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Thakur BK, Malaise Y, Choudhury SR, Neustaeter A, Turpin W, Streutker C, Copeland J, Wong EOY, Navarre WW, Guttman DS, Jobin C, Croitoru K, Martin A. Dietary fibre counters the oncogenic potential of colibactin-producing Escherichia coli in colorectal cancer. Nat Microbiol 2025; 10:855-870. [PMID: 40033140 DOI: 10.1038/s41564-025-01938-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 01/14/2025] [Indexed: 03/05/2025]
Abstract
Diet, microbiome, inflammation and host genetics have been linked to colorectal cancer development; however, it is not clear whether and how these factors interact to promote carcinogenesis. Here we used Il10-/- mice colonized with bacteria previously associated with colorectal cancer: enterotoxigenic Bacteroides fragilis, Helicobacter hepaticus or colibactin-producing (polyketide synthase-positive (pks+)) Escherichia coli and fed either a low-carbohydrate (LC) diet deficient in soluble fibre, a high-fat and high-sugar diet, or a normal chow diet. Colonic polyposis was increased in mice colonized with pks+ E. coli and fed the LC diet. Mechanistically, mucosal inflammation was increased in the LC-diet-fed mice, leading to diminished colonic PPAR-γ signalling and increased luminal nitrate levels. This promoted both pks+ E. coli growth and colibactin-induced DNA damage. PPAR-γ agonists or supplementation with dietary soluble fibre in the form of inulin reverted inflammatory and polyposis phenotypes. The pks+ E. coli also induced more polyps in mismatch-repair-deficient mice by inducing a senescence-associated secretory phenotype. Moreover, oncogenic effects were further potentiated by inflammatory triggers in the mismatch-repair-deficient model. These data reveal that diet and host genetics influence the oncogenic potential of a common bacterium.
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Affiliation(s)
| | - Yann Malaise
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | | | - Anna Neustaeter
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Williams Turpin
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Catherine Streutker
- Department of Laboratory Medicine, Unity Health Toronto, Toronto, Ontario, Canada
| | - Julia Copeland
- Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, Ontario, Canada
| | - Erin O Y Wong
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - William W Navarre
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - David S Guttman
- Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, Ontario, Canada
- Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Christian Jobin
- Department of Infectious Diseases and Pathology, University of Florida College of Veterinary Medicine, Gainesville, FL, USA
| | - Kenneth Croitoru
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Alberto Martin
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
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Pavel C, Diculescu MM, Ilie M, Plotogea OM, Sandru V, Enache V, Gheonea DI, Jichitu A, Constantinescu A, Serban RE, Bogu CV, Liscu HD, Stepan AE. Immunohistochemistry Analysis in Inflammatory Bowel Disease-Should We Bring to Light Interleukin-10? Biomedicines 2025; 13:406. [PMID: 40002819 PMCID: PMC11853417 DOI: 10.3390/biomedicines13020406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 01/26/2025] [Accepted: 01/31/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Inflammatory bowel diseases (IBDs) are chronic intestinal disorders with an unpredictable course. In parallel with the advent of new biologic therapies targeting specific interleukin pathways, end-point targets have become more stringent, aiming for mucosal and even histologic healing. Methods: We conducted a prospective study assessing immunohistochemical (IHC) parameters in 46 IBD patients treated with biologic therapy. A similar IHC analysis was performed for comparison with a cohort of 10 "non-IBD" patients. Results: The highest integrated optical density (IOD) of TNF-α was observed in patients with dysplasia, abscesses, mucin depletion and basal plasmacytosis. Non-responders had higher pre- and post-treatment TNF-α expression in both UC and CD compared to responders. On the contrary, the same analysis conducted in the subpopulation treated with anti-TNF-α therapy (Infliximab and Adalimumab) did not reveal a substantial difference in TNF-α expression between responders and non-responders. High pre-treatment interleukin-10 expression was associated with biologic therapy failure, histological inflammatory activity and longer disease duration. Conclusions: Pre-treatment assessment of IL-10 might be a useful tool for identifying a high-risk subset of IBD patients and determining a more aggressive therapy and intensive monitoring strategy.
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Affiliation(s)
- Christopher Pavel
- Department 5, Gastroenterology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.P.); (M.I.); (O.-M.P.); (V.S.); (A.C.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (A.J.); (C.V.B.)
| | - Mircea Mihai Diculescu
- Department 5, Gastroenterology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.P.); (M.I.); (O.-M.P.); (V.S.); (A.C.)
- Department of Gastroenterology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Madalina Ilie
- Department 5, Gastroenterology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.P.); (M.I.); (O.-M.P.); (V.S.); (A.C.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (A.J.); (C.V.B.)
| | - Oana-Mihaela Plotogea
- Department 5, Gastroenterology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.P.); (M.I.); (O.-M.P.); (V.S.); (A.C.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (A.J.); (C.V.B.)
| | - Vasile Sandru
- Department 5, Gastroenterology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.P.); (M.I.); (O.-M.P.); (V.S.); (A.C.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (A.J.); (C.V.B.)
| | - Valentin Enache
- Department of Pathology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania;
| | - Dan-Ionut Gheonea
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.-I.G.); (R.-E.S.)
| | - Alexandra Jichitu
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (A.J.); (C.V.B.)
| | - Alexandru Constantinescu
- Department 5, Gastroenterology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.P.); (M.I.); (O.-M.P.); (V.S.); (A.C.)
| | - Robert-Emmanuel Serban
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.-I.G.); (R.-E.S.)
| | - Cosmin Viorel Bogu
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (A.J.); (C.V.B.)
| | - Horia-Dan Liscu
- Discipline of Oncological Radiotherapy and Medical Imaging, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Alex-Emilian Stepan
- Department of Pathology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
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S L, T RM, E TG, F C, E R, S S, C B, P P, M V. Hereditary colorectal cancer syndromes and inflammatory bowel disease: results from a registry-based study. Int J Colorectal Dis 2025; 40:24. [PMID: 39863767 PMCID: PMC11762763 DOI: 10.1007/s00384-025-04808-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/07/2025] [Indexed: 01/27/2025]
Abstract
PURPOSE In this study, we investigated the progression of high-grade dysplasia (HGD)/CRC in patients with hereditary colorectal cancer syndromes (HCSS) and concomitant inflammatory bowel diseases (IBDs). METHODS We described the natural history of a series of patients with confirmed diagnosis of hereditary colorectal cancer syndromes (HCCSs) and concomitant IBDs who were referred to the Hereditary Digestive Tumors Registry at the Fondazione IRCCS Istituto Nazionale dei Tumori of Milan. RESULTS Between January 1989 and April 2024, among 450 patients with APC-associated polyposis and 1050 patients with Lynch syndrome (LS), we identified six patients with IBDs (five with UC, one with ileal penetrating CD) and concomitant HCCSs (five with LS, one with APC-associated polyposis). Three patients developed CRC (two patients with stage IIA, and one with stage IIIA); in one patient, CRC occurred over a median follow-up of 12 months after IBD diagnosis, while in two, both conditions were diagnosed simultaneously. The median age at initial diagnosis of CRC was 33 years (range 27-41). Five patients (83.3%) underwent surgical procedures (three colonic resections for carcinoma and two for other reasons). Most of them progressed to precancerous or cancerous colonic lesions at a young age. Notably, all patients with CRC had a diagnosis of UC. CONCLUSION IBD patients with coexistent HCCSs can develop early CRC onset at an advanced stage. These patients should be always referred to tertiary referral centers for strict surveillance programs and early surgical management of advanced colorectal neoplastic lesions. Noninvasive biomarkers of neoplastic changes are advocated to further improve the management of IBD patients with HCCSs.
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Affiliation(s)
- Lauricella S
- Hereditary Digestive Tract Tumors Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via Giacomo Venezian 1, 20133, Milan, Italy.
- Colorectal Surgery Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.
| | - Ricci M T
- Hereditary Digestive Tract Tumors Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via Giacomo Venezian 1, 20133, Milan, Italy
| | - Tontini G E
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Cavallaro F
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Rausa E
- Hereditary Digestive Tract Tumors Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via Giacomo Venezian 1, 20133, Milan, Italy
- Colorectal Surgery Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Signoroni S
- Hereditary Digestive Tract Tumors Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via Giacomo Venezian 1, 20133, Milan, Italy
| | - Brignola C
- Hereditary Digestive Tract Tumors Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via Giacomo Venezian 1, 20133, Milan, Italy
| | - Pasanisi P
- Nutrition Research and Metabolomics Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Vitellaro M
- Hereditary Digestive Tract Tumors Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via Giacomo Venezian 1, 20133, Milan, Italy
- Colorectal Surgery Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
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Cui G, Yuan A, Sørbye SW, Florholmen J. Th9 and Th17 Cells in Human Ulcerative Colitis-Associated Dysplastic Lesions. Clin Med Insights Oncol 2024; 18:11795549241301358. [PMID: 39651422 PMCID: PMC11624539 DOI: 10.1177/11795549241301358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 11/04/2024] [Indexed: 12/11/2024] Open
Abstract
Background Inflammation is the most important deriving force for the development of colitis-associated colorectal cancer (CAC) through the Inflammation-Pretumor dysplasia-CAC sequence. T helper (Th) subsets Th9 and Th17 cells can potentially stimulate inflammation in the ulcerative colitis (UC). Therefore, Th9 and Th17 cells may play a promoting role in the colitis-associated dysplasia (CAD). Methods Using immunohistochemistry (IHC), we evaluated the presentation patterns and densities of T lymphocytes, Th9 and Th17 cells in human UC and CAD tissues. Results A general increasing trend of CD3-positive T lymphocytes, P.U.1-positive Th9 and interleukin (IL)-17A-positive Th17 cells was illustrated throughout the normal-UC-CAD sequence, IHC images showed that these cells were very prominent in the lamina propria, and some cells were also observed in the epithelium in the CAD tissues. Density analysis revealed that numbers of Th9 and Th17 cells were progressively increased in the CAD tissues as compared with the UC and control tissues. In general, densities of Th9 and Th17 cells in the lamina propria were slightly higher in the non-adenoma-like dysplasia (NALD) tissues than that in the adenoma-like dysplasia (ALD) tissues. However, densities of neither Th9 nor Th17 cells in both the ALD and NALD subgroups were associated with the degree of dysplasia in CAD lesions. Conclusion Accumulated Th9 and Th17 cells contribute to the immune cellular composition in the CAD tissues and may represent the early conditional change for the Dysplasia-CAC transition.
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Affiliation(s)
- Guanglin Cui
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Faculty of Health Science, Nord University, Campus Levanger, Norway
| | - Aping Yuan
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Sveinung W Sørbye
- Department of Pathology, University Hospital of North Norway, University of Tromsø, Tromsø, Norway
| | - Jon Florholmen
- Department of Gastroenterology & Nutrition, University Hospital of North Norway, University of Tromsø, Tromsø, Norway
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Huang Q, Peng W, Luo Q, Zhao W, Dai W, Zeng H, Wong HLX, Hu X. Exploring the mechanism of Suxin Hugan Fang in treating ulcerative colitis based on network pharmacology. Sci Rep 2024; 14:27196. [PMID: 39516633 PMCID: PMC11549446 DOI: 10.1038/s41598-024-78833-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024] Open
Abstract
As a traditional Chinese medicine formula used in clinical practice for an extended period, Suxin-Hugan-Fang (SXHGF) exhibits excellent anti-inflammatory properties. However, the efficacy of SXHGF in treating ulcerative colitis (UC) and its mechanism of action are still unclear. In this study, the therapeutic effects of SXHGF on UC were evaluated using network pharmacology and experimental validation, while also investigating its mechanism of action. By administering DSS to C57BL/6 mice to construct a mouse model of ulcerative colitis, the therapeutic effect of SXHGF on ulcerative colitis was evaluated based on weight loss percentage, disease activity index, colon length changes, and pathological conditions as indicators. The main chemical components of SXHGF were determined by LC-MS-QTOF method. The potential targets and mechanisms of action of SXHGF in the treatment of UC were inferred using bioinformatics methods, and further validated through ELISA, IHC, and Western blotting assays. The experimental results demonstrate that SXHGF can suppress oxidative stress and oxidative damage in the colon tissue of UC mice, and alleviate DSS-induced ulcerative colitis by inhibiting the JAK2/STAT3 and NFκB pathways.
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Affiliation(s)
- Qiang Huang
- Department of Pharmacy, Xiaolan People's Hospital of Zhongshan, Zhongshan, 528415, Guangdong, PR China
| | - Weijie Peng
- Pharmacology Laboratory, Zhongshan Hospital, Guangzhou University of Chinese Medicine, Zhongshan, 528401, Guangdong, PR China
| | - Qing Luo
- Pharmacology Laboratory, Zhongshan Hospital, Guangzhou University of Chinese Medicine, Zhongshan, 528401, Guangdong, PR China
| | - Wenchang Zhao
- Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523121, Guangdong, PR China
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, 523808, Guangdong, PR China
- Clinical Trial Institution, Xiaolan Hospital, Southern Medical University, Zhongshan, 528415, Guangdong, PR China
| | - Weibo Dai
- Pharmacology Laboratory, Zhongshan Hospital, Guangzhou University of Chinese Medicine, Zhongshan, 528401, Guangdong, PR China.
| | - Huifen Zeng
- Clinical Trial Institution, Xiaolan Hospital, Southern Medical University, Zhongshan, 528415, Guangdong, PR China.
| | - Hoi Leong Xavier Wong
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, 999077, PR China
| | - Xianjing Hu
- Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523121, Guangdong, PR China.
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, 523808, Guangdong, PR China.
