mucosal inflammation, dysplasia detection and evaluation of cell shedding for disease relapse. Research application in the area of barrier dysfunction will also be discussed.
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Palma GDD, Rispo A. Confocal laser endomicroscopy in inflammatory bowel diseases: dream or reality? World J Gastroenterol 2013; 19:5593-5597. [PMID: 24039350 PMCID: PMC3769894 DOI: 10.3748/wjg.v19.i34.5593] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2013] [Revised: 06/27/2013] [Accepted: 08/04/2013] [Indexed: 02/06/2023] Open
Abstract
Confocal laser endomicroscopy (CLE) is a newly introduced procedure that provide real-time, high-resolution imaging of the gastrointestinal mucosa during endoscopy, allowing the visualization of the pathology of the mucosal epithelium with its cellular and subcellular structures. Recently, the use of CLE was reported in the study of colonic mucosa in patients with inflammatory bowel diseases and in particular in patients affected by ulcerative colitis. CLE has the potential to have an important role in management of inflammatory bowel diseases (IBD) patients as it can be used to assess the grading of colitis and in detection of microscopic colitis in endoscopically silent segments. Moreover, CLE can be used in surveillance programs especially in high-risk patients. Finally, CLE has been effectively used in diagnosing a biliary dysplasia/neoplasia in patients with primary sclerosing cholangitis, a pathological condition frequently associated with IBD, with a coexisting bile duct stricture.
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Abstract
Two types of endomicroscopy systems exist. One is integrated into a standard, high-resolution endoscope and one is probe-based, capable of passage through the working channel of a standard endoscope. Endocytoscopy allows visualization of the superficial mucosal layer. Endoscope-integrated and probe-based devices allow magnification of the mucosa up to 1400-fold. Endomicroscopy can differentiate histologic changes of Crohn disease and ulcerative colitis in vivo in real time. Endocytoscopy can discriminate mucosal inflammatory cells, allowing determination of histopathologic activity of ulcerative colitis. Molecular imaging with fluorescence-labeled probes against disease-specific receptors will enable individualized management of inflammatory bowel diseases.
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Affiliation(s)
- Helmut Neumann
- Interdisciplinary Endoscopy, Department of Medicine I, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen 91054, Germany.
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