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6
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Holcomb L, Holman JM, Hurd M, Lavoie B, Colucci L, Hunt B, Hunt T, Kinney M, Pathak J, Mawe GM, Moses PL, Perry E, Stratigakis A, Zhang T, Chen G, Ishaq SL, Li Y. Early life exposure to broccoli sprouts confers stronger protection against enterocolitis development in an immunological mouse model of inflammatory bowel disease. mSystems 2023; 8:e0068823. [PMID: 37942948 PMCID: PMC10734470 DOI: 10.1128/msystems.00688-23] [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: 07/21/2023] [Accepted: 10/02/2023] [Indexed: 11/10/2023] Open
Abstract
IMPORTANCE To our knowledge, IL-10-KO mice have not previously been used to investigate the interactions of host, microbiota, and broccoli, broccoli sprouts, or broccoli bioactives in resolving symptoms of CD. We showed that a diet containing 10% raw broccoli sprouts increased the plasma concentration of the anti-inflammatory compound sulforaphane and protected mice to varying degrees against disease symptoms, including weight loss or stagnation, fecal blood, and diarrhea. Younger mice responded more strongly to the diet, further reducing symptoms, as well as increased gut bacterial richness, increased bacterial community similarity to each other, and more location-specific communities than older mice on the diet intervention. Crohn's disease disrupts the lives of patients and requires people to alter dietary and lifestyle habits to manage symptoms. The current medical treatment is expensive with significant side effects, and a dietary intervention represents an affordable, accessible, and simple strategy to reduce the burden of symptoms.
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Affiliation(s)
- Lola Holcomb
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA
| | - Johanna M. Holman
- School of Food and Agriculture, University of Maine, Orono, Maine, USA
| | - Molly Hurd
- Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Brigitte Lavoie
- Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Louisa Colucci
- Department of Biology, Husson University, Bangor, Maine, USA
| | - Benjamin Hunt
- Department of Biology, University of Maine, Orono, Maine, USA
| | - Timothy Hunt
- Department of Biology, University of Maine, Orono, Maine, USA
| | - Marissa Kinney
- School of Food and Agriculture, University of Maine, Orono, Maine, USA
| | - Jahnavi Pathak
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA
| | - Gary M. Mawe
- Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Peter L. Moses
- Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
- Finch Therapeutics, Somerville, Massachusetts, USA
| | - Emma Perry
- Electron Microscopy Laboratory, University of Maine, Orono, Maine, USA
| | - Allesandra Stratigakis
- School of Pharmacy and Pharmaceutical Sciences, SUNY Binghamton University, Johnson City, New York, USA
| | - Tao Zhang
- School of Pharmacy and Pharmaceutical Sciences, SUNY Binghamton University, Johnson City, New York, USA
| | - Grace Chen
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Suzanne L. Ishaq
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA
| | - Yanyan Li
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA
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Jiang W, Lu M, Zhang L, Xu C, Wang R, Xu Y, Tang W, Zhang H. Optimizing individualized management of patients with ulcerative colitis: Identification of risk factors predicting ulcerative colitis-associated neoplasia. Medicine (Baltimore) 2023; 102:e34729. [PMID: 37565846 PMCID: PMC10419420 DOI: 10.1097/md.0000000000034729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 07/21/2023] [Indexed: 08/12/2023] Open
Abstract
The risk of developing colorectal neoplasia in patients with ulcerative colitis (UC) is increased. The purpose of this study is to analyze the risk factors of UC-associated neoplasia (UCAN) in UC patients and establish a clinical prediction model. 828 UC patients were included in this retrospective study. 602 patients were in discovery cohort and 226 patients were in validation cohort (internal validation cohort/external validation cohort: 120/106). Clinical and endoscopic data were collected. The discovery cohort was divided into UC group and UCAN group for univariate and multivariate binary logistic analyses. The UCAN clinical prediction model was established and verified. In the univariate analysis, 7 risk factors were related to UCAN. Multivariate logistic regression analysis showed that age at diagnosis of UC (OR: 1.018, 95% CI: 1.003-1.033), Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score (OR: 1.823, 95% CI: 1.562-2.128), and size of polyps (size1: OR: 6.297, 95% CI: 3.669-10.809; size2: OR: 12.014, 95% CI: 6.327-22.814) were independent risk factors of UCAN. A mathematical equation was established. The area under the ROC curve (AUC) of this model was calculated to be 0.845 (95%CI: 0.809-0.881). The sensitivity was 0.884 and the specificity was 0.688. The AUC of internal validation cohort was 0.901 (95%CI: 0.815, 0.988), sensitivity was 75.0% and specificity was 92.6%. The AUC of external validation cohort was 0.842 (95%CI: 0.709, 0.976), sensitivity was 62.5% and specificity was 93.9%. This prediction model is simple, practical, and effective for predicting the risk of UCAN, which is beneficial to the individualized management of patients with UC.
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Affiliation(s)
- Wenyu Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Meijiao Lu
- Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Li Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Chenjing Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Ruohan Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Ying Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Wen Tang
- Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Hongjie Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
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8
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Holcomb L, Holman JM, Hurd M, Lavoie B, Colucci L, Hunt B, Hunt T, Kinney M, Pathak J, Mawe GM, Moses PL, Perry E, Stratigakis A, Zhang T, Chen G, Ishaq SL, Li Y. Early life exposure to broccoli sprouts confers stronger protection against enterocolitis development in an immunological mouse model of inflammatory bowel disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.27.525953. [PMID: 36747766 PMCID: PMC9900910 DOI: 10.1101/2023.01.27.525953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Crohn's Disease (CD) is a presentation of Inflammatory Bowel Disease (IBD) that manifests in childhood and adolescence, and involves chronic and severe enterocolitis, immune and gut microbiome dysregulation, and other complications. Diet and gut-microbiota-produced metabolites are sources of anti-inflammatories which could ameliorate symptoms. However, questions remain on how IBD influences biogeographic patterns of microbial location and function in the gut, how early life transitional gut communities are affected by IBD and diet interventions, and how disruption to biogeography alters disease mediation by diet components or microbial metabolites. Many studies on diet and IBD use a chemically induced ulcerative colitis model, despite the availability of an immune-modulated CD model. Interleukin-10-knockout (IL-10-KO) mice on a C57BL/6 background, beginning at age 4 or 7 weeks, were fed a control diet or one containing 10% (w/w) raw broccoli sprouts, which was high in the sprout-sourced anti-inflammatory sulforaphane. Diets began 7 days prior to, and for 2 weeks after inoculation with Helicobacter hepaticus, which triggers Crohn's-like symptoms in these immune-impaired mice. The broccoli sprout diet increased sulforaphane in plasma; decreased weight stagnation, fecal blood, and diarrhea associated; and increased microbiota richness in the gut, especially in younger mice. Sprout diets resulted in some anatomically specific bacteria in younger mice, and reduced the prevalence and abundance of pathobiont bacteria which trigger inflammation in the IL-10-KO mouse, for example; Escherichia coli and Helicobacter. Overall, the IL-10-KO mouse model is responsive to a raw broccoli sprout diet and represents an opportunity for more diet-host-microbiome research.
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Affiliation(s)
- Lola Holcomb
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA 04469
| | - Johanna M. Holman
- School of Food and Agriculture, University of Maine, Orono, Maine, USA 04469
| | - Molly Hurd
- Larner College of Medicine, University of Vermont, Burlington, Vermont, USA 05401
| | - Brigitte Lavoie
- Larner College of Medicine, University of Vermont, Burlington, Vermont, USA 05401
| | - Louisa Colucci
- Department of Biology, Husson University, Bangor, Maine, USA 04401
| | - Benjamin Hunt
- Department of Biology, University of Maine, Orono, Maine, USA 04469
| | - Timothy Hunt
- Department of Biology, University of Maine, Orono, Maine, USA 04469
| | - Marissa Kinney
- School of Food and Agriculture, University of Maine, Orono, Maine, USA 04469
| | - Jahnavi Pathak
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA 04469
| | - Gary M. Mawe
- Larner College of Medicine, University of Vermont, Burlington, Vermont, USA 05401
| | - Peter L. Moses
- Larner College of Medicine, University of Vermont, Burlington, Vermont, USA 05401
- Finch Therapeutics, Somerville, Massachusetts, USA 02143
| | - Emma Perry
- Electron Microscopy Laboratory, University of Maine, Orono, Maine, USA 04469
| | - Allesandra Stratigakis
- School of Pharmacy and Pharmaceutical Sciences, SUNY Binghamton University, Johnson City, New York, USA 13790
| | - Tao Zhang
- School of Pharmacy and Pharmaceutical Sciences, SUNY Binghamton University, Johnson City, New York, USA 13790
| | - Grace Chen
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA 48109
| | - Suzanne L. Ishaq
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA 04469
| | - Yanyan Li
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA 04469
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9
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Malham M, Jansson S, Malmborg P, Olén O, Paerregaard A, Virta LJ, Jakobsen C, Kolho KL, Wewer V. Risk Factors of Cancer in Pediatric-Onset Inflammatory Bowel Disease in Denmark and Finland. J Pediatr Gastroenterol Nutr 2023; 77:55-61. [PMID: 36961906 DOI: 10.1097/mpg.0000000000003781] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/26/2023]
Abstract
OBJECTIVES Pediatric-onset inflammatory bowel disease (pIBD) increases the risk of developing several different cancer forms. In this case-control study, we aimed to assess the impact of medical treatment and disease activity on the risk of developing disease-associated cancer (DAC) and treatment-associated cancer (TAC). METHODS In a previous study, we identified 27 cases of DAC (colorectal cancer, small bowel cancer, and cholangiocarcinoma) and 28 TAC (lymphoma and skin cancer) in 6689 patients with pIBD in Denmark and Finland during the period 1992-2015. In this study, the patient charts were reviewed manually. Cancer-free patients from another population-based pIBD cohort were included as controls. We recorded data on phenotype, medical treatment, surgery, and relapses. Logistic regression was used to estimate adjusted odds ratios (aOR) with 95% confidence intervals (95% CI) to estimate the relative risk. RESULTS We included 16 cases with DAC, 21 with TAC, and 331 controls. For DAC, lower frequencies of IBD-relapses were associated with an increased risk of cancer (OR 0.2 [95% CI: 0.04-0.8]). For TAC, we found an increased risk in patients receiving thiopurines at any point during the follow-up period (aOR: 11.7 [95% CI: 2.1-116.2]) and an association with proportion of follow-up time being exposed to thiopurines (aOR 5.6 [95% CI: 1.1-31.5]). CONCLUSIONS In this nation-wide study, covering all pIBD patients from Denmark and Finland, we found that pIBD patients treated with thiopurines had an increased risk of TAC.
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Affiliation(s)
- Mikkel Malham
- From the Department of Paediatric and Adolescence Medicine, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- the Copenhagen Centre for Inflammatory Bowel Disease in Children, Adolescents and Adults, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- the Department of Paediatric and Adolescence Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Sabine Jansson
- From the Department of Paediatric and Adolescence Medicine, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- the Copenhagen Centre for Inflammatory Bowel Disease in Children, Adolescents and Adults, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | - Petter Malmborg
- Sachs' Children and Youth Hospital, Stockholm, Sweden
- the Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Ola Olén
- Sachs' Children and Youth Hospital, Stockholm, Sweden
- the Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Anders Paerregaard
- From the Department of Paediatric and Adolescence Medicine, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- the Copenhagen Centre for Inflammatory Bowel Disease in Children, Adolescents and Adults, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | - Lauri J Virta
- the Research Department, Social Insurance Institution of Finland, Turku, Finland
| | - Christian Jakobsen
- From the Department of Paediatric and Adolescence Medicine, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- the Copenhagen Centre for Inflammatory Bowel Disease in Children, Adolescents and Adults, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | - Kaija-Leena Kolho
- Children's Hospital, Helsinki University Hospital, Helsinki, Finland
| | - Vibeke Wewer
- From the Department of Paediatric and Adolescence Medicine, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- the Copenhagen Centre for Inflammatory Bowel Disease in Children, Adolescents and Adults, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
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10
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Puolanne AM, Qadri S, Vesterinen T, Hiltunen S, Mustonen A, Kurki S, Kolho KL, Arola J, Färkkilä M. Can dysplasia surveillance be better targeted in ulcerative colitis by using faecal calprotectin? Scand J Gastroenterol 2022; 57:1304-1311. [PMID: 35697499 DOI: 10.1080/00365521.2022.2084345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Background: In the inflammatory bowel diseases, chronic inflammation predisposes to dysplasia and colorectal carcinoma, leading to the need of surveillance colonoscopies. The most-used marker of colonic inflammation is faecal calprotectin. Its correlation with endoscopic and histological findings is well-documented. In this study, we evaluated the role of sequential faecal calprotectin measurements in predicting colorectal dysplasia, to identify patients with increased risk of dysplasia or colonic malignancy in ulcerative colitis.Methods: We collected the faecal calprotectin measurements and colorectal histology reports of patients with ulcerative colitis treated in Helsinki University Hospital (Helsinki, Finland) between 2007 and 2017, with a focus on IBD-associated neoplasia, inflammatory activity, and sporadic adenomas. Using the time-weighted AUC of faecal calprotectin as a marker of inflammatory burden, we tested the performance of faecal calprotectin to predict the risk for colorectal neoplasia.Results: In total, 982 patients with ulcerative colitis were included. Of them, 845 had pancolitis and 127 concomitant primary sclerosing cholangitis. Forty-one patients (4%) had IBD-associated colorectal dysplasia and seven (0.7%) developed adenocarcinoma. In patients with constantly elevated faecal calprotectin level (>500 µg/g), colorectal neoplasia was more frequent compared to those with low (<200 µg/g) calprotectin (13% and 4%, p < 0.05). Histological inflammatory activity was also related to more frequent dysplastic changes.Conclusions: Colon dysplasia and adenocarcinoma are more common among ulcerative colitis patients with constantly elevated faecal calprotectin than in patients in remission. The role of inflammatory activity in inducing neoplastic changes in colon is further supported by histology, as histological inflammatory activity correlates with dysplasia.
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Affiliation(s)
- Anna-Maija Puolanne
- Department of Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Sami Qadri
- Department of Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Tiina Vesterinen
- Department of Pathology, HUS Diagnostic Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Saara Hiltunen
- BCB Medical Ltd., Data Analyst, Data and Analytics, Espoo, Finland
| | - Aaro Mustonen
- BCB Medical Ltd., Real World Data Manager, Life Science, Scientific Medical Content and Project Management, Espoo, Finland
| | - Samu Kurki
- Institute for Molecular Medicine FIMM, University of Helsinki and Abdominal Centre, Endocrinology, Helsinki University Hospital, Helsinki, Finland
| | - Kaija-Leena Kolho
- Children's Hospital, Helsinki University and Helsinki University Hospital, Helsinki, Finland.,Tampere University, Tampere, Finland
| | - Johanna Arola
- Department of Pathology, HUS Diagnostic Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Martti Färkkilä
- Department of Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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11
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Colorectal Cancer in Ulcerative Colitis: Mechanisms, Surveillance and Chemoprevention. Curr Oncol 2022; 29:6091-6114. [PMID: 36135048 PMCID: PMC9498229 DOI: 10.3390/curroncol29090479] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/14/2022] [Accepted: 08/18/2022] [Indexed: 11/17/2022] Open
Abstract
Patients with ulcerative colitis (UC) are at a two- to three-fold increased risk of developing colorectal cancer (CRC) than the general population based on population-based data. UC-CRC has generated a series of clinical problems, which are reflected in its worse prognosis and higher mortality than sporadic CRC. Chronic inflammation is a significant contributor to the development of UC-CRC, so comprehending the relationship between the proinflammatory factors and epithelial cells together with downstream signaling pathways is the core to elucidate the mechanisms involved in developing of CRC. Clinical studies have shown the importance of early prevention, detection and management of CRC in patients with UC, and colonoscopic surveillance at regular intervals with multiple biopsies is considered the most effective way. The use of endoscopy with targeted biopsies of visible lesions has been supported in most populations. In contrast, random biopsies in patients with high-risk characteristics have been suggested during surveillance. Some of the agents used to treat UC are chemopreventive, the effects of which will be examined in cancers in UC in a population-based setting. In this review, we outline the current state of potential risk factors and chemopreventive recommendations in UC-CRC, with a specific focus on the proinflammatory mechanisms in promoting CRC and evidence for personalized surveillance.
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12
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Role of a mixed probiotic product, VSL#3, in the prevention and treatment of colorectal cancer. Eur J Pharmacol 2022; 930:175152. [PMID: 35835181 DOI: 10.1016/j.ejphar.2022.175152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/03/2022] [Accepted: 07/07/2022] [Indexed: 12/09/2022]
Abstract
Colorectal cancer (CRC) is a multifactorial disease. The incidence of this type of cancer in younger patients has increased in recent years, and more strategies are needed to prevent and delay the progression of CRC. Probiotics play an adjunctive role in the prevention and treatment of CRC and can not only prevent the onset and delay the progression of disease but also reduce the side effects after the application of anti-cancer drugs. The anti-cancer effect of individual probiotics has been extensively studied, and the exact curative effect of various probiotics has been found, but the anti-cancer effect of mixed probiotics is still not well summarized. In this review, we discuss the positive effects of mixed probiotics on CRC and the related mechanisms of action, especially VSL#3 (VSL Pharmaceuticals, Inc., Gaithersburg, MD, USA), thus providing new ideas for the treatment of CRC. Moreover, we suggest the need to search for more therapeutic possibilities, especially via the research and application of synbiotics and postbiotics.
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13
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Friedberg S, Rubin DT. Intestinal Cancer and Dysplasia in Crohn's Disease. Gastroenterol Clin North Am 2022; 51:369-379. [PMID: 35595420 DOI: 10.1016/j.gtc.2021.12.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Crohn's disease is associated with an increased risk of adenocarcinoma of the involved portions of the small bowel and colorectum and has similar risk factors to those described in ulcerative colitis, most significantly, extent of bowel involvement, PSC, and duration of unresected disease. Prevention strategies include risk stratification and secondary prevention with colonoscopic screening and surveillance to identify dysplasia or early-stage cancers, with surgery when needed. There is emerging information to suggest that control of inflammation may provide primary prevention of neoplasia, but further studies are required to test this strategy.
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Affiliation(s)
- Scott Friedberg
- University of Chicago Medicine Inflammatory Bowel Disease Center
| | - David T Rubin
- University of Chicago Medicine Inflammatory Bowel Disease Center.
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14
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Hsieh CH, Huang YW, Tsai TF. Oral Conventional Synthetic Disease-Modifying Antirheumatic Drugs with Antineoplastic Potential: a Review. Dermatol Ther (Heidelb) 2022; 12:835-860. [PMID: 35381976 PMCID: PMC9021342 DOI: 10.1007/s13555-022-00713-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Indexed: 01/17/2023] Open
Abstract
There is an increasing trend of malignancy worldwide. Disease-modifying antirheumatic drugs (DMARDs) are the cornerstones for the treatment of immune-mediated inflammatory diseases (IMIDs), but risk of malignancy is a major concern for patients receiving DMARDs. In addition, many IMIDs already carry higher background risks of neoplasms. Recently, the black box warning of malignancies has been added for Janus kinase inhibitors. Also, the use of biologic DMARDs in patients with established malignancies is usually discouraged owing to exclusion of such patients in pivotal studies and, hence, lack of evidence. In contrast, some conventional synthetic DMARDs (csDMARDs) have been reported to show antineoplastic properties and can be beneficial for patients with cancer. Among the csDMARDs, chloroquine and hydroxychloroquine have been the most extensively studied, and methotrexate is an established chemotherapeutic agent. Even cyclosporine A, a well-known drug associated with cancer risk, can potentiate the effect of some chemotherapeutic agents. We review the possible mechanisms behind and clinical evidence of the antineoplastic activities of csDMARDs, including chloroquine and hydroxychloroquine, cyclosporine, leflunomide, mycophenolate mofetil, mycophenolic acid, methotrexate, sulfasalazine, and thiopurines. This knowledge may guide physicians in the choice of csDMARDs for patients with concurrent IMIDs and malignancies.
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Affiliation(s)
- Cho-Hsun Hsieh
- Department of Medical Education, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Wei Huang
- Department of Dermatology, National Taiwan University Hospital, 7 Chung Shan S Rd, Taipei, 10048, Taiwan
| | - Tsen-Fang Tsai
- Department of Dermatology, National Taiwan University Hospital, 7 Chung Shan S Rd, Taipei, 10048, Taiwan. .,Department of Dermatology, National Taiwan University Hospital & National Taiwan University College of Medicine, Taipei, Taiwan.
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15
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Rivera AP, Flores Monar GV, Islam H, Puttagunta SM, Islam R, Kundu S, Jha SB, Sange I. Ulcerative Colitis-Induced Colorectal Carcinoma: A Deleterious Concatenation. Cureus 2022; 14:e22636. [PMID: 35371788 PMCID: PMC8959421 DOI: 10.7759/cureus.22636] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2022] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal ailment that encompasses Crohn's disease (CD) and ulcerative colitis (UC). UC is an idiopathic, chronic inflammatory condition of the colonic mucosa that begins in the rectum and progresses proximally in a continuous way over a portion of the entire colon. Chronic inflammation is linked to cancer, and IBD-related chronic colonic inflammation raises the risk of colorectal cancer. Chronic inflammation has been linked to cancer, and chronic colonic inflammation caused by IBD increases the risk of colorectal cancer (CRC). When CRC arises in people with IBD, unlike sporadic CRC, the lesions are difficult to identify due to mucosal alterations produced by inflammation. The total prevalence of IBD-associated CRC is increasing due to the rapidly increasing frequency of IBD. Screening and surveillance colonoscopy in IBD patients is considered to allow for the early diagnosis of dysplasia and cancer, improving the prognosis of IBD-related CRC by giving patients proactive therapy. This article has reviewed literature pertaining to the mechanisms related to CRC development in UC and its clinical and therapeutic implications.
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Affiliation(s)
- Ana P Rivera
- Research, Universidad Americana (UAM) Facultad de Medicina, Managua, NIC
| | | | - Hamza Islam
- Research, Faisalabad Medical University, Faisalabad, PAK
| | | | - Rabia Islam
- Research, Faisalabad Medical University, Faisalabad, PAK
| | | | | | - Ibrahim Sange
- Research, K. J. Somaiya Medical College, Hospital and Research Center, Mumbai, IND
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16
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Zhang H, Zhang M, Chen X, Guo M, Zhou R, Lv H, Li Y, Tan B, Li J, Xu H, Zheng W, Yang H, Qian J. Risk of malignancy in patients with inflammatory bowel disease: a population-based cohort study from China. Int J Cancer 2022; 150:1770-1778. [PMID: 35037241 DOI: 10.1002/ijc.33932] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/15/2021] [Accepted: 12/22/2021] [Indexed: 11/11/2022]
Abstract
Carcinogenesis is one of major complications for patients with inflammatory bowel disease (IBD) and causes poor prognosis. We aimed to describe cancer incidence in Chinese IBD cohort compared with general population-based cancer registration data and further explore associated risk factors for cancer occurrence in IBD patients. IBD inpatients from January 1998 to January 2018 were included in this study. Patients were followed up from date of IBD diagnosis until either the date of first cancer diagnosis or January 2019. Standardized incidence ratios (SIRs) of overall cancer and site-specific cancers were calculated. A total of 869 UC and 516 CD patients were finally included with median follow-up time of 7 and 5 years respectively. 53 cases developed malignancies. After standardization by age and gender, standardized incidence ratio (SIR) of total cancer occurrence in IBD patients was 1.77 (95%CI, 1.33-2.32). As for UC, digestive cancers (SIR 3.75; 95%CI, 2.29-5.80), thyroid cancer (SIR 10.34; 95%CI, 4.72-19.64) and hematological malignancies (SIR 6.25; 95%CI, 1.68-16.00) had the highest incidence, which were prominent in young and middle-aged patients. Use of steroids, immunosuppressants or infliximab did not present higher risk of malignancies in UC patients. There were no significant difference in cancer risk between CD patients and general population. In conclusion, the increased risks of multiple cancers are particularly prominent in Chinese UC patients and these findings can provide more targeted guidance for cancer monitoring in Chinese IBD patients.
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Affiliation(s)
- Huimin Zhang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mengmeng Zhang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xuanfu Chen
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mingyue Guo
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Runing Zhou
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Lv
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yue Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bei Tan
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ji Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hui Xu
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weiyang Zheng
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiaming Qian
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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17
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Reznicek E, Arfeen M, Shen B, Ghouri YA. Colorectal Dysplasia and Cancer Surveillance in Ulcerative Colitis. Diseases 2021; 9:86. [PMID: 34842672 PMCID: PMC8628786 DOI: 10.3390/diseases9040086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 12/12/2022] Open
Abstract
Ulcerative colitis (UC) is a risk factor for the development of inflammation-associated dysplasia or colitis-associated neoplasia (CAN). This transformation results from chronic inflammation, which induces changes in epithelial proliferation, survival, and migration via the induction of chemokines and cytokines. There are notable differences in genetic mutation profiles between CAN in UC patients and sporadic colorectal cancer in the general population. Colonoscopy is the cornerstone for surveillance and management of dysplasia in these patients. There are several modalities to augment the quality of endoscopy for the better detection of dysplastic or neoplastic lesions, including the use of high-definition white-light exam and image-enhanced colonoscopy, which are described in this review. Clinical practice guidelines regarding surveillance strategies in UC have been put forth by various GI societies, and overall, there is agreement between them except for some differences, which we highlight in this article. These guidelines recommend that endoscopically detected dysplasia, if feasible, should be resected endoscopically. Advanced newer techniques, such as endoscopic mucosal resection and endoscopic submucosal dissection, have been utilized in the treatment of CAN. Surgery has traditionally been the mainstay of treating such advanced lesions, and in cases where endoscopic resection is not feasible, a proctocolectomy, followed by ileal pouch-anal anastomosis, is generally recommended. In this review we summarize the approach to surveillance for cancer and dysplasia in UC. We also highlight management strategies if dysplasia is detected.
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Affiliation(s)
- Emily Reznicek
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri School of Medicine, Columbia, MO 65212, USA
| | - Mohammad Arfeen
- Department of Gastroenterology, Franciscan Health, Olympia Fields, IL 60461, USA
| | - Bo Shen
- Interventional IBD Center, Department of Medicine and Surgery, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York, NY 10032, USA
| | - Yezaz A. Ghouri
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri School of Medicine, Columbia, MO 65212, USA
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18
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Attauabi M, Zhao M, Bendtsen F, Burisch J. Systematic Review with Meta-analysis: The Impact of Co-occurring Immune-mediated Inflammatory Diseases on the Disease Course of Inflammatory Bowel Diseases. Inflamm Bowel Dis 2021; 27:927-939. [PMID: 32628745 DOI: 10.1093/ibd/izaa167] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Patients with inflammatory bowel diseases (IBDs) are at risk of developing a variety of other immune-mediated inflammatory diseases (IMIDs). The influence of co-occurring IMIDs on the disease course of IBD remains unknown. The aim of this study was therefore to conduct a systematic review and meta-analysis of the impact of IMIDs on phenotypic presentation and outcome in patients with IBD. METHODS PubMed and Embase were searched from their earliest records through December 2018 and updated in October 2019 for studies reporting proportions or ratios of IBD-related disease outcomes in patients with and without co-occurring IMIDs. Meta-analyses were performed to estimate summary proportions and risks of the main outcomes. PRISMA guidelines were used, and study quality was assessed according to the Newcastle-Ottawa Scale. RESULTS A total of 93 studies were identified, comprising 16,064 IBD patients with co-occurring IMIDs and 3,451,414 IBD patients without IMIDs. Patients with IBD and co-occurring IMIDs were at increased risk of having extensive colitis or pancolitis (risk ratio, 1.38; 95% Cl, 1.25-1.52; P < 0.01, I2 = 86%) and receiving IBD-related surgeries (risk ratio, 1.17; 95% Cl, 1.01-1.36; P = 0.03; I2 = 85%) compared with patients without IMIDs. Co-occurrence of IMIDs other than primary sclerosing cholangitis in patients with IBD was associated with an increased risk of receiving immunomodulators (risk ratio, 1.15; 95% Cl, 1.06-1.24; P < 0.01; I2 = 60%) and biologic therapies (risk ratio, 1.19; 95% Cl, 1.08-1.32; P < 0.01; I2 = 53%). CONCLUSION This meta-analysis found that the presence of co-occurring IMIDs influences the disease course of IBD, including an increased risk of surgery and its phenotypical expression.
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Affiliation(s)
- Mohamed Attauabi
- Gastrounit, Medical Division, Copenhagen University Hospital, Hvidovre, Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mirabella Zhao
- Gastrounit, Medical Division, Copenhagen University Hospital, Hvidovre, Denmark
| | - Flemming Bendtsen
- Gastrounit, Medical Division, Copenhagen University Hospital, Hvidovre, Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Johan Burisch
- Gastrounit, Medical Division, Copenhagen University Hospital, Hvidovre, Denmark
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19
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Bocchetti M, Ferraro MG, Ricciardiello F, Ottaiano A, Luce A, Cossu AM, Scrima M, Leung WY, Abate M, Stiuso P, Caraglia M, Zappavigna S, Yau TO. The Role of microRNAs in Development of Colitis-Associated Colorectal Cancer. Int J Mol Sci 2021; 22:3967. [PMID: 33921348 PMCID: PMC8068787 DOI: 10.3390/ijms22083967] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/01/2021] [Accepted: 04/08/2021] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is the third most deadly cancer worldwide, and inflammatory bowel disease (IBD) is one of the critical factors in CRC carcinogenesis. IBD is responsible for an unphysiological and sustained chronic inflammation environment favoring the transformation. MicroRNAs (miRNAs) belong to a class of highly conserved short single-stranded segments (18-25 nucleotides) non-coding RNA and have been extensively discussed in both CRC and IBD. However, the role of miRNAs in the development of colitis-associated CRC (CAC) is less clear. The aim of this review is to summarize the major upregulated (miR-18a, miR-19a, miR-21, miR-31, miR-155 and miR-214) and downregulated (miR-124, miR-193a-3p and miR-139-5p) miRNAs in CAC, and their roles in genes' expression modulation in chronic colonic-inflammation-induced carcinogenesis, including programmed cell-death pathways. These miRNAs dysregulation could be applied for early CAC diagnosis, to predict therapy efficacy and for precision treatment.
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Affiliation(s)
- Marco Bocchetti
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
- Biogem Scarl, Molecular Oncology and Precision Medicine Laboratory, via Camporeale, 83031 Ariano Irpino, Italy;
| | - Maria Grazia Ferraro
- Department of Pharmacy, School of Medicine and Surgery, University of Naples “Federico II”, via D. Montesano 49, 80131 Naples, Italy;
| | | | - Alessandro Ottaiano
- SSD-Innovative Therapies for Abdominal Metastases, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy;
| | - Amalia Luce
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
- School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
| | - Alessia Maria Cossu
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
- Biogem Scarl, Molecular Oncology and Precision Medicine Laboratory, via Camporeale, 83031 Ariano Irpino, Italy;
| | - Marianna Scrima
- Biogem Scarl, Molecular Oncology and Precision Medicine Laboratory, via Camporeale, 83031 Ariano Irpino, Italy;
| | - Wing-Yan Leung
- Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China;
| | - Marianna Abate
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
| | - Paola Stiuso
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
- Biogem Scarl, Molecular Oncology and Precision Medicine Laboratory, via Camporeale, 83031 Ariano Irpino, Italy;
| | - Silvia Zappavigna
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
| | - Tung On Yau
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
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20
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Mackiewicz T, Sowa A, Fichna J. Biomarkers for Early Detection of Colitis-associated Colorectal Cancer - Current Concepts, Future Trends. Curr Drug Targets 2021; 22:137-145. [PMID: 32077822 DOI: 10.2174/1389450121666200220123844] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 12/20/2019] [Accepted: 01/29/2020] [Indexed: 02/08/2023]
Abstract
Colitis-associated colorectal cancer (CAC) remains a critical complication of ulcerative colitis (UC) with a mortality of approximately 15%, which makes early CAC diagnosis crucial. The current standard of surveillance, with repetitive colonoscopies and histological testing of biopsied mucosa samples, is burdensome and expensive, and therefore less invasive methods and reliable biomarkers are needed. Significant progress has been made, thanks to continuous extensive research in this field, however, no clinically relevant biomarker has been established so far. This review of the current literature presents the genetic and molecular differences between CAC and sporadic colorectal cancer and covers progress made in the early detection of CAC carcinogenesis. It focuses on biomarkers under development, which can easily be tested in samples of body fluids or breath and, once made clinically available, will help to differentiate between progressors (UC patients who will develop dysplasia) from non-progressors and enable early intervention to decrease the risk of cancer development.
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Affiliation(s)
- Tomasz Mackiewicz
- Department Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | | | - Jakub Fichna
- Department Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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21
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Shah SC, Itzkowitz SH. Reappraising Risk Factors for Inflammatory Bowel Disease-associated Neoplasia: Implications for Colonoscopic Surveillance in IBD. J Crohns Colitis 2020; 14:1172-1177. [PMID: 32150256 DOI: 10.1093/ecco-jcc/jjaa040] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
One of the most feared complications of inflammatory bowel disease [IBD]-associated colitis is colorectal cancer. When considering the substantial increase in the prevalence of IBD, without any anticipated decline, coupled with decreasing colectomy rates for dysplasia and expanding medical options for effectively controlling inflammation, it is predicted that the pool of people living with-and ageing with-colonic IBD, who are recommended to undergo lifelong colonoscopic surveillance for colorectal neoplasia, will strain existing resources and challenge the sustainability of current guideline-based surveillance recommendations. At the same time, we are missing the opportunity for early detection in a group that is overlooked as high-risk, as a substantial proportion of colorectal cancers are being diagnosed in individuals with colonic IBD who have disease duration shorter than when guidelines recommend surveillance initiation. Here, we reappraise: 1] inflammation as a dynamic risk factor that considers patients' cumulative course; 2] time of screening initiation that is not based primarily on absolute disease duration; and 3] surveillance intervals as an iterative determination based on individual patient factors and consecutive colonoscopic findings. This Viewpoint supports a paradigm shift that will ideally result in a more effective and higher-value colorectal cancer prevention approach in IBD.
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Affiliation(s)
- Shailja C Shah
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Steven H Itzkowitz
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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22
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Hu AB, Burke KE, Kochar B, Ananthakrishnan AN. Yield of Random Biopsies During Colonoscopies in Inflammatory Bowel Disease Patients Undergoing Dysplasia Surveillance. Inflamm Bowel Dis 2020; 27:779-786. [PMID: 32812048 PMCID: PMC8128394 DOI: 10.1093/ibd/izaa205] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND The development of chromoendoscopy (CE) and high definition endoscopy (HDE) has improved detection of subtle colonic dysplasia in patients with inflammatory bowel diseases (IBDs). The role of random biopsies for dysplasia surveillance is unclear. METHODS We reviewed patients with IBD who underwent a CE or HDE colonoscopy and had colonic dysplasia detected. Detection of dysplasia was classified as either visible or random and graded as low grade dysplasia (LGD), high grade dysplasia (HGD), or indefinite for dysplasia. Multivariable regression adjusted for relevant confounders examined the predictors of dysplasia detectable on random biopsies alone. RESULTS The study included 300 patients (203 ulcerative colitis, 97 Crohn's disease with colonic involvement) contributing 442 colonoscopies; the mean disease duration was 24.5 years; 7.2% had primary sclerosing cholangitis (PSC). Three hundred sixty-two colonoscopies (82%) had only visible dysplasia, 52 (12%) had only random dysplasia, and 28 (6%) had both visible and random dysplasia. Longer disease duration (odds ratio, 1.04; 95% CI, 1.01-1.07), active inflammation (odds ratio, 2.89; 95% CI, 1.26-6.67), and concomitant PSC (odds ratio, 3.66; 95% CI, 1.21-11.08) were associated with detecting dysplasia on random biopsies compared with visible lesions. Patients with random dysplasia (21%) or both random and visible dysplasia (21%) were more likely to undergo surgical resection compared with those with only visible dysplasia (5%; P < 0.001) and have subsequent development of colorectal cancer (15%, 7%, 1%, respectively; P < 0.0001). CONCLUSION Nearly one fifth of dysplasia detected in patients with IBD was found on random biopsies. Patients with high risk characteristics may benefit from continuing the practice of random biopsies during surveillance examinations.
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Affiliation(s)
- Anne B Hu
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA,Harvard Medical School, Boston, MA, USA
| | - Kristin E Burke
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA,Harvard Medical School, Boston, MA, USA
| | - Bharati Kochar
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA,Harvard Medical School, Boston, MA, USA
| | - Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA,Harvard Medical School, Boston, MA, USA,Address correspondence to Ashwin N. Ananthakrishnan, MD, MPH, Massachusetts General Hospital Crohn’s and Colitis Center, 165 Cambridge Street, 9th Floor, Boston, MA 02114, USA. E-mail:
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23
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Risk of Development of More-advanced Lesions in Patients With Inflammatory Bowel Diseases and Dysplasia. Clin Gastroenterol Hepatol 2020; 18:1528-1536.e5. [PMID: 31202983 DOI: 10.1016/j.cgh.2019.05.062] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 04/30/2019] [Accepted: 05/29/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Patients with inflammatory bowel diseases (IBD) have increased risks of dysplasia and colitis-associated cancer (CAC). We evaluated the risk of development of high-grade dysplasia (HGD) or CAC after diagnosis of dysplasia using data from a national cohort of patients with IBD. METHODS We performed a multicenter retrospective analysis of data collected from 7 tertiary referral regional or academic centers in Belgium. In searches of IBD pathology databases, we identified 813 lesions (616 low-grade dysplasias [LGDs], 64 high-grade dysplasias [HGDs], and 133 CACs) in 410 patients with IBD: 299 had dysplasia (73%) and 111 had CAC (27%). The primary aim was to determine the risk of more-advanced lesions after diagnosis of LGD or HGD. RESULTS Of the 287 patients with LGD, 21 (7%) developed more-advanced lesions (HGD or CAC) after a median time period of 86 months (interquartile range, 34-214). Of the 28 patients with HGD, 4 (14%) developed CAC after a median time period of 180 months (interquartile range, 23-444). The overall cumulative incidence of CAC at 10 years after an initial diagnosis of HGD was 24.3% and after an initial diagnosis of LGD was 8.5% (P < .05). Metachronous lesions, non-polypoid lesions, and colonic stricture were associated with risk of occurrence of more-advanced lesions after LGD (P < .05). Of the 630 dysplastic lesions identified during endoscopy, 545 (86%) were removed during the same procedure or during a follow-up endoscopy or by surgery. Of 111 patients with CAC, 95 (86%) did not have prior detection of dysplasia and 64 of these 95 patients (67%) developed CAC outside of the screening or surveillance period recommended by the European Crohn's and Colitis Organisation. CONCLUSIONS In an analysis of pathology data from 7 medical centers in Belgium, we found a low rate of detection of more-advanced lesions following detection of LGD or HGD-taking into account that most of the lesions were removed. Main risk factors for development of more-advanced lesions after LGD were metachronous lesions, non-polypoid lesions, and colon strictures.
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24
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Bodén S, Myte R, Harbs J, Sundkvist A, Zingmark C, Löfgren Burström A, Palmqvist R, Harlid S, Van Guelpen B. C-reactive Protein and Future Risk of Clinical and Molecular Subtypes of Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 2020; 29:1482-1491. [PMID: 32317300 DOI: 10.1158/1055-9965.epi-19-1339] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 01/27/2020] [Accepted: 04/17/2020] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Inflammation has been implicated in colorectal cancer etiology, but the relationship between C-reactive protein (CRP) and colorectal cancer risk is unclear. We aimed to investigate the association between prediagnostic plasma CRP concentrations and the risk of clinical and molecular colorectal cancer subtypes. METHODS We used prospectively collected samples from 1,010 matched colorectal cancer case-control pairs from two population-based cohorts in Northern Sweden, including 259 with repeated samples. Conditional logistic regression and linear mixed models were used to estimate relative risks of colorectal cancer, including subtypes based on BRAF and KRAS mutations, microsatellite instability status, tumor location, stage, lag time, and (using unconditional logistic regression) body mass index. RESULTS CRP was not associated with colorectal cancer risk, regardless of clinical or molecular colorectal cancer subtype. For participants with advanced tumors and blood samples <5 years before diagnosis, CRP was associated with higher risk [OR per 1 unit increase in natural logarithm (ln) transformed CRP, 1.32; 95% confidence interval (CI), 1.01-1.73]. CRP levels increased over time, but average time trajectories were similar for cases and controls (P interaction = 0.19). CONCLUSIONS Our results do not support intertumoral heterogeneity as an explanation for previous inconsistent findings regarding the role of CRP in colorectal cancer etiology. The possible association in the subgroup with advanced tumors and shorter follow-up likely reflects undiagnosed cancer at baseline. IMPACT Future efforts to establish the putative role of chronic, low-grade inflammation in colorectal cancer development will need to address the complex relationship between systemic inflammatory factors and tumor microenvironment, and might consider larger biomarker panels than CRP alone.
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Affiliation(s)
- Stina Bodén
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
| | - Robin Myte
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Justin Harbs
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Anneli Sundkvist
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Carl Zingmark
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | | | - Richard Palmqvist
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
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25
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Yvellez OV, Rai V, Sossenheimer PH, Hart J, Turner JR, Weber C, El Jurdi K, Rubin DT. Cumulative Histologic Inflammation Predicts Colorectal Neoplasia in Ulcerative Colitis: A Validation Study. Inflamm Bowel Dis 2020; 27:203-206. [PMID: 32152624 PMCID: PMC7813748 DOI: 10.1093/ibd/izaa047] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Indexed: 01/31/2023]
Abstract
BACKGROUND Chronic inflammation in ulcerative colitis (UC) is associated with the development of colorectal neoplasia (CRN). A group at St. Mark's Hospital reported a novel cumulative inflammatory index that predicted the development of CRN in UC patients that we validated with an independent, well-described, matched, case-controlled cohort from the University of Chicago. METHODS Cumulative inflammatory burden (CIB) was calculated by summing each histological inflammatory activity (HIA) score and multiplying it by the length of the surveillance interval. Persistency was defined by the number of surveillance episodes (with a severity score >2) divided by the total number of surveillance procedures. T tests compared the mean and maximum HIA scores, assessing mean and maximum severity, CIB, and persistency. RESULTS Sixty-two UC patients (26 patients with CRN, 36 control patients without CRN) were analyzed. Fifty-five percent were men, mean disease duration was 20.6 years, and mean age at CRN diagnosis was 43.9. Of the CRN patients, 6 (23%) had colorectal cancer, 16 (62%) had low-grade dysplasia, and 4 (15%) had indefinite dysplasia. Using mean HIA scores, we found CIB to be statistically greater in CRN patients (P = 0.04). Using maximum HIA scores, we found CIB (P = 0.02), mean severity (P = 0.03), and persistency (P = 0.01) to be significantly greater in CRN patients. Maximum severity was numerically greater for mean and maximum HIA scores but did not reach significance. CONCLUSION Cumulative histologic inflammation is significantly associated with the development of CRN in UC patients. This suggests a management strategy of controlling inflammation to reduce the risk of CRN and may influence the selection of surveillance intervals.
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Affiliation(s)
- Olivia V Yvellez
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Victoria Rai
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Philip H Sossenheimer
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - John Hart
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Jerrold R Turner
- Brigham and Women’s Hospital, Pathology, Boston, Massachusetts, USA
| | - Christopher Weber
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Katia El Jurdi
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - David T Rubin
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA,Address correspondence to: David T. Rubin, MD, 5841 South Maryland Avenue, MC 4076, Chicago, IL 60637 ()
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26
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Abstract
In recent years, the therapeutic goals in ulcerative colitis (UC) have become increasingly stringent. Histological features seem to be a reliable predictor of disease outcomes after therapy, and histological remission (HR) is the new frontier in the treatment of UC. Here, we first provide a historical perspective before reviewing indexes in the era of biologics; histology as a treatment goal in UC trials; the poor correlation between symptoms, endoscopy, and histology; and the impact of histology on disease outcomes. HR seems to be a promising end point for the treatment of UC because it is typically associated with better outcomes. Two new validated indexes are available to assess histology more accurately in trials, and they may also be applicable to clinical practice. Additional interventional trials are now necessary to establish definitions of HR and its potential for disease modification.
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27
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Tranter-Entwistle I, Mullaney TG, Noah K, Pearson J, Falvey J, Gearry R, Eglinton T. Long-term incidence of dysplasia and colorectal cancer in an ulcerative colitis population-based cohort. ANZ J Surg 2020; 90:821-825. [PMID: 31970885 DOI: 10.1111/ans.15686] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/14/2019] [Accepted: 12/25/2019] [Indexed: 01/08/2023]
Abstract
BACKGROUND Ulcerative colitis (UC) is a risk factor in developing colorectal cancer (CRC). Surveillance programmes aim to identify premalignant lesions to facilitate improved treatment outcomes. Recent studies have suggested that the risk of CRC in UC has decreased. This study aims to characterize the risk of CRC in UC in a population-based New Zealand cohort. METHODS All patients in the Canterbury Inflammatory Bowel Disease Study, a comprehensive population-based cohort, were reviewed and cases of dysplasia and CRC identified. Demographic data and risk factors were assessed and standardized incidence ratios (SIRs) calculated comparing with the national population. RESULTS A total of 518 UC cases were analysed (46.3% female). Median follow-up was 17.5 years (interquartile range 12.2-25.1 years). Neoplasia developed in 42 (8.1%) patients, 14 (2.7%) of whom had CRC. The mean age at CRC diagnosis was 63.3 years, and mean duration with UC before CRC 18.4 years (0-36.8 years). The total incidence rate was 1.35/1000 person-year duration (95% confidence interval 0.74-2.27). The age-adjusted SIR was 1.74 (95% confidence interval 1.03-2.93) compared to the New Zealand population. Risk factors for any dysplasia included disease extent and male gender. CONCLUSION In this population-based cohort with long-term follow-up, the SIR of CRC in UC patients was significantly lower than the initial epidemiological studies although similar to more recent studies. This increased risk still justifies ongoing screening in the UC population.
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Affiliation(s)
| | - Tamara G Mullaney
- Department of General Surgery, Christchurch Hospital, Christchurch, New Zealand.,Department of Surgery, Otago Medical School, University of Otago, Christchurch, New Zealand
| | - Kimberley Noah
- Department of General Surgery, Christchurch Hospital, Christchurch, New Zealand
| | - John Pearson
- Department of Population Health, Otago Medical School, University of Otago, Christchurch, New Zealand
| | - James Falvey
- Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
| | - Richard Gearry
- Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
| | - Tim Eglinton
- Department of General Surgery, Christchurch Hospital, Christchurch, New Zealand.,Department of Surgery, Otago Medical School, University of Otago, Christchurch, New Zealand
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28
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Tenca A, Jaakkola T, Färkkilä M, Arola J, Kolho KL. Impact of paediatric onset primary sclerosing cholangitis on clinical course and outcome of inflammatory bowel disease: a case-control population-based study in Finland. Scand J Gastroenterol 2019; 54:984-990. [PMID: 31402720 DOI: 10.1080/00365521.2019.1648547] [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] [Indexed: 02/04/2023]
Abstract
Introduction and aim: The aim of this study was to investigate the outcome of a paediatric onset of inflammatory bowel disease (IBD) in a cohort of subjects with primary sclerosing cholangitis (PSC) and in a matched-age population-based control group without PSC. Methods: We identified 28 IBD-PSC cases (median age at IBD diagnosis 12.5 years, 25-75th: 10-16 years) and selected three IBD controls for each case matched for age and year of IBD diagnosis. All data regarding the gastrointestinal tract and liver were collected at diagnosis and at last follow-up (median 15 years). Results: At diagnosis the prevalence of pancolitis was similar between the groups (78% and 79%, respectively p = -.30), but histologic inflammation was milder in IBD-PSC (61% vs 30%, p = .06). At last follow-up (median age 29 years) pancolitis was less frequent (6% and 33%, respectively p = .04) and the remission higher (76% and 47%, respectively p = .08) in IBD-PSC patients than in IBD patients. Panproctolectomy (32% in IBD-PSC and 34% in IBD, p = 1.0) and the rate of pouchitis (62% and 70%, respectively p = .8) were similar. Conclusions: The outcome of paediatric onset IBD in patients with PSC in adulthood seems to be comparable to those with IBD only.
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Affiliation(s)
- Andrea Tenca
- Department of Medicine, Clinic of Gastroenterology, University of Helsinki and Helsinki University Hospital , Helsinki , Finland
| | - Tytti Jaakkola
- Department of Pediatric Gastroenterology, University of Helsinki and Children's Hospital , Helsinki , Finland
| | - Martti Färkkilä
- Department of Medicine, Clinic of Gastroenterology, University of Helsinki and Helsinki University Hospital , Helsinki , Finland
| | - Johanna Arola
- Department of Pathology, Helsinki University and Helsinki University Hospital , Helsinki , Finland
| | - Kaija-Leena Kolho
- Department of Pediatric Gastroenterology, University of Helsinki and Children's Hospital , Helsinki , Finland
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29
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Shah SC, Itzkowitz SH. Management of Inflammatory Bowel Disease-Associated Dysplasia in the Modern Era. Gastrointest Endosc Clin N Am 2019; 29:531-548. [PMID: 31078251 PMCID: PMC7354094 DOI: 10.1016/j.giec.2019.02.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This article begins with a brief overview of risk factors for colorectal neoplasia in inflammatory bowel disease to concretize the approach to risk stratification. It then provides an up-to-date review of diagnosis and management of dysplasia in inflammatory bowel disease, which integrates new and emerging data in the field. This is particularly relevant in an era of increased attention to cost- and resource-containment from the health systems vantage point, coupled with a heightened prioritization of patient quality of life and shared decision-making. Also provided is a brief discussion of the status of newer therapeutic techniques, such as endoscopic submucosal dissection.
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Affiliation(s)
- Shailja C. Shah
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Steven H. Itzkowitz
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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30
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Shin SA, Moon SY, Park D, Park JB, Lee CS. Apoptotic cell clearance in the tumor microenvironment: a potential cancer therapeutic target. Arch Pharm Res 2019; 42:658-671. [PMID: 31243646 DOI: 10.1007/s12272-019-01169-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 06/06/2019] [Indexed: 12/14/2022]
Abstract
Millions of cells in the human body undergo apoptosis not only under normal physiological conditions but also under pathological conditions such as infection or other diseases related to acute tissue injury. Swift apoptotic cell clearance is essential for tissue homeostasis. Defective clearance of dead cells is linked to pathogenesis of diseases such as inflammatory diseases, atherosclerosis, neurological disease, and cancer. Significance of apoptotic cell clearance has been emerging as an interesting field for disease treatment. Efficient apoptotic cell clearance plays an important role in reducing inflammation through the suppression of inappropriate inflammatory responses under healthy and diseased conditions. However, apoptotic cell clearance related to cancer pathogenesis is more complex in tumor microenvironments. Chronic inflammation resulting from the failure of apoptotic cell clearance can contribute to tumor progression. Conversely, tumor cells can exploit the anti-inflammatory effect of apoptotic cell clearance to generate an immunosuppressive tumor microenvironment. In this review, focus is on the current understanding of apoptotic cell clearance in the tumor microenvironment. Furthermore, we discuss how signaling molecules (PtdSer and PtdSer recognition receptor) mediating apoptotic cell clearance are aberrantly expressed in the tumor microenvironment and their current development state as potential therapeutic targets for clinical cancer therapy.
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Affiliation(s)
- Seong-Ah Shin
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Sun Young Moon
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Daeho Park
- School of Life Sciences and Aging Research Institute, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Jong Bae Park
- Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea.,Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea
| | - Chang Sup Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam, 52828, Republic of Korea.
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31
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Kolehmainen S, Lepistö A, Färkkilä M. Impact of anti-TNF-alpha therapy on colectomy rate and indications for colectomy in ulcerative colitis: comparison of two patient cohorts from 2005 to 2007 and from 2014 to 2016 . Scand J Gastroenterol 2019;54:707-711. [PMID: 31136207 DOI: 10.1080/00365521.2019.1620326] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Objectives: The aim of this study is to assess the impact of biological therapy on the colectomy rate and indications for colectomy in ulcerative colitis (UC) at Helsinki University Hospital (HUH) catchment area in Finland. Methods: This study was conducted retrospectively by comparing two cohorts of UC and indeterminate colitis patients that underwent colectomy in a single centre in HUH during the years 2005-2007 and 2014-2016. All patient data were collected from hospital patient records. Results: In 2005-2007 and 2014-2016, respectively, 2.3 and 18.8% of patients had received biological therapy and more specifically 2.3 and 10.5% infliximab within 3 months prior to colectomy. Colectomy rates were 8.6 (7.2-10.2) and 5.1 (4.3-6.1)/1.000 patient-years (p < .001). During 2005-2007 and 2014-2016, the indications for colectomy were: refractory disease 79.1 and 79.7%, dysplasia 16.3 and 12.8%, cancer 2.3 and 3.0% and other reasons 2.3 and 4.5%, respectively. Emergency colectomy covered 8.5 and 9.8% of the operations. Conclusions: In addition to the markedly increased use of biological therapy during the time preceding colectomy, we noticed a significantly decreased rate of surgery but no changes in the indications for colectomy. Biological therapy seems to have had a favourable effect on the colectomy rate. Even so, the main indication for surgery is still a refractory disease, suggesting urgent need for better treatment options.
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Affiliation(s)
- Sara Kolehmainen
- University of Helsinki , Helsinki , Finland.,Department of Gastroenterology, Helsinki University Hospital , Helsinki , Finland
| | - Anna Lepistö
- Department of Colorectal Surgery, Helsinki University Hospital , Helsinki , Finland
| | - Martti Färkkilä
- University of Helsinki , Helsinki , Finland.,Department of Gastroenterology, Helsinki University Hospital , Helsinki , Finland
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32
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Ankathil R, Mustapha MA, Abdul Aziz AA, Mohd Shahpudin SN, Zakaria AD, Abu Hassan MR, Musa KI. Contribution of Genetic Polymorphisms of Inflammation Response Genes on Sporadic Colorectal Cancer Predisposition Risk in Malaysian Patients - A Case Control Study. Asian Pac J Cancer Prev 2019; 20:1621-1632. [PMID: 31244280 PMCID: PMC7021613 DOI: 10.31557/apjcp.2019.20.6.1621] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 01/26/2019] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate the frequencies and association of polymorphic genotypes of IL-8 -251 T>A, TNF-α -308 G>A, ICAM-1 K469E, ICAM-1 R241G, IL-6 -174 G>C, and PPAR-γ 34 C>G in modulating susceptibility risk in Malaysian colorectal cancer (CRC) patients. Methods: In this case-control study, peripheral blood samples of 560 study subjects (280 CRC patients and 280 controls) were collected, DNA extracted and genotyped using PCR-RFLP and Allele Specific PCR. The association between polymorphic genotype and CRC susceptibility risk was determined using Logistic Regression analysis deriving Odds ratio (OR) and 95% CI. Results: On comparing the frequencies of genotypes of all single nucleotide polymorphisms ( SNPs ) in patients and controls, the homozygous variant genotypes IL-8 -251 AA and TNF-α -308 AA and variant A alleles were significantly higher in CRC patients. Investigation on the association of the variant alleles and genotypes singly, with susceptibility risk showed the homozygous variant A alleles and genotypes IL-8 -251 AA and TNF-α -308 AA to be at higher risk for CRC predisposition. Analysis based on age, gender and smoking habits showed that the polymorphisms IL8 -251 T>A and TNF – α 308 G>A contribute to a significantly higher risk among male and female who are more than 50 years and for smokers in this population. Conclusion: We observed an association between variant allele and genotypes of IL-8-251 T>A and TNF-α-308 G>A polymorphisms and CRC susceptibility risk in Malaysian patients. These two SNPs in inflammatory response genes which undoubtedly contribute to individual risks to CRC susceptibility may be considered as potential genetic predisposition factors for CRC in Malaysian population.
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Affiliation(s)
- Ravindran Ankathil
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia.
| | - Mohd Aminudin Mustapha
- Center of Pre University Study, Universiti Malaysia Sarawak, Kota Samarahan, Sarawak, Malaysia
| | - Ahmad Aizat Abdul Aziz
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia.
| | - Siti Nurfatimah Mohd Shahpudin
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia.
| | - Andee Dzulkarnaen Zakaria
- Department of Surgery, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
| | | | - Kamarul Imran Musa
- Department of Community Medicine, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
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Shah SC, Glass J, Giustino G, Hove JRT, Castaneda D, Torres J, Kumar A, Elman J, Ullman TA, Itzkowitz SH. Statin Exposure Is Not Associated with Reduced Prevalence of Colorectal Neoplasia in Patients with Inflammatory Bowel Disease. Gut Liver 2019; 13:54-61. [PMID: 30400722 PMCID: PMC6346999 DOI: 10.5009/gnl18178] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/29/2018] [Accepted: 07/07/2018] [Indexed: 12/21/2022] Open
Abstract
Background/Aims Statins have been postulated to lower the risk of colorectal neoplasia. No studies have examined any possible chemopreventive effect of statins in patients with inflammatory bowel disease (IBD) undergoing colorectal cancer (CRC) surveillance. This study examined the association of statin exposure with dysplasia and CRC in patients with IBD undergoing dysplasia surveillance colonoscopies. Methods A cohort of patients with IBD undergoing colonoscopic surveillance for dysplasia and CRC at a single academic medical center were studied. The inclusion criteria were IBD involving the colon for 8 years (or any colitis duration if associated with primary sclerosing cholangitis [PSC]) and at least two colonoscopic surveillance exams. The exclusion criteria were CRC or high-grade dysplasia (HGD) prior to or at enrollment, prior colectomy, or limited (<30%) colonic disease. The primary outcome was the frequency of dysplasia and/or CRC in statin-exposed versus nonexposed patients. Results A total of 642 patients met the inclusion criteria (57 statin-exposed and 585 nonexposed). The statin-exposed group had a longer IBD duration, longer follow-up period, and more colonoscopies but lower inflammatory scores, less frequent PSC and less use of thiopurines and biologics. There were no differences in low-grade dysplasia, HGD, or CRC development during the follow-up period between the statin-exposed and nonexposed groups (21.1%, 5.3%, 1.8% vs 19.2%, 2.9%, 2.9%, respectively). Propensity score analysis did not alter the overall findings. Conclusions In IBD patients undergoing surveillance colonoscopies, statin use was not associated with reduced dysplasia or CRC rates. The role of statins as chemopreventive agents in IBD remains controversial.
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Affiliation(s)
- Shailja C Shah
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA.,The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jason Glass
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Gennaro Giustino
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joren R Ten Hove
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Daniel Castaneda
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joana Torres
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Gastroenterology, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - Akash Kumar
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jordan Elman
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Thomas A Ullman
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Steven H Itzkowitz
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Wu XR, Zheng XB, Huang Y, Cao Q, Zhang HJ, Miao YL, Zou KF, Chen M, Zhang FM, Mei Q, Gonzalo D, Allende D, Hu PJ, Shen B, Liu XL, Lan P. Risk factors for colorectal neoplasia in patients with underlying inflammatory bowel disease: a multicenter study. Gastroenterol Rep (Oxf) 2019; 7:67-73. [PMID: 30792868 PMCID: PMC6375343 DOI: 10.1093/gastro/goy039] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 07/14/2018] [Accepted: 08/13/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND This study sought to evaluate the risk factors for the development of colitis-associated neoplasia (CAN) in Chinese patients with inflammatory bowel disease (IBD). METHODS IBD patients who developed CAN between 1999 and 2016 were identified from eight medical centers. In addition to initial pathology evaluation, a CAN diagnosis was confirmed by two expert pathologists. Patients with CAN (n = 29) were compared with non-CAN controls (n = 87). Matching was performed for gender and IBD type with a ratio of three controls to one subject. RESULTS Of the 29 patients with CAN, 8 (27.6%) had colorectal cancer (CRC), 20 (69.0%) had a final diagnosis of low-grade dysplasia and 1 (3.4%) had high-grade dysplasia. Multivariate analysis revealed that an older age at the time of IBD diagnosis and a longer IBD duration were independent risk factors for the development of CAN, with odds ratios of 1.09 [95% confidence interval (CI): 1.04-1.14, P < 0.001] and 1.14 (95% CI: 1.03-1.27, P = 0.013), respectively. Comparison between IBD patients with CRC and those with dysplasia indicated that the former were older at the time of IBD diagnosis (P = 0.012) and had longer IBD durations (P = 0.019). CONCLUSIONS Older age at the time of IBD diagnosis and longer IBD duration were found to be associated with the development of CAN in IBD patients.
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Affiliation(s)
- Xian-Rui Wu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiao-Bin Zheng
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yan Huang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Department of Pathology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Hong-Jie Zhang
- Department of Gastroenterology, Jiangsu Province Hospital, Nanjing, China
| | - Ying-Lei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Kai-Fang Zou
- Department of Gastroenterology, Wuhan Union Hospital, Wuhan, China
| | - Min Chen
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Fa-Ming Zhang
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qiao Mei
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - David Gonzalo
- Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Daniela Allende
- Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Pin-Jin Hu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Bo Shen
- Department of Gastroenterology/Hepatology, The Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Xiu-Li Liu
- Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Ping Lan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
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Wang F, Song ZY, Qu XJ, Li F, Zhang L, Li WB, Cui SX. M10, a novel derivative of Myricetin, prevents ulcerative colitis and colorectal tumor through attenuating robust endoplasmic reticulum stress. Carcinogenesis 2019; 39:889-899. [PMID: 29757351 DOI: 10.1093/carcin/bgy057] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 05/08/2018] [Indexed: 12/15/2022] Open
Abstract
Chronic gut inflammation disposes to an increased risk of colitis-associated cancer. Chemoprevention is an attractive complementary strategy. We aimed to evaluate the chemopreventive effects of M10, a novel derivative of Myricetin, in the murine azoxymethane/dextran sodium sulfate model. Oral administration of M10 at 50-100 mg/kg once a day for consecutive 12 weeks significantly prevented ulcerative colitis (UC) and colorectal tumor. Pathological analysis of intestines showed that M10 reduced the degree of chronic inflammation and prevented the progression of colorectal tumorigenesis. Flow cytometry analysis of the immunocytes isolated from intraepithelial and lamina propria showed that M10 prevented the infiltration of myeloid-derived suppressor cells and increased CD8+T and CD4+T cells in colorectal tissues. Enzyme-linked immunosorbent analysis revealed the reduction of pro-inflammatory mediators granulocyte-macrophage colony-stimulating factor/macrophage colony-stimulating factor, IL-6 and TNF-α in colonic mucosa. Western blot assay also showed M10 prevention of the NF-κB/IL-6/STAT3 pathways and the biomarkers of inflammation and colorectal tumorigenesis. Electron microscopy analysis revealed that M10 prevent robust endoplasmic reticulum (ER) stress-induced autophagy in inflamed colonic mucosal cells. In conclusion, oral administration of Myricetin derivative M10 exerts chemoprevention of UC and colorectal tumor in mice. The mechanism of chemoprevention is associated with the reduction of biomarkers of chronic inflammation and proliferation through attenuating robust ER stress in inflamed colonic mucosal cells. M10 exerts chemoprevention activity without evidence of toxicity in mice. These results justify further evaluation of M10 in clinical trials. M10 could develop a promising regimen in the chemoprevention of colitis and colorectal cancer.
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Affiliation(s)
- Feng Wang
- Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health
| | - Zhi-Yu Song
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xian-Jun Qu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Feng Li
- Department of Medicinal Chemistry, Marine Biomedical Research Institute of Qingdao, Qingdao, China
| | - Liang Zhang
- Department of Medicinal Chemistry, Marine Biomedical Research Institute of Qingdao, Qingdao, China
| | - Wen-Bao Li
- Department of Medicinal Chemistry, Marine Biomedical Research Institute of Qingdao, Qingdao, China
| | - Shu-Xiang Cui
- Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health
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Chen X, Liu R, Liu X, Xu C, Wang X. Protective Role of Coxsackie-Adenovirus Receptor in the Pathogenesis of Inflammatory Bowel Diseases. BIOMED RESEARCH INTERNATIONAL 2018; 2018:7207268. [PMID: 30175139 PMCID: PMC6106915 DOI: 10.1155/2018/7207268] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 05/14/2018] [Accepted: 05/24/2018] [Indexed: 02/06/2023]
Abstract
AIM To investigate the role of Coxsackie-adenovirus receptor (CAR) in inflammatory bowel disease (IBD). BACKGROUND CAR, a type I transmembrane protein with functions in virus attachment, has been shown to be associated with epithelial tight junctions (TJs) and mediates cell adhesion, implying its potential roles in the pathogenesis of IBD. METHODS AND MATERIALS To determine the effect of CAR in IBD using QPCR and Western blotting to determine the expression of CAD in TNF-α induced NCM460 and SW480 cells and IBD tissues compared to control groups. Furthermore, TJs dysregulation, FITC-Dextran permeability assay, qRT-PCR, Western blot, and IF assessed the permeability in CAR overexpressed cells treated with TNF-α. HE, qRT-PCR, Western blot, and IHC assay were used to assess the CAR overexpressed cells whether they have the effect to cure DSS induced ulcerative colitis rat model in vivo. RESULT We found CAR levels in human colon cell lines are significantly downregulated under the treatment of tumor necrosis factor-alpha (TNF-α). Furthermore, overexpression of CAR markedly prevented TNF-α induced inflammatory response, TJs dysregulation, and permeability disruption (FITC-Dextran permeability assay) in cells. Consistent with these findings in vitro, we found that CAR overexpression could suppress gut inflammation, attenuate the downregulation of TJ protein ZO-1 and Occludin, and limit the induction of barrier permeability in a DSS induced ulcerative colitis rat model in vivo. Together, our findings strongly suggest that CAR could protect tight junctions and has an anti-inflammatory effect during the pathogenesis of IBD. Thus CAR may serve as a therapeutic target for the diagnosis and treatment of IBD.
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Affiliation(s)
- Xiong Chen
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha City, Hunan Province, China
| | - Rui Liu
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha City, Hunan Province, China
| | - Xiaoming Liu
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha City, Hunan Province, China
| | - Canxia Xu
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha City, Hunan Province, China
| | - Xiaoyan Wang
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha City, Hunan Province, China
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Zhu Z, Mei Z, Guo Y, Wang G, Wu T, Cui X, Huang Z, Zhu Y, Wen D, Song J, He H, Xu W, Cui L, Liu C. Reduced Risk of Inflammatory Bowel Disease-associated Colorectal Neoplasia with Use of Thiopurines: a Systematic Review and Meta-analysis. J Crohns Colitis 2018; 12:546-558. [PMID: 29370346 DOI: 10.1093/ecco-jcc/jjy006] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 01/15/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS The association between thiopurines and colorectal neoplasia risk remains controversial in inflammatory bowel disease [IBD] patients. We performed a systematic review and meta-analysis examining this association. METHODS A comprehensive search of the PubMed, EMBASE and Cochrane Library databases was performed to identify relevant literature. Random-effects models were applied to calculate the pooled odds ratio [OR] and relative risk [RR] with corresponding 95% confidence intervals [CIs] among case-control and cohort studies. RESULTS Eleven cohort and 16 case-control studies involving 95397 patients were included in this study. Overall, the use of thiopurines was associated with a reduced risk of colorectal neoplasia both in case-control [OR = 0.49, 95% CI: 0.34-0.70] and cohort studies [RR = 0.96, 95% CI: 0.94-0.98]. Moreover, a protective effect of thiopurines against advanced neoplasia [high-grade dysplasia and cancer] [OR = 0.51, 95% CI: 0.31-0.84 for case-control studies; RR = 0.96, 95% CI: 0.94-0.98 for cohort studies] and colorectal cancer [CRC] [OR = 0.56, 95% CI: 0.34-0.93 for case-control studies; RR = 0.96, 95% CI: 0.94-0.98 for cohort studies] was also observed. Furthermore, when the analysis was conducted on patients at a high risk for colorectal neoplasia, the chemopreventive effect was confirmed in patients with long disease duration [> 8 years] but not in those with extensive colitis or primary sclerosing cholangitis. CONCLUSIONS This study demonstrated that thiopurine use was associated with a reduced risk of colorectal neoplasia, advanced neoplasia and CRC in IBD patients, especially those with long disease duration [> 8 years].
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Affiliation(s)
- Zhehui Zhu
- Department of Colon and Rectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Shanghai Colorectal Cancer Research Center, Shanghai, PR China
| | - Zubing Mei
- Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
| | - Yuegui Guo
- Department of Colon and Rectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Shanghai Colorectal Cancer Research Center, Shanghai, PR China
| | - Guanghui Wang
- Department of Colon and Rectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Shanghai Colorectal Cancer Research Center, Shanghai, PR China
| | - Tingyu Wu
- Department of Colon and Rectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Shanghai Colorectal Cancer Research Center, Shanghai, PR China
| | - Ximao Cui
- Department of Colon and Rectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Shanghai Colorectal Cancer Research Center, Shanghai, PR China
| | - Zhenyu Huang
- Shanghai Colorectal Cancer Research Center, Shanghai, PR China
| | - Yilian Zhu
- Department of Colon and Rectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Shanghai Colorectal Cancer Research Center, Shanghai, PR China
| | - Dongpeng Wen
- Department of Colon and Rectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Shanghai Colorectal Cancer Research Center, Shanghai, PR China
| | - Jinglve Song
- Department of Colon and Rectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Shanghai Colorectal Cancer Research Center, Shanghai, PR China
| | - Hailan He
- Department of Colon and Rectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Shanghai Colorectal Cancer Research Center, Shanghai, PR China
| | - Weimin Xu
- Department of Colon and Rectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Shanghai Colorectal Cancer Research Center, Shanghai, PR China
| | - Long Cui
- Department of Colon and Rectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Shanghai Colorectal Cancer Research Center, Shanghai, PR China
| | - Chenying Liu
- Department of Colon and Rectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Shanghai Colorectal Cancer Research Center, Shanghai, PR China
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Tanaka T, Kobunai T, Yamamoto Y, Murono K, Otani K, Yasuda K, Nishikawa T, Kiyomatsu T, Kawai K, Hata K, Nozawa H, Ishihara S, Watanabe T. Increased Copy Number Variation of mtDNA in an Array-based Digital PCR Assay Predicts Ulcerative Colitis-associated Colorectal Cancer. ACTA ACUST UNITED AC 2018; 31:713-718. [PMID: 28652445 DOI: 10.21873/invivo.11119] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Revised: 05/27/2017] [Accepted: 05/29/2017] [Indexed: 01/14/2023]
Abstract
AIM Mitochondrial dysfunction plays a central role in carcinogenesis in numerous cancer-related diseases. We examined the copy number variation of mitochondrial DNA (mtDNA) and the expression of energy-producing genes in relation to ulcerative colitis (UC)-associated carcinogenesis. MATERIALS AND METHODS We studied 17 patients with UC-associated adenocarcinoma (UC-Ca) and 16 without UC-associated adenocarcinoma (UC-nonCa). The copy number of mtDNA in non-dysplastic mucosa in both groups was quantified by an array-based digital polymerase chain reaction (PCR) assay. Simultaneously, gene expression related to mitochondrial energy metabolism was determined by a PCR array. RESULTS We observed a higher copy number of mtDNA in non-dysplastic mucosa in the UC-Ca group compared to the UC-nonCa group (484.2 vs. 747.7 copies/cell, p=0.022). The sensitivity, specificity, positive predictive value, and negative predictive value for the detection of UC-associated adenocarcinoma by mtDNA copy number were 43.8%, 100%, 100%, and 60.9%, respectively. We observed an increased expression of mitochondrial genes related to energy metabolism together with an increased copy number of mtDNA. CONCLUSION Mitochondrial function and its metabolic process play essential roles in UC carcinogenesis and are possible risk markers for the development of colitic cancer.
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Affiliation(s)
- Toshiaki Tanaka
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Takashi Kobunai
- Translational Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Yoko Yamamoto
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Koji Murono
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Kensuke Otani
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Koji Yasuda
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Takeshi Nishikawa
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | | | - Kazushige Kawai
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Keisuke Hata
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Hiroaki Nozawa
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Soichiro Ishihara
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Toshiaki Watanabe
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
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Lightner AL. Segmental Resection versus Total Proctocolectomy for Crohn's Colitis: What is the Best Operation in the Setting of Medically Refractory Disease or Dysplasia? Inflamm Bowel Dis 2018; 24:532-538. [PMID: 29462390 DOI: 10.1093/ibd/izx064] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Indexed: 12/16/2022]
Abstract
Crohn's disease (CD) may affect any part of the gastrointestinal tract. When isolated to the colon, and patients become medically refractory, there are several surgical options - segmental resection, subtotal colectomy with ileorectal anastomosis, or a total proctocolectomy and end ileostomy. Unfortunately, surgery does not cure CD, and, regardless of the extent of bowel removed, recurrence may be seen in the small bowel. This may lead to need for further immunosuppression or surgery. Therefore, when appropriate, a segmental colectomy or subtotal colectomy may prevent a permanent ostomy required with a total proctocolectomy. In the setting of dysplasia identified on colonoscopy, low quality evidence guides our treatment paradigms. Even though identification of dysplasia has greatly improved with chromoendoscopy, rates of synchronous or metachronous neoplasm remain high. Thus, a total proctocolectomy and end ileostomy, whereas a larger operation, may be best for the patient to remove all at risk tissue. Further research with prospective or randomized control trials is needed to improve our practice guidelines of both scenarios.
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Affiliation(s)
- Amy L Lightner
- Department of Colon and Rectal Surgery, Mayo Clinic, Rochester MN
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40
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Lu MJ, Qiu XY, Mao XQ, Li XT, Zhang HJ. Systematic review with meta-analysis: thiopurines decrease the risk of colorectal neoplasia in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2018; 47:318-331. [PMID: 29205426 DOI: 10.1111/apt.14436] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 08/26/2017] [Accepted: 11/04/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Patients with inflammatory bowel disease (IBD) have a high risk of developing colorectal neoplasia. AIM To investigate whether thiopurines can decrease the risk of developing colorectal neoplasia in patients with ulcerative colitis (UC) or Crohn's disease (CD). METHODS We conducted a meta-analysis of 24 observational studies involving 76,999 participants to evaluate the risks of developing colorectal neoplasia in IBD patients receiving thiopurine treatment. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for the risks of colorectal neoplasia were calculated using a random-effects model. RESULTS The overall pooled estimate revealed a protective effect of thiopurine use on colorectal neoplasia in patients with IBD (OR = 0.63, 95% CI 0.46-0.86). The effect was significant in UC patients (OR = 0.67, 95% CI 0.45-0.98), but was not significant in CD patients (OR = 1.06, 95% CI 0.54-2.09). Thiopurines exposure significantly decreased the risk of colorectal cancer (CRC) (OR = 0.65, 95% CI 0.45-0.96) and advanced colorectal neoplasia (CRC and/or high-grade dysplasia) (OR = 0.62, 95% CI 0.44-0.89), but did not decrease the risk of dysplasia alone (OR = 0.90, 95% CI 0.37-2.21). Tendencies towards the protective effect of thiopurines were distinct in clinic-based studies (OR = 0.59, 95% CI 0.42-0.82) and case-control studies (OR = 0.40, 95% CI 0.26-0.62), but not in population-based studies (OR = 0.95, 95% CI 0.55-1.62) and cohort studies (OR = 0.98, 95% CI 0.81-1.18). Interestingly, studies conducted in Europe (OR = 0.48, 95% CI 0.31-0.77), rather than in North America (OR = 0.91, 95% CI 0.67-1.24), showed the protective effect of thiopurines. CONCLUSIONS This meta-analysis revealed an antineoplastic effect of thiopurines on colorectal neoplasia in patients with IBD, particularly amongst patients with UC.
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Affiliation(s)
- M J Lu
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - X Y Qiu
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - X Q Mao
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - X T Li
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - H J Zhang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Flores BM, O'Connor A, Moss AC. Impact of mucosal inflammation on risk of colorectal neoplasia in patients with ulcerative colitis: a systematic review and meta-analysis. Gastrointest Endosc 2017; 86:1006-1011.e8. [PMID: 28750838 DOI: 10.1016/j.gie.2017.07.028] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 07/14/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Long-standing ulcerative colitis is an established risk factor for colorectal neoplasia. A number of observational studies have suggested that evidence of mucosal inflammation (endoscopic or histologic) is associated with a greater risk for colorectal neoplasia than is mucosal healing. Our goal was to systematically analyze the risk of colorectal neoplasia in patients with ulcerative colitis who have ongoing mucosal inflammation to better inform surveillance strategies. METHODS We performed a systematic review and meta-analysis of the effect of endoscopic and/or histologic inflammation on the risk of colorectal neoplasia in cohort and case-control studies. Sensitivity analyses for study setting and case definition were performed. RESULTS Six studies met the inclusion criteria, incorporating outcomes in 1443 patients. No study used a single validated measure for mucosal inflammation. The pooled odds ratio for colorectal neoplasia was 3.5 (95% confidence interval [CI], 2.6-4.8; P < .001) in those with any mucosal inflammation and 2.6 (95% CI, 1.5-4.5; P = .01) in those with histologic inflammation, when compared with those with mucosal healing. The overall quality of the studies was good. CONCLUSION The presence of objective evidence of mucosal inflammation during follow-up in patients with ulcerative colitis is associated with a greater risk of subsequent colorectal neoplasia than in those with mucosal healing. This risk factor should be considered in guidelines on surveillance intervals for these patients.
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Affiliation(s)
- Brisas M Flores
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Anthony O'Connor
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, United Kingdom
| | - Alan C Moss
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Olén O, Askling J, Sachs MC, Frumento P, Neovius M, Smedby KE, Ekbom A, Malmborg P, Ludvigsson JF. Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014. BMJ 2017; 358:j3951. [PMID: 28931512 PMCID: PMC5605779 DOI: 10.1136/bmj.j3951] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Objective To assess risk of cancer in patients with childhood onset inflammatory bowel disease in childhood and adulthood.Design Cohort study with matched general population reference individuals using multivariable Cox regression to estimate hazard ratios.Setting Swedish national patient register (both inpatient and non-primary outpatient care) 1964-2014.Participants Incident cases of childhood onset (<18 years) inflammatory bowel disease (n=9405: ulcerative colitis, n=4648; Crohn's disease, n=3768; unclassified, n=989) compared with 92 870 comparators from the general population matched for sex, age, birth year, and county.Main outcome measures Any cancer and cancer types according to the Swedish Cancer Register.Results During follow-up through adulthood (median age at end of follow-up 27 years), 497 (3.3 per 1000 person years) people with childhood onset inflammatory bowel disease had first cancers, compared with 2256 (1.5 per 1000 person years) in the general population comparators (hazard ratio 2.2, 95% confidence interval 2.0 to 2.5). Hazard ratios for any cancer were 2.6 in ulcerative colitis (2.3 to 3.0) and 1.7 in Crohn's disease (1.5 to 2.1). Patients also had an increased risk of cancer before their 18th birthday (2.7, 1.6 to 4.4; 20 cancers in 9405 patients, 0.6 per1000 person years). Gastrointestinal cancers had the highest relative risks, with a hazard ratio of 18.0 (14.4 to 22.7) corresponding to 202 cancers in patients with inflammatory bowel disease. The increased risk of cancer (before 25th birthday) was similar over time (1964-1989: 1.6, 1.0 to 2.4; 1990-2001: 2.3, 1.5 to 3.3); 2002-06: 2.9, 1.9 to 4.2; 2007-14: 2.2, 1.1 to 4.2).Conclusion Childhood onset inflammatory bowel disease is associated with an increased risk of any cancer, especially gastrointestinal cancers, both in childhood and later in life. The higher risk of cancer has not fallen over time.
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Affiliation(s)
- O Olén
- Sachs' Children and Youth Hospital, Stockholm South General Hospital, Stockholm, Sweden
- Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
- Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden
| | - J Askling
- Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden
| | - M C Sachs
- Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - P Frumento
- Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - M Neovius
- Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden
| | - K E Smedby
- Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden
| | - A Ekbom
- Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden
| | - P Malmborg
- Sachs' Children and Youth Hospital, Stockholm South General Hospital, Stockholm, Sweden
- Department of Women's and Children's health, Karolinska Institutet, Stockholm, Sweden
| | - J F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden
- Department of Pediatrics, Orebro University Hospital, Orebro, Sweden
- Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, UK
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, US
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Bonovas S, Fiorino G, Lytras T, Nikolopoulos G, Peyrin-Biroulet L, Danese S. Systematic review with meta-analysis: use of 5-aminosalicylates and risk of colorectal neoplasia in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2017; 45:1179-1192. [PMID: 28261835 DOI: 10.1111/apt.14023] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 01/12/2017] [Accepted: 02/12/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND The relationship of 5-aminosalicylates' use with the risk of colorectal neoplasia in patients with inflammatory bowel disease (IBD) has been the focus of a growing body of research. AIM To investigate this association through an updated meta-analysis of observational studies. METHODS PubMed, Scopus and major conference proceedings were searched up to December 2016. The identified studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates were calculated using random-effect models. Detailed subgroup analyses were performed. The GRADE approach was used to assess the quality of evidence. RESULTS Thirty-one independent observational studies including 2137 cases of colorectal neoplasia (of which 76% were cancers) were incorporated. Between-study heterogeneity was moderate, while strong suspicion of small-study effects was raised. The overall analysis revealed a protective association between 5-aminosalicylates' use and colorectal neoplasia (RR = 0.57, 95% CI: 0.45-0.71). When the analysis was stratified according to study design and setting, the association was significant in cohort (RR = 0.65, 95% CI: 0.43-0.99; n = 10) and case-control studies (RR = 0.53, 95% CI: 0.40-0.70; n = 21), population-based (RR = 0.70, 95% CI: 0.52-0.94; n = 12) and hospital-based studies (RR = 0.46, 95% CI: 0.34-0.61; n = 19). Exposure to 5-aminosalicylates was protective against cancer (RR = 0.58, 95% CI: 0.45-0.74) and dysplasia (RR = 0.54, 95% CI: 0.35-0.84). The reduction in colorectal neoplasia risk was strong in ulcerative colitis (RR = 0.50, 95% CI: 0.38-0.64), but nonsignificant in Crohn's disease (RR = 0.76, 95% CI: 0.43-1.33). Mesalazine (mesalamine) use was protective (RR = 0.70, 95% CI: 0.51-0.94) with evidence of a dose-effect. The effect of sulfasalazine was marginally nonsignificant (RR = 0.72, 95% CI: 0.51-1.01). CONCLUSIONS Our findings support a potential chemopreventive role of 5-aminosalicylates in IBD. Further, high-quality prospective research is warranted.
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Affiliation(s)
- S Bonovas
- IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center, Milan, Italy
| | - G Fiorino
- IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center, Milan, Italy
| | - T Lytras
- Hellenic Center for Disease Control and Prevention, Athens, Greece.,Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain.,Barcelona Institute for Global Health, Barcelona, Spain
| | | | - L Peyrin-Biroulet
- Department of Hepato-Gastroenterology and Inserm U954, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - S Danese
- IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
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Saraggi D, Fassan M, Mescoli C, Scarpa M, Valeri N, Michielan A, D'Incá R, Rugge M. The molecular landscape of colitis-associated carcinogenesis. Dig Liver Dis 2017; 49:326-330. [PMID: 28089111 DOI: 10.1016/j.dld.2016.12.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 12/07/2016] [Accepted: 12/09/2016] [Indexed: 12/11/2022]
Abstract
In spite of the well-established histopathological phenotyping of IBD-associated preneoplastic and neoplastic lesions, their molecular landscape remains to be fully elucidated. Several studies have pinpointed the initiating role of longstanding/relapsing inflammatory insult on the intestinal mucosa, with the activation of different pro-inflammatory cytokines (TNF-α, IL-6, IL-10, IFN-γ), chemokines and metabolites of arachidonic acid resulting in the activation of key transcription factors such as NF-κB. Longstanding inflammation may also modify the intestinal microbiota, prompting the overgrowth of genotoxic microorganisms, which may act as further cancer promoters. Most of the molecular dysregulation occurring in sporadic colorectal carcinogenesis is documented in colitis-associated adenocarcinoma too, but marked differences have been established in both their timing and prevalence. Unlike sporadic cancers, TP53 alterations occur early in IBD-related carcinogenesis, while APC dysregulation emerges mainly in the most advanced stages of the oncogenic cascade. From the therapeutic standpoint, colitis-associated cancers are associated with a lower prevalence of KRAS mutations than the sporadic variant. Epigenetic changes, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, are significantly involved in colitis-associated cancer development and progression. The focus now is on identifying diagnostic and prognostic biomarkers, with a view to ultimately designing patient-tailored therapies.
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Affiliation(s)
- Deborah Saraggi
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
| | - Claudia Mescoli
- Department of Surgical Oncology and Gastroenterology (DiSCOG), Gastroenterology Unit, University of Padua, Padua, Italy
| | - Marco Scarpa
- Istituto Oncologico Veneto, IOV-IRCCS, Surgical Oncology Unit, Padua, Italy
| | - Nicola Valeri
- Department of Molecular Pathology, The Institute of Cancer Research, London, UK; Department of Medicine, The Royal Marsden NHS Trust, London, UK
| | - Andrea Michielan
- Department of Surgical Oncology and Gastroenterology (DiSCOG), Gastroenterology Unit, University of Padua, Padua, Italy
| | - Renata D'Incá
- Department of Surgical Oncology and Gastroenterology (DiSCOG), Gastroenterology Unit, University of Padua, Padua, Italy
| | - Massimo Rugge
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy.
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Sturm A, Maaser C, Mendall M, Karagiannis D, Karatzas P, Ipenburg N, Sebastian S, Rizzello F, Limdi J, Katsanos K, Schmidt C, Jeuring S, Colombo F, Gionchetti P. European Crohn's and Colitis Organisation Topical Review on IBD in the Elderly. J Crohns Colitis 2017; 11:263-273. [PMID: 27797918 DOI: 10.1093/ecco-jcc/jjw188] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 09/17/2016] [Accepted: 10/18/2016] [Indexed: 12/12/2022]
Abstract
This ECCO topical review of the European Crohn's and Colitis Organisation [ECCO] focuses on the epidemiology, pathophysiology, diagnosis, management and outcome of the two most common forms of inflammatory bowel disease, Crohn's disease and ulcerative colitis, in elderly patients. The objective was to reach expert consensus to provide evidence-based guidance for clinical practice.
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Affiliation(s)
- Andreas Sturm
- Department of Gastroenterology, DRK Kliniken Berlin I Westend. Akademisches Lehrkrankenhaus der Charite, Spandauer Damm 130, 14050 Berlin, Germany
| | - Christian Maaser
- Outpatients Department of Gastroenterology and Department of Geriatrics, Hospital Lüneburg, Bögelstraße 1, 21339 Lüneburg, Germany
| | - Michael Mendall
- Croydon University Hospital, Mayday Road, CR4 7YE Thornton Heath; & St George's Medical School, Cranmer Terrace SW17 ORE, UK
| | - Dimitrios Karagiannis
- Department of Gastroenterology, Iatriko Kentro Athinon, Dervenakion St. 3, 14572 Athens, Greece
| | - Pantelis Karatzas
- Department of Gastroenterology, Evangelismos Hospital, 45-47 Ypsilantou Street, 10676 Athens, Greece
| | - Nienke Ipenburg
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC Leiden, The Netherlands
| | - Shaji Sebastian
- IBD Unit, Hull & East Yorkshire NHS Trust, Anlaby Road, Hull HU3 2JZ, UK
| | - Fernando Rizzello
- IBD Unit, DIMEC, University of Bologna, Via Massarenti, 9, 40138 Bologna, BO, Italy
| | - Jimmy Limdi
- Department of Gastroenterology, Pennine Acute Hospitals NHS Trust, Manchester M8 5RB, Institute of Inflammation and Repair, Manchester Academic Health Sciences, University of Manchester, UK
| | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, University and Medical School of Ioannina, PO Box 1186, 45110 Ioannina, Greece
| | - Carsten Schmidt
- Department of Internal Medicine IV, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
| | - Steven Jeuring
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center (MUMC), PO Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Francesco Colombo
- Dipartimento di Area Chirurgica, Ospedale "Luigi Sacco"- Polo Universitario, ASST Fatebenefratelli Sacco, Milano, Italy
| | - Paolo Gionchetti
- IBD Unit, DIMEC, University of Bologna, Via Massarenti, 9, 40138 Bologna, BO, Italy
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46
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Banday MZ, Balkhi HM, Sameer AS, Chowdri NA, Haq E. Strong association of interleukin-6 -174G/C promoter single nucleotide polymorphism with a decreased risk of colorectal cancer in ethnic Kashmiri population: A case control study. Tumour Biol 2017; 39:1010428317695940. [PMID: 28349833 DOI: 10.1177/1010428317695940] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025] Open
Abstract
Chronic inflammation increases the risk of development of various cancers, including colorectal cancer. Interleukin-6 has been described as a key regulator of colorectal cancer development and is important in the process of colorectal tumorigenesis largely through the regulation of tumor-promoting inflammation. Several studies have reported the association of various polymorphisms in human interleukin-6 gene including IL-6 -174G/C single nucleotide polymorphism with various cancers, including colorectal cancer, but the results are mixed and inconclusive. The aim of this study was to analyze the association of IL-6 -174G/C promoter single nucleotide polymorphism with colorectal cancer risk and also to evaluate the modifying effects of possible IL-6 -174G/C single nucleotide polymorphism genotypes on different risk factors of colorectal cancer or the reciprocal effect in ethnic Kashmiri population through a case control setup. The genotype frequencies of IL-6 -174G/C promoter single nucleotide polymorphism were compared between 142 colorectal cancer patients and 184 individually matched healthy controls by using polymerase chain reaction-restriction fragment length polymorphism method. The association between the IL-6 -174G/C single nucleotide polymorphism and colorectal cancer risk was examined through conditional logistic regression models adjusted for multiple possible confounding (third) variables. The possible effect measure modification of the association between the relevant single nucleotide polymorphism genotypes and colorectal cancer risk by various colorectal cancer risk factors including age, gender, and smoking status was also evaluated. Furthermore, the associations between these single nucleotide polymorphisms and various clinicopathological parameters, demographic variables, and environmental factors within the case group subjects with regard to colorectal cancer risk were also analyzed. The overall association between the IL-6 -174G/C single nucleotide polymorphism and the modulation of colorectal cancer risk was found to be highly significant (p = 0.001). The variant genotype (CC) was significantly associated with a decreased risk of colorectal cancer (odds ratio, 0.15 (95% confidence interval, 0.04-0.54); p = 0.004). Furthermore, the less common IL-6-174C allele was associated with a decreased risk of colorectal cancer (odds ratio, 0.49 (95% confidence interval, 0.33-0.73); p = 0.0006). The combined variant genotype (GC + CC) was also significantly associated with a decreased risk of colorectal cancer (odds ratio, 0.54 (95% confidence interval, 0.33-0.89); p = 0.015). This study demonstrates that there is a strong and highly significant association between the IL-6 -174G/C promoter single nucleotide polymorphism and a decreased risk of colorectal cancer in ethnic Kashmiri population. However, in order to substantiate our findings, this study needs to be replicated with larger sample size and with other ethnically defined populations with comparable colorectal cancer incidence.
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Affiliation(s)
| | | | - Aga Syed Sameer
- 2 Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Kingdom of Saudi Arabia
| | - Nissar A Chowdri
- 3 Department of Surgery, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Ehtishamul Haq
- 1 Department of Biotechnology, University of Kashmir, Srinagar, India
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Folic Acid Supplementation May Reduce Colorectal Cancer Risk in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. J Clin Gastroenterol 2017; 51:247-253. [PMID: 26905603 DOI: 10.1097/mcg.0000000000000498] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
GOALS To evaluate the role of folic acid supplementation in colorectal cancer (CRC) chemoprevention in patients with inflammatory bowel disease (IBD). BACKGROUND CRC is a serious complication of IBD. Folic acid supplementation has been shown to be chemopreventative in sporadic CRC. Patients with IBD are at risk of folate deficiency though intestinal malabsorption and also competitive inhibition by concurrent sulfasalazine use. To date, there have been several studies reporting on folic acid supplementation in patients with IBD and CRC. STUDY We searched electronic databases for studies reporting folic acid use and CRC incidence in patients with IBD. We produced a pooled hazard ratio with 95% confidence intervals using a random-effects model. Preplanned subgroup analyses were performed to explore for any potential sources of heterogeneity. RESULTS Ten studies reporting on 4517 patients were included. We found an overall protective effect for folic acid supplementation on the development of CRC, pooled hazard ratio=0.58 (95% confidence interval, 0.37-0.80). There was low to moderate heterogeneity among studies, I=29.7%. Subgroup analyses suggested that folic acid use was protective in hospital-based studies, studies from North America and those that were performed before folate fortification of foods in 1998. CONCLUSIONS CRC remains an important complication of IBD. Chemoprevention is an attractive strategy and folic acid as a cheap, safe, and well-tolerated supplement may have a role. Focused prospective studies are required to precisely define any potential effect.
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Boyd S, Mustonen H, Tenca A, Jokelainen K, Arola J, Färkkilä MA. Surveillance of primary sclerosing cholangitis with ERC and brush cytology: risk factors for cholangiocarcinoma. Scand J Gastroenterol 2017; 52:242-249. [PMID: 27806633 DOI: 10.1080/00365521.2016.1250281] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease leading to bile duct strictures and fibrosis, and predisposing to cholangiocarcinoma (CCA). Biliary dysplasia is a known precursor of CCA. In our unit, PSC patients undergo regular surveillance with ERC and brush cytology (BC), and liver transplantation is an option in case with biliary dysplasia. We evaluated the risk factors for biliary dysplasia and CCA based on ERC imaging, BC and liver function tests. PATIENTS AND METHODS Seven hundred and eighty-eight ERCs were performed with BC for 447 PSC patients. ERC images were evaluated using the modified Amsterdam score, neutrophilic inflammation was assessed in BC, and liver function tests were collected. Ploidy analysis with DNA flow cytometry was performed in cases with advanced PSC or previous suspicious BC/aneuploidy. The endpoint was either a benign disease course (follow-up for ≥2.4 years after the latest ERC), benign histology, biliary dysplasia or CCA. RESULTS Benign disease course was seen in 424/447 (including 23 cases with biliary dysplasia), and CCA in 17 (3.8%) patients. Gallbladder carcinoma/carcinoma in situ was diagnosed in three patients. Advanced ERC findings, male gender, suspicious BC, aneuploidy in flow cytometry, inflammation, and elevation of ALP, bilirubin, ALT, AST, GGT, CEA and CA19-9 represented significant risk factors for CCA in univariate analysis. CONCLUSIONS PSC patients with advanced bile duct disease and elevated liver enzymes, CEA or CA19-9, inflammation or suspicious BC are most likely to develop CCA. These patients may benefit from surveillance with BC if early liver transplantation is possible.
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Affiliation(s)
- Sonja Boyd
- a Department of Pathology , University of Helsinki, and Helsinki University Hospital , Helsinki , Finland
| | - Harri Mustonen
- b University of Helsinki and Department of Surgery, Helsinki University Hospital , Helsinki , Finland
| | - Andrea Tenca
- c University of Helsinki and Clinic of Gastroenterology, Helsinki University Hospital , Helsinki , Finland
| | - Kalle Jokelainen
- c University of Helsinki and Clinic of Gastroenterology, Helsinki University Hospital , Helsinki , Finland
| | - Johanna Arola
- a Department of Pathology , University of Helsinki, and Helsinki University Hospital , Helsinki , Finland
| | - Martti A Färkkilä
- c University of Helsinki and Clinic of Gastroenterology, Helsinki University Hospital , Helsinki , Finland
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Fang JY, Shi YQ, Chen YX, Li JN, Sheng JQ. Chinese consensus on the prevention of colorectal cancer (2016, Shanghai). J Dig Dis 2017; 18:63-83. [PMID: 28102562 DOI: 10.1111/1751-2980.12450] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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50
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Qiu X, Ma J, Wang K, Zhang H. Chemopreventive effects of 5-aminosalicylic acid on inflammatory bowel disease-associated colorectal cancer and dysplasia: a systematic review with meta-analysis. Oncotarget 2017; 8:1031-1045. [PMID: 27906680 PMCID: PMC5352032 DOI: 10.18632/oncotarget.13715] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 11/16/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS The chemopreventive effect of 5-aminosalicylic acid (5-ASA) in patients with inflammatory bowel disease (IBD) has been widely studied; however, the results remain conflicting. The aim of this study was to systematically review the literature and update evidence concerning effects of 5-ASA on the risk of colorectal cancer (CRC) and dysplasia (Dys) in patients with ulcerative colitis (UC) or Crohn's disease (CD). RESULTS 5-ASA showed a chemopreventive effect against CRC/Dys in IBD patients (OR = 0.58, 95% CI: 0.45-0.75). However, this effect was significant only in clinical-based studies (OR = 0.51; 95% CI: 0.39-0.65), but not in population-based studies (OR = 0.71; 95% CI: 0.46-1.09). Moreover, this effect was noticeable in patients with UC (OR = 0.46, 95% CI: 0.34-0.61), but not in CD (OR = 0.66, 95% CI: 0.42-1.03), and on the outcome of CRC (OR = 0.54, 95% CI: 0.39-0.74), but not Dys (OR = 0.47; 95% CI: 0.20-1.10). In IBD patients, mesalazine dosage ≥ 1.2 g/day showed greater protective effects against CRC/Dys than dosages < 1.2 g/day. However, Sulphasalazine therapy did not show any noticeable protective function regardless of the dosage administered. MATERIALS AND METHODS We performed a systematic review with a meta-analysis of 26 observational studies involving 15,460 subjects to evaluate the risks of developing CRC and Dys in IBD patients receiving 5-ASA treatment. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each evaluation index. CONCLUSIONS 5-ASA has a chemopreventive effect on CRC (but not Dys) in IBD patients. Moreover, UC patients can benefit more from 5-ASA than CD patients. Mesalazine maintenance dosage ≥ 1.2 g/day is an effective treatment for reducing CRC risk in IBD patients.
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Affiliation(s)
- Xinyun Qiu
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Jingjing Ma
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Kai Wang
- Institute of Apicultural Research, Chinese Academy of Agricultural Sciences, Beijing 100093, China
| | - Hongjie Zhang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
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